mocetinostat and Disease-Models--Animal

COVID-19 as a viral disease has brought up the need to exercise more than before due to its physiological effects on health. Therefore, this study investigates the effect of 12-week of aerobic exercise on female students' hormone levels and lipid profile with polycystic ovary syndrome (PCOS) during the COVID-19 pandemic.. Using a 12-week quasi-experimental with pretest, posttest research design among 40 Iranian female students aged 18-14 with PCOS, we randomly allocated the participants to either an experimental (they performed aerobic exercises three 60-minute sessions per week at home using content production) or a control condition. Their anthropometric and blood samples (e.g., testosterone, estrogen, prolactin, and lipid profile) were taken in two stages before and after the training protocol.. Findings demonstrated that performing aerobic exercises is an effective and non-invasive method that could have a positive effect on young girls' PCOS during COVID-19 pandemic.. La pandémie de COVID-19, en tant que maladie virale, a fait ressortir la nécessité de faire de l’exercice plus que jamais en raison de ses effets physiologiques sur la santé. Par conséquent, cette étude examine l’effet de 12 semaines d’exercice aérobique sur les niveaux hormonaux et le profil lipidique d’étudiantes atteintes du syndrome d’ovaires polykystiques (SOPK) pendant la pandémie de COVID-19.. En utilisant un modèle de recherche quasi-expérimental de 12 semaines avec pré-test, post-test auprès de 40 étudiantes iraniennes âgées de 18 à 14 ans atteintes du SOPK, nous avons réparti au hasard les participantes entre une série expérimentale (elles ont effectué des exercices aérobiques à raison de trois séances de 60 minutes par semaine à la maison) et une série contrôle. Les échantillons anthropométriques et sanguins (testostérone, œstrogène, prolactine et profil lipidique) ont été prélevés en deux étapes, avant et après le protocole d’entraînement.. Les résultats ont démontré que la pratique d’exercices d’aérobic est une méthode efficace et non invasive qui pourrait avoir un effet positif sur le SOPK des jeunes filles pendant la pandémie de COVID-19.. Our research showed that even less than 5 GBq irradiation could induce a transient testicular dysfunction in the first 3 months of therapy, but it was mostly reversible after 12 months.. The online version contains supplementary material available at 10.1007/s13204-023-02822-5.. Embelin is predicted to have a high probability of immunotoxicity potential and affect drug metabolism by inhibiting CYP2D6. In addition, it affects food intake, weight gain, and the number of implantations in pregnant rats. Therefore, it is highly recommended not to take embelin and embelin-rich plants during pregnancy. Further. The online version contains supplementary material available at 10.1007/s42965-023-00306-9.. The online version contains supplementary material available at 10.1007/s11696-023-02771-x.. The online version contains supplementary material available at 10.1007/s00477-023-02476-3.. This study ascribes for a new immunomodulatory role for IL11 during tumor development that is amenable to anti-cytokine based therapy of colon cancer.. Inflammation response do not seem to be enough to explain all the Essure-related adverse outcomes, suggesting the involvement of other biological mechanisms.. NCT03281564.. Inflammation and fibrosis are found in the surrounding tubal tissue around the Essure. Adult patients with BED with co-occurring obesity who have good responses to acute treatment with naltrexone/bupropion should be offered maintenance treatment with naltrexone/bupropion.. dp/dtmax in PiCCO parameter can be used as a bedside indicator to evaluate cardiac function in SIC patients due to its simplicity and ease of operation. Esmolol control of heart rate in SIC patients can improve cardiac function and reduce short-term mortality.. Inverted microscopy showed that compared with the NC group, the OGD/R group had poor cell status, swollen cytosol, visible cell lysis fragments and significantly lower cell activity [(49.1±2.7)% vs. (100.0±9.7)%, P < 0.01]; compared with the OGD/R group, the HW group had improved cell status and remarkably higher cell activity [(63.3±1.8)% vs. (49.1±2.7)%, P < 0.01]. Transmission electron microscopy showed that the neuronal nuclear membrane of cells in the OGD/R group was lysed and a higher number of autophagic lysosomes were visible compared with the NC group; compared with the OGD/R group, the neuronal damage of cells in the HW group was reduced and the number of autophagic lysosomes was notably decreased. The results of immunofluorescence assay showed that the expressions of LC3 and Beclin-1 were outstandingly enhanced in the OGD/R group compared with the NC group, and the expressions of LC3 and Beclin-1 were markedly weakened in the HW group compared with the OGD/R group. Western blotting assay showed that the expressions were prominently higher in both LC3II/I and Beclin-1 in the OGD/R group compared with the NC group (LC3II/I: 1.44±0.05 vs. 0.37±0.03, Beclin-1/β-actin: 1.00±0.02 vs. 0.64±0.01, both P < 0.01); compared with the OGD/R group, the protein expression of both LC3II/I and Beclin-1 in the HW group cells were notably lower (LC3II/I: 0.54±0.02 vs. 1.44±0.05, Beclin-1/β-actin: 0.83±0.07 vs. 1.00±0.02, both P < 0.01).. Hydrogen-rich water has a significant protective effect on OGD/R-causing HT22 cell injury, and the mechanism may be related to the inhibition of autophagy.. The prevalence of delirium in ICU patients is over 50%, with hypoactive delirium being the most common. Age, APACHE score at ICU admission, neurological disease, sepsis and duration of mechanical ventilation were all independent risk factors for the development of delirium in ICU patients. More than half of patients with delirium were still delirious when they discharged from the ICU.. For individuals ≥75 years, plasma Aβ42 and P-tau181 might not be associated with cognitive impairment, and MRI parameters, including PVWMH, LVBI and cortical atrophy, are related to CI. The cognitive statuses of people over 75 years old were used as the endpoint event in this study. Therefore, it can be considered that these MRI markers might have more important clinical significance for early assessment and dynamic observation, but more studies are still needed to verify this hypothesis.. We recommend using the Art/Zn complex owing to its moderate inhibitory and antiviral effects against the SARS-CoV-2 with a low cytotoxic effect on host (Vero E6) cells. We suggest conducting further prospective studies to investigate the biological effects of Art/Zn in animal models at different concentrations for testing its clinical efficacy and safety in inhibiting SARS-CoV-2 activities.. The R/T sequence resulted in a significantly longer OS and PFS and improved disease control compared with the reverse sequence. R and T given not sequentially have similar impacts on survival. More data are needed to define the best sequence and to explore the efficacy of sequential (T/R or R/T) treatment combined with molecular-targeted drugs.

Topics: Actin Cytoskeleton; Actins; Adaptor Proteins, Signal Transducing; Adenocarcinoma; Adenosine Triphosphate; Adsorption; Adult; Africa, Eastern; Aged; Air Pollutants; Air Pollution; Air Pollution, Indoor; Alcohol Drinking; Allergens; Alzheimer Disease; Amyotrophic Lateral Sclerosis; Animals; Anti-Bacterial Agents; Antibodies; Antibodies, Immobilized; Antigen Presentation; Antigens, CD; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Apoptosis; Aptamers, Nucleotide; Asthma; Asthma, Exercise-Induced; Atrophy; Autophagy; Azoospermia; Bacillus cereus; Bacterial Infections; Beclin-1; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Biofouling; Biological Monitoring; Biomarkers; Biomarkers, Tumor; Biosensing Techniques; Blastocyst; Bone Neoplasms; Bone Regeneration; Bronchoconstriction; Burkitt Lymphoma; C9orf72 Protein; Campylobacter; Campylobacter Infections; Campylobacter jejuni; Carcinogenesis; Carcinoma, Hepatocellular; Carcinoma, Pancreatic Ductal; Carcinoma, Squamous Cell; Cardiomyopathies; Caregivers; Carmine; Case-Control Studies; Catalysis; Cattle; Cause of Death; CCAAT-Enhancer-Binding Protein-alpha; CD8-Positive T-Lymphocytes; Cefepime; Cell Differentiation; Cell Line, Tumor; Cell Nucleus; Cell Transdifferentiation; Chelating Agents; Chemical and Drug Induced Liver Injury, Chronic; Chemoradiotherapy, Adjuvant; Child; Child, Preschool; China; Chlorquinaldol; Cholangiocarcinoma; Cholera; Chromatin; Clinical Trials as Topic; Cognitive Dysfunction; Cohort Studies; Colonic Neoplasms; Colorectal Neoplasms; Colorimetry; Cooking; Coordination Complexes; COVID-19; Creatinine; CRISPR-Cas Systems; Critical Care; Critical Illness; Cross-Sectional Studies; Cryopreservation; Cryoprotective Agents; Cysteine; Cytokines; Device Removal; Diet; Diet, High-Fat; Diet, Mediterranean; Dietary Supplements; Dimethyl Sulfoxide; Dipeptides; Disease Models, Animal; Dithiothreitol; DNA; DNA Repeat Expansion; DNA, Bacterial; DNA, Complementary; Dopamine; Electrochemical Techniques; Electrodes; Endocannabinoids; Environmental Exposure; Environmental Monitoring; Environmental Pollutants; Enzyme-Linked Immunosorbent Assay; Erlotinib Hydrochloride; Escherichia coli; Escherichia coli O157; Esophageal Neoplasms; Esophagitis, Peptic; Ethylene Glycol; Europium; Exanthema; Fallopian Tubes; Feces; Female; Fertilization in Vitro; Fluoresceins; Fluorescent Dyes; Follicle Stimulating Hormone; Follow-Up Studies; Food Microbiology; Forced Expiratory Volume; Forkhead Transcription Factors; Frontotemporal Dementia; G-Quadruplexes; Galactose; Gastroenteritis; Gastrointestinal Diseases; Gastrointestinal Microbiome; Gastrointestinal Neoplasms; Gastrointestinal Tract; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Genital Neoplasms, Female; Genome-Wide Association Study; Genome, Viral; Genomics; Genotype; Glucose; Glutathione; Glycerol; Gold; Graphite; GTPase-Activating Proteins; Heat-Shock Proteins; Heme Oxygenase-1; Hepacivirus; Hepatitis C; Hepatocytes; Histamine; Histocompatibility Antigens Class II; Hoarseness; Hospice and Palliative Care Nursing; Humans; Hydrogen; Hydrogen Peroxide; Hydrogen Sulfide; Hydroxybenzoates; Hydroxyl Radical; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperthermia, Induced; Hysteroscopy; Immunoassay; Indigo Carmine; Inflammation; Inflammatory Bowel Diseases; Insulin Resistance; Intensive Care Units; Interleukin-11; Interleukin-6; Interleukins; Iodine Radioisotopes; Iran; Iridium; Islets of Langerhans; Kinetics; Lactation; Lactobacillus; Lactobacillus plantarum; Lamins; Latin America; Lead; Lectins; Leukopenia; Ligands; Limit of Detection; Lipopolysaccharides; Lipoprotein Lipase; Liver; Liver Cirrhosis; Liver Neoplasms; Lolium; Luminescent Measurements; Luminol; Lung; Luteinizing Hormone; Macrophages; Magnetic Phenomena; Magnetic Resonance Imaging; Male; Malnutrition; Maltose; Manganese Compounds; Maternal Nutritional Physiological Phenomena; Melatonin; Metabolic Engineering; 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Sepsis; Shock, Septic; Signal Transduction; Silicon Dioxide; Silver; Sirtuin 1; Skin Neoplasms; Sleep Apnea, Obstructive; Soil; Spain; Spectrum Analysis, Raman; Sperm Retrieval; Spermatozoa; Spirometry; Staphylococcus aureus; STAT3 Transcription Factor; Stereoisomerism; Sterilization, Tubal; Stroke Volume; Sulfadiazine; Sulfites; Superoxide Dismutase; Surface Plasmon Resonance; tau Proteins; Testis; Testosterone; Thioredoxin-Disulfide Reductase; Thyroid Neoplasms; Thyroidectomy; Trans-Activators; Transcription Factor AP-1; Treatment Outcome; Triazoles; Triclosan; Trifluridine; Tumor Microenvironment; Tumor Necrosis Factor-alpha; United States; Uracil; Vagina; Vegetables; Ventricular Function, Left; Ventricular Pressure; Vibrio cholerae; Vietnam; Virulence; Vital Capacity; Vitrification; Walking; Water; Water Pollutants, Radioactive; Whole Genome Sequencing; Wind; YAP-Signaling Proteins; Zeolites; Zinc Oxide

Multiple system atrophy (MSA) is a rare, severe, and rapidly progressive neurodegenerative disorder categorized as an atypical parkinsonian syndrome. With a mean life expectancy of 6-9 years after diagnosis, MSA is clinically characterized by parkinsonism, cerebellar ataxia, autonomic failure, and poor l-Dopa responsiveness. Aside from limited symptomatic treatment, there is currently no disease-modifying therapy available. Consequently, distinct pharmacological targets have been explored and investigated in clinical studies based on MSA-related symptoms and pathomechanisms. Parkinsonism, cerebellar ataxia, and autonomic failure are the most important symptoms targeted by symptomatic treatments in current clinical trials. The most prominent pathological hallmark is oligodendroglial cytoplasmic inclusions containing alpha-synuclein, thus classifying MSA as synucleinopathy. Additionally, myelin and neuronal loss accompanied by micro- and astrogliosis are further distinctive features of MSA-related neuropathology present in numerous brain regions. Besides summarizing current symptomatic treatment strategies in MSA, this review critically reflects upon potential cellular targets and disease-modifying approaches for MSA such as (I) targeting α-syn pathology, (II) intervening neuroinflammation, and (III) neuronal loss. Although these single compound trials are aiming to interfere with distinct pathogenetic steps in MSA, a combined approach may be necessary to slow down the rapid progression of the oligodendroglial associated synucleinopathy.

Topics: Adrenergic alpha-1 Receptor Agonists; alpha-Synuclein; Animals; Disease Models, Animal; Humans; Induced Pluripotent Stem Cells; Monoamine Oxidase Inhibitors; Multiple System Atrophy; Neuroglia; Peroxidase

Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) is a rare and severe autoimmune multisystemic disease. Its pathogenesis involves multiple arms of the immune system, as well as complex interactions between immune cells and target organs. Experimental animal models of disease can provide the crucial link from human disease to translational research into new therapies. This is particularly true in AAV, due to low disease incidence and substantial disease heterogeneity. Animal models allow for controlled environments in which disease mechanisms can be defined, without the clinical confounders of environmental and lifestyle factors. To date, multiple animal models have been developed, each of which shed light on different disease pathways. Results from animal studies of AAV have played a crucial role in enhancing our understanding of disease mechanisms, and have provided direction toward newer targeted therapies. This review will summarize our understanding of AAV pathogenesis as has been gleaned from currently available animal models, as well as address their strengths and limitations. We will also discuss the potential for current and new animal models to further our understanding of this important condition.

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Autoantibodies; Autoimmunity; Disease Models, Animal; Glomerulonephritis; Humans; Myeloblastin; Peroxidase; Translational Research, Biomedical

Topics: Animals; Autoantigens; Autoimmunity; Biomarkers; Cardiovascular Diseases; Chromatin; Citrullination; Citrulline; Communicable Diseases; Disease Models, Animal; Extracellular Traps; Histones; Humans; Hydrolases; Inflammation; Metabolic Diseases; Neoplasms; Peroxidase; Protein-Arginine Deiminase Type 4; Protein-Arginine Deiminases; Risk Factors; Serine Proteases

Our understanding of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis has developed greatly since the discovery of ANCA, directed against neutrophil components, in 1982. Observations in human disease, and increasingly sophisticated studies in vitro and in rodent models in vivo, have allowed a nuanced understanding of many aspects of the immunopathogenesis of disease, including the significance of ANCA as a diagnostic and monitoring tool as well as a mediator of microvascular injury. The mechanisms of leukocyte recruitment and tissue injury, and the role of T cells increasingly are understood. Unexpected findings, such as the role of complement, also have been uncovered through experimental studies and human observations. This review focusses on the pathogenesis of ANCA-associated vasculitis, highlighting the challenges in finding new, less-toxic treatments and potential therapeutic targets in this disease. The current suite of rodent models is reviewed, and future directions in the study of this complex and fascinating disease are suggested.

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Autoimmunity; Bone Marrow Transplantation; Disease Models, Animal; Humans; Peroxidase; T-Lymphocytes

Accurate. Since sCD30 levels and sCD26/sCD30 ratios may contribute to the activity of the disease, they may be used to assess ITP disease activity.. hBMSCs and hFOB1.19 cells modulate the phenotype of PC3 prostate cancer cells and the expression of CD59 by activating the RANK/RANKL/OPG signaling pathway.. Results showed that the EEG responses at lower levels of the independent variables were significantly high than at higher levels; except for oxygen content, the EEG responses at lower levels were considerably lower than at a higher level. It also showed that an upsurge in the physical demand increased lifting frequency and replication and caused decreasing in alpha power, theta/beta, alpha/beta, (theta + alpha)/beta, (theta + alpha)/(alpha + beta) and increasing in the theta power and the gamma power. Furthermore, several interactions among independent variables had significant effects on the EEG responses.. The EEG implementation for the investigation of neural responses to physical demands allows for the possibility of newer nontraditional and faster methods of human performance monitoring. These methods provide effective and reliable results as compared to other traditional methods. This study will safeguard the physical capabilities and possible health risks of industrial workers. And the applications of these tasks can occur in almost all working environments (factories, warehouses, airports, building sites, farms, hospitals, offices, etc.) that are at high altitudes. It can include lifting boxes at a packaging line, handling construction materials, handling patients in hospitals, and cleaning.

Topics: Action Potentials; Adolescent; Adult; Aged; Alanine Transaminase; Analgesics; Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Antioxidants; Apoptosis; Arrhythmias, Cardiac; Atrial Fibrillation; Biological Transport; Biomarkers; Blood Gas Analysis; Blood-Brain Barrier; Blotting, Western; Bone and Bones; Bone Marrow; Bone Neoplasms; Brain; Breast Neoplasms; Calcium; Carbon Tetrachloride; Cartilage, Articular; Case-Control Studies; CD59 Antigens; CDC2 Protein Kinase; Celastrus; Cell Cycle; Cell Division; Cell Line; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chemical Fractionation; Colitis, Ulcerative; Colon; Computer Simulation; Curcumin; Cyclin B1; Cymenes; Cytokines; Dextran Sulfate; Dipeptidyl Peptidase 4; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Ectodysplasins; Electroencephalography; Endothelial Cells; Epithelial Cells; Epithelial-Mesenchymal Transition; Exosomes; Female; Flavonoids; G2 Phase; Gene Expression Regulation; Glial Cell Line-Derived Neurotrophic Factor; Heart Atria; Heart Conduction System; Heart Ventricles; HeLa Cells; Hemodynamics; Humans; Image Interpretation, Computer-Assisted; Indoles; Inflammation; Interleukin-1beta; Interleukin-6; Iridoid Glycosides; Ki-1 Antigen; Lens, Crystalline; Lifting; Liver; Liver Cirrhosis; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred ICR; Microelectrodes; Middle Aged; Models, Cardiovascular; Multiparametric Magnetic Resonance Imaging; Myeloid Differentiation Factor 88; NADPH Oxidase 1; Neoplasm Grading; NF-kappa B; Osteoarthritis; Osteoblasts; Osteoclasts; Oxidative Stress; Oxygen; Patch-Clamp Techniques; PC-3 Cells; Permeability; Peroxidase; Plant Extracts; Plant Leaves; Prostate; Prostatic Neoplasms; Protective Agents; Proto-Oncogene Proteins c-akt; Psychophysics; Purpura, Thrombocytopenic, Idiopathic; Rabbits; Rats; Rats, Sprague-Dawley; Recovery of Function; Retrospective Studies; RNA, Long Noncoding; ROC Curve; Safety; Shoes; Signal Transduction; Sodium; Sonication; Spinal Cord; Spinal Cord Injuries; Syringa; Tight Junctions; Tissue Inhibitor of Metalloproteinase-1; Toll-Like Receptor 2; Transforming Growth Factor beta2; Transient Receptor Potential Channels; Tumor Microenvironment; Tumor Necrosis Factor-alpha; Umbilical Cord; Up-Regulation; Ventricular Function; Young Adult

In patients with GN or vasculitis, ANCAs are directed against proteinase 3 (PR3) or myeloperoxidase (MPO). The differences between PR3-ANCA-associated vasculitis (AAV) and MPO-AAV described in the past have been supplemented during the last decade. In this review, we discuss the differences between these two small-vessel vasculitides, focusing especially on possible etiologic and pathophysiologic differences. PR3-AAV is more common in northern parts of the world, whereas MPO-AAV is more common in southern regions of Europe, Asia, and the Pacific, with the exception of New Zealand and Australia. A genetic contribution has been extensively studied, and there is a high prevalence of the HLA-DPB1*04:01 allele in patients with PR3-AAV as opposed to patients with MPO-AAV and/or healthy controls. Histologically, MPO-AAV and PR3-AAV are similar but show qualitative differences when analyzed carefully. Clinically, both serotypes are difficult to distinguish, but quantitative differences are present. More organs are affected in PR3-AAV, whereas renal limited vasculitis occurs more often in patients with MPO-AAV. For future clinical trials, we advocate classifying patients by ANCA serotype as opposed to the traditional disease type classification.

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Disease Models, Animal; Humans; Myeloblastin; Peroxidase

Since the discovery of anti-neutrophil cytoplasmic autoantibodies (ANCA), great strides have been made in elucidating the etiology and pathogenesis of disease. In this article, we review recent published key breakthroughs in understanding the pathogenesis of ANCA vasculitis, including some that may lead to novel therapeutics. These breakthroughs have occurred in multiple areas of investigation. A European genome-wide association study (GWAS) revealed the importance of the genetic contribution of proteinase 3 (PR3) and its endogenous inhibitor, alpha (1)-antitrypsin as well as HLA risk. Epigenetic modification of autoantigen genes appears to contribute to perpetuation of disease and possibly relapse risk. Autoantigen excision, a novel method to detect autoantibody epitopes using mass spectrometry, not only revealed pathogenic epitopes in myeloperoxidase (MPO)-ANCA vasculitis and identified unique MPO-ANCA responsible for the majority of ANCA-negative small vessel vasculitis, but has vast applicability to other autoantibody-mediated diseases. An explosion of biomarker studies has revealed circulating cytokines and alternative complement pathway products that may predict active disease. Interestingly, alternative complement pathway blockade in the murine model of disease is protective and a clinical trial in humans using an oral alternative complement pathway inhibitor is underway. Increasing clarity of the role of B and T cells in disease pathogenesis is ongoing. B cell depleting agents have shown great utility in remission induction and maintenance, and monitoring specific B cell subsets during the disease course may have predictive power for remission maintenance. Despite these substantial advances, more research is needed including, but not limited to, validation of existing discoveries. As additional novel discoveries emerge, so will novel therapies, and it is with great hope that these collective insights will ultimately lead to prevention and cure.

Topics: Alleles; Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Autoantigens; Biomarkers; Disease Models, Animal; Epigenesis, Genetic; Ethnicity; Forecasting; Genetic Predisposition to Disease; Genome-Wide Association Study; Histones; Humans; Jumonji Domain-Containing Histone Demethylases; Lymphocyte Subsets; Methylation; Myeloblastin; Peroxidase; Phenotype; Polymorphism, Single Nucleotide; Protein Processing, Post-Translational

Topics: Aged; Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Disease Models, Animal; Drugs, Investigational; Endothelial Cells; Etanercept; Humans; Immunoglobulin G; Inflammation Mediators; Interleukin 1 Receptor Antagonist Protein; Mice; Myeloblastin; Neutrophil Activation; Neutrophils; p38 Mitogen-Activated Protein Kinases; Peroxidase; Rats; Reactive Oxygen Species; Receptors, Fc; Receptors, Tumor Necrosis Factor; Tumor Necrosis Factor-alpha

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Blotting, Western; Churg-Strauss Syndrome; Cohort Studies; Cross-Sectional Studies; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Epitopes; Granulomatosis with Polyangiitis; Humans; Lysosomal Membrane Proteins; Lysosomal-Associated Membrane Protein 2; Microscopic Polyangiitis; Myeloblastin; Peroxidase; Predictive Value of Tests; Rabbits; Rats

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Disease Models, Animal; Glomerulonephritis; Humans; Mice; Mice, Inbred C57BL; Necrosis; Neutrophil Activation; Peroxidase; T-Lymphocyte Subsets

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; B-Lymphocytes, Regulatory; Disease Models, Animal; Disease Progression; Humans; Inflammation Mediators; Monocytes; Peroxidase; Prognosis; T-Lymphocytes, Regulatory

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; CD4-Positive T-Lymphocytes; Churg-Strauss Syndrome; Disease Models, Animal; Endothelium, Vascular; Humans; Interleukin-17; Interleukins; Leukocytes, Mononuclear; Mice; Mice, Inbred C57BL; Microscopic Polyangiitis; Peroxidase; T-Lymphocyte Subsets

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Churg-Strauss Syndrome; Disease Models, Animal; Humans; Mice; Mice, Transgenic; Myeloblastin; Peroxidase; Receptor, Anaphylatoxin C5a; Receptors, Complement

Neutrophil extracellular traps (NETs) are characterized by the presence of extracellular DNA fibers studded with antimicrobial proteins, including myeloperoxidase (MPO). Although NETs play an important role in the innate immune system, the scattered extracellular enzymes, such as MPO, pose risks to the host. Therefore, NETs are strictly regulated by DNase I in the serum, which prevents them from persisting. Recent studies have demonstrated that dysregulation of NETs could be involved in the pathogenesis of autoimmune diseases, including systemic lupus erythematosus. In this review, we interpret the association of disordered NETs with autoimmune diseases, especially propylthiouracil-induced MPO-ANCA-associated vasculitis.

Topics: alpha-Defensins; Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Deoxyribonuclease I; Disease Models, Animal; Humans; Neutrophils; Peroxidase; Propylthiouracil

To provide an update on animal models of antineutrophil cytoplasmic autoantibody (ANCA)-mediated vasculitis and highlight recent insights gained from studies in these models pertaining to immunopathogenesis.. Animal models support the pathogenic potential of myeloperoxidase (MPO)-ANCA. Alternative pathway complement activation has been identified as a novel inflammatory pathway in disease induction and a potential target for intervention. Interventions targeting B cells, antibodies, and signal transduction pathways may hold promise as well. The role of T cells is beginning to be explored, and studies indicate a prominent role for Th17 responses. The link between infection and ANCA vasculitis is well established. In animal models, Toll-like receptor (TLR)4 ligation is involved in disease induction. Ligation of TLRs contributes to the initiation of anti-MPO autoimmune responses in which TLR2 activation induces a Th17 response and TLR9 activation directs a Th1 response. An animal model for PR3-ANCA vasculitis is not available yet but models with a humanized immune system are being developed and show promising first results.. Animal models of MPO-ANCA vasculitis have contributed substantially to our understanding of disease immunopathogenesis and have illuminated novel targets for intervention. The development of PR3-ANCA animal models remains a challenge but recent observations in humanized model systems offer hope.

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Complement Pathway, Alternative; Disease Models, Animal; Humans; Mice; Mice, Inbred C57BL; Peroxidase; Rats; Rats, Inbred WKY; Signal Transduction; Th17 Cells

Clinical observations, including a report of neonatal vasculitis occurring in a child born from a mother with anti-neutrophil cytoplasmic antibody directed to myeloperoxidase (MPO-ANCA)-associated vasculitis, suggest a pathogenic role for ANCA. Such a role is supported by in vitro experimental data showing that ANCA can activate primed neutrophils to the production of reactive oxygen species and lytic enzymes resulting in lysis of endothelial cells. An interplay between neutrophils, the alternative pathway of complement, and MPO-ANCA resulting in systemic vasculitis including necrotizing glomerulonephritis has clearly been demonstrated in animal models. An in vivo pathogenic role of ANCA directed to proteinase 3 (PR3-ANCA) has, however, not been substantiated. In PR3-ANCA-associated vasculitis, granulomatous inflammation points to involvement of cell-mediated immunity. In vitro studies, indeed, suggest that PR3-specific Th17 CD4-positive lymphocytes are operative in lesion development. The triggering role of microbial factors is becoming more clear. In particular Staphylococcus aureus carriage and infection with Gram-negative bacteria could contribute to induction and persistence of ANCA-associated vasculitis (AAV). Insight into the pathogenic pathways involved in AAV have opened and will further open new ways to targeted treatment.

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Autoantibodies; Complement Pathway, Alternative; Disease Models, Animal; Endothelium, Vascular; Humans; Immunity, Cellular; Myeloblastin; Neutrophils; Peroxidase; Reactive Oxygen Species; Staphylococcal Infections; Staphylococcus aureus; Th17 Cells

Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides are characterised by necrotising inflammation of small vessels in conjunction with ANCA directed to either proteinase 3 (PR3) or myeloperoxidase (MPO). The aetiopathogenesis of these disorders is still not fully elucidated but clinical as well as in vitro and in vivo experimental data strongly suggest a role for the autoimmune responses to PR3 and MPO in disease development. Clinically, PR3-ANCA are strongly associated with granulomatous vasculitis as in Wegener's granulomatosis, and MPO-ANCA with necrotising small vessel vasculitis as in microscopic polyangiitis. Levels of PR3-ANCA and MPO-ANCA do, however, not fully reflect disease activity. In vitro, ANCA activate primed neutrophils to release lytic enzymes and reactive oxygen species, a process reinforced by the alternative pathway of complement. In the context of endothelial cells, this process leads to endothelial detachment and lysis. In vivo experimental studies have clearly demonstrated the pathogenic potential of MPO-ANCA for necrotising glomerulonephritis and pulmonary capillaritis. For PR3-ANCA-associated granulomatous vasculitis, an animal model is lacking. Here, effector T cells, in particular Th17 cells, appear to have a major pathogenic role in addition to ANCA. Finally, microbial factors, derived in particular from S aureus and Gram-negative bacteria, could play a part in disease induction and expression. These new insights into the pathogenesis of ANCA-associated vasculitides have opened new ways for targeted treatment.

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Disease Models, Animal; Humans; Mice; Myeloblastin; Peroxidase; Rats

Antineutrophil cytoplasmic autoantibodies (ANCAs) are associated with vasculitis. Current therapy involves administration of toxic therapy that is not optimally effective. This review will summarize evidence for the pathogenicity of ANCAs, which will suggest possible strategies for improving treatment.. Pauci-immune small vessel vasculitis is associated with antibodies against myeloperoxidase (MPO-ANCA) and proteinase 3 (PR3-ANCA). One research group has reported a high frequency of autoantibodies against lysosomal-associated membrane protein 2 (LAMP-2) in patients with MPO-ANCA or PR3-ANCA. Epigenetic dysregulation appears to be the basis for increased MPO and PR3 neutrophil gene expression in ANCA disease. Release of neutrophil extracellular traps may be involved in initiating the ANCA autoimmune response and causing vessel injury. Generation of C5a by alternative pathway activation is involved in pathogenesis in mouse models. Intervention strategies in mice that target antigens, antibodies and inflammatory signaling pathways may translate into novel therapies. Animal models of LAMP-ANCA and PR3-ANCA disease have been proposed. Molecular mimicry and responses to complementary peptides may be initiating events for ANCAs. T cells, including regulatory T cells, have been implicated in the origin and modulation of the ANCAs, as well as in the induction of tissue injury.. Our basic understanding of the origins and pathogenesis of ANCA disease is advancing. This deeper understanding already has spawned novel therapies that are being investigated in clinical trials. This brief review shows that there are more questions than answers, and new questions are emerging faster than existing questions are being answered.

Topics: Animals; Antibodies, Antineutrophil Cytoplasmic; Disease Models, Animal; Humans; Lysosomal-Associated Membrane Protein 2; Myeloblastin; Peroxidase; Vasculitis

Antineutrophil cytoplasmic autoantibodies (ANCAs) directed to proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA) are strongly associated with the ANCA-associated vasculitides--Wegener's granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome. Clinical observations, including the efficacy of B-cell depletion via rituximab treatment, support--but do not prove--a pathogenic role for ANCA in the ANCA-associated vasculitides. In vitro experimental studies show that the interplay of ANCA, neutrophils, the alternative pathway of the complement system, and endothelial cells could result in lysis of the endothelium. A pathogenic role for MPO-ANCA is strongly supported by in vivo experimental studies in mice and rats, which also elucidate the pathogenic mechanisms involved in lesion development. Unfortunately, an animal model for PR3-ANCA-associated Wegener's granulomatosis is not yet available. Here, cellular immunity appears to play a major role as well, particularly via interleukin-17-producing T cells, in line with granulomatous inflammation in the lesions. Finally, microbial factors, in particular Staphylococcus aureus and gram-negative bacteria, seem to be involved in disease induction and expression, but further studies are needed to define their precise role in disease development.

Topics: Animals; Antibodies, Antineutrophil Cytoplasmic; Cells, Cultured; Disease Models, Animal; Humans; Immunity, Cellular; Mice; Microscopic Polyangiitis; Myeloblastin; Neutrophils; Peroxidase; Rats; Staphylococcus aureus; Th17 Cells

The term pauci-immune glomerulonephritis with vasculitis encompasses a group of auto-immune disorders, which includes Wegener's granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome, and renal-limited vasculitis. Over the past few years, progress has been made in understanding the epidemiology and environmental and genetic risk factors of the role of antineutrophil cytoplasmic antibodies (ANCA) in kidney pathogenesis and the utilization of ANCA in diagnosis. However, certain aspects are still subject to debate including the classification and the place of ANCA in treatment.

Topics: Animals; Antibodies, Antineutrophil Cytoplasmic; Disease Models, Animal; Glomerulonephritis; Granulomatosis with Polyangiitis; Humans; Kidney; Myeloblastin; Peroxidase; Risk Factors

To review the clinical, in-vitro and experimental animal model evidence for the pathogenicity of antineutrophil cytoplasmic autoantibodies.. Recent reports on the value of plasma exchange in the treatment of severe antineutrophil cytoplasmic autoantibody-associated glomerulonephritis support the importance of circulating antibodies. The correlation of antineutrophil cytoplasmic autoantibody positivity with renal disease in Churg-Strauss syndrome suggests that the vasculitic component of this syndrome may be induced by antineutrophil cytoplasmic autoantibodys but that other components have a different pathogenesis. In-vitro studies indicate that myeloperoxidase antineutrophil cytoplasmic autoantibody immunoglobulin G may be involved in pathogenesis not only by activating neutrophils but also by having pathophysiologic effects on the function of myeloperoxidase molecules. Findings using the mouse model of antineutrophil cytoplasmic autoantibody disease that is induced by intravenous injection of anti-myeloperoxidase indicate an unexpected role for the alternative pathway of complement activation in the pathogenesis of antineutrophil cytoplasmic autoantibody disease. This is substantiated by in-vitro observations showing that human myeloperoxidase antineutrophil cytoplasmic autoantibody immunoglobulin G and proteinase 3 antineutrophil cytoplasmic autoantibody immunoglobulin G cause neutrophils to release factors that activate complement.. Clinical, in-vitro and experimental animal model evidence continues to mount in favor of a pathogenic role of antineutrophil cytoplasmic autoantibody immunoglobulin G in the induction of vasculitis and glomerulonephritis. This emerging understanding of the pathogenic process may reveal novel and more effective approaches to treatment.

Topics: Animals; Antibodies, Antineutrophil Cytoplasmic; Disease Models, Animal; Humans; Myeloblastin; Peroxidase; Vasculitis

The low density lipoprotein (LDL) oxidation hypothesis has generated considerable interest in oxidative stress and how it might affect atherosclerosis. However, the failure of antioxidants, particularly vitamin E, to affect the progression of the disease in humans has convinced even staunch supporters of the hypothesis to take a step backwards and reconsider alternatives. Preponderant evidence for the hypothesis came from animal antioxidant intervention studies. In this review we point out basic differences between animal and human atherosclerosis development and suggest that human disease starts where animal studies end. While initial oxidative steps in the generation of early fatty streak lesions might be common, the differences might be in the steps involved in the decomposition of peroxidized lipids into aldehydes and their further oxidation into carboxylic acids. We suggest that these steps may not be amenable to attenuation by antioxidants and antioxidants might actually counter the stabilization of plaque by preventing the formation of carboxylic acids which are anti-inflammatory in nature. The formation of such dicarboxylic acids may also be conducive to plaque stabilization by trapping calcium. We suggest that agents that would prevent the decomposition of lipid peroxides and promote the formation and removal of lipid hydroxides, such as paraoxonase (PON 1) or apo A1/high density lipoprotein (HDL) might be more conducive to plaque regression.

Topics: Aldehydes; Animals; Antioxidants; Atherosclerosis; Carboxylic Acids; Clinical Trials as Topic; Disease Models, Animal; Disease Progression; Estradiol; Humans; Inflammation; Lipid Peroxidation; Lipoproteins, LDL; Oxidation-Reduction; Oxidative Stress; Peroxidase; Risk Factors

Recent studies provided new insights into the pathogenesis of vasculitides associated with antineutrophil cytoplasm antibodies (ANCA). They yield more information about the pathogenic role of ANCA, the initiation of the immune response against proteinase 3, the expression of ANCA target antigens on neutrophil surfaces, endothelial damage and the mechanisms of vasculitis associated with propylthiouracil. The pathogenic role of antimyeloperoxidase antibodies has been established in vitro and in vivo in animal models and in human. A pathogenic role for antiproteinase 3 antibodies has not yet been clearly established in vivo although it is well documented in vitro.

Topics: Adult; Animals; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Chemokines; Churg-Strauss Syndrome; Dendritic Cells; Disease Models, Animal; Epitopes; Female; Granulomatosis with Polyangiitis; Humans; Infant, Newborn; Male; Mice; Myeloblastin; Peroxidase; Polymorphism, Genetic; Propylthiouracil; Rats; Rats, Inbred WKY; Risk; Vasculitis

Within the last year, a growing body of evidence for a distinct role of antineutrophil cytoplasmic antibodies (ANCA) in the pathogenesis of ANCA-associated vasculitides (AAV) has developed. An experimental model of myeloperoxidase (MPO)-ANCA-associated vasculitis provided direct and convincing in vivo evidence that MPO-ANCA are primary pathogenic factors in small-vessel vasculitis by augmenting of leukocyte-vessel wall interaction and leukocyte-mediated vascular injury. Determination of bacterial lipopolysaccharide (LPS) effects on disease severity in a mouse model of anti-MPO-induced glomerulonephritis showed that ANCA and other proinflammatory stimuli of infectious origin acted in synergism in the development of destructive inflammation.

Topics: Animals; Antibodies, Antineutrophil Cytoplasmic; Disease Models, Animal; Glomerulonephritis; Humans; Mice; Models, Immunological; Peroxidase; Vasculitis

Anti-neutrophil cytoplasmic autoantibodies (ANCA) with specificity for myeloperoxidase (MPO) or proteinase 3 (Pr3) are associated with systemic small-vessel vasculitides (SVV). Detection of ANCA is an established clinical tool in disease diagnosis and monitoring. Based on clinical and in vitro experimental evidence, a pathogenic role for ANCA has long been suspected, however, in vivo models in which causality can be tested have been lacking. Recently, an exciting novel rat model of MPO-ANCA-associated vasculitis has been described, which provides compelling evidence that MPO-ANCA are a primary pathogenic factor in SVV by augmenting leukocyte-endothelial interactions and vascular wall damage.

Topics: Animals; Antibodies, Antineutrophil Cytoplasmic; Cell Adhesion; Disease Models, Animal; Endothelial Cells; Humans; Leukocytes; Models, Immunological; Myeloblastin; Peroxidase; Rats; Serine Endopeptidases

The pathogenesis of different types of systemic vasculitis positive for antineutrophil cytoplasmic antibodies (ANCA) remains incompletely understood. ANCA constitute a heterogeneous group of antibodies that are associated with different types of small-vessel vasculitis, including Wegener's granulomatosis (WG), microscopic polyangiitis (MPA) and Churg-Strauss syndrome (CSS). Anti-proteinase 3 ANCA are present in more than 90% of patients with systemic WG, and anti-myeloperoxidase (MPO) ANCA in 50-75% of those with MPA and 40-60 % of those with CSS. The pathogenic role of ANCA has been well documented in vivo: passive transfer of anti-MPO ANCA in an MPO knockout mouse model immunized with MPO is sufficient to induce the disease. In vitro, mouse and human anti-proteinase 3 ANCA can activate neutrophils primed with TNF-a and contribute to vasculitic lesions. T-cells are also involved: type 1 helper cytokines have been detected in tissue lesions of limited forms of WG, while type 2 helper cytokines have been identified in its systemic forms. Eosinophils may play a key role in the development of vasculitic lesions in CSS, although this remains to be proved.

Topics: Adoptive Transfer; Animals; Antibodies, Antineutrophil Cytoplasmic; Churg-Strauss Syndrome; Cytokines; Disease Models, Animal; Eosinophils; Granulomatosis with Polyangiitis; Humans; Immunization; Mice; Mice, Inbred BALB C; Mice, Knockout; Monocytes; Neutrophils; Peroxidase; Prevalence; T-Lymphocytes; Vasculitis

Wegener's granulomatosis (WG), microscopic polyangiitis, and Churg-Strauss syndrome belong to the group of ANCA-associated vasculitides. Numerous in vitro studies underscored the role of antineutrophil cytoplasmic antibodies (ANCA) in the pathogenesis of vasculitis. More recently, a mouse model provided in vivo evidence of the pathogenic role of ANCA by inducing a vasculitis after the transfer of splenocytes or MPO-ANCA. The target antigens of ANCA, myeloperoxidase (MPO) and proteinase 3 (PR3), are translocated onto the cell surface after priming of neutrophil granulocytes with cytokines. ANCA bind to target antigens and activate neutrophil granulocytes resulting in premature degranulation and endothelial cell damage (ANCA-cytokine sequence theory). Both the F(ab')2 end and the FcgammaR(eceptor) end of the ANCA are involved in activating neutrophil granulocytes. This mode of activation might account for differences to normal neutrophil activation via the FcgammaR. In addition, an expansion of T-cells lacking the co-stimulatory molecule CD28 is seen in WG suggesting an altered cellular immune response. Data from European multicenter studies demonstrated, among other things, that azathioprine can be used for the maintenance of remission after successful induction of remission with cyclophosphamide in ANCA-associated vasculitides.

Topics: Animals; Antibodies, Antineutrophil Cytoplasmic; Autoantigens; Azathioprine; CD28 Antigens; Churg-Strauss Syndrome; Cyclophosphamide; Disease Models, Animal; Granulomatosis with Polyangiitis; Humans; Immunoglobulin Fab Fragments; Immunosuppressive Agents; Mice; Multicenter Studies as Topic; Myeloblastin; Neutrophil Activation; Peroxidase; Randomized Controlled Trials as Topic; Receptors, IgG; Remission Induction; Serine Endopeptidases; T-Lymphocytes; Vasculitis

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Arginine; Blotting, Western; Colitis; Disease Models, Animal; Drug Evaluation, Preclinical; Enzyme Inhibitors; Inflammatory Bowel Diseases; Injections, Subcutaneous; Instillation, Drug; Male; Models, Animal; Neutrophils; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Peroxidase; Rats; Rats, Wistar; Trinitrobenzenesulfonic Acid

The role of ANCA, ANCA antigens, endothelial cell damage, genetic and environmental pressures, and the "activatability" of leukocytes will probably prove to be important variables in human ANCA vasculitis. The advent of a reliable animal model may open new areas of investigation and treatment of these vasculitic conditions.

Topics: Animals; Antibodies, Antineutrophil Cytoplasmic; Autoantigens; Disease Models, Animal; Humans; Myeloblastin; Neutrophil Activation; Peroxidase; Serine Endopeptidases; Signal Transduction; Vasculitis

Topics: Animals; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Autoimmune Diseases; CD4-Positive T-Lymphocytes; Disease Models, Animal; Female; Glomerulonephritis; Male; Mercuric Chloride; Mice; Mice, Inbred Strains; Mice, Mutant Strains; Mutation; Nephritis; Peroxidase; Rats; Vasculitis

Oxygen radicals particularly superoxide and hydroxyl radicals are very reactive species believed to be involved in cell and tissue damage in a variety of diseases including inflammatory bowel disease (IBD). Today there are four major arguments for such a role in IBD: Infiltration of the inflamed intestinal mucosa with myeloperoxidase containing activated neutrophils able to produce superoxide, hydroxyl and hypochlorite, increased chemoluminescence response of peripheral and mucosal phagocytic cells to various stimuli, decreased inflammation following specific scavenger treatment in animal models of colitis and defined radical scavenger and inhibitory properties of drugs, especially aminosalicylates used in the therapy of IBD. In the absence of a specific therapy, radical scavenging and/or inhibition may be an adjunctive modality in IBD.

Topics: Aminosalicylic Acids; Animals; Colitis, Ulcerative; Crohn Disease; Disease Models, Animal; Free Radicals; Humans; Hydroxides; Hydroxyl Radical; Luminescent Measurements; Neutrophils; Oxygen; Peroxidase; Superoxides

Topics: Acetates; Acetic Acid; Animals; Arachidonic Acid; Arachidonic Acids; Carrageenan; Colitis; Disease Models, Animal; Edema; Flavonoids; Humans; In Vitro Techniques; Lipoxygenase Inhibitors; Peroxidase; Phospholipases A; Pleurisy; Prostaglandin-Endoperoxide Synthases; Quercetin

COVID-19 as a viral disease has brought up the need to exercise more than before due to its physiological effects on health. Therefore, this study investigates the effect of 12-week of aerobic exercise on female students' hormone levels and lipid profile with polycystic ovary syndrome (PCOS) during the COVID-19 pandemic.. Using a 12-week quasi-experimental with pretest, posttest research design among 40 Iranian female students aged 18-14 with PCOS, we randomly allocated the participants to either an experimental (they performed aerobic exercises three 60-minute sessions per week at home using content production) or a control condition. Their anthropometric and blood samples (e.g., testosterone, estrogen, prolactin, and lipid profile) were taken in two stages before and after the training protocol.. Findings demonstrated that performing aerobic exercises is an effective and non-invasive method that could have a positive effect on young girls' PCOS during COVID-19 pandemic.. La pandémie de COVID-19, en tant que maladie virale, a fait ressortir la nécessité de faire de l’exercice plus que jamais en raison de ses effets physiologiques sur la santé. Par conséquent, cette étude examine l’effet de 12 semaines d’exercice aérobique sur les niveaux hormonaux et le profil lipidique d’étudiantes atteintes du syndrome d’ovaires polykystiques (SOPK) pendant la pandémie de COVID-19.. En utilisant un modèle de recherche quasi-expérimental de 12 semaines avec pré-test, post-test auprès de 40 étudiantes iraniennes âgées de 18 à 14 ans atteintes du SOPK, nous avons réparti au hasard les participantes entre une série expérimentale (elles ont effectué des exercices aérobiques à raison de trois séances de 60 minutes par semaine à la maison) et une série contrôle. Les échantillons anthropométriques et sanguins (testostérone, œstrogène, prolactine et profil lipidique) ont été prélevés en deux étapes, avant et après le protocole d’entraînement.. Les résultats ont démontré que la pratique d’exercices d’aérobic est une méthode efficace et non invasive qui pourrait avoir un effet positif sur le SOPK des jeunes filles pendant la pandémie de COVID-19.. Our research showed that even less than 5 GBq irradiation could induce a transient testicular dysfunction in the first 3 months of therapy, but it was mostly reversible after 12 months.. The online version contains supplementary material available at 10.1007/s13204-023-02822-5.. Embelin is predicted to have a high probability of immunotoxicity potential and affect drug metabolism by inhibiting CYP2D6. In addition, it affects food intake, weight gain, and the number of implantations in pregnant rats. Therefore, it is highly recommended not to take embelin and embelin-rich plants during pregnancy. Further. The online version contains supplementary material available at 10.1007/s42965-023-00306-9.. The online version contains supplementary material available at 10.1007/s11696-023-02771-x.. The online version contains supplementary material available at 10.1007/s00477-023-02476-3.. This study ascribes for a new immunomodulatory role for IL11 during tumor development that is amenable to anti-cytokine based therapy of colon cancer.. Inflammation response do not seem to be enough to explain all the Essure-related adverse outcomes, suggesting the involvement of other biological mechanisms.. NCT03281564.. Inflammation and fibrosis are found in the surrounding tubal tissue around the Essure. Adult patients with BED with co-occurring obesity who have good responses to acute treatment with naltrexone/bupropion should be offered maintenance treatment with naltrexone/bupropion.. dp/dtmax in PiCCO parameter can be used as a bedside indicator to evaluate cardiac function in SIC patients due to its simplicity and ease of operation. Esmolol control of heart rate in SIC patients can improve cardiac function and reduce short-term mortality.. Inverted microscopy showed that compared with the NC group, the OGD/R group had poor cell status, swollen cytosol, visible cell lysis fragments and significantly lower cell activity [(49.1±2.7)% vs. (100.0±9.7)%, P < 0.01]; compared with the OGD/R group, the HW group had improved cell status and remarkably higher cell activity [(63.3±1.8)% vs. (49.1±2.7)%, P < 0.01]. Transmission electron microscopy showed that the neuronal nuclear membrane of cells in the OGD/R group was lysed and a higher number of autophagic lysosomes were visible compared with the NC group; compared with the OGD/R group, the neuronal damage of cells in the HW group was reduced and the number of autophagic lysosomes was notably decreased. The results of immunofluorescence assay showed that the expressions of LC3 and Beclin-1 were outstandingly enhanced in the OGD/R group compared with the NC group, and the expressions of LC3 and Beclin-1 were markedly weakened in the HW group compared with the OGD/R group. Western blotting assay showed that the expressions were prominently higher in both LC3II/I and Beclin-1 in the OGD/R group compared with the NC group (LC3II/I: 1.44±0.05 vs. 0.37±0.03, Beclin-1/β-actin: 1.00±0.02 vs. 0.64±0.01, both P < 0.01); compared with the OGD/R group, the protein expression of both LC3II/I and Beclin-1 in the HW group cells were notably lower (LC3II/I: 0.54±0.02 vs. 1.44±0.05, Beclin-1/β-actin: 0.83±0.07 vs. 1.00±0.02, both P < 0.01).. Hydrogen-rich water has a significant protective effect on OGD/R-causing HT22 cell injury, and the mechanism may be related to the inhibition of autophagy.. The prevalence of delirium in ICU patients is over 50%, with hypoactive delirium being the most common. Age, APACHE score at ICU admission, neurological disease, sepsis and duration of mechanical ventilation were all independent risk factors for the development of delirium in ICU patients. More than half of patients with delirium were still delirious when they discharged from the ICU.. For individuals ≥75 years, plasma Aβ42 and P-tau181 might not be associated with cognitive impairment, and MRI parameters, including PVWMH, LVBI and cortical atrophy, are related to CI. The cognitive statuses of people over 75 years old were used as the endpoint event in this study. Therefore, it can be considered that these MRI markers might have more important clinical significance for early assessment and dynamic observation, but more studies are still needed to verify this hypothesis.. We recommend using the Art/Zn complex owing to its moderate inhibitory and antiviral effects against the SARS-CoV-2 with a low cytotoxic effect on host (Vero E6) cells. We suggest conducting further prospective studies to investigate the biological effects of Art/Zn in animal models at different concentrations for testing its clinical efficacy and safety in inhibiting SARS-CoV-2 activities.. The R/T sequence resulted in a significantly longer OS and PFS and improved disease control compared with the reverse sequence. R and T given not sequentially have similar impacts on survival. More data are needed to define the best sequence and to explore the efficacy of sequential (T/R or R/T) treatment combined with molecular-targeted drugs.

Topics: Actin Cytoskeleton; Actins; Adaptor Proteins, Signal Transducing; Adenocarcinoma; Adenosine Triphosphate; Adsorption; Adult; Africa, Eastern; Aged; Air Pollutants; Air Pollution; Air Pollution, Indoor; Alcohol Drinking; Allergens; Alzheimer Disease; Amyotrophic Lateral Sclerosis; Animals; Anti-Bacterial Agents; Antibodies; Antibodies, Immobilized; Antigen Presentation; Antigens, CD; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Apoptosis; Aptamers, Nucleotide; Asthma; Asthma, Exercise-Induced; Atrophy; Autophagy; Azoospermia; Bacillus cereus; Bacterial Infections; Beclin-1; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Biofouling; Biological Monitoring; Biomarkers; Biomarkers, Tumor; Biosensing Techniques; Blastocyst; Bone Neoplasms; Bone Regeneration; Bronchoconstriction; Burkitt Lymphoma; C9orf72 Protein; Campylobacter; Campylobacter Infections; Campylobacter jejuni; Carcinogenesis; Carcinoma, Hepatocellular; Carcinoma, Pancreatic Ductal; Carcinoma, Squamous Cell; Cardiomyopathies; Caregivers; Carmine; Case-Control Studies; Catalysis; Cattle; Cause of Death; CCAAT-Enhancer-Binding Protein-alpha; CD8-Positive T-Lymphocytes; Cefepime; Cell Differentiation; Cell Line, Tumor; Cell Nucleus; Cell Transdifferentiation; Chelating Agents; Chemical and Drug Induced Liver Injury, Chronic; Chemoradiotherapy, Adjuvant; Child; Child, Preschool; China; Chlorquinaldol; Cholangiocarcinoma; Cholera; Chromatin; Clinical Trials as Topic; Cognitive Dysfunction; Cohort Studies; Colonic Neoplasms; Colorectal Neoplasms; Colorimetry; Cooking; Coordination Complexes; COVID-19; Creatinine; CRISPR-Cas Systems; Critical Care; Critical Illness; Cross-Sectional Studies; Cryopreservation; Cryoprotective Agents; Cysteine; Cytokines; Device Removal; Diet; Diet, High-Fat; Diet, Mediterranean; Dietary Supplements; Dimethyl Sulfoxide; Dipeptides; Disease Models, Animal; Dithiothreitol; DNA; DNA Repeat Expansion; DNA, Bacterial; DNA, Complementary; Dopamine; Electrochemical Techniques; Electrodes; Endocannabinoids; Environmental Exposure; Environmental Monitoring; Environmental Pollutants; Enzyme-Linked Immunosorbent Assay; Erlotinib Hydrochloride; Escherichia coli; Escherichia coli O157; Esophageal Neoplasms; Esophagitis, Peptic; Ethylene Glycol; Europium; Exanthema; Fallopian Tubes; Feces; Female; Fertilization in Vitro; Fluoresceins; Fluorescent Dyes; Follicle Stimulating Hormone; Follow-Up Studies; Food Microbiology; Forced Expiratory Volume; Forkhead Transcription Factors; Frontotemporal Dementia; G-Quadruplexes; Galactose; Gastroenteritis; Gastrointestinal Diseases; Gastrointestinal Microbiome; Gastrointestinal Neoplasms; Gastrointestinal Tract; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Genital Neoplasms, Female; Genome-Wide Association Study; Genome, Viral; Genomics; Genotype; Glucose; Glutathione; Glycerol; Gold; Graphite; GTPase-Activating Proteins; Heat-Shock Proteins; Heme Oxygenase-1; Hepacivirus; Hepatitis C; Hepatocytes; Histamine; Histocompatibility Antigens Class II; Hoarseness; Hospice and Palliative Care Nursing; Humans; Hydrogen; Hydrogen Peroxide; Hydrogen Sulfide; Hydroxybenzoates; Hydroxyl Radical; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperthermia, Induced; Hysteroscopy; Immunoassay; Indigo Carmine; Inflammation; Inflammatory Bowel Diseases; Insulin Resistance; Intensive Care Units; Interleukin-11; Interleukin-6; Interleukins; Iodine Radioisotopes; Iran; Iridium; Islets of Langerhans; Kinetics; Lactation; Lactobacillus; Lactobacillus plantarum; Lamins; Latin America; Lead; Lectins; Leukopenia; Ligands; Limit of Detection; Lipopolysaccharides; Lipoprotein Lipase; Liver; Liver Cirrhosis; Liver Neoplasms; Lolium; Luminescent Measurements; Luminol; Lung; Luteinizing Hormone; Macrophages; Magnetic Phenomena; Magnetic Resonance Imaging; Male; Malnutrition; Maltose; Manganese Compounds; Maternal Nutritional Physiological Phenomena; Melatonin; Metabolic Engineering; Metal Nanoparticles; Metallocenes; Metaplasia; Methicillin-Resistant Staphylococcus aureus; Methylation; Mevalonic Acid; Mexico; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microbial Sensitivity Tests; Microbiota; MicroRNAs; Milk; Mitomycin; Molecular Diagnostic Techniques; Molecular Docking Simulation; Monte Carlo Method; Moringa oleifera; Multiple Sclerosis; Muscle Strength; Muscle, Skeletal; Nanocomposites; Nanotubes, Carbon; Neoadjuvant Therapy; Neoplasms; Neurodegenerative Diseases; Neurotransmitter Agents; NF-E2-Related Factor 2; Nickel; Nitrogen Dioxide; Non-alcoholic Fatty Liver Disease; Nucleic Acid Amplification Techniques; Nucleic Acid Hybridization; Nucleocapsid Proteins; Nutritional Status; Obesity; Osteogenesis; Osteosarcoma; Oxidation-Reduction; Oxides; Oxygen; Oxyquinoline; Pain; Palliative Care; Pancreatic Neoplasms; Pandemics; Particulate Matter; Peroxidase; Peroxidases; Phagocytosis; Phaseolus; Photothermal Therapy; Point-of-Care Systems; Polyethyleneimine; Polymers; Polymorphism, Single Nucleotide; Polysomnography; Postoperative Complications; Pregnancy; Pregnant Women; Prenatal Exposure Delayed Effects; Prevalence; Printing, Three-Dimensional; Probability; Probiotics; Prognosis; Prophages; Prospective Studies; Proteomics; Proto-Oncogene Proteins; Pseudomonas aeruginosa; Pseudomonas putida; Pulmonary Disease, Chronic Obstructive; Pulmonary Embolism; Pyridines; Pyrroles; Quality of Life; Quinolones; Rabbits; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Real-Time Polymerase Chain Reaction; Receptors, Histamine; Receptors, Histamine H2; Recombinases; Rectal Neoplasms; Reperfusion Injury; Respiration; Respiratory Function Tests; Respiratory Rate; Respiratory Sounds; Retrospective Studies; rho GTP-Binding Proteins; Risk Assessment; Risk Factors; RNA; RNA, Messenger; RNA, Ribosomal, 16S; Robotic Surgical Procedures; Running; Rural Population; Saccharomyces cerevisiae; Salpingectomy; Sarcopenia; SARS-CoV-2; Seeds; Semen; Sensitivity and Specificity; Sepsis; Shock, Septic; Signal Transduction; Silicon Dioxide; Silver; Sirtuin 1; Skin Neoplasms; Sleep Apnea, Obstructive; Soil; Spain; Spectrum Analysis, Raman; Sperm Retrieval; Spermatozoa; Spirometry; Staphylococcus aureus; STAT3 Transcription Factor; Stereoisomerism; Sterilization, Tubal; Stroke Volume; Sulfadiazine; Sulfites; Superoxide Dismutase; Surface Plasmon Resonance; tau Proteins; Testis; Testosterone; Thioredoxin-Disulfide Reductase; Thyroid Neoplasms; Thyroidectomy; Trans-Activators; Transcription Factor AP-1; Treatment Outcome; Triazoles; Triclosan; Trifluridine; Tumor Microenvironment; Tumor Necrosis Factor-alpha; United States; Uracil; Vagina; Vegetables; Ventricular Function, Left; Ventricular Pressure; Vibrio cholerae; Vietnam; Virulence; Vital Capacity; Vitrification; Walking; Water; Water Pollutants, Radioactive; Whole Genome Sequencing; Wind; YAP-Signaling Proteins; Zeolites; Zinc Oxide

Sepsis-induced inflammatory lung injury is a key factor causing failure of the lungs and other organs, as well as death, during sepsis. In the present study, a caecal ligation and puncture (CLP)-induced sepsis model was established to investigate the effect of β-catenin on sepsis-induced inflammatory lung injury and the corresponding underlying mechanisms. C57BL/6 mice were randomly divided into five groups, namely, the sham, CLP, β-catenin knockout (KO) + CLP, XAV-939 + CLP, and ICG-001 + CLP groups; the XAV-939 + CLP and ICG-001 + CLP groups were separately subjected to intraperitoneal injections of the β-catenin inhibitors XAV-939 and ICG-001 for 1 week preoperatively and 2 days postoperatively, respectively. Forty-eight hours after CLP, we measured β-catenin expression in lung tissues and evaluated mouse mortality, histopathological characteristics of hematoxylin and eosin (H&E)-stained lung tissues, serum cytokine (tumor necrosis factor [TNF]-α, interleukin [IL]-10, and IL-1β) levels, lung myeloperoxidase (MPO) activity, and the number of apoptotic cells in the lung tissues. Our results indicated that both the inhibition of β-catenin expression and blockage of β-catenin/CREB-binding protein (CBP) interactions by ICG-001 effectively decreased mouse mortality, alleviated pathological lung injury, and reduced the serum TNF-α, IL-10, and IL-1β levels, in addition to reducing the lung MPO activity and the number of apoptotic cells in lung tissues of the sepsis model mice. Therefore, it can be deduced that the β-catenin/CBP signaling axis participates in regulating sepsis-induced inflammatory lung injury.

Topics: Animals; beta Catenin; CREB-Binding Protein; Cytokines; Disease Models, Animal; Eosine Yellowish-(YS); Hematoxylin; Interleukin-10; Lung; Lung Injury; Mice; Mice, Inbred C57BL; Peroxidase; Sepsis; Tumor Necrosis Factor-alpha

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new strain of coronavirus not previously identified in humans. Globally, the number of confirmed cases and mortality rates of coronavirus disease 2019 (COVID-19) have risen dramatically. Currently, there are no FDA-approved antiviral drugs and there is an urgency to develop treatment strategies that can effectively suppress SARS-CoV-2-mediated cytokine storms, acute respiratory distress syndrome (ARDS), and sepsis. As symptoms progress in patients with SARS-CoV-2 sepsis, elevated amounts of cell-free DNA (cfDNA) are produced, which in turn induce multiple organ failure in these patients. Furthermore, plasma levels of DNase-1 are markedly reduced in SARS-CoV-2 sepsis patients. In this study, we generated recombinant DNase-1-coated polydopamine-poly(ethylene glycol) nanoparticulates (named long-acting DNase-1), and hypothesized that exogenous administration of long-acting DNase-1 may suppress SARS-CoV-2-mediated neutrophil activities and the cytokine storm. Our findings suggest that exogenously administered long-acting nanoparticulate DNase-1 can effectively reduce cfDNA levels and neutrophil activities and may be used as a potential therapeutic intervention for life-threatening SARS-CoV-2-mediated illnesses.

Topics: Animals; COVID-19; Cytokine Release Syndrome; Deoxyribonuclease I; Dexamethasone; Disease Models, Animal; DNA; Drug Carriers; Drug Evaluation, Preclinical; Extracellular Traps; Humans; Indoles; Male; Mice; Mice, Inbred C57BL; Multiple Organ Failure; Nanoparticles; Neutrophils; NF-kappa B; Peroxidase; Polyethylene Glycols; Polyglactin 910; Polymers; SARS-CoV-2; Sepsis

Mastitis is a common disease occurs in breast-feeding mothers, but published data are poor. This study aimed to study the effects of Tanshinones on treating mastitis.. Clinical trials performed in 58 breast-feeding mothers were carried out. B-ultrasound and blood test were used to measure the size of breast mass and the change of blood cell counts. BALB/c mice were injected with LPS and then treated by Tanshinone I or Tanshinone IIA/B. Myeloperoxidase (MPO) activity and the release of inflammatory cytokines were tested by MPO kit, RT-qPCR and ELISA. Mouse mammary epithelial cells (mMECs) were isolated and the effects of Tanshinones were measured by conducting CCK-8 assay, flow cytometry, RT-qPCR and ELISA.. Patients treated by Cefprozil combined with Tanshinone got better outcomes than patients treated by Cefprozil alone. In animal trials, Tanshinone I and Tanshinone IIA/B significantly reduced MPO activity, and the levels of TNF-α, IL-1β and IL-6 in serum and mammary gland tissues. In mMECs, Tanshinone I and Tanshinone IIA/B attenuated LPS-induced viability loss and apoptosis. And they effectively inhibited the release of TNF-α, IL-1β and IL-6. Also, Tanshinone I and Tanshinone IIA/B significantly attenuated LPS-evoked NF-κB activation.. Tanshinone I and Tanshinone IIA/B have potentials in treating mastitis. The beneficial effects might be through regulating NF-κB activation.

Topics: Abietanes; Adult; Animals; Anti-Infective Agents; Apoptosis; Breast Feeding; Cefprozil; Cephalosporins; Disease Models, Animal; Drug Therapy, Combination; Female; Humans; Inflammation; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; Mammary Glands, Animal; Mammary Glands, Human; Mastitis; Mice, Inbred BALB C; NF-kappa B p50 Subunit; Peroxidase; Tumor Necrosis Factor-alpha; Ultrasonography, Mammary

The most effective way of treating liver cancer is surgical resection, which usually requires blocking the hepatic portal circulation, and may result in hepatic ischemia-reperfusion injury (HIRI). It is of paramount importance to control HIRI for liver cancer surgical resection. In this study, a 70% ischemia-reperfusion (I/R) model of rat liver was established, and the protective effect and mechanism of limb ischemic post-conditioning (LIPOC) on HIRI was investigated. We show that LIPOC has a protective effect on hepatic ischemia-reperfusion injury in rats, which reduces the elimination of superoxide dismutase, thereby increasing oxygen free radical scavenging, decreasing lipid peroxidation, inhibiting neutrophil aggregation, as well as reducing TNFα, IL1β, and other inflammatory cytokines. In addition, LIPOC inhibited the apoptosis of hepatocytes induced by I/R injury, and decreased the Bax/Bcl-2 ratio. Furthermore, LIPOC promoted the phosphorylation of Akt and ERK1/2. The use of PI3K inhibitor LY294002 and ERK1/2 blocker PD98059 inhibited the phosphorylation of Akt and ERK1/2 caused by LIPOC and abolished the injury protection of liver I/R. Moreover, through 16 cases of hepatocellular carcinoma resections, we found that short-term LIPOC treatment significantly suppressed the elevated alanine aminotransferase, aspartic transaminase, and total bilirubin in the early post-operation of liver resection, and reduced reperfusion injury to the ischemic liver. In summary, our study demonstrates that LIPOC could be an effective method for HIRI in the clinical implementation of liver resection and uncovers the potential mechanism of LIPOC in the protective effects of HIRI.

Topics: Adult; Aged; Alanine Transaminase; Animals; Apoptosis; Blotting, Western; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Humans; In Situ Nick-End Labeling; Ischemia; Ischemic Postconditioning; Liver Neoplasms; Male; Malondialdehyde; MAP Kinase Signaling System; Middle Aged; Peroxidase; Phosphatidylinositol 3-Kinases; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Superoxide Dismutase

Traumatic brain injury (TBI) is a major human health concern that has the greatest impact on young men and women. The breakdown of the blood-brain barrier (BBB) is an important pathological consequence of TBI that initiates secondary processes, including infiltration of inflammatory cells, which can exacerbate brain inflammation and contribute to poor outcome. While the role of inflammation within the injured brain has been examined in some detail, the contribution of peripheral/systemic inflammation to TBI pathophysiology is largely unknown. Recent studies have implicated vagus nerve regulation of splenic cholinergic nicotinic acetylcholine receptor α7 (nAChRa7) signaling in the regulation of systemic inflammation. However, it is not known whether this mechanism plays a role in TBI-triggered inflammation and BBB breakdown. Following TBI, we observed that plasma TNF-α and IL-1β levels, as well as BBB permeability, were significantly increased in nAChRa7 null mice (Chrna7(-/-)) relative to wild-type mice. The administration of exogenous IL-1β and TNF-α to brain-injured animals worsened Evans Blue dye extravasation, suggesting that systemic inflammation contributes to TBI-triggered BBB permeability. Systemic administration of the nAChRa7 agonist PNU-282987 or the positive allosteric modulator PNU-120596 significantly attenuated TBI-triggered BBB compromise. Supporting a role for splenic nAChRa7 receptors, we demonstrate that splenic injection of the nicotinic receptor blocker α-bungarotoxin increased BBB permeability in brain-injured rats, while PNU-282987 injection decreased such permeability. These effects were not seen when α-bungarotoxin or PNU-282987 were administered to splenectomized, brain-injured rats. Together, these findings support the short-term use of nAChRa7-activating agents as a strategy to reduce TBI-triggered BBB permeability.. Breakdown of the blood-brain barrier (BBB) in response to traumatic brain injury (TBI) allows for the accumulation of circulating fluids and proinflammatory cells in the injured brain. These processes can exacerbate TBI pathology and outcome. While the role of inflammation in the injured tissue has been examined in some detail, the contribution of peripheral inflammation in BBB breakdown and ensuing pathology has not been well defined. We present experimental evidence to indicate that the stimulation of nicotinic acetylcholine α7 receptors (nAChRa7s) can reduce peripheral inflammation and BBB breakdown after TBI. These results suggest that activators of nAChRa7 may have therapeutic utility for the treatment of TBI.

Topics: alpha7 Nicotinic Acetylcholine Receptor; Analysis of Variance; Animals; Blood-Brain Barrier; Brain Injuries; Disease Models, Animal; Encephalitis; Enzyme-Linked Immunosorbent Assay; Interleukin-1beta; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Permeability; Peroxidase; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha; von Willebrand Factor

Randomized experimental study.. The study aimed to investigate the therapeutic efficacy and molecular mechanisms of A-68930 in a rat model of spinal cord injury (SCI)-induced acute lung injury (ALI).. China.. The influences of A-68930 on the pulmonary edema, histological changes, proinflammatory cytokines levels, myeloperoxidase (MPO) activity and NLRP3 inflammasome protein expression were estimated.. SCI significantly promoted NLRP3 inflammasome activation, increased proinflammatory cytokine productions and MPO activity, and induced pulmonary edema and tissue damage in the SCI group as compared with the control group. A-68930 administration significantly inhibited NLRP3 inflammasome activation and reduced inflammatory cytokines levels and MPO activity. Moreover, A-68930 administration attenuated pulmonary edema and histopathology.. Our experimental findings indicated that A-68930 exhibited a protective effect on SCI-induced ALI by the alleviations of inflammatory response with the inhibition NLRP3 inflammasome activation 72 h post injury. The present study indicated that A-68930 could be a potentially efficient therapeutic strategy for the treatment of SCI-induced ALI.

Topics: Acute Lung Injury; Animals; Capillary Permeability; Chromans; Cytokines; Disease Models, Animal; Dopamine Agonists; Dose-Response Relationship, Drug; Female; Gene Expression Regulation; NLR Family, Pyrin Domain-Containing 3 Protein; Organ Size; Peroxidase; Rats; Rats, Sprague-Dawley; Spinal Cord Injuries; Time Factors

Cerebral aneurysm (CA) affects 3% of the population and is associated with hemodynamic stress and inflammation. Myeloperoxidase, a major oxidative enzyme associated with inflammation, is increased in patients with CA, but whether myeloperoxidase contributes to CA is not known. We tested the hypotheses that myeloperoxidase is increased within human CA and is critical for formation and rupture of CA in mice.. Blood was drawn from the lumen of CAs and femoral arteries of 25 patients who underwent endovascular coiling of CA, and plasma myeloperoxidase concentrations were measured with ELISA. Effects of endogenous myeloperoxidase on CA formation and rupture were studied in myeloperoxidase knockout mice and wild-type (WT) mice using an angiotensin II-elastase induction model of CA. In addition, effects of myeloperoxidase on inflammatory gene expression in endothelial cells were analyzed.. Plasma concentrations of myeloperoxidase were 2.7-fold higher within CA than in femoral arterial blood in patients with CA. myeloperoxidase-positive cells were increased in aneurysm tissue compared with superficial temporal artery of patients with CA. Incidence of aneurysms and subarachnoid hemorrhage was significantly lower in myeloperoxidase knockout than in WT mice. In cerebral arteries, proinflammatory molecules, including tumor necrosis factor-α, cyclooxygenase-2 (COX2), chemokine (C-X-C motif) ligand 1 (CXCL1), chemokine (C motif) ligand (XCL1), matrix metalloproteinase (MMP) 8, cluster of differentiation 68 (CD68), and matrix metalloproteinase 13, and leukocytes were increased, and α-smooth muscle actin was decreased, in WT but not in myeloperoxidase knockout mice after induction of CA. Myeloperoxidase per se increased expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in endothelial cells.. These findings suggest that myeloperoxidase may contribute importantly to formation and rupture of CA.

Topics: Aneurysm, Ruptured; Angiotensin II; Animals; Disease Models, Animal; Gene Expression Regulation; Humans; Inflammation Mediators; Intercellular Adhesion Molecule-1; Intracranial Aneurysm; Leukocyte Count; Male; Mice; Mice, Knockout; Pancreatic Elastase; Peroxidase; Vascular Cell Adhesion Molecule-1; Vasoconstrictor Agents

Oxidants derived from myeloperoxidase (MPO) contribute to inflammatory diseases. In vivo MPO activity is commonly assessed by the accumulation of 3-chlorotyrosine (3-Cl-Tyr), although 3-Cl-Tyr is formed at low yield and is subject to metabolism. Here we show that MPO activity can be assessed using hydroethidine (HE), a probe commonly employed for the detection of superoxide. Using LC/MS/MS, (1)H NMR, and two-dimensional NOESY, we identified 2-chloroethidium (2-Cl-E(+)) as a specific product when HE was exposed to hypochlorous acid (HOCl), chloramines, MPO/H2O2/chloride, and activated human neutrophils. The rate constant for HOCl-mediated conversion of HE to 2-Cl-E(+) was estimated to be 1.5 × 10(5) M(-1)s(-1). To investigate the utility of 2-Cl-E(+) to assess MPO activity in vivo, HE was injected into wild-type and MPO-deficient (Mpo(-/-)) mice with established peritonitis or localized arterial inflammation, and tissue levels of 2-Cl-E(+) and 3-Cl-Tyr were then determined by LC/MS/MS. In wild-type mice, 2-Cl-E(+) and 3-Cl-Tyr were detected readily in the peritonitis model, whereas in the arterial inflammation model 2-Cl-E(+) was present at comparatively lower concentrations (17 versus 0.3 pmol/mg of protein), and 3-Cl-Tyr could not be detected. Similar to the situation with 3-Cl-Tyr, tissue levels of 2-Cl-E(+) were decreased substantially in Mpo(-/-) mice, indicative of the specificity of the assay. In the arterial inflammation model, 2-Cl-E(+) was absent from non-inflamed arteries and blood, suggesting that HE oxidation occurred locally in the inflamed artery. Our data suggest that the conversion of exogenous HE to 2-Cl-E(+) may be a useful selective and sensitive marker for MPO activity in addition to 3-Cl-Tyr.

Topics: Animals; Arteritis; Disease Models, Animal; Humans; Hydrogen Peroxide; Mice; Mice, Knockout; Oxidants; Peritonitis; Peroxidase; Phenanthridines

Silymarin has intracellular antioxidant property and inhibits activation of nuclear factor-κB (NF-κB) in low concentrations and reduces tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6 levels, cyclooxygenase (COX), and angiogenesis. Selenium is one of the necessary trace element nutrients for human and animals. Selenium nanoparticles (nano-Se) have more bioavailability with less toxicity.. To investigate the combination effect of silymarin and nano-Se on inhibition of NF-κB, proinflammatory cytokines, and oxidative stress biomarkers in the experimental colitis.. Trinitrobenzene sulfonic acid (TNBS) was used to induce colitis. After TNBS instillation, rats were distributed into six groups, containing silymarin and nano-Se alone or in combination, dexamethasone, negative control with no treatment and the last one was normal sham rats. All drugs were administered for 7 days. Colon samples were scored macroscopically and microscopically. The levels of activated NF-κB, IL-1β, TNF-α, myeloperoxidase (MPO), lipid peroxidation, protein carbonyl (PC), and the antioxidant power of the colon homogenates were determined.. A significant decrease in NF-κB activity in treated groups was observed. The levels of TNF-α, IL-1β, MPO, lipid peroxidation, and PC were reduced and an improvement in antioxidant power of treated groups was seen. Combination of silymarin and nano-Se were more effective than each one alone in improvement of NF-κB, TNF-α, antioxidant power, and lipid peroxidation values, although this difference was not significant in other factors.. Co-administration of silymarin and nano-Se with a good antioxidant profile and inhibition of NF-κB is a possible candidate for better management of inflammatory bowel disease.

Topics: Animals; Antioxidants; Biomarkers; Colitis; Colon; Disease Models, Animal; Interleukin-1beta; Lipid Peroxidation; Male; Nanoparticles; NF-kappa B; Oxidative Stress; Peroxidase; Protein Carbonylation; Rats; Rats, Wistar; Selenium; Silymarin; Tumor Necrosis Factor-alpha

The influence of fungal colonization on the course of ulcerative colitis (UC) has not been thoroughly studied. We determined the activity of the disease using clinical, endoscopic and histological index (IACH) criteria in UC patients with fungal colonization and the healing process of UC induced by an intrarectal administration of trinitrobenzene sulfonic acid (TNBS) in rats infected with Candida, without and with antifungal (fluconazole) or probiotic (lacidofil) treatment. The intensity of the healing of the colonic lesions was assessed by macro- and microscopic criteria as well as functional alterations in colonic blood flow (CBF). Myeloperoxidase (MPO) content and plasma proinflammatory cytokines IL-1beta and TNF-alpha levels were evaluated. Candida more frequently colonized patients with a history of UC within a 5-year period, when compared with those of shorter duration of IBS. Among Candida strains colonizing intestinal mucosa, Candida albicans was identified in 91% of cases. Significant inhibition of the UC activity index as reflected by clinical, endoscopical and histological criteria was observed in the Candida group treated with fluconazole, when compared to that without antifungal treatment. In the animal model, Candida infection significantly delayed the healing of TNBS-induced UC, decreased the CBF and raised the plasma IL-1beta and TNF-alpha levels, with these effects reversed by fluconazole or lacidofil treatment. We conclude that 1) Candida delays healing of UC in both humans and that induced by TNBS in rats, and 2) antifungal therapy and probiotic treatment during Candida infection could be beneficial in the restoration and healing of colonic damage in UC.

Topics: Adolescent; Adult; Aged; Animals; Antifungal Agents; Candida albicans; Candidiasis; Colitis, Ulcerative; Colon; Disease Models, Animal; Female; Fluconazole; Humans; Interleukin-1beta; Male; Middle Aged; Peroxidase; Probiotics; Rats; Rats, Wistar; Time Factors; Tumor Necrosis Factor-alpha; Young Adult

The complement system is implicated in the pathogenesis of human inflammatory bowel disease, but the specific role of C5a has never been examined. We have compared the efficacy of an orally active human C5a receptor antagonist (AcPhe[Orn-Pro-D-cyclohexylalanine-Trp-Arg]), prednisolone, and infliximab against trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats. The drugs were administered either 2 days before or 24 h after TNBS instillation, and rats were then examined after 8 days. Drug-free colitis control rats showed severe disease pathology with significant mortality (39%). Rats pre or posttreated with the C5a antagonist (10 mg/kg/day peroral, 0.3 mg/kg/day s.c.) had reduced mortality and significantly improved macroscopic scores, colon edema, colon myeloperoxidase levels, reduced concentrations of TNF-alpha levels in the colon and serum, and had greater food intake resulting in greater weight gains than colitis-only rats. Rats pretreated with prednisolone (1 mg/kg/day s.c.) displayed significant improvement in parameters measured, but posttreatment was ineffective. Single dose pretreatment with the TNF-alpha inhibitor infliximab (3 mg/kg i.v.) also had significant improvements in the parameters measured. Rats pretreated with a combination of the C5a antagonist and prednisolone showed no greater improvements than either drug alone. These findings suggest a central role for complement, particularly C5a, in the pathology of TNBS-induced colitis in rats, indicating a possible therapeutic role for C5a antagonists in inflammatory bowel disease.

Topics: Animals; Antibodies, Monoclonal; Body Weight; Colon; Disease Models, Animal; Eating; Edema; Humans; Inflammatory Bowel Diseases; Infliximab; Male; Peptides, Cyclic; Peroxidase; Prednisolone; Rats; Rats, Wistar; Receptor, Anaphylatoxin C5a; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

We hypothesized that modifying resuscitation would alter hemorrhagic shock-induced respiratory dysfunction and correlate with nuclear factor-kappa B and cytokine expression.. Randomized, controlled, prospective study.. University hospital trauma research laboratory.. Female, Swiss Webster mice, 8-12 wks old.. Hemorrhagic shock was induced by removing 0.025 mL of blood/g of body weight via a carotid catheter. Animals were resuscitated 30 mins later. Mice were randomized into four groups: group I was cannulated but not bled (sham); group II received normal saline to three times their shed blood volume; group III received their shed blood; and group IV received shed blood + normal saline at two times shed blood volume.. We measured the following: serum lactates at the end of shock and after resuscitation, pulmonary function before any instrumentation and after 24 hrs, cytokine concentrations by enzyme-linked immunosorbent assay, and nuclear factor-kappa B activity by electrophoretic mobility shift assay. Groups that were hemorrhaged had significant hypotension and a significant increase in serum lactates over 30 mins. Resuscitation returned the blood pressure to baseline in all groups, and lactates improved in all groups except group II. Group II also demonstrated a significant decrease in pulmonary function characterized by increased airway resistance and decreases in minute volume, lung compliance, and alveolar function. Bronchoalveolar fluid and serum interleukin-6 and whole lung nuclear factor-kappa B activity also were elevated significantly in group II.. Group II demonstrated the least improvement in serum lactate after resuscitation, the most significant acute lung injury, and the greatest interleukin-6 and nuclear factor-kappa B response. Group IV mice had the least acute lung injury, with no detectable interleukin-6 response. Improved resuscitation with crystalloid and shed blood minimized acute lung injury. The reduction in pulmonary dysfunction after improved resuscitation may be attributable to a blunting of the nuclear factor-kappa B and interleukin-6 responses to hemorrhage.

Topics: Airway Resistance; Animals; Blood Pressure; Bronchoalveolar Lavage Fluid; Cardiopulmonary Resuscitation; Disease Models, Animal; Female; Interleukin-6; Lactic Acid; Lung; Lung Injury; Mice; NF-kappa B; Peroxidase; Prospective Studies; Respiratory Distress Syndrome; Shock, Hemorrhagic; Statistics as Topic; Survival Analysis; Time Factors

Recent studies have suggested that heparin is effective for treatment of inflammatory bowel disease (IBD) and its various effects (in addition to the anticoagulant effect). We evaluated the effects of argatroban as an antithrombin drug on trinitrobenzene sulfonic acid (TNB)-induced colitis, an established model of IBD.. Rats were randomly assigned to four groups in which mini-osmotic pumps containing saline (TNB-S), argatroban (TNB-A), or 100 U/kg heparin (TNB-H) were intraperitoneally implanted. Three days after the pumps were implanted, TNB was infused via the anus, and colitis was induced. After 5 days, prothrombin time (PT), activated partial prothrombin time (APTT), antithrombin III (AT-III), platelet, fibrinogen, colonic wet weight, macroscopic damage score, histological score, mucosal myeloperoxidase activity and mucosal leukotrien B4 (LTB4) levels were compared among the four groups.. The APTT was prolonged in the heparin treatment group but only slightly prolonged in the argatroban treatment group. The platelet count and the fibrinogen level were higher in the TNB-S group than in the healthy control group and the AT-III level was slightly lower in the TNB-S group than in the healthy control group and lower still in the TNB-H group.. The colonic wet weight was similar among the four groups while the macroscopic damage score, histological score, mucosal myeloperoxidase activity and the mucosal LTB4 level were significantly decreased in the TNB-A and TNB-H groups. Argatroban, as well as heparin may be effective for treatment of TNB-induced colitis.

Topics: Analysis of Variance; Animals; Antithrombins; Arginine; Blood Coagulation Tests; Colitis; Disease Models, Animal; Heparin; Immunoenzyme Techniques; Infusion Pumps, Implantable; Leukotriene B4; Male; Nitrobenzenes; Peroxidase; Pipecolic Acids; Rats; Rats, Wistar; Sulfonamides; Sulfonic Acids

The short chain fatty acid (SCFA) butyrate provides energy for colonocytes, stimulates colonic fluid and electrolyte absorption and is recognised as an effective treatment for multiple types of colitis.. To examine the impact of butyrate enema therapy on the clinical course, severity of inflammation, and SCFA stimulated Na+ absorption in a chronic experimental colitis.. Distal colitis was induced in rats with a trinitrobenzenesulphonic acid (TNBS) enema. Five days after induction, rats were divided into groups to receive: no treatment, saline enemas, or 100 mM Na-butyrate enemas daily. On day 24, colonic damage score and tissue myeloperoxidase (MPO) activity were evaluated. Colon was mounted in Ussing chambers and Na+ transport and electrical activities were measured during a basal period and after stimulation with 25 mM butyrate.. In the untreated and the saline enema treated TNBS groups, diarrhoea and extensive colonic damage were seen, associated with increased tissue MPO activities and absent butyrate stimulated Na+ absorption. In contrast, in the butyrate enema treated TNBS group, diarrhoea ceased, colonic damage score improved, and tissue MPO activity as well as butyrate stimulated Na+ absorption recovered to control values.. Butyrate enema therapy stimulated colonic repair, as evidenced by clinical recovery, decreased inflammation, and restoration of SCFA stimulated electrolyte absorption.

Topics: Animals; Butyrates; Colitis; Colon; Disease Models, Animal; Enema; Ion Transport; Male; Mucous Membrane; Peroxidase; Rats; Rats, Wistar; Trinitrobenzenesulfonic Acid

To determine the effects of the 21-aminosteroid, U-74389G, on reperfusion of the equine jejunum, using total (TVO) and partial (PVO) vascular occlusion during the ischemic period.. TVO: 16 healthy horses were randomly allotted to 3 groups-4 horses received the vehicle alone, 6 horses received a low dosage (3 mg/kg o body weight), and 6 horses a high dosage (10 mg/kg) of U-7438G. PVO: 10 healthy horses were randomly allotted to 2 groups--5 horses received the vehicle alone, and 5 horses received the low dosage (3 mg/kg) of U-74389G.. TVO was induced for 1 hour followed by 2 hours of reperfusion. During PVO, blood flow was reduced to 20% of baseline for 2 hours, followed by 2 hours of reperfusion. For both models, either the vehicle alone or the drug was given 15 minutes prior to reperfusion. Samples were obtained before, during, and after ischemia for determination of myeloperoxidase (MPO) activity, malondealdehyde (MDA) concentration, concentration of conjugated dienes (PVO experiment only), and morphometric analysis.. TVO: tissue concentration of MDA and MPO activity were not altered in any group by ischemia or reperfusion. During ischemia, mucosal volume and surface area were reduced. After reperfusion, no further reduction occurred. After initial decrease in submucosal volume during ischemia, there was a significant increase after reperfusion in the vehicle-only group (P < 0.05). PVO: there were no alterations in the concentration of either MDA or conjugated dienes. There was significant increase in the activity of MPO during ischemia and reperfusion (P < 0.05). These effects were similar for the vehicle-only and drug groups. During ischemia, there was a significant decrease in mucosal surface area and volume (P < 0.05), that was continued during reperfusion for the vehicle-only (P < 0.05). Submucosal volume increased during ischemia and reperfusion.. Reduced blood flow during ischemia (PVO group) caused continued loss in mucosal volume and surface area during reperfusion. At the dosage given, the 21-aminosteroid, U-74389G, was not effective in preventing continued reduction in mucosal volume and surface area after restoration of blood supply in the horses subjected to reduced blood flow.

Topics: Animals; Antioxidants; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Horse Diseases; Horses; Infusions, Intravenous; Intestinal Mucosa; Jejunum; Male; Malondialdehyde; Mesenteric Vascular Occlusion; Peroxidase; Pregnatrienes; Reperfusion Injury; Time Factors

Selenium-enriched Lactobacillus plantarum and Bifidobacterium longum mutants were used as a protector against Piroxicam-induced ulcerative colitis (UC). In this study, 32 BALB/c male mice were distributed to four groups: the control group, the Piroxicam group which was given 0.8 mg Piroxicam, SP and SB groups which were given 0.8 mg Piroxicam, and plus Lactobacillus plantarum and Bifidobacterium longum selenium-enriched mutants, respectively. Bodyweight; serum content of IgG, IgM, TNF-α, IL-2, IL-6, and IL-10; CBC; myeloperoxidase enzyme activity; histopathological examination of colon and spleen; and expression of TNF-α, IL-2, IL-6, and IL-10 genes in colon and spleen with qRT-PCR were determined. Bodyweight was found to reduce in the Piroxicam group and then recovery in the SB group. Serum content of IgG, IL-2, and IL-10 reduced in the Piroxicam group, whereas IgG, TNF-α, and IL-6 increased in the Piroxicam group in comparison to the other groups. Myeloperoxidase activity witnessed a significant increase in the Piroxicam group compared with the other groups. No significant differences were observed between all groups in measurements of red cells, hemoglobin, neutrophil, monocyte, eosinophil, and basophil in blood. Meanwhile, the white blood cells and platelets recorded the highest and lowest value, respectively, in the Piroxicam group. The colon of the Piroxicam group showed a noticeably massive infiltration of inflammatory cells in the lamina propria. These inflammations were mildly reduced in the SP group, while the reduction in the SB group was significant. In the Piroxicam group, splenic parenchyma saw an increase in the number of melanomacrophages, while hypertrophic plasma cells were observed in the SP group. The spleen of the SB group exhibits a nearly normal form. TNF-α and IL-6 genes had significantly upregulated in the colon of the Piroxicam group compared to the control group, while they were significantly downregulated in the SB group. In contrast, IL-2 and IL-10 genes had upregulated in the colon of the SB group compared to the control groups, while they had downregulated in the Piroxicam group. The expression of these genes had not recorded significant differences between all groups in the spleen. Therefore, this study recommends Bifidobacterium longum selenium-enriched mutants as anti-inflammatory and immunomodulatory supplements.

Topics: Animals; Anti-Inflammatory Agents; Colitis, Ulcerative; Colon; Disease Models, Animal; Immunoglobulin G; Interleukin-10; Interleukin-2; Interleukin-6; Male; Mice; Peroxidase; Piroxicam; Probiotics; Selenium; Tumor Necrosis Factor-alpha

Crohn's disease (CD) and ulcerative colitis (UC) are two chronic relapsing inflammatory bowel diseases (IBD). Although there are several treatment options available to improve the symptoms of IBD patients, there is no effective treatment that provides a definitive solution. In the present study, we aim to investigate the antioxidative/anti-inflammatory effects of oral administration of boric acid and Bacillus clausii in a rat trinitrobenzenesulfonic acid (TNBS)-induced colitis model. The effects of boric acid and B. clausii were examined in serum and colon tissues with the help of some biochemical and histological analyses. Elevated inflammation and oxidative damage were found in the blood and colon tissue samples in the TNBS-induced group according to the complete blood count (CBC), tumor necrosis factor (TNF) alpha, interleukin-35 (IL-35), malondialdehyde (MDA), glutathione peroxidase (GPx), myeloperoxidase (MPO), nitric oxide (NO), and histological findings. Particularly, the highest IL-35 level (70.09 ± 12.62 ng/mL) in the combined treatment group, highest catalase activity (5322 ± 668.1 U/mg protein) in the TNBS-induced group, and lower relative expression of inducible nitric oxide synthase in the TNBS-induced group than the control group were striking findings. According to our results, it can be concluded that boric acid showed more curative effects, even if B. clausii probiotics was partially ameliorative.

Topics: Animals; Antioxidants; Bacillus clausii; Colitis, Ulcerative; Colon; Disease Models, Animal; Inflammatory Bowel Diseases; Interleukins; Peroxidase; Rats; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

Xianglian Pill (XLP) is a classical Chinese medicine prescription applied for controlling ulcerative colitis (UC). Whereas, the underlying mechanism remains unclear.. The present work was aimed to investigate the mechanism of XLP in dextran sulfate sodium (DSS)-induced UC via the Toll Like Receptor 4 (TLR4)/Myeloid Differentiation factor 88 (MyD88)/Nuclear Factor kappa-B (NF-κB) signaling in mice.. The major components of XLP were detected by high-performance liquid chromatography-diode array detection (HPLC-DAD). The ulcerative colitis model was induced by DSS in mice. 5-Amino Salicylic Acid (5-ASA) group and XLP group were intragastrically treated. Disease activity index (DAI) and colon length were monitored and hematoxylin-eosin (HE) staining was conducted. Gasdermin D (GSDMD)-N and TLR4 expressions in colon tissues were visualized by immunofluorescence. TLR4 mRNA was measured by Real Time Quantitative PCR (RT-qPCR). The expressions of NOD-like receptor thermal protein domain associated protein 3 (NLRP3), active-caspase-1, GSDMD-N, TLR4, MYD88, NF-κB, p-NF-κB, and the ubiquitination of TLR4 in colon tissues were detected by Western blot. Myeloperoxidase (MPO) enzyme activity was examined and serum inflammatory factors Interleukin (IL)-1β, IL-6, Tumor Necrosis Factor-α (TNF-α), and IL-18 were determined by Enzyme-linked Immunosorbent Assay (ELISA). TLR4. The XLP treatment extended colon length, reduced DAI, and attenuated histopathological alteration in DSS-induced mice. XLP administration suppressed MPO activity and reduced the content of IL-1β, IL-6, TNF-α and IL-18 in serum. XLP also inhibited the expression levels of GSDMD-N, TLR4, NLRP3, active-caspase-1, MyD88, p-NF-κB/NF-κB in colon tissues of DSS-induced mice. TLR4. XLP might treat ulcerative colitis by regulating the TLR4/MyD88/NF-κB signaling pathway.

Topics: Animals; Caspases; Colitis, Ulcerative; Colon; Dextran Sulfate; Disease Models, Animal; Drugs, Chinese Herbal; Eosine Yellowish-(YS); Hematoxylin; Interleukin-18; Interleukin-6; Mice; Myeloid Differentiation Factor 88; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Peroxidase; RNA, Messenger; Signal Transduction; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Pancreatic ductal adenocarcinoma (PDAC) is expected to be the second most deadly cancer by 2040, owing to the high incidence of metastatic disease and limited responses to treatment

Topics: Animals; Autophagy; Carcinoma, Pancreatic Ductal; Disease Models, Animal; Fecal Microbiota Transplantation; Germ-Free Life; Glutathione Peroxidase; Humans; Indoleacetic Acids; Metabolomics; Metagenome; Mice; Microbiota; Neutrophils; Pancreatic Neoplasms; Peroxidase; Reactive Oxygen Species; Tryptophan

Mildronate is a useful anti-ischemic agent and has antiinflammatory, antioxidant, and neuroprotective activities. The aim of this study is to investigate the potential neuroprotective effects of mildronate in the experimental rabbit spinal cord ischemia/reperfusion injury (SCIRI) model.. Rabbits were randomized into 5 groups of 8 animals as groups 1 (control), 2 (ischemia), 3 (vehicle), 4 (30 mg/kg methylprednisolone [MP]), and 5 (100 mg/kg mildronate). The control group underwent only laparotomy. The other groups have the spinal cord ischemia model by a 20-minute aortic occlusion just caudal to the renal artery. The malondialdehyde and catalase levels and caspase-3, myeloperoxidase, and xanthine oxidase activities were investigated. Neurologic, histopathologic, and ultrastructural evaluations were also performed.. The serum and tissue myeloperoxidase, malondialdehyde, and caspase-3 values of the ischemia and vehicle groups were statistically significantly higher than those of the MP and mildronate groups (P < 0.001). Serum and tissue catalase values of the ischemia and vehicle groups were statistically significantly lower than those of the control, MP, and mildronate groups (P < 0.001). The histopathologic evaluation showed a statistically significantly lower score in the mildronate and MP groups than in the ischemia and vehicle groups (P < 0.001). The modified Tarlov scores of the ischemia and vehicle groups were statistically significantly lower than those of the control, MP, and mildronate groups (P < 0.001).. This study presented the antiinflammatory, antioxidant, antiapoptotic, and neuroprotective effects of mildronate on SCIRI. Future studies will elucidate its possible use in clinical settings in SCIRI.

Topics: Animals; Antioxidants; Caspase 3; Catalase; Disease Models, Animal; Ischemia; Malondialdehyde; Methylprednisolone; Neuroprotective Agents; Peroxidase; Rabbits; Reperfusion Injury; Spinal Cord; Spinal Cord Ischemia

The digestive system is exposed to severe inflammation as a result of taking some medications that have gastrointestinal side effects. Sixty Swiss-albino male mice were randomly distributed into six groups to treat inflammations of the colon, stomach, and small intestine caused by taking high doses of diclofenac (D), with two novel synthesized compounds, pyrazolo [3,4 d] pyridazine derivatives (Co1 and Co2). Myeloperoxidase enzyme activity was determined in the colon and small intestinal tissues. Serum contents of TNF-α, IL-22, IgG, and IgM were determined by ELISA. Histopathological examinations of the colon, small intestinal, and stomach tissues were microscopically analyzed. TNF-α, IL-22, and TNFSF11 gene expression were measured in the colon, intestinal, and spleen using qRT-PCR. Diclofenac caused surface columnar epithelial cell loss, focal necrosis of the gastric mucosa, inflammatory cell infiltration, and congested blood vessels in the stomach, colon, and small intestinal tissues. Co1 component was found to be better than Co2 component in reducing the focal necrosis of gastric mucosa and improving the histological structures of the stomach, colon, and small intestinal tissues. After 14 days, the activity of the myeloperoxidase enzyme was increased in group D and decreased in groups DCo1, DCo2, Co1, and Co2. Serum concentrations of TNF-α and IgG were increased, while IL-22 and IGM were reduced in the D, DCo1, and DCo2 groups compared with the Co1 and control groups. TNF-α gene was upregulated in the D group and downregulated in the Co1 group, while the IL-22 gene was downregulated in the D group and upregulated in the Co1 group compared with the control group. The CO1 component may be useful in reducing digestive system inflammation.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Carbon Dioxide; Colitis; Colon; Diclofenac; Disease Models, Animal; Immunoglobulin G; Immunoglobulin M; Inflammation; Intestinal Mucosa; Mice; Necrosis; Peroxidase; Tumor Necrosis Factor-alpha

Metal ion-facilitated chemodynamic therapy (CDT) is an emerging method for treating cancer. However, its potential is hindered by its low catalytic performance in weakly acidic tumor microenvironments (TMEs) and the severe toxicity of free metal ions. A new approach to tumor therapy, chemodynamic vascular disruption (CVD), is introduced using metal-free, peroxidase (POD)-mimetic multihydroxylated [70] fullerene (MHF) nanocatalysts. The research shows that MHF contains C···O active sites, as demonstrated by density functional theory (DFT) calculations, and converts H

Topics: Animals; Cardiovascular Diseases; Cell Line, Tumor; Disease Models, Animal; Endothelium, Vascular; Hydrogen Peroxide; Mice; Neoplasms; Peroxidase; Peroxidases; Tumor Microenvironment

Expression of myeloperoxidase (MPO), a key inflammatory enzyme restricted to myeloid cells, is negatively associated with the development of solid tumours. Activated myeloid cell populations are increased in multiple myeloma (MM); however, the functional consequences of myeloid-derived MPO within the myeloma microenvironment are unknown. Here, the role of MPO in MM pathogenesis was investigated, and the capacity for pharmacological inhibition of MPO to impede MM progression was evaluated. In the 5TGM1-KaLwRij mouse model of myeloma, the early stages of tumour development were associated with an increase in CD11b

Topics: Animals; Bone Marrow; Disease Models, Animal; Mice; Multiple Myeloma; Myeloid Cells; Peroxidase; Tumor Microenvironment

Duchenne muscular dystrophy (DMD) is a fatal X-linked disease characterised by severe muscle wasting. The mechanisms underlying the DMD pathology likely involve the interaction between inflammation, oxidative stress and impaired Ca

Topics: Animals; Disease Models, Animal; Hypochlorous Acid; Inflammation; Mice; Mice, Inbred C57BL; Mice, Inbred mdx; Muscle, Skeletal; Muscular Dystrophy, Duchenne; Peroxidase

Retinal inflammation is a central feature of ocular neovascular diseases such as diabetic retinopathy and retinopathy of prematurity, but the contribution of neutrophils to this process is not fully understood. We studied oxygen-induced retinopathy (OIR) which develops in two phases, featuring hyperoxia-induced retinal vaso-obliteration in phase I, followed by retinal neovascularization in phase II. As neutrophils are acute responders to tissue damage, we evaluated whether neutrophil depletion with an anti-Ly6G mAb administered in phase I OIR influenced retinal inflammation and vascular injury. Neutrophils were measured in blood and spleen via flow cytometry, and myeloperoxidase, an indicator of neutrophil activity, was evaluated in the retina using Western blotting. Retinal vasculopathy was assessed by quantitating vaso-obliteration, neovascularization, vascular leakage, and VEGF levels. The inflammatory factors, TNF, MCP-1, and ICAM-1 were measured in retina. In the OIR controls, neutrophils were increased in the blood and spleen in phase I but not phase II OIR. In OIR, the anti-Ly6G mAb reduced neutrophils in the blood and spleen, and myeloperoxidase, inflammation, and vasculopathy in the retina. Our findings revealed that the early rise in neutrophils in OIR primes the retina for an inflammatory and angiogenic response that promotes severe damage to the retinal vasculature.

Topics: Animals; Animals, Newborn; Disease Models, Animal; Inflammation; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; Neutrophils; Oxygen; Peroxidase; Retina; Retinal Neovascularization; Retinopathy of Prematurity; Vascular Endothelial Growth Factor A

Vagus nerve stimulation has been shown to exert anti-inflammation activities in sepsis. However, surgical implantation of stimulation devices is performed under general anesthesia, which limits its clinical application. Auricular vagus nerve stimulation (AVNS) is a minimal invasive technique that delivers electrical currents to the auricular branch of the vagus nerve. The purpose of this study was to determine the effects of AVNS on systemic inflammation, lung injury, neutrophil infiltration, and neutrophil extracellular traps (NETs) formation in the lung. In a LPS challenge lung-injury mice model, AVNS was applied to bilateral ears. Twelve hours after LPS administration, samples of blood, bronchoalveolar lavage fluid (BALF), and lung tissues were processed for investigations. We found that the treatment with AVNS significantly attenuated histopathological changes and neutrophil infiltration in the lung tissue, inhibited inflammatory cytokine elevations in serum and BALF, and decreased protein concentrations in BALF. Besides, AVNS decreased leukocyte and neutrophil accounts in BALF. Furthermore, colocalization of citrullination of histone H3 and myeloperoxidase expressions (highly specific marker of NETs) was reduced in AVNS mice. In conclusion, AVNS reduced systemic inflammation, attenuated lung edema, and inhibited neutrophil infiltration and NETs formation in the lung in LPS mice.

Topics: Acute Lung Injury; Animals; Bronchoalveolar Lavage Fluid; Cytokines; Disease Models, Animal; Extracellular Traps; Histones; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Neutrophil Infiltration; Neutrophils; Peroxidase; Vagus Nerve Stimulation

Sepsis is a systemic inflammatory syndrome, and acute lung injury (ALI) is one of the most common fatal complications of sepsis. Isoorientin (ISO) exerts a momentous role in the regulation of inflammation. However, whether ISO has a protective effect on sepsis-induced ALI remains unknown. This research aimed to elucidate the function of ISO on sepsis-induced ALI and its mechanism. In this study, the sepsis-induced ALI was established in the male C57BL/6 J mice. Functionally, ISO reduced the total protein concentration in BALF, lung wet/dry ratio and the numbers of neutrophils and macrophages in BALF as well as ameliorated lung injury. Besides, ISO treatment decreased the cytokine expressions and oxidative stress, and repressed the adhesion and migration of inflammatory cells induced by CLP. Mechanistically, ISO reduced the shedding of EPCR in the endothelial cell membrane; ISO treatment activated the JAK2/STAT3 signaling pathway through EPCR and the JAK2/STAT3 pathway inhibitors repressed the anti-inflammatory and antioxidant effects of ISO. In general, ISO suppressed sepsis-induced ALI in mice by activating an EPCR-dependent JAK2/STAT3 pathway.

Topics: Acute Lung Injury; Animals; Blotting, Western; Bronchoalveolar Lavage Fluid; Cell Movement; Disease Models, Animal; Endothelial Protein C Receptor; Enzyme-Linked Immunosorbent Assay; Janus Kinase 2; Luteolin; Male; Malondialdehyde; Mice; Mice, Inbred C57BL; Peroxidase; Reactive Oxygen Species; Sepsis; Signal Transduction; STAT3 Transcription Factor; Superoxide Dismutase

The purpose of the present study was to assess whether optic nerve sheath diameter (ONSD) measured by ultrasound could predict brain injury in sepsis associated encephalopathy (SAE).. A total of 48 male New Zealand White rabbits were used to establish sepsis model. The levels of neuro-specific enolase (NSE), S100B, myeloperoxidase (MPO), and tumor necrosis factor-α (TNF-α) were detected by enzyme-linked immuno sorbent assay and ONSD were measured before modeling, 6 h, 12 h and 24 h after modeling. Sixteen rabbits were sacrificed for hematoxylin-eosin (HE) staining of brain tissue and the brain water content at above time points. Rabbits demonstrated brain injury by HE staining were included in the SAE group, the others were enrolled in the control group. The correlation between ONSD and MPO, NSE and S100B in the SAE group were analyzed. Receiver operator characteristic curves were generated to analyze the area under the curve (AUC), specificity and sensitivity of ONSD values for SAE.. Twenty-nine of 48 rabbits had brain injury, while 19 cases were enrolled in the control group. The level of MPO, NSE, S100B, TNF-α at 6 h, 12 h and 24 h in SAE group were all higher than those of the control group with statistical significance. The ONSD in SAE group increased with time and significantly wider than those in the control group. Correlation analysis revealed that ONSD was positively correlated with MPO, NSE and S100B in the SAE group. The AUCs for the ONSD value in diagnosing SAE at 6 h, 12 h and 24 h were 0.864, 0.957, 0.877, respectively.. Alterations in ONSD strongly correlated with MPO, NSE and S100B among SAE rabbits. Monitoring of ONSD exhibited a high predictive value for SAE.

Topics: Animals; Biomarkers; Disease Models, Animal; Humans; Male; Optic Nerve; Peroxidase; Phosphopyruvate Hydratase; Predictive Value of Tests; Rabbits; S100 Calcium Binding Protein beta Subunit; Sepsis-Associated Encephalopathy; Ultrasonography

Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial disease of the lung tissue that causes symptoms such as coughing and asthma. It is caused by inflammatory factors and oxidative stress. In vivo model of IPF is induced by bleomycin (BLM,) a chemotherapeutic agent. We have investigated the effect of dapsone on bleomycin-induced IPF in adult male Wistar rats due to its anti-inflammatory and anti-oxidative stress effects. The animals were randomly divided into 5 groups (Control, BLM, BLM + dapsone 1, BLM + Dapsone 3, BLM + Dapsone 10). The control group received normal water and food. In the fibrosis group, bleomycin (BLM) (5 mg/kg) was used to induce pulmonary fibrosis by intratracheal administration. Three groups of animals were treated daily with single doses of 1, 3, and 10 mg dapsone by intraperitoneal injection 1 h after receiving BLM for 2 weeks. The activity of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), and oxidative stress markers such as myeloperoxidase (MPO), malondialdehyde (MDA), protein carbonyl (PC) and nitrite were measured to evaluate bleomycin and therapeutic effect of dapsone. The histological assays of lung tissues were done by Hematoxylin-eosin (H & E) and Masson's trichrome staining. BLM reduced the activity of oxidative enzymes and increased the oxidative stress markers, while treatment with dapsone has reversed the results. In addition, the total number of cells as inflammatory cells such as neutrophils and eosinophils were examined. It has been indicated BLM increased these cells, and dapsone decreased them. The results of H & E and Masson's trichrome staining showed that dapsone reduced inflammation and alveolar wall thickness and BLM-induced pulmonary fibrosis. According to the findings of this study, dapsone seems to have therapeutic effects on pulmonary fibrosis through its anti-inflammatory and anti-oxidative stress properties and reduction of the toxic effects of bleomycin.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Bleomycin; Catalase; Dapsone; Disease Models, Animal; Glutathione Peroxidase; Histocytochemistry; Lung; Oxidative Stress; Peroxidase; Pulmonary Fibrosis; Rats; Rats, Wistar; Superoxide Dismutase

Gout is a common and complex form of arthritis that has brought great inconveniences to the normal lives of patients. It is reported that oxidative stress and nod-like receptor family protein 3 (NLRP3) inflammasome-mediated inflammatory reactions are involved in the pathogenesis of gout arthritis. S14G-humanin (S14G-HNG) is a modified peptide of HNG with higher inhibitory activity on the accumulation and deposition of Aβ. Recently, S14G-HNG has been reported to exert great anti-inflammatory effects. The present study proposed to explore the possible therapeutic property of S14G-HNG against gout arthritis. An animal model was established by stimulation with mono-sodium urate (MSU) crystals, followed by treatment with colchicine and S14G-HNG, respectively. The elevated Gait score promoted synovitis score and activated myeloperoxidase (MPO) observed in MSU crystals-treated mice were significantly reversed by colchicine and S14G-HNG. Bone marrow-derived macrophages (BMDMs) were isolated from mice and stimulated with MSU crystals, followed by being treated with 25 and 50 μM S14G-HNG. The increased mitochondrial reactive oxygen species (ROS) and Malondialdehyde (MDA) levels, upregulated NADPH oxidase-4 (NOX-4), activated NLRP3 inflammasome, and elevated production of inflammatory factors in MSU crystals-treated BMDMs were dramatically reversed by S14G-HNG, accompanied by the upregulation of sirtuin type-1 (SIRT1). Lastly, the protective effects of S14G-HNG against MSU crystals-induced NLRP3 inflammasome activation were significantly abolished by the knockdown of SIRT1. In conclusion, our data reveal that S14G-HNG could possess potential benefits against MSU crystals-induced gout arthritis, with colchicine displaying a better effect.

Topics: Animals; Arthritis, Gouty; Cells, Cultured; Colchicine; Disease Models, Animal; Macrophages; Malondialdehyde; Mice; NADPH Oxidase 4; NLR Family, Pyrin Domain-Containing 3 Protein; Peptides; Peroxidase; Reactive Oxygen Species; Treatment Outcome; Uric Acid

Aberrant TGF‑β/Smad7 signaling has been reported to be an important mechanism underlying the pathogenesis of ulcerative colitis. Therefore, the present study aimed to investigate the effects of a number of potential anti‑colitis agents on intestinal epithelial permeability and the TGF‑β/Smad7 signaling pathway in an experimental model of colitis. A mouse model of colitis was first established before anti‑TNF‑α and 5‑aminosalicyclic acid (5‑ASA) were administered intraperitoneally and orally, respectively. Myeloperoxidase (MPO) activity, histological index (HI) of the colon and the disease activity index (DAI) scores were then detected in each mouse. Transmission electron microscopy (TEM), immunohistochemical and functional tests, including Evans blue (EB) and FITC‑dextran (FD‑4) staining, were used to evaluate intestinal mucosal permeability. The expression of epithelial phenotype markers E‑cadherin, occludin, zona occludens (ZO‑1), TGF‑β and Smad7 were measured. In addition, epithelial myosin light chain kinase (MLCK) expression and activity were measured. Anti‑TNF‑α and 5‑ASA treatments was both found to effectively reduce the DAI score and HI, whilst decreasing colonic MPO activity, plasma levels of FD‑4 and EB permeation of the intestine. Furthermore, anti‑TNF‑α and 5‑ASA treatments decreased MLCK expression and activity, reduced the expression of Smad7 in the small intestine epithelium, but increased the expression of TGF‑β. In mice with colitis, TEM revealed partial epithelial injury in the ileum, where the number of intercellular tight junctions and the expression levels of E‑cadherin, ZO‑1 and occludin were decreased, all of which were alleviated by anti‑TNF‑α and 5‑ASA treatment. In conclusion, anti‑TNF‑α and 5‑ASA both exerted protective effects on intestinal epithelial permeability in an experimental mouse model of colitis. The underlying mechanism may be mediated at least in part by the increase in TGF‑β expression and/or the reduction in Smad7 expression, which can inhibit epithelial MLCK activity and in turn reduce mucosal permeability during the pathogenesis of ulcerative colitis.

Topics: Animals; Cadherins; Colitis, Ulcerative; Colon; Dextran Sulfate; Disease Models, Animal; Female; Intestinal Mucosa; Male; Mesalamine; Mice, Inbred C57BL; Myosin-Light-Chain Kinase; Occludin; Peroxidase; Severity of Illness Index; Signal Transduction; Smad7 Protein; Tight Junctions; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Zonula Occludens-1 Protein

Roflumilast, a highly selective oral phosphodiesterase IV inhibitor, exerts anti-inflammatory and anti-fibrotic effects. Oral roflumilast causes gastrointestinal side effects, especially vomiting, which could be reduced by administering roflumilast via off-label routes. Inhaled roflumilast reportedly improved inflammatory and histopathological changes in asthmatic mice. The current study investigated the effects of oral and rectal roflumilast on trinitrobenzenesulfonic acid (TNBS)-induced chronic colitis in rats, an experimental model resembling human Crohn's disease. Five groups of rats (n=8) were used: normal control, TNBS-induced colitis, and three TNBS-treated colitic groups, which received oral sulfasalazine (500 mg·kg-1·day-1), oral roflumilast (5 mg·kg-1·day-1), or rectal roflumilast (5 mg·kg-1·day-1) for 15 days after colitis induction. Then, the following were assessed: the colitis activity score, tumor necrosis factor (TNF)-α, interleukin (IL)-2, and IL-6 serum levels, colonic length, and myeloperoxidase, malonaldehyde, and glutathione levels. Histological examinations employed H&E, Masson trichrome, and PAS stains in addition to immunostaining for KI-67 and TNF-α. The TNBS-induced colitis rats showed significant increases in disease activity scores, serum TNF-α, IL-2, and IL-6 levels, and colonic myeloperoxidase and malonaldehyde content. They also showed significant decreases in colonic length and glutathione levels in addition to histopathological and immunohistochemical changes. All the treatments significantly improved all these changes. Sulfasalazine provided the greatest improvement, followed by oral roflumilast, and then rectal roflumilast. In conclusion, both oral and rectal roflumilast partially improved TNBS-induced chronic colitis, suggesting the potential of roflumilast as an additional treatment for Crohn's disease.

Topics: Aminopyridines; Animals; Benzamides; Colitis; Cyclopropanes; Disease Models, Animal; Mice; Peroxidase; Rats; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

Fermented camel's milk has various health beneficial prebiotics and probiotics. This study aimed to evaluate the preventive efficacy of

Topics: Animals; Bacillus amyloliquefaciens; Camelus; Colitis; Colon; Cytokines; Disease Models, Animal; Mice; Milk; Peroxidase; Proliferating Cell Nuclear Antigen; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

Dexpanthenol (DXP) reportedly protects tissues against oxidative damage in various inflammation models. This study aimed to evaluate its effects on oxidative stress, inflammation, apoptosis, and neurological recovery in an experimental rabbit spinal cord ischemia/reperfusion injury (SCIRI) model.. Rabbits were randomized into 5 groups of 8 animals each: group 1 (control), group 2 (ischemia), group 3 (vehicle), group 4 (methylprednisolone, 30 mg/kg), and group 5 (DXP, 500 mg/kg). The control group underwent laparotomy only, whereas other groups were subjected to spinal cord ischemia by aortic occlusion (just caudal to the 2 renal arteries) for 20 min. After 24 h, a modified Tarlov scale was employed to record neurological examination results. Malondialdehyde and caspase-3 levels and catalase and myeloperoxidase activities were analyzed in tissue and serum samples. Xanthine oxidase activity was measured in the serum. Histopathological and ultrastructural evaluations were also performed in the spinal cord.. After SCIRI, serum and tissue malondialdehyde and caspase-3 levels and myeloperoxidase and serum xanthine oxidase activities were increased (P < 0.05-0.001). However, serum and tissue catalase activity decreased significantly (P < 0.001). DXP treatment was associated with lower malondialdehyde and caspase-3 levels and reduced myeloperoxidase and xanthine oxidase activities but increased catalase activity (P < 0.05-0.001). Furthermore, DXP was associated with better histopathological, ultrastructural, and neurological outcome scores.. This study was the first to evaluate antioxidant, anti-inflammatory, antiapoptotic, and neuroprotective effects of DXP on SCIRI. Further experimental and clinical investigations are warranted to confirm that DXP can be administered to treat SCIRI.

Topics: Animals; Antioxidants; Caspase 3; Catalase; Disease Models, Animal; Inflammation; Malondialdehyde; Neuroprotective Agents; Peroxidase; Rabbits; Reperfusion Injury; Spinal Cord; Spinal Cord Ischemia; Xanthine Oxidase

Currently, inflammatory bowel disease (IBD) has become a global chronic idiopathic disease with ever-rising morbidity and prevalence. Accumulating evidence supports the IBD-hygiene hypothesis that helminths and their derivatives have potential therapeutic value for IBD. Clonorchis sinensis (C. sinensis) mainly elicit Th2/Treg-dominated immune responses to maintain long-term parasitism in the host. This study aimed to evaluate the therapeutic effects of cysteine protease (CsCP) and adult crude antigen (CsCA) of C. sinensis, and C. sinensis (Cs) infection on DSS-induced colitis mice.. BALB/c mice were given 5% DSS daily for 7 days to induce colitis. During this period, mice were treated with rCsCP, CsCA or dexamethasone (DXM) every day, or Cs infection which was established in advance. Changes in body weight, disease activity index (DAI), colon lengths, macroscopic scores, histopathological findings, myeloperoxidase (MPO) activity levels, regulatory T cell (Treg) subset levels, colon gene expression levels, serum cytokine levels, and biochemical indexes were measured.. Compared with Cs infection, rCsCP and CsCA alleviated the disease activity of acute colitis more significant without causing abnormal blood biochemical indexes. In comparison, rCsCP was superior to CsCA in attenuating colonic pathological symptoms, enhancing the proportion of Treg cells in spleens and mesenteric lymph nodes, and improving the secretion of inflammatory-related cytokines (e.g., IL-2, IL-4, IL-10 and IL-13) in serum. Combined with RNA-seq data, it was revealed that CsCA might up-regulate the genes related to C-type lectin receptor and intestinal mucosal repair related signal pathways (e.g., Cd209d, F13a1 and Cckbr) to reduce colon inflammation and benefit intestinal mucosal repair. Dissimilarly, rCsCP ameliorated colitis mainly through stimulating innate immunity, such as Toll like receptor (TLR) signaling pathway, down-regulating the expression of inflammatory cytokines (e.g., IL-12b, IL-23r and IL-7), thereby restraining the differentiation of Th1/Th17 cells.. Both rCsCP and CsCA showed good therapeutic effects on the treatment of acute colitis, but rCsCP is a better choice. rCsCP is a safe, effective, readily available and promising therapeutic agent against IBD mainly by activating innate immunity and regulating the IL-12/IL-23r axis.

Topics: Animals; Clonorchis sinensis; Colitis; Colon; Cysteine Proteases; Cytokines; Dexamethasone; Dextran Sulfate; Disease Models, Animal; Inflammatory Bowel Diseases; Interleukin-10; Interleukin-12; Interleukin-13; Interleukin-2; Interleukin-4; Interleukin-7; Lectins, C-Type; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Peroxidase; Toll-Like Receptors

Probiotics have shown good efficacy in the prevention of ulcerative colitis (UC), but the specific mechanism remains unclear. Therefore, shotgun metagenomic and transcriptome analyses were performed to explore the preventive effect of a potential probiotic

Topics: Animals; Claudin-1; Claudin-2; Colitis; Colitis, Ulcerative; Colon; Dextran Sulfate; Disease Models, Animal; Gastrointestinal Microbiome; Humans; Intercellular Adhesion Molecule-1; Interleukin-10; Interleukin-6; Lactobacillus plantarum; Mice; Mice, Inbred C57BL; NF-kappa B; Peroxidase; RNA, Messenger; Transforming Growth Factor beta1; Transforming Growth Factor beta2; Tumor Necrosis Factor-alpha

The intestine requires a great deal of energy to maintain its health and function; thus, energy deficits in the intestinal mucosa may lead to intestinal damage. Aspartate (Asp) is an essential energy source in the intestinal mucosa and plays a vital part in gut health. In the current study, we hypothesized that dietary supplementation of Asp could alleviate DSS-induced colitis via improvement in the colonic morphology, oxidative stress, cell apoptosis, and microbiota composition in a mouse model of dextran. Asp administration decreased the disease activity index, apoptosis, myeloperoxidase, eosinophil peroxidase, and proinflammatory cytokine (IL-1β and TNF-α) concentrations in the colonic tissue, but improved the body weight, average daily food intake, colonic morphology, and antioxidant-related gene (GPX1 and GPX4) expression in DSS-treated mice. Expression levels of RIPK1 and RIPK3 were increased in the colon following Asp administration in the DSS-induced mice, whereas the MLKL protein expression was decreased. 16S rRNA sequencing showed that Asp treatment increased the abundance of

Topics: Animals; Antioxidants; Aspartic Acid; Colitis; Colitis, Ulcerative; Colon; Cytokines; Dextran Sulfate; Disease Models, Animal; Eosinophil Peroxidase; Gastrointestinal Microbiome; Mice; Mice, Inbred C57BL; Peroxidase; RNA, Ribosomal, 16S; Tumor Necrosis Factor-alpha

Researchers are currently trying to find new therapies with better symptomatic activity and fewer side effects to manage Parkinson's disease (PD). Although the protective effect of pre-treatment by Gastrodin (Gst) on a PD model has been evaluated, in the current experimental study, we investigated the symptomatic therapeutic effects of Gst microinjection in the same PD model but in the post-parkinsonism induction condition.. Parkinsonism was induced by unilateral infusion of 6- hydroxydopamine (6-OHDA; 8 μg/ 2 μl/ rat) into the central region of the substantia nigra pars compacta (SNc). After the recovery period and confirmation of parkinsonism, daily Gst treatment in three doses (20, 40, 80 µg/ 2 µ/ rat, continued for ten days with motor monitoring by bar test and rotarod examinations. Moreover, lipid peroxidation and myeloperoxidase activity were evaluated.. In this model of 6-OHDA-induced parkinsonism, Gst treatment in all three doses showed a dose dependent symptomatic improvement in motor imbalance (P < 0.001) catalepsy (P < 0.001), decreased lipid peroxidation (P < 0.001) and SNc myeloperoxidase activity (P < 0.001).. 6-OHDA induced parkinsonism symptomatically improved behaviorally with Gst post-induction treatment along with decreased markers of oxidative stress and microglial activation. We suggest that this agent is a candidate for symptomatic treatment of human PD.

Topics: Animals; Disease Models, Animal; Humans; Motor Disorders; Oxidative Stress; Oxidopamine; Parkinson Disease; Parkinsonian Disorders; Peroxidase; Rats; Rats, Wistar; Substantia Nigra

Chlorogenic acid (CA) and sodium alginate (SA) each have good therapeutic effects on ulcerative colitis (UC) owing to their antioxidant and anti-inflammatory activity. This study aimed to investigate the effects of CA alone and in combination with SA on inflammatory cells and UC mice. In the Lipopolysaccharide (LPS)-induced RAW 264.7 inflammatory cell model, Nitric oxide (NO) and interleukin-6 (IL-6) levels were significantly lower after treatment with CA plus SA than with CA alone. In the DSS-induced UC mouse model, compared with CA alone, CA plus SA showed a better ability to alleviate weight loss, reduce the disease activity index (DAI), improve the colonic mucosa, reduce the expression of inflammatory factors in the serum and myeloperoxidase (MPO) in colonic tissue, increase superoxide dismutase (SOD) levels, protect the intestinal mucosa and regulate the abundance of Actinobacteriota,

Topics: Alginates; Animals; Anti-Inflammatory Agents; Antioxidants; Chlorogenic Acid; Colitis, Ulcerative; Colon; Dextran Sulfate; Disease Models, Animal; Gastrointestinal Microbiome; Inflammation; Interleukin-6; Lipopolysaccharides; Mice; Nitric Oxide; Peroxidase; Superoxide Dismutase

Qingchang Wenzhong Decoction (QCWZD), a chinese herbal prescription, is widely used for ulcerative colitis (UC). Nevertheless, the active ingredients and mechanism of QCWZD in UC have not yet been explained clearly.. This research focuses on the identification of the effective ingredients of QCWZD and the prediction and verification of their potential targets.. The UC mice were established by adding 3.0% dextran sulfate sodium (DSS) to sterile water for one week. Concurrently, mice in the treatment group were gavage QCWZD or mesalazine. LC-MS analyzed the main components absorbed after QCWZD treatment, and network pharmacology predicted their possible targets. ELISA, qPCR, immunohistochemistry and immunofluorescence experiments were used to evaluate the colonic inflammation level and the intestinal barrier completeness. The percentage of Th17 and Treg lymphocytes was detected by flow cytometry.. After QCWZD treatment, twenty-seven compounds were identified from the serum. In addition, QCWZD treatment significantly reduced the increased myeloperoxidase (MPO) and inflammatory cell infiltration caused by DSS in the colonic. In addition, QCWZD can reduce the secretion of inflammatory factors in serum and promote the expression of mRNAs and proteins of occludin and ZO-1. Network pharmacology analysis indicated that inhibiting IL-6-STAT3 pathway may be necessary for QCWZD to treat UC. Flow cytometry analysis showed that QCWZD can restore the normal proportion of Th17 lymphocytes in UC mice. Mechanistically, QCWZD inhibited the phosphorylation of JAK2-STAT3 pathway, reducing the transcriptional activation of RORγT and IL-17A.. Overall, for the first time, our work revealed the components of QCWZD absorbed into blood, indicated that the effective ingredients of QCWZD may inhibit IL-6-STAT3 pathway and inhibit the differentiation of Th17 lymphocytes to reduce colon inflammation.

Topics: Animals; Colitis, Ulcerative; Colon; Dextran Sulfate; Disease Models, Animal; Inflammation; Interleukin-17; Interleukin-6; Mesalamine; Mice; Mice, Inbred C57BL; Nuclear Receptor Subfamily 1, Group F, Member 3; Occludin; Peroxidase; Th17 Cells; Water

Contact hypersensitivity (CHS) is an experimental model of allergic contact dermatitis (ACD) that can be studied in mice. This study aims to present an objective laboratory method that may help to study the CHS reaction in mice, which can be measured and quantified by various tests. To induce CHS, on day "0", mice were sensitized on a previously shaved spot by abdominal skin painting with the hapten 2,4,6-trinitrochlorobenzene (TNCB) in an acetone-ethanol mixture, whereas negative control mice were sham sensitized with vehicle alone-acetone-ethanol mixture. On day "4", the baseline ear thickness was measured with a micrometer prior to the elicitation of CHS (challenge) by painting both ears with diluted TNCB both in the test and control groups. After 24 h, the ear swelling was measured with a micrometer. CHS is an example of a T cell-mediated immune response that causes swelling in inflamed tissue, peaking 24 h after the skin challenge with the same hapten. An increase in ear edema correlated with augmented ear weight, myeloperoxidase (MPO) activity, pro-inflammatory cytokine concentration in the ear extracts, increased thickening of the edematous dermis in the histological examination, and ear vascular permeability. There was also an increase in the concentration of TNP-specific IgG1 antibodies in the sera of the test group when compared with the control mice. Additionally, CHS can be successfully transferred with the CHS-effector cells obtained from donors previously sensitized with TNCB. The CHS-effector cells were administered intravenously into naïve recipient mice, which were subsequently challenged with the same diluted hapten. Ear swelling was measured with a micrometer 24 h later.

Topics: Acetone; Animals; Cytokines; Dermatitis, Allergic Contact; Disease Models, Animal; Ethanol; Haptens; Immunoglobulin G; Mice; Mice, Inbred BALB C; Peroxidase; Picryl Chloride

Currently there are no established therapies to treat high-risk patients with unstable atherosclerotic lesions that are prone to rupture and can result in thrombosis, abrupt arterial occlusion, and a precipitous infarction. Rather than being stenotic, rupture-prone non-occlusive plaques are commonly enriched with inflammatory cells and have a thin fibrous cap. We reported previously that inhibition of the pro-inflammatory enzyme myeloperoxidase (MPO) with the suicide inhibitor AZM198 prevents formation of unstable plaque in the Tandem Stenosis (TS) mouse model of plaque instability. However, in our previous study AZM198 was administered to animals before unstable plaque was present and hence it did not test the significant unmet clinical need present in high-risk patients with vulnerable atherosclerosis. In the present study we therefore asked whether pharmacological inhibition of MPO with AZM198 can stabilize pre-existing unstable lesions in an interventional setting using the mouse model of plaque instability. In vivo molecular magnetic resonance imaging of arterial MPO activity using bis-5-hydroxytryptamide-DTPA-Gd and histological analyses revealed that arterial MPO activity was elevated one week after TS surgery, prior to the presence of unstable lesions observed two weeks after TS surgery. Animals with pre-existing unstable plaque were treated with AZM198 for one or five weeks. Both short- and long-term intervention effectively inhibited arterial MPO activity and increased fibrous cap thickness, indicative of a more stable plaque phenotype. Plaque stabilization was observed without AZM198 affecting the arterial content of Ly6B.2

Topics: Animals; Atherosclerosis; Cardiovascular Diseases; Disease Models, Animal; Mice; Peroxidase; Plaque, Atherosclerotic

Ulcerative colitis is an inflammatory bowel disease characterized by symptoms such as abdominal pain, diarrhea, bleeding, and weight loss. Ulcerative colitis is typically treated with anti-inflammatory drugs; however, these drugs are associated with various side effects, limiting their use. β-Caryophyllene (BCP), a natural compound derived from cloves, has antioxidant, antibacterial, and anti-inflammatory activities. In this study, we aimed to investigate the effects of BCP on colitis in a dextran sulfate sodium (DSS)-induced colitis mouse model. BCP was administered for seven days, followed by 2.5% DSS for additional seven days to induce colitis. Changes in stool weight, recovery of gut motility, colon length, colon histology, myeloperoxidase activity, inflammatory cytokines (TNF-α, IL-1β, IL-6, IgA, and IgG), and the gut microbiota were observed. Administration of BCP increased stool weight, restored gut motility, and considerably increased colon length compared to those in the untreated colitis mouse model. In addition, the amount of mucin and myeloperoxidase activity in the colon increased, whereas the concentrations of IL-1β, IL-6, and TNF-α decreased following the administration of BCP. Furthermore, BCP reduced the abundance of Proteobacteria which can cause intestinal immune imbalance. These results suggest that BCP has a potential to be developed as a preventive agent for colitis.

Topics: Animals; Anti-Inflammatory Agents; Colitis; Colitis, Ulcerative; Dextran Sulfate; Disease Models, Animal; Gastrointestinal Microbiome; Inflammation; Interleukin-6; Mice; Peroxidase; Syzygium; Tumor Necrosis Factor-alpha

Hypertrophic cardiomyopathy (HCM) is characterized by cardiomyocyte hypertrophy and disarray, and myocardial stiffness due to interstitial fibrosis, which result in impaired left ventricular filling and diastolic dysfunction. The latter manifests as exercise intolerance, angina, and dyspnoea. There is currently no specific treatment for improving diastolic function in HCM. Here, we investigated whether myeloperoxidase (MPO) is expressed in cardiomyocytes and provides a novel therapeutic target for alleviating diastolic dysfunction in HCM.. Human cardiomyocytes derived from control-induced pluripotent stem cells (iPSC-CMs) were shown to express MPO, with MPO levels being increased in iPSC-CMs generated from two HCM patients harbouring sarcomeric mutations in the MYBPC3 and MYH7 genes. The presence of cardiomyocyte MPO was associated with higher chlorination and peroxidation activity, increased levels of 3-chlorotyrosine-modified cardiac myosin binding protein-C (MYBPC3), attenuated phosphorylation of MYBPC3 at Ser-282, perturbed calcium signalling, and impaired cardiomyocyte relaxation. Interestingly, treatment with the MPO inhibitor, AZD5904, reduced 3-chlorotyrosine-modified MYBPC3 levels, restored MYBPC3 phosphorylation, and alleviated the calcium signalling and relaxation defects. Finally, we found that MPO protein was expressed in healthy adult murine and human cardiomyocytes, and MPO levels were increased in diseased hearts with left ventricular hypertrophy.. This study demonstrates that MPO inhibition alleviates the relaxation defect in hypertrophic iPSC-CMs through MYBPC3 phosphorylation. These findings highlight cardiomyocyte MPO as a novel therapeutic target for improving myocardial relaxation associated with HCM, a treatment strategy which can be readily investigated in the clinical setting, given that MPO inhibitors are already available for clinical testing.

Topics: Animals; Cardiac Myosins; Cardiomyopathy, Hypertrophic; Carrier Proteins; Cell Line; Disease Models, Animal; Enzyme Inhibitors; Humans; Hypertrophy, Left Ventricular; Induced Pluripotent Stem Cells; Male; Mice, Inbred C57BL; Mutation, Missense; Myocardial Contraction; Myocytes, Cardiac; Myosin Heavy Chains; Peroxidase; Phosphorylation; Reactive Oxygen Species; Tyrosine; Ventricular Function, Left

Neutrophil extracellular traps (NETs)-mediated tissue damage is a hallmark in abdominal sepsis. Under certain conditions, microRNAs (miRs) can regulate protein expression and cellular functions. The aim of this study was to investigate the role of miR-155 in sepsis-induced NET formation, lung inflammation, and tissue damage. Abdominal sepsis was induced in wild-type (WT) C57BL/6 and miR-155 gene-deficient mice by cecal ligation and puncture (CLP). The amount of DNA-histone complex formation as well as myeloperoxidase (MPO) and citrullinated histone 3 in neutrophils isolated from bone marrow were examined by ELISA and flow cytometry. NETs were detected by electron microscopy in the septic lung. Levels of PAD4 and citrullinated histone 3 were determined by Western blot in the blood neutrophils. Lung levels of MPO, CXC chemokines, and plasma levels of DNA-histone complexes and CXC chemokines were quantified. In vitro studies revealed that neutrophils from miR-155 gene-deficient mice had less NETs forming ability than WT neutrophils. In the miR-155 gene-deficient mice, CLP yielded much less NETs in the lung tissue compared with WT control. CLP-induced PAD4 levels, histone 3 citrullination, edema, MPO activity, and neutrophil recruitment in the lung were markedly reduced in the mice lacking miR-155. Furthermore, tissue and plasma levels of CXCL1 and CXCL2 were significantly lower in the miR-155 gene-deficient mice compared with WT after induction of abdominal sepsis. Taken together, our findings suggest that miR-155 regulates pulmonary formation of NETs in abdominal sepsis via PAD4 up-regulation and histone 3 citrullination. Thus, targeting miR-155 could be a useful target to reduce pulmonary damage in abdominal sepsis.

Topics: Acute Lung Injury; Animals; Disease Models, Animal; Extracellular Traps; Histones; Male; Mice; Mice, Inbred C57BL; MicroRNAs; Neutrophil Infiltration; Peroxidase; Pneumonia; Protein-Arginine Deiminase Type 4; Sepsis

Lupeol is a pentacyclic triterpene with known anti-inflammatory effects. However, its role in the treatment of noninfectious uveitis has not been explored. This work investigated anti-inflammatory activity of lupeol in ocular tissues with in vitro and in vivo models. First, we evaluated the effect of lupeol (100 µM) on inflammatory response induced by lipopolysaccharide (LPS) in retinal pigment epithelium cells (ARPE-19) by measuring levels of released interleukins (IL-6 and IL-8). Then, we investigated the anti-inflammatory action of intravitreal lupeol in a rodent model of panuveitis induced by Mycobacterium bovis Calmette-Guérin Bacillus (BCG). Rats were submitted to electroretinography and clinical analyses on days 3, 7, and 15 after uveitis induction. In addition, histopathological analysis, and indirect quantification of myeloperoxidase (MPO) and N-acetylglucosaminidase (NAG) in the posterior segment were performed. Treatment with lupeol (100 µM) significantly decreased IL-6 and IL-8 levels in comparison to untreated LPS-activated ARPE-19 cells. This reduction was similar to that detected in ARPE-19 cells treated with dexamethasone. The results of the in vivo assay demonstrated that intravitreal lupeol is able to modulate inflammation in the anterior and posterior segment of the rat eyes, indicating that it should be further investigated as a novel potential candidate for management of uveitis.

Topics: Acetylglucosaminidase; Animals; Anti-Inflammatory Agents; BCG Vaccine; Cell Line; Cytokines; Disease Models, Animal; Down-Regulation; Eye; Humans; Inflammation Mediators; Intravitreal Injections; Lipopolysaccharides; Male; Pentacyclic Triterpenes; Peroxidase; Rats, Wistar; Retinal Pigment Epithelium; Uveitis

Ulcerative colitis (UC) is a gastrointestinal inflammatory disease with a multifactorial pathophysiology. This study aims to investigate the immunomodulatory effect of Portulaca oleracea leaf ethanolic extract (POE) on acetic acid (AA)-induced UC in mice. Experimental animals received oral doses of POE (200 mg/kg for 7 days) after an induction of colitis by intrarectal AA administration. In mice with AA-induced UC treated with POE, the results revealed a significant modulation in body weight and colon length. Moreover, treatment with POE downregulated the interleukin 1, 6, and 17, tumor necrosis factor-alpha, gamma interferon, and nuclear factor-kappa B levels compared with the colitis group. Furthermore, POE markedly inhibited histological damage, decreased myeloperoxidase activity and reduced fecal calprotectin level compared with the colitis group. These data are consistent with the reduction in total bacterial content in the colon. Taken together, treatment with POE may reduce colonic inflammation by alleviating the immune response and inhibiting the severity of colitis. The HPLC analysis of POE resulted in the identification of seven medicinal compounds comprising two phenolic acids (ferulic and caffeic acids) and five flavonoids (kaempferol, quercetin, rutin, narenginin and hesperidin). Subsequent analysis of POE by GC-MS revealed ten phytocomponents; the major percentages were hexadecenoic acid, methyl ester (29.8119%), α-linolenic acid (25.8431%), 16-octadecenoic acid, methyl ester (15.1578%) and α-tocopherol (10.7848%). Delta-lactams and alkanes were the minor components. Such natural plant-derived substances and their probable synergistic action appear to contribute to a promising therapeutic protocol for colitis.

Topics: Animals; Colitis; Cytokines; Disease Models, Animal; Gastrointestinal Microbiome; Immunomodulating Agents; Inflammation Mediators; Leukocyte L1 Antigen Complex; Male; Mice; NF-kappa B; Peroxidase; Phytochemicals; Plant Extracts; Plant Leaves; Portulaca

Topics: Amylases; Animals; Anti-Inflammatory Agents; Arginine; Cattle; Colostrum; Cytokines; Disease Models, Animal; Fatty Acids, Nonesterified; Female; Ghee; Inflammation; Lipase; Lung; Male; Mice; Mice, Inbred C57BL; Pancreas; Pancreatitis; Peroxidase; Pregnancy; Receptors, G-Protein-Coupled

Recent studies suggest that lipids, including free fatty acids (FFAs), are necessary for proper μ opioid receptor (MOR) binding and that activation of opioid receptors (ORs) improves intestinal inflammation. The objective of the study was to investigate a possible interaction between the ORs and FFA receptors (FFARs) ligands in the colitis.. The potential synergistic effect of ORs and FFARs ligands was evaluated using mouse model of acute colitis induced by dextran sulfate sodium (DSS, 4%). Compounds were injected intraperitoneally (i.p.) once or twice daily at the doses of 0.01 or 0.02 mg/kg body weight (BW) (DAMGO-an MOR agonist), 0.3 mg/kg BW (DPDPE-a δ OR (DOR) agonist) and 1 mg/kg BW (naloxone-a non-selective OR antagonist, GLPG 0974-a FFAR2 antagonist, GSK 137647-a FFAR4 agonist and AH 7614-a FFAR4 antagonist) for 4 days.. Myeloperoxidase (MPO) activity was significantly decreased after DAMGO (0.02 mg/kg BW) and GSK 137647 (1 mg/kg BW) administration and co-administration as compared to DSS group.. Treatment with ligands of ORs and FFARs may affect the immune cells in the inflammation; however, no significant influence on the severity of colitis and no synergistic effect were observed.

Topics: Aniline Compounds; Animals; Butyrates; Colitis; Disease Models, Animal; Drug Synergism; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Inflammation; Ligands; Male; Mice; Mice, Inbred BALB C; Naloxone; Narcotic Antagonists; Peroxidase; Receptors, G-Protein-Coupled; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu; Sulfonamides; Thiophenes; Xanthenes

To investigate whether the mechanism underlying the anti-inflammatory effects of electroacupuncture (EA) at ST36 involves dopamine (DA) and its receptor and whether it is mediated by the vagus nerve in a rat model of intestinal ischaemia-reperfusion (I/R) injury.. Rats were subjected to gut ischaemia for 30 min and then received EA for 30 min with or without abdominal vagotomy or intraperitoneal administration of butaclamol (D1 receptor antagonist) or spiperone (D2 receptor antagonist). Plasma levels of DA and tumour necrosis factor (TNF)-α were assessed 1 or 4 h after reperfusion. Myeloperoxidase (MPO) activity and malondialdehyde (MDA) content in intestinal tissues were assessed using enzyme-linked immunosorbent assay (ELISA) kits. Intestinal tissue injury was assessed by observation of the pathological lesions and permeability to 4 kDa fluorescein isothiocyanate (FITC)-dextran.. EA significantly increased levels of DA and lowered levels of TNF-α. EA also inhibited intestinal levels of MPO and MDA and intestinal tissue injury and decreased intestinal permeability to FITC-dextran. Abdominal vagotomy and intraperitoneal administration of butaclamol (but not spiperone) inhibited the effects of EA.. These findings suggest that EA at ST36 could attenuate intestinal I/R-induced inflammatory injury and that the underlying mechanism may involve EA-induced increases in levels of DA, mediated by the vagus nerve and D1 receptors.

Topics: Acupuncture Points; Animals; Disease Models, Animal; Dopamine; Electroacupuncture; Humans; Intestines; Ischemia; Male; Peroxidase; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

Tumor necrosis factor-alpha (TNF-α) has an important role in hypoxia/reoxygenation (H/R)-induced intestinal damage. It was shown that blocking TNF-α with infliximab has beneficial effects on experimental necrotizing enterocolitis and hypoxic intestinal injury. However, there is no data about the effect of adalimumab on H/R-induced intestinal damage. Therefore, we aimed to determine potential dose-dependent benefits of adalimumab in such damage in neonatal rats. Wistar albino rat pups were assigned to one of the four groups: control group, hypoxia group, low-dose adalimumab (5 mg/kg/day) treated group (LDAT), and high-dose adalimumab (50 mg/kg/day) treated group (HDAT). On the fourth day of the experiment, all rats except for the control group were exposed to H/R followed by euthanasia. Malondialdehyde (MDA), myeloperoxidase (MPO), TNF-α, total antioxidant capacity (TAC), and total oxidant capacity (TOC) were measured in intestinal tissue. TAC and TOC values were used to calculate the oxidative stress index (OSI). Histopathological injury scores (HIS) were also evaluated in the tissue samples. MDA levels were significantly lower in the LDAT and HDAT groups (p < 0.001). TNF-α levels were significantly lower in the LDAT group (p < 0.001). OSI was significantly higher in the H/R group than in the control and LDAT groups (p < 0.001). Mean HIS values in the LDAT group were significantly lower than those in the H/R and HDAT groups (p < 0.001). This experimental study showed that low-dose adalimumab appears to have a beneficial effect on intestinal injury induced with H/R in neonatal rats.

Topics: Adalimumab; Animals; Animals, Newborn; Antioxidants; Disease Models, Animal; Dose-Response Relationship, Drug; Enterocolitis, Necrotizing; Hypoxia; Malondialdehyde; Oxidative Stress; Peroxidase; Rats; Rats, Wistar; Reperfusion Injury

The p-coumaric acid is a phenolic compound present in large quantities in the extract of Baccharis dracunculifolia DC, a Brazilian medicinal plant used to treat gastric ulcer. Given the necessity for finding new chemical components capable of accelerating gastric healing, in this study, the effects of the p-coumaric acid were evaluated in the acetic acid-induced ulcer model in rats, where histological, inflammatory, and oxidative parameters were analyzed. The healing property was also evaluated in the scratch assay on fibroblast cells (L929) and the cytotoxicity of p-coumaric acid was assessed in both L929 and human gastric adenocarcinoma (AGS) cells by MTT assay. The treatment with p-coumaric acid (10 mg/kg, p.o.) for 7 days, twice a day, decreased by 44.6% the acetic acid-induced gastric ulcer compared with the vehicle-treated group. The vehicle control-treated group showed a larger extension of the ulcer base and an extensive damage into the mucosa and submucosa layers, which were mitigated by the treatment with p-coumaric acid. This beneficial effect was also associated with increased levels of mucin and reduced glutathione, decreased amount of lipid hydroperoxides, and increased superoxide dismutase and catalase activities without interfering with the activity of myeloperoxidase in the gastric tissue. The compound promoted the restructuring of the cell monolayer in the scratch test and did not show toxicity in the L929 cell line, while reduced the viability of the AGS, a lineage of human gastric adenocarcinoma. Thus, p-coumaric acid may be considered a natural source for the treatment of gastric ulcers, by reinforcing protective factors of gastric mucosa and by accelerating gastric healing.

Topics: Acetic Acid; Animals; Anti-Ulcer Agents; Baccharis; Catalase; Cell Line; Cell Proliferation; Cell Survival; Coumaric Acids; Disease Models, Animal; Female; Gastric Mucosa; Glutathione; Humans; Mice; Peroxidase; Phytotherapy; Rats; Stomach Ulcer; Superoxide Dismutase

Solidagenone (SOL) is a labdane-type diterpenoid found in Solidago chilensis, a plant traditionally used to treat skin diseases, kidney pain and ovarian inflammation. In this study, the topical anti-inflammatory activity of SOL was evaluated using in vivo and in silico assays. Croton oil-, arachidonic acid (AA)- and phenol-induced ear oedema mouse models were applied in the in vivo studies. Myeloperoxidase (MPO) and N-acetyl-β-D-glucosaminidase (NAG) activities and tumour necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and nitric oxide (NO) levels were determined, as well as histopathological analyses were conducted. Interaction profiles between SOL and cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), glucocorticoid receptor, estradiol-17-β-dehydrogenase and prostaglandin-E(2)-9-reductase were established using molecular docking. SOL significantly inhibited croton oil-, AA- and phenol-induced ear oedema (P < .001) at doses of 0.1, 0.5 and 1.0 mg/ear. The MPO and NAG activities and TNF-α, IL-6 and NO levels were decreased (P < .001). The histopathological data revealed that inflammatory parameters (oedema thickness, leucocyte infiltration and vasodilatation) were reduced by treatment with SOL at doses of 0.1, 0.5 and 1.0 mg/ear. The docking study showed that SOL interacts with COX-1 and prostaglandin-E(2)-9-reductase through hydrogen bonding, inhibiting these enzymes. These results indicate that SOL may be a promising compound for the treatment of cutaneous inflammatory disorders and has potential as a topical anti-inflammatory agent.

Topics: Acetylglucosaminidase; Animals; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Dermatitis; Disease Models, Animal; Edema; Furans; Hydrogen Bonding; Hydroxyprostaglandin Dehydrogenases; Interleukin-6; Male; Membrane Proteins; Mice; Molecular Docking Simulation; Naphthalenes; Nitric Oxide; Peroxidase; Plant Extracts; Protein Binding; Signal Transduction; Skin; Solidago; Tumor Necrosis Factor-alpha

GPR18 is a recently deorphanized receptor which was reported to act with several endogenous cannabinoid ligands. Here, we aimed to describe the role of GPR18 in intestinal inflammation and inflammatory pain.. The anti-inflammatory activity of selective GPR18 agonist, PSB-KK-1415, and antagonist, PSB-CB5, was characterized in semi-chronic and chronic mouse models of colitis induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS). The extent of inflammation was evaluated based on the macroscopic and microscopic scores, quantification of myeloperoxidase (MPO) activity, and Western blot analyses of tumor necrosis factor-α (TNF-α) and interleukin-6 in colonic tissue. The expression of GPR18 in colonic samples from patients with Crohn's disease (CD) was quantified using real-time PCR. The anti-nociceptive potential of the agonist in intestinal inflammation was evaluated in the mouse model of inflammatory pain.. In semi-chronic colitis, PSB-KK-1415 reduced macroscopic score (1.79 ± 0.22 vs. 2.61 ± 0.48), expression of TNF-α (1.89 ± 0.36 vs. 2.83 ± 0.64), and microscopic score (5.00 ± 0.33 vs. 6.45 ± 0.40), all compared to mice with colitis. In chronic colitis, PSB-KK-1415 decreased macroscopic score (3.33 ± 1.26 vs. 4.00 ± 1.32) and MPO activity (32.23 ± 8.51 vs. 41.33 ± 11.64) compared to inflamed mice. In the mouse model of inflammatory pain, PSB-KK-1415 decreased the number of pain-induced behaviors in both, controls (32.60 ± 2.54 vs. 58.00 ± 6.24) and inflamed mice (60.83 ± 2.85 vs. 85.00 ± 5.77) compared to animals without treatment with PSB-KK-1415 (P < 0.005 for both). Lastly, we showed an increased expression of GPR18 in CD patients compared to healthy controls (3.77 ± 1.46 vs. 2.38 ± 0.66, p = 0.87).. We showed that GPR18 is worth considering as a potential treatment target in intestinal inflammation and inflammatory pain.

Topics: Adult; Aged; Aged, 80 and over; Animals; Case-Control Studies; Colitis; Crohn Disease; Disease Models, Animal; Female; Humans; Inflammation; Male; Mice; Middle Aged; Nociception; Nociceptive Pain; Peroxidase; Receptors, G-Protein-Coupled

The aim of the present study was to investigate the regulatory functions of microRNA (miR)‑26a‑5p on lipopolysaccharide (LPS)‑induced acute lung injury (ALI) and its molecular mechanisms. The role of miR‑26a‑5p on an ALI mouse model was evaluated by examining the histological changes, wet/dry (W/D) ratio, myeloperoxidase (MPO) activity, malondialdehyde (MDA) expression levels in lung tissues and the survival of ALI mice. Moreover, the protein concentration and the number of neutrophils and lymphocytes in bronchoalveolar lavage fluid (BALF) was analyzed. To explore the effect of miR‑26a‑5p on inflammatory responses and apoptosis, the expression levels of tumour necrosis factor‑α (TNF‑α), interleukin (IL)‑1β and IL‑6 and apoptosis were measured by ELISA, terminal deoxynucleotidyl transferase‑mediated dUTP nick end labelling staining and flow cytometry in BALF, A549 cells and lung tissues. B‑cell lymphoma‑2 (Bcl‑2), Bax and cleaved caspase‑3 in lung tissues were measured by western blotting and reverse transcription‑quantitative PCR. Connective tissue growth factor (CTGF) was predicted as a direct target of miR‑26a‑5p using dual luciferase reporter assay. The present study sought to determine whether CTGF overexpression reversed the effect of miR‑26a‑5p on apoptosis and inflammatory responses in LPS‑induced A549 cells. The data revealed that miR‑26a‑5p overexpression ameliorated LPS‑induced ALI, which was implicated by fewer histopathological changes, W/D ratio, apoptosis in lung tissues and the survival of ALI mice. Moreover, miR‑26a‑5p overexpression alleviated LPS‑induced inflammatory responses in ALI mice via the reduction of total protein, neutrophil and lymphocyte counts and the expression levels of TNF‑α, IL‑1β, IL‑6, MDA and MPO activity in BALF. Similarly, miR‑26a‑5p overexpression decreased apoptosis and the expression of TNF‑α, IL‑1β and IL‑6 in LPS‑induced A549 cells. CTGF was a direct target of miR‑26a‑5p. CTGF overexpression reversed the effect of miR‑26a‑5p on cell apoptosis and inflammatory responses in LPS‑induced A549 cells. The present study demonstrated that miR‑26a‑5p could attenuate lung inflammation and apoptosis in LPS‑induced ALI by targeting CTGF.

Topics: A549 Cells; Acute Lung Injury; Animals; Bronchoalveolar Lavage Fluid; Connective Tissue Growth Factor; Disease Models, Animal; Gene Expression Regulation; Humans; Lipopolysaccharides; Lymphocyte Count; Male; Malondialdehyde; Mice; MicroRNAs; Peroxidase

Gastric ulcers are a very common public health problem affecting up to 10% worldwide. Russelioside B is a steroidal glycoside isolated from several Caralluma species. No study tested the ulcer healing potential of the compound. The current study aimed to assess the protective effect of russelioside B against ethanol-induced gastric mucosal injury in rats. Ulcer was induced on rats by a single intragastric dose of absolute ethanol (5 mL/kg). Rats were randomly assorted into four groups (n = 8) and given treatments (Antodine, 20 mg/kg or russelioside B, 50 mg/kg) by oral gavage 1 h before ulcer induction. Pretreatment with russelioside B (50 mg/kg) attenuated the gastric mucosal injury as proved by a decrease of ulcer index, and histological scores. It suppressed the gastric inflammation by a significant lowering the tumor necrosis factor-α and interleukin-6 levels with myeloperoxidase activity (which are also aggravating factors in the case of Covid-19 infection). In addition, administration of russelioside B halted the gastric oxidative stress via inhibition of lipid peroxides by maintaining reduced glutathione and by decreasing malondialdehyde. It was able also to restore the sharp drop in the levels of heat shock protein-70, vascular endothelial growth factor and prostaglandin E2 induced by ethanol. Additionally, it showed carbonic anhydrase inhibition activity. The gastroprotective action of russelioside B was umpired through multi mechanistic actions; suppression of gastric oxidative stress, inflammation, anti-apoptotic activities and enhanced gastric mucosal protection by up-regulation of endothelial growth factor, normalization of heat shock protein-70 and prostaglandin E2. These actions were comparable in part to some classical antiulcer drugs such as Antodine.

Topics: Animals; Anti-Ulcer Agents; Apocynaceae; COVID-19; COVID-19 Drug Treatment; Dinoprostone; Disease Models, Animal; Ethanol; Gastric Mucosa; Gene Expression Regulation; Glycosides; HSP70 Heat-Shock Proteins; Humans; Interleukin-6; Oxidative Stress; Peroxidase; Pregnanes; Rats; SARS-CoV-2; Stomach Ulcer; Tumor Necrosis Factor-alpha

Neutrophils are vital to both the inflammatory cascade and tissue repair after an injury. Neutrophil heterogeneity is well established but there is less evidence for significant, different functional roles for neutrophil subsets. OLFM4 (Olfactomedin-4) is expressed by a subset of neutrophils, and high expression of

Topics: Adult; Animals; Cytokines; Disease Models, Animal; Female; Granulocyte Colony-Stimulating Factor; Humans; Inflammation; Lung; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Neutrophils; Peroxidase; Prospective Studies; Sepsis; Shock, Hemorrhagic; Up-Regulation

Anti-oxidant and anti-inflammatory properties of caffeic acid (CA) have been reported recently. In this study, the therapeutic effects of CA on ethanol-induced ulcer and the roles of nitric oxide and cholinergic pathways in these effects were investigated. Ulcer was induced by ethanol via oral gavage. Ulcer induced rats were treated with either vehicle (ulcer group) or CA (100, 250 or 500 mg/kg, per oral gavage). Macroscopic evaluation showed that 250 mg/kg CA was the effective dose. To elucidate the action mechanism of CA, 10 mg/kg l-NAME or 1 mg/kg atropine sulfate was administered to 250 mg/kg CA treated groups. All rats were decapitated 1 h after ulcer induction and gastric samples were scored macroscopically and microscopically, and analyzed for myeloperoxidase (MPO), malondialdehyde (MDA), and glutathione (GSH) levels. ANOVA test was used for statistical analyses. Macroscopic and microscopic damage scores, MDA levels and MPO activity were increased while GSH levels were decreased in ulcer group. Treatment with 250 mg/kg and 500 mg/kg CA reduced macroscopic and microscopic damage scores, decreased MPO activity and MDA levels, and preserved the depleted glutathione significantly. l-NAME administration before CA treatment elevated MDA levels, MPO activity and depleted glutathione. However, atropine sulfate had no effect on biochemical parameters. We conclude that CA ameliorates ethanol-induced gastric mucosal damage, and NO pathway contributes to this effect. On the other hand, there is a lack of evidence for the contribution of the muscarinic cholinergic system.

Topics: Animals; Anti-Inflammatory Agents; Anti-Ulcer Agents; Antioxidants; Caffeic Acids; Cholinergic Agents; Disease Models, Animal; Ethanol; Gastric Mucosa; Glutathione; Male; Malondialdehyde; NG-Nitroarginine Methyl Ester; Nitric Oxide; Peroxidase; Phytotherapy; Plant Extracts; Rats; Rats, Sprague-Dawley; Stomach Ulcer

Dilodendron bipinnatum (Sapindaceae) stem bark decoction and macerate were used to treat uterine inflammation, pain in general, dermatitis and bone fractures. These homemade preparations also have diuretic, stimulant, expectorants and sedative effects and are effective in treating worm infections in the Brazilian Pantanal population. Our previous research confirmed the anti-inflammatory activity of the hydroethanolic extract of inner stem bark of D. bipinnatum (HEDb).. This work aimed to investigate the efficacy of HEDb in ameliorating experimental colitis in rats and to elucidate the possible mechanisms involved in the anti-ulcerative colitis properties of HEDb in rats and Caco-2 cell line.. The effects on cell viability, IL-8 and TNF-α in human colon adenocarcinoma (Caco-2) were determined by flow cytometer and ELISA. Wistar rats (n = 6-7) were orally gavaged with, vehicle (0.9% saline), HEDb at doses of 20, 100 or 500 mg/kg, or mesalazine at a dose of 500 mg/kg, at 48, 24 and 1 h prior to the administration of trinitrobenzene sulfonic acid via rectal administration to induce colitis. The anti-inflammatory effects of HEDb were assessed macroscopically, by myeloperoxidase (MPO) activity and for glutathione (GSH) concentration in the colon. Additionally, colonic histopathological analyses of UC severity were conducted by different staining methods (H&E, PAS and toluidine blue). Pro-inflammatory cytokines TNF-α and IL-1β were quantified in colonic tissue by ELISA and colonic expressions of COX-2 and IL-17 were analyzed by western blotting.. HEDb was shown to be non-cytotoxic with mean viability of 80% in Caco-2 cells. HEDb pre-treatments of 1, 5 or 20 μg/mL significantly reduced TNF-α production in Caco-2 cells by 21.8% (p < 0.05), 60.5 and 82.1% (p < 0.001) respectively following LPS treatment compared to LPS alone. However, no change in IL-8 production was observed. HEDb pre-treatment of rats subjected to TNBS significantly (p < 0.001) reduced colonic lesion score. Higher doses (100 and 500 mg/kg) caused a sharp downregulation of haemorrhagic damage, leukocyte infiltration, edema and restoration of mucus production. Moreover, mast cell degranulation was inhibited. Colonic MPO activity was reduced following all doses of HEDb, reaching 51.1% ± 1.51 (p < 0.05) with the highest dose. GSH concentration was restored by 58% and 70% following 100 and 500 mg/kg of HEDb, respectively. The oral treatment of HEDb at doses 20, 100 and 500 mg/kg decreased the concentrations of TNF-α and IL-1β at all doses in comparison to vehicle treated control. In addition, HEDb inhibited the COX-2 and IL-17 expressions with maximal effect at 500 mg/kg (60.3% and 65% respectively; p < 0.001). In all trials, the effect of HEDb at all doses being 20, 100 and 500 mg/kg was statistically comparable to mesalazine (500 mg/kg).. HEDb reduces colonic damage in the TNBS colitis model and relieves oxidative and inflammatory events, at least in part, by increasing mucus production, reducing leukocyte migration and reducing TNF-α (in vivo and in vitro), IL-1β, IL-17 and COX-2 expression. Therefore, HEDb requires further investigation as a candidate for treating IBD.

Topics: Animals; Antioxidants; Brazil; Caco-2 Cells; Cell Survival; Colitis, Ulcerative; Cyclooxygenase 2; Disease Models, Animal; Edema; Glutathione; Humans; Interleukin-17; Interleukin-1beta; Interleukin-8; Lipopolysaccharides; Mast Cells; Mucus; Peroxidase; Plant Bark; Plant Extracts; Rats, Wistar; Sapindaceae; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

Ventilator-induced lung injury (VILI) is an additional inflammatory injury caused by mechanical ventilation (MV). This study aimed to determine the effects of microRNA-214 (miR-214) on VILI and its underlying mechanism of action.. To develop a VILI mouse model, mice were subjected to MV. The expression of miR-214 was detected by qRT-PCR. The macrophages, fibroblasts, epithelial cells, and endothelial cells were isolated from lung tissues by fluorescence-activated cell sorting. The histopathological changes of lung, lung wet/dry weight (W/D) ratio, and myeloperoxidase (MPO) activity were used to evaluate the degree of lung injury. The levels of pro-inflammatory cytokines in bronchoalveolar lavage fluid (BALF) were measured by enzyme-linked immunosorbent assay (ELISA). Dual-luciferase reporter assay was performed to determine the interactions between miR-214 and FGFR1. Western blot was used to detect the protein expression of FGFR1, p-AKT, and p-PI3K.. The expression of miR-214 was increased in lung tissues and macrophages, fibroblasts, epithelial cells, and endothelial cells isolated from lung tissues in VILI mice. MiR-214 inhibition decreased the histopathological changes of lung, lung W/D ratio, MPO activity, and pro-inflammatory cytokines levels in BALF in VILI mice. FGFR1 was targeted by miR-214. The protein expression of FGFR1 was decreased in VILI mice. Ponatinib (FGFR1 inhibitor) reversed the suppressive effects of miR-214 inhibition on lung injury and inflammation of VILI mice. MiR-214 increased the activity of PI3K/AKT pathway by regulating FGFR1.. Inhibition of miR-214 attenuated lung injury and inflammation in VILI mice by increasing FGFR1 expression, providing a novel therapeutic target for VILI.

Topics: Acute Lung Injury; Animals; Bronchoalveolar Lavage Fluid; Cytokines; Disease Models, Animal; Endothelial Cells; Epithelial Cells; Fibroblasts; Imidazoles; Inflammation; Lung; Macrophages; Mice, Inbred C57BL; MicroRNAs; Peroxidase; Protein Kinase Inhibitors; Pyridazines; Receptor, Fibroblast Growth Factor, Type 1; Ventilator-Induced Lung Injury

Inflammation theory has suggested that the pathogenesis of postoperative ileus (POI) involves the steroid receptor coactivator-3 (SRC-3). Therefore, we investigated the role of SRC-3 in the muscles of the small intestine using a mouse POI model. Here, we reported that intestinal manipulation (IM) significantly reduced the extent of phenol red migration in the entire gastrointestinal tract, and the calculated geometric center (GC) value in wild-type (WT) mice at 24 h after surgery was higher than that in the knockout (KO) mice and in the sham-operated control group. The expression of SRC-3 was upregulated in the mouse intestinal muscularis at 24 h after surgical manipulation, and the mRNA and protein levels of inflammatory cytokines were upregulated compared with those in the control group. At 24 h after IM, the number of neutrophils in the experimental group was significantly higher than that in the control group; in the IM group, the number of neutrophils in the SRC-3

Topics: Animals; Cytokines; Disease Models, Animal; Female; Gastrointestinal Motility; Ileus; Inflammation Mediators; Intestine, Small; Jejunum; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth; Neutrophil Infiltration; Nuclear Receptor Coactivator 3; Peroxidase; Postoperative Complications; Tissue Culture Techniques

Ulcerative colitis (UC) is a chronic multifactorial inflammatory bowel disease that severely impairs patients' life quality. microRNAs (miRNAs) have been reported to exhibit potential therapeutic effects in the management of UC. With the aim to investigate the regulatory effects of miR-330 on UC-related colon tissue damage and inflammation, a rat model of experimental colitis was established by oral administration of dextran sodium sulfate (DSS). DSS-treated rats showed mucosal damage, colonic inflammation, and elevated myeloperoxidase activity compared with the healthy controls. Dual-luciferase reporter assay confirmed the binding of interleukin-1 receptor-associated kinase 1 (IRAK1) and miR-330. Subsequently, rats were intracolonically injected with miR-330 argomir with/without administration of IRAK1 during DSS treatment. The miR-330 overexpression reduced DSS-induced colonic injury and the production of proinflammatory cytokines. The level of IRAK1 was negatively regulated by the expression of miR-330. IRAK1 overexpression abolished the protective effect of miR-330 on DSS-induced colonic inflammation and mucosal injury in rats. In conclusion, we clarify the role of miR-330 in pathogenesis of UC, suggesting miR-330 alleviated DSS-induced colitis by downregulating IRAK1, shedding lights on miR-330 as a therapeutic candidate for UC treatment.

Topics: Animals; Colitis, Ulcerative; Colon; Cytokines; Dextrans; Disease Models, Animal; Down-Regulation; Gene Expression Regulation; Inflammation; Interleukin-1 Receptor-Associated Kinases; Intestinal Mucosa; Intestines; Male; MicroRNAs; Peroxidase; Rats; Rats, Sprague-Dawley; Signal Transduction; Sulfates

Ulcerative colitis (UC), one of the two main types of inflammatory bowel disease, has no effective treatment. Rosmarinic acid (RA) is a polyphenol that, when administered orally, is metabolised in the small intestine, compromising its beneficial effects. We used chitosan/nutriose-coated niosomes loaded with RA to protect RA from gastric degradation and target the colon and evaluated their effect on acute colitis induced by 4% dextran sodium sulphate (DSS) for seven days in mice. RA-loaded nanovesicles (5, 10 and 20 mg/kg) or free RA (20 mg/kg) were orally administered from three days prior to colitis induction and during days 1, 3, 5 and 7 of DSS administration. RA-loaded nanovesicles improved body weight loss and disease activity index as well as increased mucus production and decreased myeloperoxidase activity and TNF-α production. Moreover, RA-loaded nanovesicles downregulated protein expression of inflammasome components such as NLR family pyrin domain-containing 3 (NLRP3), adaptor protein (ASC) and caspase-1, and the consequent reduction of IL-1β levels. Furthermore, nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) protein expression increased after the RA-loaded nanovesicles treatment However, these mechanistic changes were not detected with the RA-free treatment. Our findings suggest that the use of chitosan/nutriose-coated niosomes to increase RA local bioavailability could be a promising nutraceutical strategy for oral colon-targeted UC therapy.

Topics: Animals; Cinnamates; Colitis; Depsides; Disease Models, Animal; Heme Oxygenase-1; In Vitro Techniques; Inflammasomes; Inflammation; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Nanomedicine; Nanoparticles; NF-E2-Related Factor 2; NLR Family, Pyrin Domain-Containing 3 Protein; Oxidative Stress; Peroxidase; Rosmarinic Acid; Signal Transduction; Tumor Necrosis Factor-alpha

Severe acute pancreatitis (SAP) is one of the most common diseases of the gastrointestinal tract, characterized by a complicated pathogenesis, multiple organ failure, and high mortality. The primary aim of the present study was to observe the effect of intestinal lymphatic ligation on intestinal injury and modification in rats with SAP. Male Sprague-Dawley (SD) rats were randomly divided into: (a) Saline group (SO); (b) SAP group; and (c) SAP + ligation group. We evaluated the effect of mesenteric lymphatic duct ligation on the pancreas and intestine tissue by HE. The histopathology of the pancreas in SAP + ligation rats was alleviated slightly compared with SAP rats, but aggravated in the intestine of SAP + ligation rats. Treatment of mesenteric lymphatic duct ligation resulted in an increase in the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and myeloperoxidase compared with the small intestinal tissues of SAP rats. In addition, the expression of nucleotide-binding oligomerization domain-like receptors 3, apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD) (ASC), and caspase-1 in the intestine were higher in the SAP + ligation group. The ratio of Th1/Th2 and regulatory T cells (Tregs) in the mesenteric lymph nodes of the SAP group was lower than those in the SAP + ligation group. The present results indicated that ligation of the mesenteric lymph duct can effectively prevent intestinal inflammatory mediators entering the body through the mesenteric lymph duct, but these mediators assembled in the intestine where they induced an excessive immune response and intestinal injury during SAP.

Topics: Animals; Biomarkers; Caspase 1; Cytokines; Disease Models, Animal; Disease Susceptibility; Gene Expression; Immunity, Mucosal; Immunoglobulin A, Secretory; Immunophenotyping; Intestinal Mucosa; Lymphatic Vessels; Lymphoid Tissue; Male; Pancreatitis; Peroxidase; Rats; Severity of Illness Index; T-Lymphocyte Subsets

Palmitoylethanolamide (PEA), a fatty acid amide, has been widely investigated for its analgesic and anti-inflammatory properties. The ultra-micronized formulation of PEA (um-PEA), that has an enhanced rate of dissolution, is extensively used. Acetyl-l-carnitine (LAC), employed for the treatment of neuropathic pain in humans, is able to cause analgesia by up-regulating type-2 metabotropic glutamate (mGlu2) receptors. In the present study, we tested different associations of um-PEA, LAC and non-micronized PEA (non-m-PEA) in a rat model of carrageenan (CAR)-induced paw edema. Intraplantar injection of CAR into the hind paw of animals caused edema, thermal hyperalgesia, accumulation of infiltrating inflammatory cells and augmented myeloperoxidase (MPO) activity. All these parameters were decreased in a significantly manner by oral administration of a compound constituted by a mixture of um-PEA and LAC in relation 1:1 (5 mg/kg), but not with the association of single compounds administered one after the other. These findings showed the superior anti-inflammatory and anti-nociceptive action displayed by oral administration of um-PEA and LAC versus LAC plus, separate but consecutive, um-PEA in the rat paw CAR model of inflammatory pain.

Topics: Acetylcarnitine; Amides; Animals; Carrageenan; Cell Count; Cyclooxygenase 2; Disease Models, Animal; Edema; Ethanolamines; Hyperalgesia; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-1beta; Male; Mast Cells; Nitric Oxide Synthase Type II; Pain; Palmitic Acids; Peroxidase; Rats, Sprague-Dawley; Time Factors; Tumor Necrosis Factor-alpha

Respiratory syncytial virus (RSV) is the primary cause of viral bronchiolitis resulting in hospitalization and a frequent cause of secondary respiratory bacterial infection, especially by Streptococcus pneumoniae (Spn) in infants. While murine studies have demonstrated enhanced morbidity during a viral/bacterial co-infection, human meta-studies have conflicting results. Moreover, little knowledge about the pathogenesis of emerging Spn serotype 22F, especially the co-pathologies between RSV and Spn, is known. Here, colostrum-deprived neonate lambs were divided into four groups. Two of the groups were nebulized with RSV M37, and the other two groups were mock nebulized. At day three post-RSV infection, one RSV group (RSV/Spn) and one mock-nebulized group (Spn only) were inoculated with Spn intratracheally. At day six post-RSV infection, bacterial/viral loads were assessed along with histopathology and correlated with clinical symptoms. Lambs dually infected with RSV/Spn trended with higher RSV titers, but lower Spn. Additionally, lung lesions were observed to be more frequent in the RSV/Spn group characterized by increased interalveolar wall thickness accompanied by neutrophil and lymphocyte infiltration and higher myeloperoxidase. Despite lower Spn in lungs, co-infected lambs had more significant morbidity and histopathology, which correlated with a different cytokine response. Thus, enhanced disease severity during dual infection may be due to lesion development and altered immune responses rather than bacterial counts.

Topics: Animals; Animals, Newborn; Bronchoalveolar Lavage Fluid; Cytokines; Disease Models, Animal; Lung; Lymphocytes; Neutrophils; Peroxidase; Pneumococcal Infections; Respiratory Syncytial Virus Infections; Respiratory Syncytial Viruses; RNA, Viral; Serogroup; Sheep; Streptococcus pneumoniae

Myeloperoxidase ANCA-associated vasculitis is a major cause of ESKD. Efficacy of anti-CD20 mAb treatment was tested in a mouse model of the disease.. MPO immunization induced anti-MPO autoimmunity, and a subnephritogenic dose of sheep anti-mouse GBM globulin triggered GN.. Anti-CD20 mAb treatment increased the numbers and immunomodulatory capacity of MPO-specific T regulatory cells (Tregs) and attenuated T cell-mediated and humoral anti-MPO autoimmunity and GN. Disabling of Tregs negated the therapeutic benefit of anti-CD20 treatment. The mechanism of enhancement of Treg activity could be attributed to anti-CD20 mAb effects on inducing B cell apoptosis. Administering anti-CD20 mAb-induced apoptotic splenocytes to mice developing anti-MPO GN was as effective as anti-CD20 mAb treatment in inducing Tregs and attenuating both anti-MPO autoimmunity and GN. A nonredundant role for splenic macrophages in mediating the anti-CD20 mAb-induced immunomodulation was demonstrated by showing that administration of anti-CD20 mAb. Collectively, these data suggest that, as well as reducing humoral autoimmunity, anti-CD20 mAb more rapidly induces protective anti-MPO Treg-mediated immunomodulation by splenic processing of anti-CD20-induced apoptotic B cells.

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Apoptosis; B-Lymphocytes; Disease Models, Animal; Immunologic Factors; Male; Mice; Peroxidase; Rituximab; T-Lymphocytes, Regulatory

Zuojin Pill (ZJP) has been a classic prescription for the treatment of gastrointestinal diseases in China since ancient times. But its effect on non-steroidal anti-inflammatory drugs (NSAIDs) induced gastric injury (GI) is still uncharted.. This study aims to investigate the therapeutic effect and molecular mechanism of ZJP on indomethacin (IDO) induced gastric injury.. GI was induced in rat by oral administration of 5 mg/kg IDO. Then the rats were treated with ZJP (1.26, 2.52, 5.04 g/kg, ig). The changes of food intake, body weight, gastric pH and general state observation were carried out to determine the improvement of ZJP in IDO-induced GI: HE staining and AB-PAS staining was analyzed to characterize the thickness of gastric mucosa and micro mucosal injury; in order to elucidate the effect of ZJP on IDO-induced inflammatory injury, the inflammatory infiltration of gastric tissue was observed by MPO immunohistochemical method, and the contents of TNF-α, IL-6 and IL-10 were measured. Furthermore, the regulatory mechanism of ZJP in treating IDO-induced GI was predicted with the help of network pharmacology, and the expression levels of key proteins ERK, p-ERK, P38, p-P38, JNK, p-JNK were determined to elucidate the molecular mechanism of ZJP.. Current data strongly demonstrated that ZJP alleviated food intake reduction, weight loss and gastric injury caused by IDO and made gastric pH and mucosal thickness return to normal. In addition, ZJP could reduce the level of MPO to alleviate the inflammatory infiltration of gastric tissue. Simultaneously, ZJP could down regulate the expression of TNF-α and IL-6 and up regulate the expression of IL-10 to reduce the damage caused by inflammatory, and create a healing environment. Furthermore, ZJP could significantly inhibit the phosphorylation of ERK, p38 and JNK, which leaded to the increase of inflammatory factors and the damage of gastric mucosa.. ZJP improved local inflammation by inhibiting MAPK signaling pathway, and had a good therapeutic effect on IDO-induced GI. This study has reference significance for the study of ZJP in the prevention and treatment of NSAID induced gastric injury. In addition, ZJP may be a new treatment option for the prevention and treatment of NSAID induced gastric disease.

Topics: Animals; Anti-Inflammatory Agents; Body Weight; Cytokines; Disease Models, Animal; Drugs, Chinese Herbal; Eating; Gastric Mucosa; Indomethacin; Inflammation; Male; MAP Kinase Signaling System; Peroxidase; Protein Interaction Maps; Rats, Sprague-Dawley; Stomach Diseases

we present a rat experimental model used to evaluate the possible reduction in the extent of pancreatic tissue injury in acute pancreatitis cases, after administration of eugenol.. one hundred and twenty Wistar rats were used, which were randomly assigned in 3 groups: sham (n=20), control (n=50) and eugenol (n=50). Acute pancreatitis was induced by biliopancreatic ligation in the control and eugenol groups, but not in the Sham group. In the eugenol group, eugenol was administered per-os. Five histopathological parameters, such as edema, inflammatory infiltration, duct dilatation, hemorrhage and acinar necrosis were evaluated.. at 72 h from acute pancreatitis induction, the total histological score was diminished in the eugenol group (p<0.0005) and duct dilatation and inflammatory infiltration were reduced compared to the control group (p<0.05). In addition, at 72 h, eugenol reduced pancreatic myeloperoxidase activity (p<0.0005).. eugenol, a highly free radical scavenger agent, may have a preventive role in acute pancreatic injury, as it was evident in our rat experimental model.

Topics: Acute Disease; Animals; Disease Models, Animal; Eugenol; Free Radical Scavengers; Male; Pancreas; Pancreatitis; Peroxidase; Rats; Rats, Wistar

Myeloperoxidase (MPO) is a key component of innate immunity but can damage tissues when secreted abnormally. We developed a new generation of a highly efficient MPO-activatable MRI probe (heMAMP) to report MPO activity. heMAMP has improved Gd stability compared to bis-5-HT-Gd-DTPA (MPO-Gd) and demonstrates no significant cytotoxicity. Importantly, heMAMP is more efficiently activated by MPO compared to MPO-Gd, 5HT-DOTA(Gd), and 5HT-DOTAGA-Gd. Molecular docking simulations revealed that heMAMP has increased rigidity via hydrogen bonding intramolecularly and improved binding affinity to the active site of MPO. In animals with subcutaneous inflammation, activated heMAMP showed a 2-3-fold increased contrast-to-noise ratio (CNR) compared to activated MPO-Gd and 4-10 times higher CNR compared to conventional DOTA-Gd. This increased efficacy was further confirmed in a model of unstable atherosclerotic plaque where heMAMP demonstrated a comparable signal increase and responsiveness to MPO inhibition at a 3-fold lower dosage compared to MPO-Gd, further underscoring heMAMP as a potential translational candidate.

Topics: Animals; Atherosclerosis; Binding Sites; Calcium; Catalytic Domain; Cell Survival; Contrast Media; Disease Models, Animal; Drug Design; Female; Gadolinium DTPA; Half-Life; Magnetic Resonance Imaging; Mice; Mice, Inbred BALB C; Peroxidase; RAW 264.7 Cells; Signal-To-Noise Ratio; Tissue Distribution; Zinc

Neutrophil (PMN) recruitment to sites of insult is critical for host defense, however excessive PMN activity and tissue accumulation can lead to exacerbated inflammation and injury. Myeloperoxidase (MPO) is a PMN azurophilic granule enzyme, which together with H

Topics: Animals; Chemotaxis, Leukocyte; Disease Models, Animal; Endothelial Cells; Gene Expression; Inflammation; Mice; Mice, Knockout; Neutrophil Infiltration; Neutrophils; Peroxidase

C-type lectin-like receptor-1 (CLEC-1) is a member of the Dectin-1 cluster of pattern recognition receptors (PRRs). It is involved in host immunity, has immunoregulatory function, and supports allograft tolerance. Our study aimed to describe the role of CLEC-1 in response to fungal keratitis, in situ, in vivo, and in vitro.. Quantitative polymerase chain reaction (qRT-PCR) and immunofluorescence were used to detect the expression of CLEC-1 in corneas of patients with Aspergillus fumigatus (A. fumigatus) keratitis. In vitro and in vivo experiments were designed in THP-1 macrophages and C57BL/6 mouse models, respectively. The expression of CLEC-1 in corneas of mice model was determined by qRT-PCR, Western blot, and immunofluorescence. CLEC-1 overexpression in mouse corneas was achieved by intrastromal injection of adeno-associated virus (AAV) vectors. Disease response was evaluated by slit-lamp photography, clinical score, and colony forming unit (CFU). Bioluminescence imaging system image acquisition, myeloperoxidase (MPO) assays, immunofluorescence staining, qRT-PCR, and Western blot were used to investigate the role of CLEC-1. To further define the role of CLEC-1, we used lentivirus vectors to overexpress CLEC-1 or/and Dectin-1 in THP-1 macrophages.. The expression of CLEC-1 was increased in corneas of patients with A. fumigatus keratitis. In corneas of mice from the A. fumigatus keratitis model, the expression of CLEC-1 was decreased in the acute inflammatory stage and increased during convalescence. Following Natamycin treatment, CLEC-1 was upregulated in A. fumigatus keratitis mice. Compared with normal C57BL/6 mice, overexpression of CLEC-1 converted the characteristic susceptible response to resistance, as demonstrated by slit-lamp photography and clinical score. In vivo studies revealed decreased MPO levels and neutrophils recruitment and higher fungal load after the upregulation of CLEC-1. Compared with control corneas, CLEC-1 overexpression impaired corneal pro-inflammatory cytokine IL-1β production.. These findings demonstrate that CLEC-1 may act as a negative regulator of Dectin-1 induced host inflammatory response via suppressing neutrophils recruitment and production of pro-inflammatory cytokine IL-1β production in response to A. fumigatus keratitis.

Topics: Animals; Aspergillosis; Aspergillus fumigatus; Blotting, Western; Cytokines; Dependovirus; Disease Models, Animal; Eye Infections, Fungal; Female; Gene Expression Regulation; Genetic Vectors; Humans; Keratitis; Lectins, C-Type; Macrophages; Membrane Proteins; Mice; Mice, Inbred C57BL; Microscopy, Fluorescence; Neutrophil Infiltration; Peroxidase; Real-Time Polymerase Chain Reaction; Receptors, Mitogen; Slit Lamp Microscopy

Adiponectin is a hormone secreted by adipocytes, which exhibits insulin-sensitizing and anti-inflammatory properties and acts through adiponectin receptors: AdipoR1 and AdipoR2. The aim of the study was to evaluate whether activation of adiponectin receptors AdipoR1 and AdipoR2 with an orally active agonist AdipoRon has gastroprotective effect and to investigate the possible underlying mechanism.. We used two well-established mouse models of gastric ulcer (GU) induced by oral administration of EtOH (80% solution in water) or diclofenac (30 mg/kg, p.o.). Gastroprotective effect of AdipoRon (dose 5 and 50 mg /kg p.o) was compared to omeprazole (20 mg/kg p.o.) or 5% DMSO solution (control). Clinical parameters of gastroprotection were assessed using macroscopic (gastric lesion area) and microscopic (evaluation of the gastric mucosa damage) scoring. To establish the molecular mechanism, we measured: myeloperoxidase (MPO), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) activities; glutathione (GSH) level; and IL-1β, adenosine monophosphate-activated protein kinase (AMPK), and phosphorylated AMPK expression in gastric tissue.. AdipoRon produced a gastroprotective effect in both GU mouse models as evidenced by significantly lower macroscopic and microscopic damage scores. AdipoRon exhibited anti-inflammatory effect by reduction in MPO activity and IL-1β expression in the gastric tissue. Moreover, AdipoRon induced antioxidative action, as demonstrated with higher GSH levels, and increased SOD and GPX activity.. Activation of AdipoR1 and AdipoR2 using AdipoRon reduced gastric lesions and enhanced cell response to oxidative stress. Our data suggest that AdipoR1 and AdipoR2 activation may be an attractive therapeutic strategy to inhibit development of gastric ulcers.

Topics: Administration, Oral; Animals; Catalase; Diclofenac; Disease Models, Animal; Ethanol; Male; Mice; Omeprazole; Oxidative Stress; Peroxidase; Piperidines; Receptors, Adiponectin; Stomach Ulcer; Superoxide Dismutase; Treatment Outcome

Vanillin, the main constituents of vanillin beans, has been reported to exhibit anti-inflammatory effects. However, the effects of vanillin on the cadmium-induced lung injury are still unclear. Therefore, we assay whether vanillin has potential preventive activity on cadmium-induced lung injury in mice. Mice were given vanillin (5, 10, 20 mg/kg) and treated with cadmium for 7 days. The detection data of vanillin on lung tissue changes were analyzed after the cadmium treatment. The results displayed that vanillin obviously decreased the lung histological alterations and myeloperoxidase (MPO) activity. Vanillin also suppressed the levels of TNF-α, IL-1β, and IL-6 in BALF. Furthermore, vanillin prevented cadmium-induced NF-κB activation and upregulation the expression of tight junction protein ZO-1 and occludin. In addition, vanillin significantly increased the expression of aryl hydrocarbon receptor (AhR), and inhibition of AhR by its agonist could reverse the protective effects of vanillin on cadmium-induced lung injury. To sum up, vanillin could be a potential drug for the treatment of cadmium-induced lung injury.

Topics: Animals; Anti-Inflammatory Agents; Basic Helix-Loop-Helix Transcription Factors; Benzaldehydes; Cadmium Chloride; Cytokines; Disease Models, Animal; Inflammation Mediators; Lung; Lung Injury; Male; Mice, Inbred BALB C; NF-kappa B; Occludin; Peroxidase; Pneumonia; Pulmonary Edema; Receptors, Aryl Hydrocarbon; Signal Transduction; Tight Junctions; Zonula Occludens-1 Protein

Experimental autoimmune vasculitis (EAV) is a model of antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) induced by immunisation of susceptible rat strains with myeloperoxidase (MPO). Animals develop circulating MPO-ANCA, pulmonary haemorrhage, and glomerulonephritis, although renal injury is mild and recovers spontaneously without treatment. In this study we aimed to augment the severity of glomerulonephritis. Following induction of EAV on day 0, a sub-nephritogenic dose of nephrotoxic serum (NTS) containing heterologous antibodies to glomerular basement membrane was administered on day 14. This resulted in a significant increase in disease severity at day 28 compared to MPO immunisation alone - with more urinary abnormalities, infiltrating glomerular leucocytes, and crescent formation that progressed to glomerular and tubulointerstitial scarring by day 56, recapitulating important features of human disease. Importantly, the glomerulonephritis remained pauci-immune, and was strictly dependent on the presence of autoimmunity to MPO, as there was no evidence of renal disease following administration of sub-nephritogenic NTS alone or after immunisation with a control protein in place of MPO. Detailed phenotyping of glomerular leucocytes identified an early infiltrate of non-classical monocytes following NTS administration that, in the presence of autoimmunity to MPO, may initiate the subsequent influx of classical monocytes which augment glomerular injury. We also showed that this model can be used to test novel therapeutics by using a small molecule kinase inhibitor (fostamatinib) that rapidly attenuated both glomerular and pulmonary injury over a 4-day treatment period. We believe that this enhanced model of MPO-AAV will prove useful for the study of glomerular leucocyte behaviour and novel therapeutics in AAV in the future. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Autoantibodies; Autoantigens; Disease Models, Animal; Glomerular Basement Membrane; Glomerulonephritis; Male; Peroxidase; Rats

We investigated, the effects of aprepitant (APRE) on the lung tissues of rats with an experimental polymicrobial sepsis model (CLP: cecal ligation and puncture) biochemically, molecularly and histopathologically.. A total of 40 rats were divided into 5 groups with 8 animals in each group. Group 1 (SHAM), control group; Group 2 (CLP), cecal ligation and puncture; Group 3 (CLP + APRE10), rats were administered CLP + 10 mg/kg aprepitant; Group 4 (CLP + APRE20), rats were administered CLP + 20 mg/kg aprepitant; and Group 5 (CLP + APRE40), rats were administered CLP + 40 mg/kg aprepitant. A polymicrobial sepsis model was induced with CLP. After 16 h, lung tissues were taken for examination. Tumour necrosis factor α (TNF-α) and nuclear factor-kappa b (NFK-b) messenger ribonucleic acid (mRNA) expressions were analysed by real-time PCR (RT-PCR), biochemically antioxidant parameters such as superoxide dismutase (SOD) and glutathione (GSH) and oxidant parameters such as malondialdehyde (MDA) and lung damage histopathologically.. The GSH level and SOD activity increased while the MDA level and the expressions of TNF-α and NFK-b were reduced in the groups treated with APRE, especially in the CLP + APRE40 group. The histopathology results supported the molecular and biochemical results.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Antiemetics; Antioxidants; Aprepitant; Cecum; Disease Models, Animal; Female; Glutathione; Inflammation; Ligation; Lung; Malondialdehyde; NF-kappa B; Oxidative Stress; Peroxidase; Rats, Sprague-Dawley; Sepsis; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Psoriasis is a most common chronic autoimmune-arbitrated cutaneous inflammatory skin disorder by unclear pathogenesis. In this current study we demonstrated the effect of galangin (GAL) on imiquimod (IMQ)-induced psoriasis-like skin inflammation and decipher its possible protective mechanism which has not been investigated. The in vivo results revealed that GAL at 1% w/w and 2% w/w for six consecutive days markedly reduced IMQ-induced PASI scoring, skin, ear thickness, hematological markers, levels of nitrites, TBARS, MPO, histopathological, as well modulated the protein levels of pro-inflammatory mediators of COX-2, iNOS, NF-κB pathway and pro-inflammatory cytokines IL-17, IL-23, IL-1β in the skin and also IL-6, TNF-α in both skin and serum. Besides, GAL restored the levels of antioxidants markers such as SOD, CAT, GST, GSH, GR and Vit-C, anti-inflammatory cytokine of IL-10, and the protein levels of Nrf2/HO-1 in the skin compared to the IMQ group. Finally, our study demonstrates that GAL exerted its protective effect by up-regulating the anti-inflammatory and the antioxidant markers against psoriasis pre-clinical models indicating its potency for treating psoriasis in humans.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Body Weight; Cytokines; Dermatitis; Disease Models, Animal; Down-Regulation; Flavonoids; Heme Oxygenase-1; Imiquimod; Male; Membrane Proteins; Mice, Inbred BALB C; NF-E2-Related Factor 2; NF-kappa B; Oxidative Stress; Peroxidase; Psoriasis; Signal Transduction; Spleen

Nanomaterials having enzyme-like activities are recognized as potentially important self-therapeutic nanomedicines. Herein, a peroxidase-like artificial enzyme is developed based on novel biodegradable boron oxynitride (BON) nanostructures for highly efficient and multi-mode breast cancer therapies. The BON nanozyme catalytically generates cytotoxic hydroxyl radicals, which induce apoptosis of 4T1 cancer cells and significantly reduce the cell viability by 82% in 48 h. In vivo experiment reveals a high potency of the BON nanozyme for breast tumor growth inhibitions by 97% after 14-day treatment compared with the control, which are 10 times or 1.3 times more effective than the inert or B-releasing boron nitride (BN) nanospheres, respectively. This work highlights the BON nanozyme and its functional integrations within the BN nanomedicine platform for high-potency breast cancer therapies.

Topics: Animals; Antineoplastic Agents; Biocompatible Materials; Boron Compounds; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Disease Models, Animal; Female; Mice; Mice, Inbred BALB C; Nanomedicine; Nanostructures; Peroxidase

Peptic ulcer has a serious impact on people's health around the world, and traditional medicines can cause adverse reactions. This study investigated the protective effects of tilapia collagen oligopeptides (TCOPs) on gastroduodenal injury. Seventy-two specific pathogen-free (SPF) male Sprague Dawley (SD) rats were randomly divided into six groups according to body weight: normal control group, ethanol group, whey protein group (500 mg/kg BW), and three TCOPs dose groups (250, 500, 1000 mg/kg BW). After intragastric administration for 30 days, the acute gastroduodenal injury was induced by anhydrous ethanol (5 mL/kg, intragastrically) in all groups except the normal control group. Biomarkers in gastric and duodenal tissue and serum were measured. Furthermore, western blot was used to detect the expression of apoptosis-related proteins. The results showed that the administration with TCOPs significantly reduced gastric and duodenal ulcer index, increased gastric juice pH, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities, along with the reduction of malondialdehyde (MDA) contents. TCOPs decreased tumor Necrosis Factor-α (TNF-α), interleukin-1β (IL-1β), and myeloperoxidase (MPO) levels, while interleukin- 10 (IL-10) levels were increased. Furthermore, pepsinogens 1 (PG1), pepsinogens 2 (PG2), gastrin (GAS), and the pepsinogen ratio (PGR) were decreased, the prostaglandin E2 (PGE2) and NO contents were increased after TCOPs intervention. Moreover, TCOPs up-regulated the expression of Bcl-2 and inhibited the expression of Bax and Caspase-3. In conclusion, TCOPs have protective effects on ethanol-induced gastroduodenal injury through gastrointestinal mucosal microcirculation promotion, antioxidation, anti-inflammation, and anti-apoptosis mechanisms.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Biomarkers; Catalase; Collagen; Cytokines; Disease Models, Animal; Ethanol; Gastrointestinal Tract; Interleukin-1beta; Male; Malondialdehyde; Oligopeptides; Peroxidase; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Tilapia; Tumor Necrosis Factor-alpha

In this study, we aimed to investigate the influence of N-acetylcysteine (NAC) on the gene expression profile, neoangiogenesis, neutrophils and macrophages in a rat model of incisional wounds. Before creating wounds on the backs of 24 Sprague-Dawley rats, intradermal injections were made. Lidocaine-epinephrin solutions were supplemented with 0.015%, 0.03% or 0.045% solutions of NAC, or nothing (control group). Scars were harvested on the 3rd, 7th, 14th and 60th day post-surgery. We performed immunohistochemical staining in order to visualize macrophages (anti-CD68), neutrophils (anti-MPO) and newly formed blood vessels (anti-CD31). Additionally, RT-qPCR was used to measure the relative expression of 88 genes involved in the wound healing process. On the 14th day, the number of cells stained with anti-CD68 and anti-CD31 antibodies was significantly larger in the tissues treated with 0.03% NAC compared with the control. Among the selected genes, 52 were upregulated and six were downregulated at different time points. Interestingly, NAC exerted a significant effect on the expression of 45 genes 60 days after its administration. In summation, a 0.03% NAC addition to the pre-incisional anesthetic solution improves neovasculature and increases the macrophages' concentration at the wound site on the 14th day, as well as altering the expression of numerous genes that are responsible for the regenerative processes.

Topics: Acetylcysteine; Anesthesia, Local; Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Disease Models, Animal; Gene Expression Regulation; Hypoxia-Inducible Factor 1, alpha Subunit; Mitogen-Activated Protein Kinase 1; Oxidative Stress; Peroxidase; Platelet Endothelial Cell Adhesion Molecule-1; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta1; Wound Healing

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

Herein, we report the effect of gold nanoparticles (AuNP) and n-acetylcysteine (NAC) isolated or in association as important anti-inflammatory and antioxidant compounds on brain dysfunction in septic rats. Male Wistar rats after sham operation or caecal ligation and perforation (CLP) were treated with subcutaneously injection of AuNP (50 mg/kg) and/or NAC (20 mg/kg) or saline immediately and 12 h after surgery. Twenty-four hours after CLP, hippocampus and prefrontal cortex were obtained and assayed for myeloperoxidase (MPO) activity, cytokines, lipid peroxidation, protein carbonyls formation, mitochondrial respiratory chain, and CK activity. AuNP + NAC association decreased MPO activity and pro-inflammatory cytokines production, being more effective than NAC or AuNP isolated treatment. AuNP + NAC association and NAC isolated treatment decreased oxidative stress to lipids in both brain structures, while protein oxidation decreased only in the hippocampus of AuNP + NAC association-treated animals. Complex I activity was increased with AuNP + NAC association and NAC isolated in the hippocampus. Regarding CK activity, AuNP and AuNP + NAC association increased this marker in both brain structures after CLP. Our data provide the first experimental demonstration that AuNP and NAC association was able to reduce sepsis-induced brain dysfunction in rats by decreasing neuroinflammation, oxidative stress parameters, mitochondrial dysfunction and CK activity.

Topics: Acetylcysteine; Animals; Antioxidants; Cytokines; Disease Models, Animal; Gold; Hippocampus; Inflammation; Male; Metal Nanoparticles; Mitochondria; Oxidation-Reduction; Oxidative Stress; Peroxidase; Rats; Rats, Wistar; Sepsis

Increasing evidence has confirmed that the antimicrobial and anti-inflammatory effects of cinnamon essential oil (CEO) contribute to protection against inflammatory bowel disease (IBD). The dextran sodium sulfate (DSS)-induced colitis mouse model was established to investigate the correlation between the protective effects of CEO and the regulation of intestinal microflora. The symptoms of IBD were assessed by measuring the hemoglobin content, myeloperoxidase activity, histopathological observation, cytokines, and toll-like receptor (TLR4) expression. The alteration of the fecal microbiome composition was analyzed by 16S rRNA gene sequencing. The results indicated that the oral administration of CEO enriched with cinnamaldehyde effectively alleviated the development of DSS-induced colitis. In contrast to the inability of antibiotics to regulate flora imbalance, the mice fed with CEO had an improved diversity and richness of intestinal microbiota, and a modified community composition with a decrease in Helicobacter and Bacteroides and an increase in Bacteroidales_S24-7 family and short-chain fatty acids (SCFA)-producing bacteria (Alloprevotella and Lachnospiraceae_NK4A136_group). Moreover, the correlation analysis showed that TLR4 and tumor necrosis factor-α was positively correlated with Helicobacter, but inversely correlated with SCFA-producing bacteria. These findings indicated from a new perspective that the inhibitory effect of CEO on IBD was closely related to improving the intestinal flora imbalance.

Topics: Animals; Bacteria; Bacteroides; Cinnamomum zeylanicum; Colitis; Cytokines; Dextran Sulfate; Disease Models, Animal; Fatty Acids, Volatile; Feces; Female; Gastrointestinal Microbiome; Helicobacter; Hemoglobins; Inflammatory Bowel Diseases; Mice; Mice, Inbred C57BL; Oils, Volatile; Peroxidase; RNA, Ribosomal, 16S; Sulfates; Toll-Like Receptor 4

Excessive reactive oxygen species (ROS) production can induce tissue injury involved in a variety of neurodegenerative disorders such as neurodegeneration observed in pilocarpine-induced temporal lobe epilepsy. Ketamine, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist has beneficial effects in pilocarpine-induced temporal lobe epilepsy, when administered within minutes of seizure to avoid the harmful neurological lesions induced by pilocarpine. However, the enzymes involved in ROS productions and the effect of ketamine on this process remain less documented. Here we show that during pilocarpine-induced epilepsy in mice, the expression of the phagocyte NADPH oxidase NOX2 subunits (NOX2/gp91

Topics: Animals; Brain; Disease Models, Animal; Epilepsy, Temporal Lobe; Excitatory Amino Acid Antagonists; Ketamine; Mice; NADPH Oxidase 2; NADPH Oxidases; Peroxidase; Phagocytes; Phosphorylation; Pilocarpine; Reactive Oxygen Species

This study aimed to compare acacetin adverse effect besides a cisplatin low dose on male reproductive and urinary systems on mice. In this study, 36 male Balb/c mice were received Dimethyl sulfoxide, cisplatin (1 mg/kg) or acacetin (10, 25, 50 mg/kg) for 3 days, while the sixth group, treated with acacetin (50 mg/kg) for 10 days. All treatments were done consequence daily and intraperitoneally. Histological and biochemical factors to male reproductive and urinary systems were assayed. Only in cisplatin exposed group, significant differences were seen with the others. So that, some reproductive criteria were significantly decreased; serum levels of follicle-stimulating hormone, luteinizing hormone, testosterone, sperm parameters, the diameters of seminiferous tubules, Johnsen's score and from the urinary system; renal corpuscles' space, Mg

Topics: Acute Kidney Injury; Animals; Blood Urea Nitrogen; Cisplatin; Creatinine; Disease Models, Animal; Dose-Response Relationship, Drug; Flavones; Humans; Kidney; Male; Mice; Orchitis; Peroxidase; Testis; Tumor Necrosis Factor-alpha

Edaravone is a potent free radical scavenger that has a promising role in combating many acute lung injuries. Ischemia/reperfusion process is a serious condition that may lead to multiple organ dysfunctions. This work was designed to investigate novel mechanisms underlying ischemia/reperfusion-induced lung injury and to evaluate the protective role of edaravone. Thirty adult male rats were divided into three experimental groups; operated with no ischemia (Sham-group), ischemia/reperfusion (I/R) group and edaravone-I/R group. Hind limb ischemia was carried out by clamping the femoral artery. After two hours of ischemia for the hind limb, the rat underwent 24h of reperfusion. Rats in the edaravone-I/R group received edaravone (3mg/kg), 30min before induction of ischemia. At the end of the I/R trial, specimens from the lungs were processed for histological, immunohistochemical, enzyme assay, and RT-qPCR studies. Specimens from I/R group showed focal disruption of the alveolar architecture. Extensive mononuclear cellular infiltration particularly with neutrophils and dilated congested blood capillaries were observed. A significant increase in iNOS, NF-κB, and COX-2 immunoreaction was detected and confirmed by RT-qPCR. Ultrastructural examination showed RBCs and fluid inside alveoli, cellular infiltration, and vacuolations of the inter-alveolar septum. In addition to the presence of extravasated neutrophils and RBCs within the inter-alveolar septum. In contrast, minimal changes were observed in rats which received edaravone before the onset of the ischemia. It could be concluded that edaravone exerted a potent protective effect against lung injury induced by a hind limb I/R in rats through its antioxidant and anti-inflammatory activities.

Topics: Animals; Biochemical Phenomena; Disease Models, Animal; Edaravone; Electron Transport Complex IV; Hindlimb; Immunohistochemistry; Lung; Lung Injury; Male; Microscopy, Electron, Transmission; Neuroprotective Agents; NF-kappa B; Nitric Oxide Synthase Type II; Oxidative Stress; Peroxidase; Random Allocation; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Reperfusion Injury

Visfatin acts as a significant regulator of inflammatory cytokines. However, the immunological response and therapeutic effects of visfatin under bacterial stress in murine lung tissue are still not clear. To investigate the role of visfatin on lipopolysaccharide (LPS)-induced acute lung injury (ALI), thirty Kunming mice were divided into Saline, LPS, and LPS + visfatin groups. After routine blood examination, the effects of visfatin on inflammatory cytokines, lung tissue structure, and expression of inflammatory mediators were explored through hematoxylin-eosin (H&E), Masson and immunohistochemical staining, quantitative polymerase chain reaction (Q-PCR), and Western blotting. Compared with the Saline group, neutrophil percentage, peripheral blood neutrophil count, and the ratio of lymphocyte count (NLR) were upregulated in LPS group. Moreover, Masson staining showed alterations in lung tissue structure; the mRNA level of different cytokines (IL-6, IL-1β, TNF-α, IL-10, TLR4, IFN-γ) was upregulated; and the protein expression of interleukin (IL)-6, myeloperoxidase (MPO), and transforming growth factor-β1 (TGF-β) was significantly (p < 0.05) different in LPS group. Compared with LPS group, neutrophil percentage significantly decreased (p < 0.01), the numbers of lymphocytes significantly (p < 0.05) increased, NLR decreased, Masson staining of the lung was extremely different (p < 0.01), the structure of the lung was slightly damaged, and the myeloperoxidase values of lung showed no differences in LPS + visfatin. Hence, visfatin inhibits the lung inflammation induced by ALI. During the ALI, visfatin acts by decreasing NLR, downregulated the expression of MPO, enhanced antioxidant capacity, and regulated the inflammatory factors IL-1β, IL-6, IL-10, and TNF-α to reduce the lung injury.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Cytokines; Disease Models, Animal; Inflammation Mediators; Lipopolysaccharides; Lung; Mice; Nicotinamide Phosphoribosyltransferase; Peroxidase; Pulmonary Fibrosis; Transforming Growth Factor beta1

Topics: Animals; Anti-Ulcer Agents; Antioxidants; Brazil; Catalase; Disease Models, Animal; Gastric Mucosa; Male; Medicine, Traditional; Mice; Peroxidase; Phenylpropionates; Plant Extracts; Propolis; Protective Agents; Rats; Rats, Wistar; Stomach Ulcer; Superoxide Dismutase; Wound Healing

Myeloperoxidase-specific ANCA (MPO-ANCA) are implicated in the pathogenesis of vasculitis and GN. Kinins play a major role during acute inflammation by regulating vasodilatation and vascular permeability and by modulating adhesion and migration of leukocytes. Kinin system activation occurs in patients with ANCA vasculitis. Previous studies in animal models of GN and sclerosing kidney diseases have demonstrated protective effects of bradykinin receptor 1 (B1R) blockade. To investigate the role of B1R in a murine model of MPO-ANCA GN, we evaluated effects of B1R genetic ablation and pharmacologic blockade. We used bone marrow chimeric mice to determine the role of B1R in bone marrow-derived cells (leukocytes) versus nonbone marrow-derived cells. We elucidated mechanisms of B1R effects using. B1R deficiency or blockade prevented or markedly reduced ANCA-induced glomerular crescents, necrosis, and leukocyte influx in mice. B1R was not required for. The leukocyte B1R plays a critical role in the pathogenesis of MPO-ANCA-induced GN in a mouse model by modulating neutrophil-endothelial interaction. B1R blockade may have potential as a therapy for ANCA GN and vasculitis.

Topics: Animals; Antibodies, Antineutrophil Cytoplasmic; Bradykinin B1 Receptor Antagonists; Cell Adhesion; Disease Models, Animal; Endothelial Cells; Glomerulonephritis; Mice; Mice, Inbred C57BL; Neutrophils; Peroxidase; Receptor, Bradykinin B1

In Turkish folk medicine, leaves of Sorbus domestica are used for the treatment of burns, cough, stomachache, bradyuria, kidney stone. The fruits of this plant are used for diarrhoea.. This study was carried out to investigate the effect of S. domestica on ulcerative colitis induced by acetic acid in rats.. The crude methanolic extract of fruits was sequentially fractionated into five subextracts; dichloromethane, diethyl ether, ethyl acetate, n-butanol and aqueous extracts. Effects of the extract, subextracts and fractions were investigated in acetic acid-induced rat colitis model. The colonic interleukin-6 (IL-6), tumor necrosis factor (TNF-α), nitrite, superoxide dismutase (SOD), glutathione (GSH), lipid peroxidation (LPO), catalase (CAT), and malondialdehyde (MDA) levels as well as the caspase-3 and myeloperoxidase (MPO) activities were measured to determine the activity. Histopathological analyzes were also performed on the colon tissue of rats.. The methanolic extract and diethylether subextract have led to a noteworthy decrease in MPO, caspase-3, IL-6, TNF-α, MDA, and nitrite levels in the colon tissue and blood. In addition, histopathological analysis results were supported by biochemical parameters. After confirmation of the activity against ulcerative colitis, the diethyl ether subextract was subjected to more chromatographic separation for the isolation of compounds 1, 2 and 3. The structures of these three compounds were elucidated as vanillic acid 4-O-α-L-rhamnopyranoside (1), protocateuic acid anhydrite (2) and trivanilloyl-(1,3,4-trihydroxybenzol) ester (3).. In this study, the potential of S. domestica in the treatment of colitis was investigated. Fruits of this plant were found to have important anti-inflammatory and antioxidant activities. Through isolation techniques, vanillic acid 4-O-α-L-rhamnopyranoside, protocateuic acid anhydrite and trivanilloyl-(1,3,4-trihydroxybenzol) ester were determined as the main active components of the fruits. Consequently, S domestica might be a promising candidate for upcoming use the prevention and treatment of various disorders, such as inflammatory bowel diseases, irritable bowel syndrome and Clostridium difficile infection.

Topics: Acetic Acid; Animals; Anti-Inflammatory Agents; Antioxidants; Catalase; Colitis, Ulcerative; Colon; Disease Models, Animal; Fruit; Glutathione; Interleukin-6; Lipid Peroxidation; Male; Malondialdehyde; Nitrites; Peroxidase; Plant Extracts; Rats, Sprague-Dawley; Sorbus; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Kidney ischemia reperfusion (IR) injury is an important health problem resulting in acute kidney failure. The oxidative stress and inflammatory process are the underlying mechanisms of IR injury. It has been purposed in this study to research the possible protective effects of fraxin on kidney injury induced by IR.. 32 Sprague Dawley male rats were divided into 4 groups. The groups were organized as follows; sham, IR, IR + fraxin 10 mg/kg, and IR + 50 mg/kg fraxin groups. Some oxidant, antioxidant and inflammatory parameters were evaluated in kidney tissues removed at the end of our experimental study.. It was detected that the oxidant and proinflammatory markers increased and antioxidant parameters decreased in IR group but the results significantly reversed in treatment groups compared to IR group. And also, 8-OHdG, NF-κB, HAVCR1 immunopositivities were at severe levels and these results attenuated in IR fraxin + 10 mg/kg, and IR + fraxin 50 mg/kg groups.. These presented results have shown that fraxin performed protective effects against kidney injury induced by IR.

Topics: Acute Kidney Injury; Animals; Antioxidants; Coumarins; Disease Models, Animal; Kidney; Male; Malondialdehyde; Peroxidase; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Superoxide Dismutase

Incidents of male infertility are mushrooming worldwide. Oxidative stress plays a prime role for its onset. Considering this background, the study was designed to focus the direct role of lycopene on cyproterone acetate (CPA) induced testicular hypofunction in rat. Four groups have been considered including the vehicle-treated control, lycopene-treated control, CPA-treated and CPA+ lycopene-treated groups. Androgenic, antioxidant and toxicity profiles were assessed. Results focused a nonsignificant (p > .05) difference in recovery of testicular Δ

Topics: 17-Hydroxysteroid Dehydrogenases; 3-Hydroxysteroid Dehydrogenases; Androgens; Animals; Catalase; Cyproterone Acetate; Disease Models, Animal; Drug Evaluation, Preclinical; Free Radical Scavengers; Glutathione Transferase; Humans; Infertility, Male; Lycopene; Male; Oxidative Stress; Peroxidase; Rats; Rats, Wistar; Sperm Count; Superoxide Dismutase; Testis

A growing body of evidence has indicated that the release of nociceptive factors, such as interleukins and chemokines, by activated immune and glial cells has crucial significance for neuropathic pain generation and maintenance. Moreover, changes in the production of nociceptive immune factors are associated with low opioid efficacy in the treatment of neuropathy. Recently, it has been suggested that CC chemokine receptor type 1 (CCR1) signaling is important for nociception. Our study provides evidence that the development of hypersensitivity in rats following chronic constriction injury (CCI) of the sciatic nerve is associated with significant up-regulation of endogenous CCR1 ligands, namely, CCL2, CCL3, CCL4, CCL6, CCL7 and CCL9 in the spinal cord and CCL2, CCL6, CCL7 and CCL9 in dorsal root ganglia (DRG). We showed that single and repeated intrathecal administration of J113863 (an antagonist of CCR1) attenuated mechanical and thermal hypersensitivity. Moreover, repeated administration of a CCR1 antagonist enhanced the analgesic properties of morphine and buprenorphine after CCI. Simultaneously, repeated administration of J113863 reduced the protein levels of IBA-1 in the spinal cord and MPO and CD4 in the DRG and, as a consequence, the level of pronociceptive factors, such as interleukin-1β (IL-1β), IL-6 and IL-18. The data obtained provide evidence that CCR1 blockade reduces hypersensitivity and increases opioid-induced analgesia through the modulation of neuroimmune interactions.

Topics: Analgesics; Animals; Buprenorphine; Calcium-Binding Proteins; Chemokine CCL2; Disease Models, Animal; Drug Synergism; Ganglia, Spinal; Gene Expression Regulation; Hyperalgesia; Interleukin-18; Interleukin-1beta; Interleukin-6; Male; Microfilament Proteins; Morphine; Neuralgia; Nociception; Peroxidase; Protein Isoforms; Rats; Rats, Wistar; Receptors, CCR1; Sciatic Nerve; Signal Transduction; Xanthenes

Neuromodulation based on the vagal anti-inflammatory reflex has emerged as an exciting therapeutic approach for chronic inflammatory diseases. However, it is unclear whether direct stimulation of the vagus or of pelvic nerves coming from sacral roots, providing the bulk of colonic parasympathetic innervation, is the best approach. We hypothesized that sacral nerve stimulation (SNS) would be an effective treatment for colitis. Age and sex-matched Sprague-Dawley rats were administered 5% dextran sulphate sodium (DSS) in drinking water ad libitum for 7 days. A group of rats was sacrificed after DSS treatment, and the remaining rats were randomized to either sham-SNS or SNS groups, which were performed for 1 hr daily for 10 days. Stimulations were delivered via chronically implanted electrodes using an 8-channel universal pulse generator. Sacral nerve stimulation promoted recovery of colitis demonstrated by decreased disease activity index, myeloperoxidase activity, tissue TNF-alpha, and histological scores as well as an increased colonic M2 macrophage population. Heart rate variability analysis demonstrated a decrease in low frequency and increase in high frequency with SNS, corresponding to increased vagal tone. Additionally, plasma pancreatic peptide was increased and norepinephrine was decreased after SNS in colitis while colon tissue acetylcholine was increased with SNS. This is the first study to the best of our knowledge that demonstrates the benefit of SNS with autonomic mediation. SNS alters the expression of inflammatory cytokines and macrophages as well as modulates neurotransmitters involved in systemic inflammation.

Topics: Animals; Colitis; Colon; Dextran Sulfate; Disease Models, Animal; Electric Stimulation Therapy; Heart Rate; Lumbosacral Plexus; Macrophages; Neuroimmunomodulation; Parasympathetic Nervous System; Peroxidase; Random Allocation; Rats; Rats, Sprague-Dawley; Spinal Nerves; Tumor Necrosis Factor-alpha

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, has gradually emerged as a public health challenge worldwide. Carrageenan is a popular food additive that has been in use for decades. However, controversy exists regarding to the safety of carrageenan due to its exacerbation of colitis in experimental models. In this study, we studied the effects of vehicle and host intestinal microflora on carrageenan inflammatory properties in C57BL/6 J mice. We found that in high-fat diet model, native carrageenan in drinking water increased the disease activity index (DAI), myeloperoxidase (MPO) activity and the mRNA expression of TLR4 in colon, whereas carrageenan-supplemented diet has no visible effects. However, no signs of colitis were observed under low-fat diet regardless of the mode of vehicle used. Moreover, we discovered that carrageenan-induced colitis in high-fat diet model was robustly correlated with changes in the composition of gut microbiota, specifically Alistipes finegoldii and Bacteroides acidifaciens. Hence, we propose that the inflammatory property of carrageenan is influenced greatly by its intake form via modification of host intestinal microecology.

Topics: Animals; Carrageenan; Colitis; Colon; Diet, High-Fat; Disease Models, Animal; Drinking Water; Gastrointestinal Microbiome; Host-Pathogen Interactions; Inflammation; Intestines; Male; Mice, Inbred C57BL; Molecular Weight; Monosaccharides; Peroxidase; Principal Component Analysis; Spectroscopy, Fourier Transform Infrared; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Acute kidney injury (AKI) complicated by acute lung injury has a detrimental effect on mortality among critically ill patients. Recently, a renal ischemia-reperfusion (IR) model suggested the involvement of histones and neutrophil extracellular traps (NETs) in the development of distant lung injury after renal IR. Given that recombinant thrombomodulin (rTM) has anti-inflammatory roles by binding to circulating histones, we aimed to clarify its effect on distant lung injury induced by AKI in a murine bilateral renal IR model. Both pretreatment and delayed treatment with rTM significantly decreased pulmonary myeloperoxidase activity, but they did not affect renal dysfunction at 24 h after renal IR. Additionally, rTM mitigated the renal IR-augmented expression of proinflammatory cytokines (tumor necrosis factor-α, interleukin-6, and keratinocyte-derived chemokine), and vascular leakage, as well as the degree of lung damage. Intense histone accumulation and active NET formation occurred in both the kidneys and the lungs; however, rTM significantly decreased the histone and NET accumulation only in the lungs. Administration of rTM may have protective impact on the lungs after renal IR by blocking histone and NET accumulation in the lungs, although no protection was observed in the kidneys. Treatment with rTM may be an adjuvant strategy to attenuate distant lung injury complicating AKI.

Topics: Acute Lung Injury; Animals; Blood Urea Nitrogen; Disease Models, Animal; Histones; HMGB1 Protein; Interleukin-6; Kidney; Lung; Male; Mice; Mice, Inbred C57BL; Peroxidase; Recombinant Proteins; Reperfusion Injury; Thrombomodulin; Tumor Necrosis Factor-alpha

This study sets out to establish the comparative contribution of PD-L1 expression by pulmonary endothelial cells (ECs) and/or epithelial cells (EpiCs) to the development of indirect acute lung injury (iALI) by taking advantage of the observation that treatment with naked siRNA by intratracheal delivery in mice primarily affects lung EpiCs, but not lung ECs, while intravenous delivery of liposomal-encapsulated siRNA largely targets vascular ECs including the lung, but not pulmonary EpiCs. We showed that using a mouse model of iALI [induced by hemorrhagic shock followed by septic challenge (Hem-CLP)], PD-L1 expression on pulmonary ECs or EpiCs was significantly upregulated in the iALI mice at 24 h post-septic insult. After documenting the selective ability of intratracheal versus intravenous delivery of PD-L1 siRNA to inhibit PD-L1 expression on EpiCs versus ECs, respectively, we observed that the iALI-induced elevation of cytokine/chemokine levels (in the bronchoalveolar lavage fluid, lung lysates, or plasma), lung myeloperoxidase and caspase-3 activities could largely only be inhibited by intravenous, but not intratracheal, delivery of PD-L1 siRNA. Moreover, intravenous, but not intratracheal, delivery led to a preservation of normal tissue architecture, lessened pulmonary edema, and reduced neutrophils influx induced by iALI. In addition, in vitro mouse endothelial cell line studies showed that PD-L1 gene knockdown by siRNA or knockout by CRISPR/Cas9-mediated gene manipulation, reduced monolayer permeability, and maintained tight junction protein levels upon recombinant IFN-γ stimulation. Together, these data imply a critical role for pulmonary vascular ECs in mediating PD-1:PD-L1-driven pathological changes resulting from systemic stimuli such as Hem-CLP.

Topics: Acute Lung Injury; Animals; B7-H1 Antigen; Bronchoalveolar Lavage Fluid; Cells, Cultured; Chemokines; Cytokines; Disease Models, Animal; Endothelial Cells; Epithelial Cells; Lung; Male; Mice; Mice, Inbred C57BL; Neutrophils; Peroxidase; RNA, Small Interfering; Sepsis; Shock, Hemorrhagic

There is evidence for a disturbed intestinal barrier function in inflammatory bowel diseases [IBD] but the underlying mechanisms are unclear. Because mucins represent the major components of the mucus barrier and disturbed mucin expression is reported in the colon of IBD patients, we studied the association between mucin expression, inflammation and intestinal permeability in experimental colitis.. We quantified 4-kDa FITC-dextran intestinal permeability and the expression of cytokines, mucins, junctional and polarity proteins at dedicated time points in the adoptive T cell transfer and dextran sodium sulfate [DSS]-induced colitis models. Mucin expression was also validated in biopsies from IBD patients.. In both animal models, the course of colitis was associated with increased interleukin-1β [IL-1β] and tumour necrosis factor-α [TNF-α] expression and increased Muc1 and Muc13 expression. In the T cell transfer model, a gradually increasing Muc1 expression coincided with gradually increasing 4-kDa FITC-dextran intestinal permeability and correlated with enhanced IL-1β expression. In the DSS model, Muc13 expression coincided with rapidly increased 4-kDa FITC-dextran intestinal permeability and correlated with TNF-α and Muc1 overexpression. Moreover, a significant association was observed between Muc1, Cldn1, Ocln, Par3 and aPKCζ expression in the T cell transfer model and between Muc13, Cldn1, Jam2, Tjp2, aPkcζ, Crb3 and Scrib expression in the DSS model. Additionally, MUC1 and MUC13 expression was upregulated in inflamed mucosa of IBD patients.. Aberrantly expressed MUC1 and MUC13 might be involved in intestinal barrier dysfunction upon inflammation by affecting junctional and cell polarity proteins, indicating their potential as therapeutic targets in IBD.

Topics: Actins; Animals; CD4-Positive T-Lymphocytes; Cell Adhesion Molecules; Colitis; Colitis, Ulcerative; Crohn Disease; Cytokines; Dextran Sulfate; Dextrans; Disease Models, Animal; Female; Fluorescein-5-isothiocyanate; Humans; Interleukin-10; Interleukin-1beta; Interleukin-6; Intestinal Mucosa; Male; Mice, Inbred BALB C; Mice, SCID; Mucins; Myosin-Light-Chain Kinase; Permeability; Peroxidase; Tight Junction Proteins; Tumor Necrosis Factor-alpha

Oleic acid (OA) is reported to show anti-inflammatory activity toward activated neutrophils. It is also an important material in nanoparticles for increased stability and cellular internalization. We aimed to evaluate the anti-inflammatory activity of injectable OA-based nanoparticles for treating lung injury. Different sizes of nanocarriers were prepared to explore the effect of nanoparticulate size on inflammation inhibition.. The nanoparticles were fabricated with the mean diameters of 105, 153, and 225 nm. The nanocarriers were ingested by isolated human neutrophils during a 5-min period, with the smaller sizes exhibiting greater uptake. The size reduction led to the decrease of cell viability and the intracellular calcium level. The OA-loaded nanosystems dose-dependently suppressed the superoxide anion and elastase produced by the stimulated neutrophils. The inhibition level was comparable for the nanoparticles of different sizes. In the ex vivo biodistribution study, the pulmonary accumulation of nanoparticles increased following the increase of particle size. The nanocarriers were mainly excreted by the liver and bile clearance. Mice were exposed to intratracheal lipopolysaccharide (LPS) to induce acute respiratory distress syndrome (ARDS), like lung damage. The lipid-based nanocarriers mitigated myeloperoxidase (MPO) and cytokines more effectively as compared to OA solution. The larger nanoparticles displayed greater reduction on MPO, TNF-α, and IL-6 than the smaller ones. The histology confirmed the decreased pulmonary neutrophil recruitment and lung-architecture damage after intravenous administration of larger nanoparticles.. Nanoparticulate size, an essential property governing the anti-inflammatory effect and lung-injury therapy, had different effects on activated neutrophil inhibition and in vivo therapeutic efficacy.

Topics: Animals; Anti-Inflammatory Agents; Cytokines; Disease Models, Animal; Drug Liberation; Humans; Lipids; Lipopolysaccharides; Lung; Mice; Mice, Inbred C57BL; Nanocapsules; Neutrophil Activation; Neutrophils; Oleic Acid; Pancreatic Elastase; Particle Size; Peroxidase; Respiratory Distress Syndrome; Superoxides; Surface Properties; Tissue Distribution; Treatment Outcome

The aim of the present study was to investigate the antioxidant mechanisms of dexmedetomidine against lung injury during intestinal ischemia reperfusion (IIR) in rats. The model of IIR‑induced acute lung injury was established by occluding the superior mesenteric artery (SMA) for 1 h and reperfusing for 2 h using Sprague‑Dawley rats. Pathological examination was used to assess the extent of the lung injury. Oxidative stress was evaluated by measuring malondialdehyde, myeloperoxidase and superoxide dismutase in the lung and plasma. The proinflammatory cytokines tumor necrosis factor‑α and interleukin‑6 were determined via an enzyme‑linked immunosorbent assay. The mRNA and protein expression of nuclear factor‑erythroid 2 related factor 2 (Nrf2) and heme oxygenase 1 (HO‑1) were determined using a reverse transcription‑quantitative polymerase chain reaction and western blotting. Pretreatment with dexmedetomidine significantly inhibited the oxidative stress response and proinflammatory factor release caused by IIR compared with the normal saline group (MDA and SOD in lung and plasma, P<0.05; MPO, IL‑1β and TNF‑α in lung and plasma, P<0.05). Dexmedetomidine improved pulmonary pathological changes in IIR rats compared with the normal saline group. Investigations into the molecular mechanism revealed that dexmedetomidine increased the expression levels of Nrf2 and HO‑1 via activating α2 adrenergic receptors compared with the normal saline group. The antagonism of α2 adrenergic receptors may reverse the protective effect of dexmedetomidine on lung injury during IIR, including decreasing the expression levels of Nrf2 and HO‑1, elevating the oxidative stress response and increasing the proinflammatory factor release. In conclusion, pretreatment with dexmedetomidine demonstrated protective effects against lung injury during IIR via α2 adrenergic receptors. The Nrf2/HO‑1 signaling pathway may serve a function in the protective effect of dexmedetomidine.

Topics: Acute Lung Injury; Animals; Antioxidants; Cytokines; Dexmedetomidine; Disease Models, Animal; Heme Oxygenase-1; Lung; Male; Malondialdehyde; NF-E2 Transcription Factor; Oxidative Stress; Peroxidase; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Signal Transduction; Superoxide Dismutase

The activation of NLRP3 inflammasome and NF-κB pathway, associating with oxidativestress, have been implicated in the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). NecroX-5 has been reported to exhibit theeffectsofanti-oxidation and anti-stress in various diseases. However, the role of NecroX-5 in ALI has not been explicitly demonstrated. The aim of this study was to explore the therapeutic effects and potential mechanism action of NecroX-5 on ALI. Here, we found that NecroX-5 pretreatment dramatically diminished the levels of IL-1β, IL-18 and ROS in in RAW264.7 cells challenged with LPS and ATP. Furthermore, NecroX-5 suppressed the activation of NLRP3 inflammasome and NF-κB signalpathway. In addition, NecroX-5 also inhibited the thioredoxin-interacting protein (TXNIP) expression. In vivo, NecroX-5 reduced the LPS-induced lung histopathological injury, the number of TUNEL-positive cells, lung wet/dry (W/D) ratio, levels of total protein and inflammatory cytokines in the bronchoalveolar lavage fluid (BALF) in mice. Additionally, LPS-induced upregulation of myeloperoxidase (MPO), ROS production and malondialdehyde (MDA) were inhibited by NecroX-5 administration. Thus, our results demonstrate that NecroX-5 protects against LPS-induced ALI by inhibiting TXNIP/NLRP3 and NF-κB.

Topics: Animals; Anti-Inflammatory Agents; Carrier Proteins; Disease Models, Animal; Gene Expression Regulation; Heterocyclic Compounds, 4 or More Rings; Humans; Lipopolysaccharides; Lung; Male; Mice; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Peroxidase; RAW 264.7 Cells; Respiratory Distress Syndrome; Signal Transduction; Sulfones; Thioredoxins

This study evaluated the effects of

Topics: Animals; Bifidobacterium longum; Colitis; Colon; Cytokines; Disease Models, Animal; Eosinophil Peroxidase; Female; Immunoglobulin A, Secretory; Inflammation; Inflammatory Bowel Diseases; Interleukin-1beta; Intestinal Mucosa; Intestines; Mice; Mice, Inbred BALB C; Peroxidase; Probiotics

The proteolytic fraction (P1G10) from Vasconcellea cundinamarcensis, displays gastric protective and healing activities in different skin lesions in mice and human. In an excisional model, this fraction accelerates resolution of lesions and modulates inflammatory mediators. Based on these data, we assessed its anti-inflammatory activity in murine colitis model, induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS) adopted by its physiopathological similarity with human colitis. Twenty four hours after colitis induction followed by three days of treatment, P1G10 at 0.3 and 3.0 mg/Kg induced 30% increase in body weight (p < 0.0001) and ~80% reduction in colon macroscopic damage score (p < 0.05) compared to the untreated TNBS-induced colitis group. Histological analyses showed that 0.3 mg/Kg P1G10 reduced the inflammatory profile and tissue damage (47%, p < 0.05) when it was proteolytically active. Compared to TNBS group, 0.3 mg/Kg P1G10 reduced MPO activity (80%, p < 0.01), MCP-1 (47%, p < 0.05) and TNF-α (50%, no significant) and increased IL-10 (330%, p < 0.001) levels in the supernatant of colonic tissue homogenate. P1G10 treatment also reduced COX-2 expression (60%, p < 0.05) and metalloprotease-2 activity (39%, p < 0.05) while increased globet cell density (140%, p < 0.01), that contributes to mucus layer protection in colonic tissue. Taken together, these findings suggest that low doses of active P1G10 promotes lesion resolution, at least in part by its anti-inflammatory activity, in TNBS-colitis model.

Topics: Animals; Anti-Inflammatory Agents; Caricaceae; Colitis; Colon; Cyclooxygenase 2; Cytokines; Disease Models, Animal; Hexosaminidases; Humans; Inflammation Mediators; Latex; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Peroxidase; Proteolysis; Trinitrobenzenesulfonic Acid; Weight Loss

Ping weisan (PWS), a complex formulation used in traditional Chinese medicine, is first described in 1107 AD and published in the Prescriptions of Taiping Benevolent Dispensary. We have previously confirmed that PWS has the effect of alleviating DSS-induced chronic ulcerative colitis (UC) in mice.. We aimed to examine whether PWS protects mice from chronic UC by regulating intestinal microbiota composition.. Chronic colitis was induced in C57BL/6 mice with 2.5% DSS in drinking water. PWS (8 g/kg) was orally administered throughout the experiment. Body weight changes, stool consistency and myeloperoxidase (MPO) activity were measured in these mice. Interleukin-17A (IL-17A) and interferon gamma (IFN-γ) mRNA levels were detected by qRT-PCR. The alterations of fecal microflora were investigated by 16S rRNA sequencing. Furthermore, intestinal tight junction protein including occludin, and serum lipopolysaccharide (LPS) level were also detected.. PWS relieved DSS-induced loss of body weight, and improved stool consistency and MPO activity in mice. The levels of IL-17A and IFN-γ mRNA were also reduced after treatment with PWS. PWS not only regulated occludin level but also decreased serum LPS. We further showed DSS-induced changes in intestinal microbial composition and richness are significantly regulated by PWS. PWS treatment significantly decreased the abundance of Bacteroidetes, but increased the abundance of Firmicutes in chronic UC mice induced by DSS.. Combining with our previous results, we found that PWS could exert anti-UC role by rebalancing intestinal bacteria.

Topics: Animals; Chronic Disease; Colitis; Colon; Dextran Sulfate; Disease Models, Animal; Drugs, Chinese Herbal; Dysbiosis; Gastrointestinal Agents; Gastrointestinal Microbiome; Interferon-gamma; Interleukin-17; Lipopolysaccharides; Male; Mice, Inbred C57BL; Occludin; Peroxidase; Weight Loss

Myeloperoxidase (MPO) is a heme peroxidases protein associated with many inflammation-related diseases. Although many fluorescent probes have been constructed for the assessment of MPO activity, it still remains a challege to develop a nanoprobe for highly sensitive biosensing and high-resolution bioimaging in biological system. In this work, we developed a novel luminescent nanoprobe based on upconversion nanoparticles (UCNPs) conjugated with phycocyanin (PC), which could detect the fluctuation of MPO. By grafting PC onto the surface of UCNPs through amidation reaction, the luminescence of UCNPs is quenched by PC via energy transfer. Due to the specific recognition by PC, the nanoprobe can be used for sensitive evaluation the bioactivity of MPO. The nanoprobe based on PC-UCNPs has been successfully applied for the bioimaging of MPO in living cells and an inflammatory process by taking an acute liver injury mouse as a model.

Topics: Animals; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Female; HeLa Cells; Humans; Inflammation; Luminescence; Mice; Mice, Inbred BALB C; Nanostructures; Optical Imaging; Peroxidase; Phycocyanin; RAW 264.7 Cells

Fluoroquinolones are reported to possess immunomodulatory activity; hence, a novel benzoquinolizine fluoroquinolone, levonadifloxacin, was evaluated in lipopolysaccharide-stimulated human whole-blood (HWB) and mouse acute lung injury (ALI) models. Levonadifloxacin significantly mitigated the inflammatory responses in an HWB assay through inhibition of proinflammatory cytokines and in the ALI model by lowering lung total white blood cell count, myeloperoxidase, and cytokine levels. The immunomodulatory effect of levonadifloxacin, along with promising antibacterial activity, is expected to provide clinical benefits in the treatment of infections.

Topics: Acute Lung Injury; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Bacteria; Cytokines; Disease Models, Animal; Humans; Immunologic Factors; Immunomodulation; Inflammation; Leukocyte Count; Lipopolysaccharides; Mice; Microbial Sensitivity Tests; Peroxidase; Quinolizines; Quinolones

Topics: Animals; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Hesperidin; Humans; Inflammation; Interleukin-6; Interleukin-8; Lung; Mice; NF-kappa B; Oxidative Stress; Peroxidase; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Pulmonary Disease, Chronic Obstructive; Signal Transduction; Sirtuin 1; Smoke; Superoxide Dismutase; Transcription Factor RelA

Chemical safety evaluation is in the midst of a transition from traditional whole-animal toxicity testing to molecular pathway-based in vitro assays and in silico modeling. However, to facilitate the shift in reliance on apical effects for risk assessment to predictive surrogate metrics having characterized linkages to chemical mechanisms of action, targeted in vivo testing is necessary to establish these predictive relationships. In this study, we demonstrate a means to predict thyroid-related metamorphic success in the model amphibian Xenopus laevis using relevant biochemical measurements during early prometamorphosis. The adverse outcome pathway for thyroperoxidase inhibition leading to altered amphibian metamorphosis was used to inform a pathway-based in vivo study design that generated response-response relationships. These causal relationships were used to develop Bayesian probabilistic network models that mathematically determine conditional dependencies between biochemical nodes and support the predictive capability of the biochemical profiles. Plasma thyroxine concentrations were the most predictive of metamorphic success with improved predictivity when thyroid gland sodium-iodide symporter gene expression levels (a compensatory response) were used in conjunction with plasma thyroxine as an additional regressor. Although thyroid-mediated amphibian metamorphosis has been studied for decades, this is the first time a predictive relationship has been characterized between plasma thyroxine and metamorphic success. Linking these types of biochemical surrogate metrics to apical outcomes is vital to facilitate the transition to the new paradigm of chemical safety assessments.

Topics: Animals; Antithyroid Agents; Disease Models, Animal; Enzyme Inhibitors; Gene Expression Regulation, Developmental; Larva; Metamorphosis, Biological; Peroxidase; Thyroid Gland; Thyroxine; Xenopus laevis

Saccular aneurysms are thought to have a worse prognosis than fusiform aneurysms in humans, due to hemodynamic reasons. However, data comparing hemodynamic and biology in saccular and fusiform aneurysms are lacking. The main objective was to evaluate the impact of aneurysm morphology on intra-luminal thrombus (ILT) formation and activity.. Forty Lewis rats were ran-domly divided into 2 groups of 20: "saccular" (Group A) and "fusiform" (Group B) aneurysms. Decellularized thoracic aortas from guinea pigs were xenografted to create saccular or fusiform aneurysms. Final imaging evaluation of the aneurysms was carried out during the third week, by quantitative Doppler ultrasound and magnetic resonance imaging. Assays of myeloperoxidase (MPO), platelet factor 4 (PF4), advanced oxidation protein products (AOPPs) iron and matrix metallopeptidase-9 (MMP-9) were performed as biological criteria.. Quantitatively, saccular aneurysms are characterized by a more thicker ILT, lower inflow velocities and more important relative backflow velocities as compared to fusiform aneurysms. Compared to fusiform, saccular aneurysms released significantly more MPO (p = 0.004), PF4 (p = 0.02), AOPPs (p < 0.002), iron (p < 0.0001) and MMP-9 (p < 0.04).. Experimental saccular and fusiform aneurysms show differential specific hemodynamics, which seem to impact the histology and the biology of the ILT in each type of aneurysm.

Topics: Advanced Oxidation Protein Products; Animals; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Disease Models, Animal; Guinea Pigs; Hemodynamics; Iron; Male; Matrix Metalloproteinase 9; Peroxidase; Platelet Factor 4; Rats, Inbred Lew; Thrombosis; Time Factors

A novel pharmacological mechanism of valproate was analyzed using a hamster model of adhesion.. Valproate or placebo was administered just after cecal injury and adhesion severity scores and histological were analyzed.. The adhesion severity scores in the placebo- and valproate-treated groups were 2.67 ± 0.42 and 1.0 ± 0.37, respectively, with a significant difference between the groups. A significant increase in mast cell numbers was observed in the placebo-treated group vs. the sham-operated group; however, the mast cell number in the adhesive lesion was significantly lower in the valproate-treated group than in the placebo-treated group. The number of cells positive for chymase, an enzyme in mast cells, in the adhesive lesion was significantly higher in the placebo-treated group, but its increase was attenuated significantly by treatment with valproate. The myeloperoxidase gene expression level in the cecum was significantly higher in the placebo-treated group than in the sham-operated group, but there was no significant difference in the myeloperoxidase gene expression level between the sham-operated and valproate-treated groups in. In an in vitro experiment, valproate inhibited purified human and hamster chymases dose-dependently.. The chymase inhibitory effect of valproate may contribute to prevent adhesion formation after abdominal injury.

Topics: Animals; Cecum; Cell Count; Cells, Cultured; Chymases; Cricetinae; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Expression; Humans; Male; Mast Cells; Peritoneal Diseases; Peroxidase; Severity of Illness Index; Tissue Adhesions; Valproic Acid

Induction of colitis was performed by intrarectally injection of dinitrobenzene sulfonic acid (DNBS). Cashew nuts were administered daily orally (100 mg/kg) in DNBS-injected mice.. Four days after DNBS, histological and macroscopic colon alterations as well as marked clinical signs and increased cytokine production were observed. Neutrophil infiltration, measured by myeloperoxidase (MPO) positive immunostaining, was correlated with up-regulation of adhesion molecules ICAM-1 and P-selectin in colons. Oxidative stress was detected with increased malondialdehyde (MDA) levels, nitrotyrosine, and poly ADP-ribose polymerase (PARP) positive staining in inflamed colons. Oral treatment with cashew nuts reduced histological, macroscopic damage, neutrophil infiltration, pro-inflammatory cytokines and MDA levels, as well as nitrotyrosine, PARP and ICAM-1, and P-selectin expressions. Colon inflammation could be related to nuclear factor (NF)-kB pathway activation and reduced manganese superoxide dismutase (MnSOD) antioxidant activity. Cashew nuts administration inhibited NF-kB and increased MnSOD antioxidant expressions.. The results suggested that oral assumption of cashew nuts may be beneficial for the management of colitis.

Topics: Anacardium; Animals; Anti-Inflammatory Agents; Antioxidants; Biomarkers; Colitis; Cytokines; Disease Models, Animal; Intestinal Mucosa; Lipid Metabolism; Male; Malondialdehyde; Mice; Neutrophils; Nitric Oxide Synthase Type II; Nuts; Oxidative Stress; Peroxidase; Rats

Food allergy is triggered when there is an abnormal activation of the immune system by food allergens. Currently, there is no curative therapy for this pathological condition. Due to the immunomodulatory properties of probiotics they are potential candidates as therapeutic tools for food allergy. Therefore, the aim of this study was to evaluate the probiotic effect of

Topics: Administration, Oral; Animals; Disease Models, Animal; Female; Food Hypersensitivity; Immunoglobulin E; Immunologic Factors; Inflammation; Interleukin-17; Mice; Mice, Inbred BALB C; Microbial Viability; Peroxidase; Probiotics; Saccharomyces cerevisiae

IL-17A combined with TNF-α plays a vital role in inflammatory response and interference of the synergistic effect is an effective strategy for treating inflammatory diseases. Ellipticine, a natural alkaloid, has biological activities on anti-tumor and anti-HIV. However, it is still unknown whether ellipticine can inhibit IL-17A and TNF-α-mediated signaling and has treatment effect on PALI. Here, we reported that ellipticine significantly inhibited the production of pro-inflammatory cytokines and chemokines in pulmonary epithelial cell BEAS-2B treated with IL-17A and TNF-α, but not IL-17A or TNF-α alone. Meanwhile, ellipticine attenuated NF-κB and MAPKs activation in response to IL-17A and TNF-α treatment, inhibited Act1 and TRAF6-mediated NF-κB activation, and blocked the interaction of Act1 with TRAF6. Furthermore, we found that ellipticine significantly alleviated CAE and LPS-induced SAP/PALI. Ellipticine treatment dramatically reduced inflammatory cells infiltration, MPO activity, serum amylase and lipase activity and the protein concentration of BALF. Collectively, our findings indicate that ellipticine inhibits the synergistic effect of IL-17A and TNF-α by targeting on Act1 and TRAF6 interaction and is a potential therapeutic agent for the treatment of SAP/PALI.

Topics: Acute Lung Injury; Adaptor Proteins, Signal Transducing; Amylases; Animals; Anti-Inflammatory Agents; Cell Line, Transformed; Ceruletide; Disease Models, Animal; Ellipticines; Epithelial Cells; Gene Expression Regulation; HEK293 Cells; Humans; Interleukin-17; Lipase; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; NF-kappa B; Pancreatitis; Peroxidase; Signal Transduction; TNF Receptor-Associated Factor 6; Tumor Necrosis Factor-alpha

Sepsis is a life-threatening organ dysfunction resulting from inflammatory responses instigated by toxins secreted by bacteria. Immunomodulatory effect of clindamycin is earlier reported in a murine lipopolysaccharide (LPS)-induced sepsis model. There are no studies demonstrating the immunomodulatory effect of clindamycin in combination with ceftriaxone in a clinically relevant murine polymicrobial sepsis model induced by cecal ligation and puncture (CLP). Ceftriaxone is combined to control the bacterial growth. Following 3 h of CLP challenge, Swiss albino mice were administered vehicle, ceftriaxone alone (100 mg/kg, subcutaneously), and in combination with clindamycin at immunomodulatory dose (200 mg/kg, intraperitoneally). Survival was assessed for 5 days, and bacterial count and biochemical and physiological parameters were measured after 18 h of CLP challenge. Ceftriaxone alone caused significant reduction in bacterial count in blood, peritoneal fluid, lung, liver, and kidney homogenate which was not further substantially reduced by ceftriaxone and clindamycin combination. Day 5 survival was greatly improved by combination compared with ceftriaxone alone which was also evident through marked drop in blood glucose, total white blood cell (WBC) count, and body temperature. The combination group significantly mitigated the cytokine (tumor necrosis factor (TNF)-α and interleukin (IL)-6) and myeloperoxidase (MPO) levels in plasma, lung, liver, and kidney of CLP-challenged mice, which further helped in significantly suppressing the elevated levels of liver and kidney function parameters. Clindamycin at immunomodulatory dose in combination with ceftriaxone attenuated organ damage and improved survival of septic mice by suppressing infection, inflammatory responses, and oxidative stress.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Antioxidants; Bacterial Load; Ceftriaxone; Clindamycin; Disease Models, Animal; Drug Therapy, Combination; Female; Inflammation Mediators; Interleukin-6; Mice; Oxidative Stress; Peroxidase; Sepsis; Tumor Necrosis Factor-alpha

Nootkatone (NTK) is a sesquiterpenoid found in essential oils of many species of

Topics: Acute-Phase Reaction; Animals; Anti-Inflammatory Agents; Capillary Permeability; Carrageenan; Cotton Fiber; Cyclooxygenase 2; Disease Models, Animal; Edema; Female; Granuloma; Histamine; Inflammation; Interleukin-1beta; Leukocytes; Male; Mice; Molecular Docking Simulation; Peritonitis; Peroxidase; Pleurisy; Polycyclic Sesquiterpenes; Receptors, Histamine; Tumor Necrosis Factor-alpha

While thioridazine (Tio) inhibits the antioxidant defenses of Trypanosoma cruzi, the gold standard antitrypanosomal drug benznidazole (Bz) has potent anti-inflammatory and pro-oxidant properties. The combination of these drugs has never been tested to determine the effect on T. cruzi infection. Thus, we compared the impact of Tio and Bz, administered alone and in combination, on the development of skeletal myositis and liver inflammation in T. cruzi-infected mice. Swiss mice were randomized into six groups: uninfected untreated, infected untreated, treated with Tio (80 mg/kg) alone, Bz (50 or 100 mg/kg) alone, or a combination of Tio and Bz. Infected animals were inoculated with a virulent T. cruzi strain (Y) and treated by gavage for 20 days. Mice untreated or treated with Tio alone developed the most intense parasitemia, highest parasitic load, elevated IL-10, IL-17, IFN-γ, and TNF-α plasma levels, increased N-acetylglucosaminidase and myeloperoxidase activity in the liver and skeletal muscle, as well as severe myositis and liver inflammation (P < 0.05). All parameters were markedly attenuated in animals receiving Bz alone (P < 0.05). However, the co-administration of Tio impaired the response to Bz chemotherapy, causing a decrease in parasitological control (parasitemia and parasite load), skeletal muscle and liver inflammation, and increased microstructural damage, when compared to the group receiving Bz alone (P < 0.05). Altogether, our findings indicated that Tio aggravates systemic inflammation, skeletal myositis and hepatic inflammatory damage in T. cruzi-infected mice. By antagonizing the antiparasitic potential of Bz, Tio limits the anti-inflammatory, myoprotectant and hepatoprotective effects of the reference chemotherapy, aggravating the pathological remodeling of both organs. As the interaction of T. cruzi infection, Bz and Tio is potentially toxic to the liver, inducing inflammation and microvesicular steatosis; this drug combination represents a worrying pharmacological risk factor in Chagas disease.

Topics: Acetylglucosaminidase; Animals; Chagas Disease; Cytokines; Disease Models, Animal; Drug Combinations; Female; Glycogen; Hepatitis; Mice; Muscle, Skeletal; Myositis; NADH, NADPH Oxidoreductases; Nitroimidazoles; Parasite Load; Parasitemia; Peroxidase; Thioridazine; Transaminases; Trypanocidal Agents; Trypanosoma cruzi

Neutrophil gelatinase-associated lipocalin (NGAL) is a diagnostic marker of intrinsic kidney injury produced by damaged renal cells and by neutrophils. ANCA-associated vasculitis features necrotizing crescentic GN (NCGN), and ANCA-activated neutrophils contribute to NCGN. Whether NGAL plays a mechanistic role in ANCA-associated vasculitis is unknown.. Our findings support that bone marrow-derived, presumably neutrophil, NGAL protects from ANCA-induced NCGN by downregulating T

Topics: Adult; Aged; Aged, 80 and over; Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; CD28 Antigens; CD3 Complex; CD4-Positive T-Lymphocytes; Cell Proliferation; Chimera; Disease Models, Animal; Female; Glomerulonephritis; Humans; Immunity, Cellular; Interleukin-17; Kidney; Lipocalin-2; Male; Mice; Middle Aged; Neutrophils; Peroxidase; Siderophores; Spleen; Th17 Cells

Premature birth is a major problem that results in an increased risk of mortality and morbidity. The management of such infants consists of supraphysiological oxygen therapy, which affects brain development due, in part, to the deterioration caused by reactive oxygen species (ROS). We showed previously that exogenously administered uridine provides neuroprotection in a neonatal rat model of hyperoxic brain injury. Hence, the aim of the present study was to investigate the effects of uridine on ROS in the same setting.. Hyperoxic brain injury was induced by subjecting a total of 53 six-day-old rat pups to 80% oxygen (the hyperoxia group) for a period of 48 h. The pups in the normoxia group continued breathing room air (21% oxygen). Normoxia + saline or hyperoxia + saline or hyperoxia + uridine 100 mg/kg or hyperoxia + uridine 300 mg/kg or hyperoxia + uridine 500 mg/kg was injected intraperitoneally (i. p.) 15 min prior to the hyperoxia procedure. The pups were decapitated and the brains were homogenized to analyze superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), myeloperoxidase (MPO), and malondialdehyde (MDA) enzymes as well as DJ-1 (protein deglycase DJ-1) — an oxidative stress-sensitive protein.. Hyperoxia-induced may cause overproduction of oxygen radicals and the oxidant/antioxidant balance may be disturbed in the brain. Brain MPO and MDA levels were significantly increased in saline-receiving pups exposed to hyperoxia. Brain SOD and GSH-Px levels were significantly decreased in saline-receiving pups exposed to hyperoxia. Our results showed that uridine administration prevented the hyperoxia-induced decrease in SOD and GSH-Px while counteracting the hyperoxia-induced increase in MPO and MDA in a dose-dependent manner. Uridine also increased the DJ-1 levels in brains of rat pups subjected to hyperoxia.. These data suggest that uridine exhibits antioxidative properties which may mediate the protective effects of uridine in a neonatal rat model of hyperoxic brain injury.

Topics: Animals; Animals, Newborn; Antioxidants; Brain Injuries; Disease Models, Animal; Glutathione Peroxidase; Hyperoxia; Malondialdehyde; Neuroprotective Agents; Peroxidase; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Superoxide Dismutase; Uridine

Inflammatory Bowel Disease (IBD) is an autoimmune ailment of the gastrointestinal (GI) tract, which is characterized by enhanced activation of proinflammatory cytokines. It is suggested that the sigma-1 receptor (σ1R) confers anti-inflammatory effects. As the exact pathogenesis of IBD is still unknown and treatment options are limited, we aimed to investigate the effects of σ1R in 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced experimental colitis. To this end, male Wistar-Harlan rats were used to model colitic inflammation through the administration of TNBS. To investigate the effects of σ1R, Fluvoxamine (FLV, σ1R agonist) and BD1063 (σ1R antagonist) were applied via intracolonic administration to the animals once a day for three days. Our radioligand binding studies indicated the existence of σ1Rs as [

Topics: Animals; Colitis; Cytokines; Disease Models, Animal; Disease Susceptibility; Fluvoxamine; Gene Expression Regulation; Heme Oxygenase (Decyclizing); Inflammation Mediators; Interleukin-6; Ligands; NF-kappa B; Nitric Oxide Synthase Type II; Peroxidase; Protein Binding; Rats; Receptors, sigma; Severity of Illness Index; Sigma-1 Receptor; Signal Transduction; Trinitrobenzenesulfonic Acid; Ubiquitin Thiolesterase

Many injuries cause pain and inflammation, which are one of the major challenges for physicians. In this study, the analgesic and the anti-inflammatory effects of milnacipran were investigated on carrageenan-induced nociception and inflammation in male rats.. Pain and inflammation were induced by injection of λ-carrageenan (1% v/v) into the hind paw. Indomethacin (10 mg/kg: ip) or milnacipran (10, 20 and 40 mg/kg: ip) were administered 30 min before carrageenan. Analgesia and inflammation were measured by hot plate and plethysmometer. Finally, lipid peroxidation, tumor necrosis factor alpha (TNF-α), Interleukin 1 beta (IL-1β), Interleukin 6 (IL-6), myeloperoxidase (MPO) activity, nitric oxide (NO) and total antioxidant capacity (TAC) status evaluated in the hind paw tissue.. The results showed that carrageenan caused hyperalgesia and inflammation in the hind paw tissue. Milnacipran (20 and 40 mg/kg) significantly and dose-dependently attenuated (65 ± 3.2%; p ≤0.01 and 42 ± 6.2%; p ≤ 0.001, respectively) carrageenan-induced inflammation and significantly increased (p ≤ 0.001) nociception threshold. Also, milnacipran (20 and 40 mg/kg) significantly suppressed levels of malondialdehyde (MDA), NO (p ≤ 0.05), MPO activity, TNF-α, IL-1β and IL-6 (p ≤ 0.001) following carrageenan injection. Additionally, milnacipran (10, 20 and 40 mg/kg) significantly augmented (p ≤ 0.05) TAC status following carrageenan in the hind paw tissue.. In the present study, milnacipran showed anti-nociceptive and anti-inflammatory effects on carrageenan-induced hyperalgesia and inflammation in a dose-dependent manner. Milnacipran reduced inflammatory edema and increased the paw withdrawal threshold probably through suppression of MDA, NO, TNF-α, IL-1β, IL-6 and MPO activity, and increase of TAC status in the hind paw tissue. Therefore, milnacipran holds important potential as an anti-inflammatory and anti-nociceptive drug. Although, further clinical trials to confirm this issue, is required.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Carrageenan; Cytokines; Disease Models, Animal; Edema; Hyperalgesia; Indomethacin; Inflammation; Interleukin-1beta; Interleukin-6; Male; Malondialdehyde; Milnacipran; Nitric Oxide; Nitrosative Stress; Oxidative Stress; Pain; Peroxidase; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

Acute respiratory distress syndrome (ARDS) is a critical clinical syndrome with high mortality rate, and few effective therapies have been found in the past 50 years, indicating that the pathogenesis of ARDS remains unclear. Exosomes, a novel cross-communication mechanism, are involved in critical diseases. However, the role of circulating exosomes in the development of ARDS remains poorly understood.. In the present study, naive mice were treated with circulating exosomes from lipopolysaccharide (LPS)-induced ARDS mice or exosome-depleted serum. Histological lung damage, bronchoalveolar lavage fluid (BALF), and endoplasmic reticulum (ER) stress were measured.. Increased tumor necrosis factor (TNF)-α, interleukin (IL)-6, total cell counts, polymorphonuclear (PMN) leukocyte proportions and myeloperoxidase (MPO) activity in BALF, and increased wet/dry weight ratios and protein concentrations in BALF were found in mice after exosome injection but not in mice treated with exosome-depleted serum. Furthermore, western blot analysis showed that circulating exosomes from ARDS mice upregulated glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) expression and downregulated β-Catenin and VE-cadherin expression in lung tissues.. Collectively, these data demonstrate that circulating exosomes from LPS-induced ARDS mice trigger ER stress in lung tissue, facilitating the development of ARDS, at least partly by promoting endothelial dysfunction.

Topics: Animals; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Exosomes; Interleukin-6; Lipopolysaccharides; Lung; Male; Mice; Mice, Inbred C57BL; Neutrophils; Peroxidase; Respiratory Distress Syndrome; Tumor Necrosis Factor-alpha

Silver nanoparticles have been used in a range of applications and although they are already employed in medicine, there are new, promising possibilities for their utilization. We investigated the potential of silver nanoparticles obtained with the use of blackcurrant extract in vitro in the LPS-stimulated RAW264.7 macrophages and in vivo in the murine DSS-induced colitis model. The examined formulations contained particles of 95 nm (Ag95) and 213 nm (Ag213) diameter. In vitro, both formulations inhibited nitric oxide (NO) release. In vivo, the preparations alleviated colitis as evidenced by a decreased macroscopic score and myeloperoxidase activity (indicative of neutrophil infiltration). In both cases, the nanoparticles of larger diameter showed better anti-inflammatory properties. Although further tests are required, our results indicate a plausible new use of silver nanoparticles in inflammatory bowel diseases.

Topics: Animals; Cell Survival; Colitis; Disease Models, Animal; Lipopolysaccharides; Male; Metal Nanoparticles; Mice; Mice, Inbred BALB C; Particle Size; Peroxidase; Plant Extracts; RAW 264.7 Cells; Ribes; Silver; Technology, Pharmaceutical

To investigate the effects of bradykinin on reperfusion injury in an experimental intestinal ischemia reperfusion model.. We used 32 Wistar-Albino rats. We composed 4 groups each containing 8 rats. Rats in sham group were sacrified at 100 minutes observation after laparotomy. Thirty minutes reperfusion was performed following 50 minutes ischaemia in control group after observing 20 minutes. Ischaemic preconditioning was performed in one group of the study. We performed the other study group pharmacologic preconditioning by infusional administration of 10 μg/kg/minute bradykinin intravenously. We sacrified all of the rats by taking blood samples to evaluate the lactate and lactate dehydrogenase (LDH) after resection of jejunum for detecting tissue myeloperoxidase (MPO) activity.. Lactate and LDH levels were significantly higher in control and study groups than the sham group (P<0.001). There is no difference between the study groups statistically. (P>0.05). The results were the same for MPO levels. Although definitive cell damage was determinated in the control group by hystopatological evaluation, the damage in the study groups observed was lower in different levels. However, there was no significant difference between the study groups statistically (P>0.05).. Either ischeamic preconditioning or pharmacologic preconditioning made by bradykinin reduced the ischemia reperfusion injury at jejunum.

Topics: Animals; Bradykinin; Disease Models, Animal; Female; Intestine, Small; Ischemic Preconditioning; Laparotomy; Peroxidase; Random Allocation; Rats, Wistar; Reference Values; Reperfusion Injury; Reproducibility of Results; Time Factors; Treatment Outcome; Vasodilator Agents

Sepsis-induced lung injury was the most common cause of death in patients. Topiroxostat, a novel xanthine oxidoreductase inhibitors, possessed obvious organ protectives effects. Xanthine oxidase played a vital role in acute lung injury. The study aimed to investigate the roles of Topiroxostat in sepsis-induced lung injury. The sepsis rats were established using cecum ligation and perforation. The lung damage induced by sepsis was evaluated by Hematoxylin and Eosin staining and lung tissue wet to dry ratio. The oxidative stress was detected by measurement of reactive oxygen species, malondialdehyde, myeloperoxidase and superoxide dismutase (SOD). The pro-inflammatory mediators, tumor necrosis factor-α, interleukin (IL)-1β, IL-6 and monocyte chemotactic protein 1, were measured by Enzyme-Linked Immunosorbent Assay. The cell apoptosis in lung was detected by TUNNEL staining and western blot analysis of apoptosis-related proteins including pro-apoptosis proteins, Bax, cleaved caspase9, cleaved caspase3 and anti-apoptosis protein Bcl2. The results showed that Topiroxostat significantly reduced lung damage, along with decreased oxidative stress, inflammation response and apoptosis in sepsis rats. Topiroxostat exerted markedly protective effects in sepsis-induced lung injury and could be an antioxidant in treating sepsis-induced lung injury.

Topics: Animals; Antioxidants; Apoptosis; Disease Models, Animal; Gene Expression Regulation; Humans; Inflammation; Interleukin-1beta; Lung Injury; Nitriles; Oxidative Stress; Peroxidase; Pyridines; Rats; Sepsis; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Antiinflammatory properties of pulsed magnetic field (PMF) treatments or administration of antiLy6G antibody have been previously reported. In this study, we hypothesized that, the combination of PMF treatments and antiLy6G administration may synergistically potentiate their antiinflammatory actions. The effects of the combination of PMF treatments and antiLy6G administration were investigated by examining the inflammatory signs, histopathological properties of the inflamed site, and measuring the macrophage inflammatory protein-1 alpha (MIP-1α/CCL3) and myeloperoxidase (MPO) levels of inflamed paw tissues in rats with carrageenan-induced acute paw inflammation. In this present study, PMF treatments alone or administration of antiLy6G alone ameliorated the acute inflammation. However, their combination exacerbated the inflammatory signs, hyperalgesia, allodynia, edema and fever, and aggravated the inflammatory conditions by excessive infiltration of inflammatory cells to the inflamed site. These opposing effects of the combined treatments may correlate with enhanced levels of MIP-1α and MPO in inflamed paws. Present results indicated that the combination of the PMF treatments and antiLy6G administration may not provide additional benefits and may actually cause an aggravation of the acute inflammatory process. Findings may also suggest that during neutrophil or immune cell-targeted treatments for inflammatory states, magnetic field exposure may cause unexpected negative consequences.

Topics: Animals; Anti-Inflammatory Agents; Antibodies, Monoclonal; Antigens, Ly; Carrageenan; Chemokine CCL3; Disease Models, Animal; Edema; Fever; Hyperalgesia; Inflammation; Magnetic Field Therapy; Male; Peroxidase; Rats, Wistar

Atheroprotective functions of high-density lipoproteins (HDL) are related to the activity of HDL-associated enzymes such as paraoxonase 1 (PON1). We examined the impact of inhibition of myeloperoxidase (MPO)-mediated HDL oxidation by PON1 on HDL malondialdehyde (MDA) content and HDL function. In the presence of PON1, crosslinking of apoAI in response to MPO-mediated oxidation of HDL was abolished, and MDA-HDL adduct levels were decreased. PON1 prevented the impaired cholesterol efflux capacity of MPO-oxidized HDL from

Topics: Animals; Anti-Inflammatory Agents; Apolipoprotein A-I; Aryldialkylphosphatase; ATP Binding Cassette Transporter 1; Benzylamines; Disease Models, Animal; Free Radical Scavengers; Humans; Hypercholesterolemia; Hyperlipoproteinemia Type II; Lipoproteins, HDL; Macrophages; Malondialdehyde; Mice; Mice, Inbred C57BL; Oxidation-Reduction; Peroxidase; Pyridoxine

Nerolidol (NED) is a naturally occurring sesquiterpene alcohol present in various plants with potent anti-inflammatory effects. In the current study, we investigated NED as a putative anti-inflammatory compound in an experimental model of colonic inflammation. C57BL/6J male black mice (C57BL/6J) were administered 3% dextran sodium sulfate (DSS) in drinking water for 7 days to induce colitis. Six groups received either vehicle alone or DSS alone or DSS with oral NED (50, 100, and 150 mg/kg body weight/day by oral gavage) or DSS with sulfasalazine. Disease activity index (DAI), colonic histology, and biochemical parameters were measured. TNF-α-treated HT-29 cells were used as in vitro model of colonic inflammation to study NED (25 µM and 50 µM). NED significantly decreased the DAI and reduced the inflammation-associated changes in colon length as well as macroscopic and microscopic architecture of the colon. Changes in tissue Myeloperoxidase (MPO) concentrations, neutrophil and macrophage mRNA expression (CXCL2 and CCL2), and proinflammatory cytokine content (IL-1β, IL-6, and TNF-α) both at the protein and mRNA level were significantly reduced by NED. The increase in content of the proinflammatory enzymes, COX-2 and iNOS induced by DSS were also significantly inhibited by NED along with tissue nitrate levels. NED promoted Nrf2 nuclear translocation dose dependently. NED significantly increased antioxidant enzymes activity (Superoxide dismutase (SOD) and Catalase (CAT)), Hemeoxygenase-1 (HO-1), and SOD3 mRNA levels. NED treatment in TNF-α-challenged HT-29 cells significantly decreased proinflammatory chemokines (CXCL1, IL-8, CCL2) and COX-2 mRNA levels. NED supplementation attenuates colon inflammation through its potent antioxidant and anti-inflammatory activity both in in vivo and in vitro models of colonic inflammation.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Antioxidants; Colon; Cytokines; Disease Models, Animal; HT29 Cells; Humans; Inflammation Mediators; Inflammatory Bowel Diseases; Macrophages; Male; Mice, Inbred C57BL; Neutrophils; NF-E2-Related Factor 2; Peroxidase; Phytochemicals; Phytotherapy; Sesquiterpenes

Abnormal glycerophospholipid (GPL) metabolism represented by phosphatidylcholine (PC) and phosphatidylethanolamine (PE) has been as a universal metabolic hallmark of cancer, which is involved in tumor progression. Our previous finding showed that peroxidase from foxtail millet bran (FMBP) exhibited significant anticolorectal cancer (CRC) activity in vitro and in nude mice. Presently, the potential of FMBP in clinical application was further evaluated by an azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colitis-associated carcinogenesis (CAC) mice model, revealed the pivotal role of GPL metabolism in anti-CRC effects of FMBP. Excitedly, FMBP significantly reduced the number and volume of CAC polyps of mice and effectively improved physiological indexes of CAC mice. Meanwhile, the elevated expressions of CRC early markers (cyclooxygenase 2, tumor-proliferating nuclear antigen Ki-67, and EGF module-containing mucin-like receptor 1) in CAC mice were efficiently prevented by FMBP treatment. Metabolomics analysis showed that the elevated abundances of PC and PE involved in GPL metabolism in CAC mice were markedly decreased in FMBP-treated groups, which was also verified in human CRC cells. Further, FMBP reduced the expression levels of PE and PC key metabolic enzymes, resulting in the blockage of GPL metabolism and insufficient adenosine triphosphate to maintain CRC growth. Collectively, FMBP has the potential as a preventive and therapeutic candidate for CRC through the blockage of GPL metabolism.

Topics: Animals; Benzofurans; Carcinogenesis; Cell Line, Tumor; Colitis; Colorectal Neoplasms; Dextran Sulfate; Disease Models, Animal; Glycerophospholipids; Humans; Male; Mice; Mice, Nude; Peroxidase; Plant Proteins; Quinolines; Setaria Plant

The digestive enzyme chymotrypsin protects the pancreas against pancreatitis by reducing harmful trypsin activity. Genetic deficiency in chymotrypsin increases pancreatitis risk in humans and pancreatitis severity in mice. Pancreatic chymotrypsin is produced in multiple isoforms including chymotrypsin B1, B2, C and chymotrypsin-like protease (CTRL). Here we investigated the role of CTRL in cerulein-induced pancreatitis in mice. Biochemical experiments with recombinant mouse enzymes demonstrated that CTRL cleaved trypsinogens and suppressed trypsin activation. We generated a novel CTRL-deficient strain (Ctrl-KO) using CRISPR-Cas9 genome engineering. Homozygous Ctrl-KO mice expressed no detectable CTRL protein in the pancreas. Remarkably, the total chymotrypsinogen content in Ctrl-KO mice was barely reduced indicating that CTRL is a low-abundance isoform. When given cerulein, Ctrl-KO mice exhibited lower intrapancreatic chymotrypsin activation and a trend for higher trypsin activation, compared with C57BL/6N mice. Despite the altered protease activation, severity of cerulein-induced acute pancreatitis was similar in Ctrl-KO and C57BL/6N mice. We conclude that CTRL is a minor chymotrypsin isoform that plays no significant role in cerulein-induced pancreatitis in mice.

Topics: Acute Disease; Animals; Biopsy; Cell Line; Chymotrypsin; Disease Models, Animal; Enzyme Activation; Gene Expression; Humans; Immunohistochemistry; Mice; Mice, Knockout; Pancreas; Pancreatitis; Peroxidase; Serine Endopeptidases; Severity of Illness Index; Trypsin

Topics: Animals; Disease Models, Animal; Hypoxia-Inducible Factor 1, alpha Subunit; Intercellular Adhesion Molecule-1; Lactic Acid; Lung; Lung Injury; Male; Peroxidase; Pneumonia; Pyruvic Acid; Rats, Sprague-Dawley; Respiratory Distress Syndrome

Blunt chest trauma with hemorrhagic shock frequently induces pulmonary inflammation that leads to acute lung injury (ALI). The present study aimed to explore the protective effects of dexmedetomidine (Dex) in blunt chest trauma and hemorrhagic shock‑resuscitation (THSR)‑induced ALI by mediating nucleotide binding and oligomerization domain‑like receptor family pyrin domain‑containing protein 3 (NLRP3) inflammasome formation in rats. An ALI model in rats induced by THSR was constructed and Dex was administered intraperitoneally (5 µg/kg/h) immediately after blunt chest trauma. Blood samples were collected for the determination of proinflammatory factor levels, and lung tissue specimens were harvested for wet/dry (W/D) weight ratio, hematoxylin and eosin staining, and transmission electron microscopy analyses. Additionally, malondialdehyde (MDA), superoxide dismutase (SOD), lactate dehydrogenase (LDH) and myeloperoxidase (MPO) activity were evaluated, and the expression of protein in lung tissues was examined via western blot analysis. Compared with the sham group, pathological alterations in the ALI group and the W/D ratios were significantly increased. MDA, LDH and MPO activity, and the levels of interleukin (IL)‑1β, IL‑18, IL‑6 and tumor necrosis factor‑α were significantly elevated. NLRP3, apoptosis‑associated speck‑like protein containing a caspase recruitment domain and caspase‑1 expression was significantly increased. Conversely, Dex treatment significantly reversed these changes. The present study demonstrated that by reducing inflammatory responses, Dex exerted protective effects against THSR‑ALI in rats, potentially via the inhibition of NLRP3 signaling pathways.

Topics: Acute Lung Injury; Animals; Cytokines; Dexmedetomidine; Disease Models, Animal; Gene Expression Regulation; Injections, Intraperitoneal; L-Lactate Dehydrogenase; Male; Malondialdehyde; NLR Family, Pyrin Domain-Containing 3 Protein; Peroxidase; Rats; Resuscitation; Shock, Hemorrhagic; Signal Transduction; Superoxide Dismutase; Thoracic Injuries; Wounds, Nonpenetrating

Mastitis, inflammation in the breast, affects breastfeedingwomenin the postpartumperiod. In the present study, we investigated the protective effects of piperine against mastitis using a mouse mastitis model. LPS-induced mastitis was established by injecting LPS into the canals of the mammary gland. Piperine was given intraperitoneally 1 h before and 12 h after LPS treatment. The results showed that the LPS-induced mammary histopathological changes and MPO activity were attenuated by piperine. LPS-induced inflammatory cytokines TNF-α andIL-1β were also inhibited by piperine. Furthermore, LPS-induced NF-κB activation was suppressed by the treatment with piperine. In addition, we found piperine dose-dependently increased the expression of PPARγ. All of these results suggested that piperine had protective effects against LPS-induced mastitis and that the mechanism may be mediated through the activation of PPARγ.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents; Benzodioxoles; Disease Models, Animal; Female; Humans; Immunohistochemistry; Interleukin-1beta; Lipopolysaccharides; Mammary Glands, Human; Mastitis; Mice; Mice, Inbred BALB C; NF-kappa B; Peroxidase; Piperidines; Polyunsaturated Alkamides; PPAR gamma; Tumor Necrosis Factor-alpha; Up-Regulation

Sepsis is a life-threatening organ dysfunction syndrome arising from uncontrolled inflammatory responses. Liver injury is a crucial factor for the prognosis of sepsis. Camptothecins (CPTs) have been reported to suppress the inflammatory response induced by sepsis. G2, a CPT-bile acid conjugate, has been demonstrated the property of liver targeting in our previous research. This study aimed to research the effects of G2 on liver injury induced by cecal ligation and puncture (CLP).. C57BL/6 mice were subjected to CLP surgery, and effects of G2 on liver damage and survival rates of CLP-induced mice were evaluated. To detect the related markers of hepatic injury or neutrophil infiltration, inflammatory cytokines and protein levels, hematoxylin-eosin staining assay, corresponding Detection Kits assay, ELISA and Western blot analysis were performed.. Intraperitoneal administration of G2 reduced liver injury and enhanced the survival rates in mice with sepsis. Treatment with G2 decreased the levels of hepatic injury markers aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in the serum of mice induced by CLP. The hepatic level of neutrophil infiltration marker myeloperoxidase (MPO) was reduced in G2 administration group. And the levels of serum inflammatory cytokines, including Tumor Necrosis Factor-α (TNFα), Interleukin-6 (IL-6) and IL-1β, were decreased by G2. Furthermore, the results of Western blot analysis indicated that G2 suppressed the up-regulation of NF-κB p-P65 and p-IκBα. It suggested that G2 suppressed the activation of NF-κB signaling pathway.. G2 alleviated sepsis-induced liver injury via inhibiting the NF-κB signaling pathway.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Bile Acids and Salts; Blotting, Western; Camptothecin; Cytokines; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Liver Diseases; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Peroxidase; Sepsis; Signal Transduction

To explore the mechanism of Shenmai injection (SMI) on severe acute pancreatitis (SAP) through heme oxygenase-1 (HO-1) signaling.. A total of 40 male Sprague-Dawley (SD) rats (220-260 g) were grouped into the following four categories (n = 10): SAP + SMI + Zinc protoporphyrin (ZnPP), SAP + SMI, SAP, and sham surgery groups. ZnPP is a specific inhibitor of HO-1. Four percent of sodium taurocholate (1 mL/kg) was retrogradely injected via the pancreatic duct to induce the SAP model. The SAP group rats received 1.6 mL/kg saline by intravenous injection 30 min after the induction of SAP. The SAP + SMI group rats received 1.6 mL/kg SMI by intravenous injection 30 min after the induction of SAP. The SAP + SMI + ZnPP group rats received an intravenous injection of 1.6 mL/kg SMI and intraperitoneal administration of 30 mg/kg ZnPP 30 min after the SAP induction. Twenty-four hours after the SAP induction, blood samples were collected for the measurement of amylase, lipase, creatinine, myeloperoxidase, interleukin-10 (IL-10), tumor necrosis factor-α (TNF-α), and HO-1 level, while tissue specimens were harvested for the determination of HO-1, TNF-α, and IL-10 mRNA level. Meanwhile, histopathological changes in organs (pancreas, lung, and kidney) were stored.. The serum concentration of amylase, lipase, creatinine, and myeloperoxidase was higher in the SAP group than in the SAP + SMI group. Treatment with SMI increased HO-1 and IL-10 level and reduced TNF-α level in serum and tissues compared to the SAP group (P < 0.05). Treatment with SMI abolished the organ-damaging effects of SAP (P < 0.05). Furthermore, suppression of HO-1 expression by ZnPP canceled the aforementioned effects.. SMI confers protection against the SAP-induced systemic inflammatory response and multiple organs damage via HO-1 upregulation.

Topics: Amylases; Animals; Disease Models, Animal; Drug Combinations; Drugs, Chinese Herbal; Heme Oxygenase (Decyclizing); Humans; Lipase; Male; Pancreas; Pancreatitis; Peroxidase; Rats; Severity of Illness Index; Systemic Inflammatory Response Syndrome; Up-Regulation

Astragalin is a flavonoid existed in several edible and medicinal plants and was recorded to have multiple biological and pharmacological significances. This work aimed to assess the possible protective effect of astragalin administration against oxidative tension, acute inflammation and histopathological deformations in a mouse paw edema model induced following intra sub-plantar injection of carrageenan. Thirty-six male Swiss mice were divided into four groups: control, carrageenan, astragalin (75 mg/kg) + carrageenan, and indomethacin (10 mg/kg) + carrageenan. Astragalin administration for five consecutive days to carrageenan injected mice showed a significant reduction in the development of paw in a time dependent effect, inhibited lipoperoxidation by-product, malondialdehyde and increased superoxide dismutase and catalase activities. Astragalin was found also to suppress the inflammatory signaling in the inflamed tissue as exhibited by the decreased myeloperoxidase activity along with the decreased protein and transcriptional level of pro-inflammatory cytokines including tumor necrosis factor-alpha, interleukin-1 beta and interleukin-6. Moreover, inducible nitric oxide synthase and cyclooxygenase-2 expressions and their products (nitric oxide and prostaglandin E2) were downregulated. Additionally, astragalin decreased monocyte chemoattractant protein-1 and nuclear factor kappa B expression in the inflamed paw tissue. The recorded findings provide evidences for the potential application of astragalin as a plant-derived remedy for the treatment of acute inflammation due to its promising antioxidant and anti-inflammatory activities along with its ameliorative impact against the histopathological changes in the paw tissue.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Carrageenan; Catalase; Chemokine CCL2; Cyclooxygenase 2; Dinoprostone; Disease Models, Animal; Edema; Immunohistochemistry; Inflammation; Interleukin-1beta; Interleukin-6; Kaempferols; Male; Malondialdehyde; Mice; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase; Oxidative Stress; Peroxidase; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Sepsis is a severe clinical condition that is a result of the cellular and biochemical response to infection. The present study evaluated the therapeutic potential of tryptophan against lipopolysaccharide (LPS)-induced acute lung injury (ALI) in rats. Rats were grouped into sham, control (ALI), and ALI + 1, 25, and 50 mg/kg body weight L-tryptophan. Supplementation with 1, 25, and 50 mg/kg L-tryptophan reduced the total protein content by 4.9%, 33.4%, and 64.5%; the levels of neutrophils (12.5%, 31.8%, and 65.1%), lymphocytes (15.1%, 41.7%, and 63.3%), total cells (12.6%, 42.4%, and 65.7%); lipid peroxidation (9.4%, 28.4%, and 68.7%); myeloperoxidase levels (12.1%, 33.4%, and 68.2%); migration inhibitory factor (12.7%, 39.5%, and 68.2%), interleukin (IL)-8 (5.5%, 46.8%, and 78.5%), tumor necrosis factor (TNF)-α (10.8%, 39.8%, and 72.2%), respectively. Supplementation with 1, 25, and 50 mg/kg L-tryptophan reduced mRNA expression of TNF-α (4.5%, 21.8%, and 41.8%), IL-1β (5.2%, 17.9%, and 46.2%); and the protein expression of TNF-α (2.8%, 15.2%, and 35.7%) and IL-1β (5.2%, 15.6%, and 28.6%), respectively. It also reduced glutathione (to near normal levels), neutrophilic infiltration and edema, and the wet/dry ratio of lung tissue. It significantly increased catalase, superoxide dismutase, glutathione peroxidase levels, as well as the partial pressure of oxygen (PaO

Topics: Acute Lung Injury; Animals; Disease Models, Animal; Interleukin-8; Lipid Peroxidation; Lipopolysaccharides; Lung; Lymphocytes; Macrophage Migration-Inhibitory Factors; Male; Neutrophils; Peroxidase; Rats; Rats, Wistar; Tryptophan; Tumor Necrosis Factor-alpha

Biofilms of Pseudomonas aeruginosa can cause complicated urinary tract infections especially in people with indwelling catheters which may result in pyelonephritis. Microorganisms in biofilm demonstrate high resistance to both antibiotics and host protection mechanisms, often resulting in chronic and difficult-to-treat infections. This study is aimed to assess in vivo and ex vivo efficacy of Zingerone nanoparticles (Z-NPs) against P. aeruginosa biofilm-associated murine acute pyelonephritis. In the present study, Zingerone and chitosan acted synergistically in the form of Z-NPs and found to be nontoxic to the kidney cell lines as depicted in MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay demonstrating their cytocompatibility. In vivo experiments indicated that Z-NPs (100 mg/kg) treatment reduced P. aeruginosa pathogenicity and enhanced the clearance of bacterial count from the renal and bladder tissue. Z-NPs improved the disease outcome by lowering the levels of various inflammatory markers, and histopathological examination revealed better recovery in renal and bladder tissue. Besides, ex vivo efficacy also confirmed that Z-NPs enhanced serum bactericidal effect along with increased phagocytic uptake and intracellular killing of P. aeruginosa as confirmed by fluorescent microscopy. To the best of our knowledge, this is the first study to provide evidence that Z-NPs are effective therapeutic agents for combating P. aeruginosa associated pyelonephritis.

Topics: Animals; Biofilms; Disease Models, Animal; Guaiacol; HEK293 Cells; Humans; Inflammation; Malondialdehyde; Mice; Microscopy, Electron, Scanning; Nanoparticles; Peroxidase; Phagocytosis; Pseudomonas aeruginosa; Pseudomonas Infections; Pyelonephritis; Stem Cells; Tetrazolium Salts; Thiazoles

Therapies aimed at modulating cytokines have been used to treat inflammatory illnesses, such as inflammatory bowel disease. On the other hand, patients may become intolerant, refractory, or present with several side effects.. All mice (C57BL/6 male) were evaluated daily for their food and water intake, bodyweight variations, and clinical signs of disease. Colon inflammation was induced by exposure to DSS for 6 consecutive days. SPI was given orally at 50, 100, and 250 mg/kg/day. ELISA was performed to assess the production of cytokines. Myeloperoxidase and nitric oxide were also investigated. The level of microscopic damage was assessed by staining colon sections with hematoxylin and eosin.. SPI attenuated the DSS-induced inflammation, with improvements in the clinical signs and a decrease in the production of inflammatory cytokines, such as tumor necrosis factor-α and interferon-γ. In addition, particularly at 250 mg/kg, SPI attenuated the severity of colitis by modulating the level of mucosal and submucosal cell infiltration, which preserved the epithelial barrier.. SPI may be an alternative source of bioactive molecules with immunomodulatory properties, and has great potential to be used in the treatment of inflammatory diseases.

Topics: Animals; Colitis; Dextran Sulfate; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Immunologic Factors; Interferon-gamma; Mice; Mice, Inbred C57BL; Nitric Oxide; Peroxidase; Spirulina; Tumor Necrosis Factor-alpha

Duchenne muscular dystrophy (DMD) is a lethal, X-chromosome linked muscle-wasting disease affecting about 1 in 3500-6000 boys worldwide. Myofibre necrosis and subsequent loss of muscle mass are due to several molecular sequelae, such as inflammation and oxidative stress. We have recently shown increased neutrophils, highly reactive oxidant hypochlorous acid (HOCl) generation by myeloperoxidase (MPO), and associated oxidative stress in muscle from the GRMD dog and mdx mouse models for DMD. These findings have led us to hypothesise that generation of HOCl by myeloperoxidase released from neutrophils has a significant role in dystropathology. Since access to muscle from DMD patients is limited, the aim of this study was to develop methods to study this pathway in urine. Using immunoblotting to measure markers of protein oxidation, we show increased labelling of proteins with antibodies to dinitrophenylhydrazine (DNP, oxidative damage) and DiBrY (halogenation by reactive oxidants from myeloperoxidase) in GRMD and mdx urine. A strong positive correlation was observed between DiBrY labelling in dog urine and muscle. A strong positive correlation was also observed when comparing DNP and DiBrY labelling (in muscle and urine) to markers of dystropathology (plasma creatine kinase) and neutrophil presence (muscle MPO). Our results indicate the presence of neutrophil mediated oxidative stress in both models, and suggest that urine is a suitable bio-fluid for the measurement of such biomarkers. These methods could be employed in future studies into the role of neutrophil mediated oxidative stress in DMD and other inflammatory pathologies.

Topics: Animals; Antibodies; Biomarkers; Creatine Kinase; Disease Models, Animal; Dogs; Female; Hydrazines; Male; Mice; Mice, Inbred C57BL; Mice, Inbred mdx; Muscle, Skeletal; Muscular Dystrophy, Duchenne; Neutrophils; Oxidative Stress; Peroxidase; Protein Carbonylation

Acute lung injury (ALI) is a pulmonary disease that acts as a severe acute inflammatory response with no specific drugs. iNOS, a catalyst of the excessive production of NO, has been demonstrated to participate in the inflammatory process, and targeting iNOS may be a promising therapeutic pathway to alleviate ALI. In our research, eighteen new disubstituted benzoxazolone derivatives were synthesized, characterized, and evaluated for activity against NO production in an LPS-induced RAW264.7 cell. The results showed that these compounds could obviously inhibit the over-generation of NO and disubstitution at the 4, N-position of the benzoxazolone ring, presenting better potency than substitution only at the 4-position. Among the analogues generated, compounds 2c, 2d, and 3d showed NO inhibitory activity with IC

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Benzoxazoles; Disease Models, Animal; Drug Design; Edema; Gene Expression Regulation; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; Lung; Macrophages; Mice; Nitric Oxide; Nitric Oxide Synthase Type II; Peroxidase; RAW 264.7 Cells

Appendicitis is one of the most frequent emergencies in pediatric surgery, yet current biomarkers for diagnosis are unspecific and have low predictive values. As neutrophils and extracellular traps (ETs) are an essential component of the immune defense against bacterial infections, and appendicitis is considered an inflammation reaction of the appendix, we hypothesized that neutrophil activation and NET formation play an essential role in appendicitis development and maintenance. Therefore, this pilot study aimed to establish a murine model of appendicitis and to evaluate ETs markers to diagnose appendicitis in mice and humans. The study used 20 (12 appendicitis- and 8 controls) 6-week old mice which underwent advanced appendicitis induction using a modified caecal ligation puncture procedure. During the study, cell-free DNA, neutrophil elastase (NE), myeloperoxidase (MPO), and citrullinated Histone H3 (H3cit) were assessed. Additionally, samples of 5 children with histologically confirmed appendicitis and 5 matched controls with catarrhal appendicitis, were examined for the same biomarkers. Moreover, NE, MPO, and H3cit were assessed histologically via immunofluorescence in mice and humans. All mice in the appendicitis group developed an advanced form of appendicitis with focal peritonitis. In mice and humans with appendicitis, markers of neutrophil activation and ETs formation (especially cfDNA, NE and H3cit) were significantly elevated in blood and tissue compared to controls. Ultimately, biomarkers correlated extremely well with tissue expression and thus disease severity. It appears that neutrophil activation and possibly NETs contribute to appendicitis development and biomarkers of neutrophil activation and ET formation reflect disease severity and thus could be used as biomarkers for appendicitis. However, large prospective clinical studies are needed to confirm our findings.

Topics: Animals; Appendicitis; Biomarkers; Case-Control Studies; Cell-Free Nucleic Acids; Child; Citrullination; Disease Models, Animal; Extracellular Traps; Female; Histones; Humans; Inflammation; Leukocyte Elastase; Male; Mice; Mice, Inbred C57BL; Neutrophil Activation; Neutrophils; Peroxidase; Pilot Projects; Predictive Value of Tests

The present study was to investigate the effect of mesenteric lymph duct drainage on lung inflammatory response, histological alteration, and endothelial cell apoptosis in septic rats. Animals were randomly assigned into four groups: control, sham surgery, sepsis, and sepsis plus mesenteric lymph drainage. We used the colon ascendens stent peritonitis (CASP) procedure to induce the septic model in rats, and mesenteric lymph drainage was performed with a polyethylene (PE) catheter inserted into mesenteric lymphatic. The animals were sacrificed at the end of CASP in 6 h. The mRNA expression levels of inflammatory mediators were measured by qPCR, and the histologic damage were evaluated by the pathological score method. It was found that mesenteric lymph drainage significantly reduced the expression of TNF-

Topics: Animals; Apoptosis; Biological Factors; Disease Models, Animal; Drainage; Endothelial Cells; Gene Expression Regulation; Interleukin-1beta; Interleukin-6; Lymph; Lymphatic Vessels; Male; Mesentery; Peritonitis; Peroxidase; Pneumonia; Primary Cell Culture; Pulmonary Edema; Rats; Rats, Sprague-Dawley; Sepsis; Tumor Necrosis Factor-alpha

Fish oil (FO) is a natural source of omega-3 fatty acids, with well-established beneficial effects in inflammatory diseases when FO is orally administered. This study investigated the effects of a topically applied FO preparation (FOP) on phenol-induced ear edema and evaluated the percutaneous penetration of FOP in ear tissue. After applying phenol, groups of mice received FOP on the ear. After 1 h, ear tissue was collected to determine the percent inhibition of edema, myeloperoxidase activity, and to perform photoacoustic spectroscopy (PAS). Treatment with FOP did not reduce edema, but reduced myeloperoxidase activity. The FOP decreased the area of bands that characterize inflamed tissue and penetrated into the tissue. These results indicated an inhibitory effect of FOP on leukocyte recruitment in phenol-induced ear edema. These data support the applicability of PAS as a non-destructive method for evaluating the inflammatory response, percutaneous penetration and antiinflammatory activity of compounds.

Topics: Administration, Topical; Animals; Disease Models, Animal; Ear; Edema; Fish Oils; Inflammation; Leukocytes; Mice; Peroxidase; Phenol; Photoacoustic Techniques; Skin; Skin Absorption

Alveolar epithelial cell (AEC) death, which is classified as apoptosis or necrosis, plays a critical role in the pathogenesis of acute respiratory distress syndrome (ARDS). In addition to apoptosis, some types of necrosis are known to be molecularly regulated, and both apoptosis and necrosis can be therapeutic targets for diseases. However, the relative contribution of apoptosis and necrosis to AEC death during ARDS has not been elucidated. Here, we evaluated which type of AEC death is dominant and whether regulated necrosis is involved in lipopolysaccharide (LPS)-induced lung injury, an experimental ARDS model. In the bronchoalveolar lavage fluid from the LPS-induced lung injury mice, both the levels of cytokeratin 18-M65 antigen (a marker of total epithelial cell death) and cytokeratin 18-M30 antigen (an epithelial apoptosis marker) were increased. The M30/M65 ratio, which is an indicator of the proportion of apoptosis to total epithelial cell death, was significantly lower than that in healthy controls. In addition, the number of propidium iodide-positive, membrane-disrupted cells was significantly higher than the number of TUNEL-positive apoptotic cells in the lung sections of lung injury mice. Activated neutrophils seemed to mediate AEC death. Finally, we demonstrated that necroptosis, a regulated necrosis pathway, is involved in AEC death during LPS-induced lung injury. These results indicate that necrosis including necroptosis, rather than apoptosis, is the dominant type of AEC death in LPS-induced lung injury. Although further studies investigating human ARDS subjects are necessary, targeting necrosis including its regulated forms might represent a more efficient approach to protecting the alveolar epithelial barrier during ARDS.

Topics: Alveolar Epithelial Cells; Animals; Apoptosis; Bronchoalveolar Lavage Fluid; Cell Death; Disease Models, Animal; Flow Cytometry; Leukocyte Count; Lipopolysaccharides; Lung; Male; Mice; Mice, Inbred C57BL; Necrosis; Neutrophils; Peroxidase; Receptor for Advanced Glycation End Products; Respiratory Distress Syndrome; Reverse Transcriptase Polymerase Chain Reaction

In chronic inflammatory joint diseases, such as rheumatoid arthritis, there is an important bone loss. Parathyroid hormone-related protein (PTHrP) and related peptides have shown osteoinductive properties in bone regeneration models, but there are no data on inflammatory joint destruction. We have investigated whether the PTHrP (107-111) C-terminal peptide (osteostatin) could control the development of collagen-induced arthritis in mice. Administration of osteostatin (80 or 120 μg/kg s.c.) after the onset of disease decreased the severity of arthritis as well as cartilage and bone degradation. This peptide reduced serum IgG2a levels as well as T cell activation, with the downregulation of RORγt+CD4+ T cells and upregulation of FoxP3+CD8+ T cells in lymph nodes. The levels of key cytokines, such as interleukin(IL)-1β, IL-2, IL-6, IL-17, and tumor necrosis factor-α in mice paws were decreased by osteostatin treatment, whereas IL-10 was enhanced. Bone protection was related to reductions in receptor activator of nuclear factor-κB ligand, Dickkopf-related protein 1, and joint osteoclast area. Osteostatin improves arthritis and controls bone loss by inhibiting immune activation, pro-inflammatory cytokines, and osteoclastogenesis. Our results support the interest of osteostatin for the treatment of inflammatory joint conditions.

Topics: Animals; Arthritis, Experimental; Biomarkers; Biopsy; Bone and Bones; Cytokines; Disease Models, Animal; Disease Progression; Disease Susceptibility; Immunoglobulin G; Inflammation Mediators; Male; Mice; Osteogenesis; Parathyroid Hormone-Related Protein; Peptide Fragments; Peroxidase; T-Lymphocytes

Sepsis is a severe, life-threatening condition caused primarily by the cellular response to infection. Sepsis leads to increased tissue damage and mortality in patients in the intensive care unit. L-Lysine is an essential amino acid required for protein biosynthesis and is abundant in lamb, pork, eggs, red meat, fish oil, cheese, beans, peas, and soy. The present study investigates the protective effect of L-lysine against sepsis-induced acute lung injury (ALI) in a lipopolysaccharide-induced mouse model. In the present study, mice were divided into sham, control, 5 mg/kg body weight L-lysine, and 10 mg/kg body weight L-lysine treatment groups. At the end of the treatment period, we determined the levels of oxidative and inflammatory markers, myeloperoxidase (MPO) and catalase activities, total cell count, the wet/dry ratio of lung tissue, and total protein content. The effects of L-lysine on the cellular architecture of lung tissue were also evaluated. L-Lysine treatment significantly reduced the magnitude of lipid peroxidation; total protein content; wet/dry ratio of lung tissue; tumor necrosis factor alpha, interleukin-8, and macrophage inhibitory factor levels; MPO activity; and total cell, neutrophil, and lymphocyte counts. It also increased the levels of reduced glutathione and the activities of glutathione peroxidase, superoxide dismutase, and catalase. A normal cellular architecture was noted in mice in the sham group, whereas proinflammatory changes such as edema and neutrophilic infiltration were detected in mice in the control group. L-lysine significantly ameliorated these proinflammatory changes. Taking all these data together, it is suggested that the L-lysine was effective against sepsis-induced ALI.

Topics: Acute Lung Injury; Animals; Cell Count; Cytokines; Disease Models, Animal; Glutathione; Lipid Peroxidation; Lipopolysaccharides; Lung; Lysine; Mice; Organ Size; Peroxidase; Sepsis; Superoxide Dismutase

Topics: Alcohol Drinking; Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Chemotaxis, Leukocyte; Disease Models, Animal; Leukocytes; Male; Myocardial Infarction; Myocardium; Peroxidase; Rats, Sprague-Dawley; Wine

Paraquat poisoning is one of leading intoxication worldwide without an effective antidote and treatment protocol. Among the other organs, cardiotoxicity of paraquat has been frequently reported.. The protective effects of atorvastatin (STN) on paraquat-induced cardiotoxicity and the role of peroxisome proliferator-activated receptors γ in the mediation of STN effects were investigated.. Forty-two male Wistar rats were aliquoted into control or test groups. The animals in test groups in addition of paraquat received saline normal (PQ), pioglitazone (PGT), atorvastatin (STN), PGT + STN, PGT + GW9662, and/or STN + GW9662 for 14 days.. PGT and STN lowered lipid peroxidation rate, nitric oxide concentration, and activity of myeloperoxidase and CK/MB in the heart. PGT and STN protected from thiol molecules reduction and PQ-induced histopathological injuries. STN regulated the PQ-induced upregulation of COX-II expression in the heart. All STN-related protective effects were reversed by GW9662 as PPARγ antagonist.. These data suggest a cardioprotective effect for STN against the PQ-induced inflammation and oxidative stress. The pharmacologic approach of these findings indicates that STN through PPARγ pathway lowered the PQ-induced cardiotoxicity.

Topics: Animals; Antioxidants; Atorvastatin; Cardiotoxicity; Creatine Kinase, MB Form; Cyclooxygenase 2; Disease Models, Animal; Heart Diseases; Lipid Peroxidation; Male; Myocytes, Cardiac; Nitric Oxide; Oxidative Stress; Paraquat; Peroxidase; PPAR gamma; Rats, Wistar; Signal Transduction; Sulfhydryl Compounds

The reno-protective effects of antidiabetic dipeptidyl peptidase (DPP)-4 inhibitors have been studied regarding their antioxidant and anti-inflammatory properties. However, the potential ability of saxagliptin to ameliorate renal injury by enhancing neovascularization has not been elucidated. To address this issue, saxagliptin (10 and 30 mg/kg) was administered to Wistar rats after the induction of renal ischaemia/reperfusion (I/R). Our results showed that saxagliptin operated through different axes to ameliorate I/R injury. By inhibiting DPP-4, saxagliptin maintained stromal cell-derived factor-1α expression and upregulated its chemokine receptor CXCR4 to trigger vasculogenesis through the enhanced migration of endothelial progenitor cells (EPCs). Additionally, this compound rescued the levels of glucagon-like peptide-1 and its downstream mediator cAMP to increase vascular endothelial growth factor (VEGF) and CXCR4 levels. Moreover, saxagliptin stimulated atrial natriuretic peptide/endothelial nitric oxide synthase to increase nitric oxide levels and provoke angiogenesis and renal vasodilation. In addition to inhibiting DPP-4, saxagliptin increased the renal kidney injury molecule-1/pY705-STAT3/hypoxia-inducible factor-1α/VEGF pathway to enhance angiogenesis. Similar to other gliptins, saxagliptin exerted its anti-inflammatory and antioxidant effects by suppressing the renal contents of p (S536)-nuclear factor-κB p65, tumour necrosis factor-α, monocyte chemoattractant protein-1, myeloperoxidase, and malondialdehyde while boosting the glutathione content. These events improved the histological structure and function of the kidney, as evidenced by decreased serum creatinine, blood urea nitrogen, and cystatin C and increased serum albumin. Accordingly, in addition to its anti-inflammatory and antioxidant activities, saxagliptin dose-dependently ameliorated I/R-induced renal damage by enhancing neovascularization through improved tissue perfusion and homing of bone marrow-derived EPCs to mediate repair processes.

Topics: Adamantane; Animals; Atrial Natriuretic Factor; Cell Adhesion Molecules; Chemokine CXCL12; Cyclic AMP; Dipeptides; Disease Models, Animal; Glucagon-Like Peptide 1; Glutathione; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney; Male; Malondialdehyde; Neovascularization, Physiologic; Nitric Oxide; Nitric Oxide Synthase Type III; Oxidative Stress; Peroxidase; Rats; Rats, Wistar; Receptors, CXCR4; Reperfusion Injury; Signal Transduction; STAT3 Transcription Factor; Vascular Endothelial Growth Factor A

Crohn's Disease (CD), one of the types of inflammatory bowel disease, poses a significant challenge to modern healthcare. This condition severely impacts patients' quality of life, and its incidence is continuously rising. Despite constant research, current treatment options are limited and largely unsuccessful and result in serious side effects, therefore new therapy alternatives are needed. Liposomal formulation provides a new hope for disease management. In our study, we characterized the anti-inflammatory activity of mesalazine (5-ASA) and chlorogenic acid (CGA) encapsulated in liposomal formulation in the animal model of CD. Liposomes were obtained by thin film hydration method and characterized in terms of suspension stability and particle size and distribution. Colitis was induced in mice by intracolonic (i.c.) administration of 2,4,6-trinitrobenzenesulfonic acid (TNBS). The effect of treatment with liposomal suspensions of 5-ASA and CGA was evaluated macroscopically and by measuring myeloperoxidase (MPO) activity. We observed that liposome-encapsulated 5-ASA (5 mg/kg), but not CGA (20 mg/kg) attenuated colitis as evidenced by a decreased macroscopic and microscopic scores. It may be hypothesized that the composition of liposomal lipid bilayer as well as the switch in macrophage populations leading to unfavorable accumulation of anti-inflammatory agents in the cells may underly the efficiency of obtained liposomes and need to be taken into consideration in further studies on drug delivery.

Topics: Animals; Anti-Inflammatory Agents; Chlorogenic Acid; Colitis; Colon; Disease Models, Animal; Inflammatory Bowel Diseases; Liposomes; Male; Mesalamine; Mice; Mice, Inbred BALB C; Peroxidase; Quality of Life; Trinitrobenzenesulfonic Acid

The aim of the present study was to investigate the effect of resveratrol on cytokine levels and oxidative stress in intestinal ischemia/reperfusion (I/R) injuries.. To induce intestinal I/R, the superior mesenteric artery was occluded for 30 min and then reperfused for 150 min or 24 h. The therapeutic effects of resveratrol on the damage from intestinal I/R were investigated using an isolated organ bath, along with oxidant/antioxidant and inflammatory factors such as glutathione (GSH), malondialdehyde (MDA), myeloperoxidase (MPO), interleukin-(IL)-1β, and tumor necrosis factor alpha (TNF-α).. I/R control animals demonstrated severe deterioration of smooth muscle motor function as a significant decrease in potassium chloride- and acetylcholine-induced a contractile responses; high oxidative stress as an increase in lipid peroxidation and a decrease in GSH level; and an increase of MPO, IL-1β, and TNF-α activity. Pretreatment of animals with resveratrol restored intestinal dysfunction; reduced elevated MDA, MPO, IL-1β, and TNF-α levels; and reversed the depleted intestine GSH levels after both 150 min and 24 h reperfusion periods.. The results indicated that resveratrol can reverse the effects of disrupted smooth muscle contractility, probably because of its antioxidant and anti-inflammatory effects on MPO, IL-1β, and TNF-α activities.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Disease Models, Animal; Glutathione; Interleukin-1beta; Intestine, Small; Male; Malondialdehyde; Muscle Contraction; Muscle, Smooth; Oxidative Stress; Peroxidase; Rats, Wistar; Reperfusion Injury; Resveratrol; Signal Transduction; Tumor Necrosis Factor-alpha

Background Despite advances in immunomodulatory agents, most current therapies for multiple sclerosis target lymphocytes or lymphocytic function. However, therapy response may be less than optimal due to demyelination and axonal damage caused by myeloid cells. Purpose To determine if myeloperoxidase (MPO) molecular MRI can evaluate whether combination therapy targeting both lymphoid and myeloid inflammation can improve autoimmune neuroinflammation compared with either drug alone, even at suboptimal doses. Materials and Methods Four groups of 94 female mice (8-10 weeks old) were induced with experimental autoimmune encephalomyelitis (EAE) from August 2, 2016, to March 30, 2018, and divided into saline control (

Topics: Aniline Compounds; Animals; Brain; Contrast Media; Disease Models, Animal; Drug Therapy, Combination; Encephalomyelitis, Autoimmune, Experimental; Female; Gadolinium; Glatiramer Acetate; Image Enhancement; Immunosuppressive Agents; Magnetic Resonance Imaging; Mice; Peroxidase; Saline Solution

Endometritis, a common inflammation of the uterus, often causes severe damage to human and animal reproductive health. Polydatin is a polyphenol extracted from the rhizome of Polygonum cuspidatum that has anti-inflammatory and anti-oxidative effects. The purpose of this study was to investigate the underlying protective effects and mechanisms of polydatin against lipopolysaccharide (LPS)-induced endometritis in mice. The mouse model of endometritis was established by injection of LPS through the vagina. The uterine tissues of each group were gathered to analyze histopathological changes, inflammatory cytokine production, and the degree of activation of the NF-κB and Nrf2 signaling pathways. The myeloperoxidase (MPO) activity assay indicated that polydatin treatment significantly alleviated inflammatory cell infiltration in LPS-induced endometritis mice. Furthermore, polydatin treatment remarkably impeded the expression of TNF-α, IL-1β, and IL-6 by ELISA assay. Hematoxylin-eosin staining (H&E) showed that polydatin significantly decreased impairment of the uterus. In addition, polydatin was also found to suppress LPS-induced NF-κB activation in a dose-dependent manner. The expression of Nrf2 and HO-1 was enhanced by polydatin treatment. All the results suggest that polydatin helpfully alleviates LPS-induced endometritis by suppressing the NF-ĸB signaling pathway and activating the Nrf2 signaling pathway.

Topics: Animals; Anti-Inflammatory Agents; Cytokines; Disease Models, Animal; Endometritis; Female; Glucosides; Heme Oxygenase-1; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; Membrane Proteins; Mice; Mice, Inbred BALB C; NF-E2-Related Factor 2; NF-kappa B; Peroxidase; Protective Agents; Signal Transduction; Stilbenes; Tumor Necrosis Factor-alpha; Uterus; Vagina

This study aimed to investigate the effect of lutein on methotrexate (MTX)-induced pulmonary toxicity in rats biochemically and histopathologically.. The rats in the MTX + lutein (MTXL, n = 6) group were given 1 mg/kg of lutein orally. A 0.9% NaCl solution was administered orally to the MTX (n = 6) group and the healthy group (HG, n = 6). One hour later, a single 20 mg/kg dose of MTX was injected intraperitoneally in the MTXL and MTX. Lutein or 0.9% NaCl solution was administered once a day for 5 days. At the end of this period, malondialdehyde (MDA), myeloperoxidase (MPO), total glutathione (tGSH), interleukin 1 beta (IL-1β), and tumor necrosis factor alpha (TNF-α) were measured in the lung tissues from the animals euthanized with 50 mg/kg thiopental sodium anesthesia. Subsequently, histopathological examinations were performed.. The levels of MDA, MPO, IL-1β, and TNF-α in the lung tissue of the MTX were significantly higher than those of the MTXL and HG groups (p < 0.0001), and the amount of tGSH was lower. The histopathological findings in the MTX group, in which the oxidants and cytokines were higher, were more severe.. Lutein prevented the MTX-induced oxidative lung damage biochemically and histopathologically. This result indicates that lutein may be useful in the treatment of MTX-induced lung damage.

Topics: Animals; Antioxidants; Disease Models, Animal; Glutathione; Interleukin-1beta; Lung; Lung Diseases; Lutein; Male; Malondialdehyde; Methotrexate; Oxidative Stress; Peroxidase; Rats, Wistar; Tumor Necrosis Factor-alpha

Intestinal inflammation is the predominant contributor to the genesis of postoperative ileus. Janus kinase 1 plays an important role during inflammation. Here, we investigated the role of Janus kinase 1 in postoperative ileus and whether inhibition of Janus kinase 1 could mitigate postoperative ileus.. A mouse model of postoperative ileus was induced by intestinal manipulation. Janus kinase 1 inhibitor GLPG0634 or placebo was administered orally before intestinal manipulation. At the indicated time points post operation, neutrophil infiltration was assessed by immunohistochemistry and enzyme-linked immunosorbent assay; proinflammatory gene expression was quantified by quantitative reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay; and Janus kinase 1 activation was detected by Western blot. Functional studies were conducted to evaluate intestinal motility.. We found that intestinal manipulation led to marked activation of Janus kinase 1, with increased proinflammatory gene expression and upregulated myeloperoxidase level. Moreover, intestinal manipulation resulted in an impairment of intestinal transit in vivo and inhibition of smooth muscle contractility in vitro. Preoperative administration of GLPG0634 markedly lowered the expression of proinflammatory cytokines, the myeloperoxidase level in the muscularis layer after bowel manipulation, and significantly ameliorated smooth muscle contractile function and intestinal transit ability.. Our data showed that Janus kinase 1 activation mediated intestinal manipulation-induced resident macrophage activation after intestinal manipulation, and subsequent complex inflammatory cascade and gut dysmotility. Janus kinase 1 inhibition appears to be a prospective and convenient approach for the prevention of postoperative ileus.

Topics: Animals; Disease Models, Animal; Gastrointestinal Motility; Humans; Ileus; Inflammation Mediators; Intestinal Mucosa; Janus Kinase 1; Jejunum; Male; Mice; Muscle Contraction; Muscle, Smooth; Peroxidase; Postoperative Complications; Preoperative Care; Pyridines; Signal Transduction; Triazoles; Up-Regulation

Children born by cesarean section (CS) have an increased risk of developing inflammatory bowel disease (IBD), possibly due to skewed microbial colonization during birth and consequently impaired bacterial stimulation of the developing immune system. The aim of this study was to investigate the association between CS and experimental colitis in a murine model of IBD. It was hypothesized that CS aggravates colonic inflammation due to a change in gut microbiota (GM) composition. C57BL/6 mice, delivered by CS or vaginal delivery (VD), were intra-rectally challenged with oxazolone at 8 weeks of age and monitored for colitis symptoms. The results showed that CS delivered mice experienced an increased body weight loss and colon weight, together with higher colonic concentrations of TNF-α and MPO compared with VD mice. Increased infiltration of inflammatory cells was present in CS delivered mice, as well as a downregulation in expression of the gut integrity genes occludin and tight junction protein 1 indicative of an impaired barrier function. The GM from CS delivered mice without colitis partly contributed to the increase in colitis symptoms when inoculated into germ-free recipient mice. In conclusion, CS increased sensitivity to oxazolone induced colitis in mice.

Topics: Animals; Cesarean Section; Colitis; Colon; Disease Models, Animal; Fecal Microbiota Transplantation; Female; Gastrointestinal Microbiome; Inflammation Mediators; Intestinal Mucosa; Mice, Inbred C57BL; Oxazolone; Peroxidase; Pregnancy; Severity of Illness Index; Tumor Necrosis Factor-alpha

Inflammatory bowel disease (IBD) is a continual ailment condition which engrosses the entire alimentary canal. The IBD can be primarily distinguished into two forms, ulcerative colitis, and Crohn's disease. The major symptoms of IBD include pustules or abscesses, severe abdominal pain, diarrhea, fistula, and stenosis, which may directly affect the patient's quality of life. A variety of mediators can stimulate the circumstances of IBD, some examples include infections by microbes such as bacteria, perturbation of the immune system and the surrounding environment of the intestines. Severe colitis was stimulated in the experimental animals through administering 4% dextran sulfate sodium (DSS) which is mixed in water ad libitum for 6 days. Eriocitrin (30 mg/kg) was then administered to the experimental animals followed by the induction of severe colitis to evaluate the therapeutic prospective of eriocitrin against the colon inflammation stimulated by DSS. In this study, eriocitrin (30 mg/kg) demonstrated significant (P < .05) attenuation activity against the DSS-stimulated severe colitis in experimental animals. Eriocitrin counteracted all of the clinical deleterious effects induced by DSS, such as body-weight loss, colon shortening, histopathological injury, accretion of infiltrated inflammatory cells at the inflamed region and the secretion of inflammatory cytokines. The results clearly showed that eriocitrin effectively attenuated DSS-induced acute colitis in experimental animals.

Topics: Animals; Anti-Inflammatory Agents; Citrus; Colitis; Colon; Cyclooxygenase 2; Cytokines; Dextran Sulfate; Disease Models, Animal; Flavanones; Inflammation; Male; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; NF-kappa B; Nitric Oxide Synthase Type II; Peroxidase; Plant Extracts; Severity of Illness Index; Weight Loss

To investigate the effect of sevoflurane preconditioning on ischemia/reperfusion (I/R)-induced pulmonary/hepatic injury.. Fifty-one Wistar rats were randomly grouped into sham, I/R, and sevoflurane groups. After reperfusion, the structural change of the lung was measured by Smith score, the wet and dry weights (W/D) were determined, malondialdehyde (MDA) myeloperoxidase (MPO) content was determined colorimetrically and by fluorescence, respectively, and matrix metalloprotein-9 (MMP-9) mRNA was quantified by RT-PCR. Biopsy and morphological analyses were performed on liver tissue, activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were determined, and tumor necrosis factor-alpha (TNF-α) level was determined.. The sham group showed no changes in tissue structure. Structural lesions in the sevoflurane and I/R groups were mild and severe, respectively. Smith score, W/D, MDA, MPO, and MMP mRNA showed the same trend, and were increased in the I/R group and recovered in the sevoflurane group, compared with the sham group (both P<0.05). AST and ALT were significantly increased compared to the sham group (AST: 655±52.06 vs . 29±9.30 U/L; ALT: 693±75.56 vs . 37±6.71 U/L; P<0.05). In the sevoflurane group, AST and ALT levels were significantly decreased (464±47.71 and 516±78.84 U/L; P<0.001). TNF-α presented similar results.. The protection of lung and liver by sevoflurane may be mediated by inhibited leukocyte recruitment and MMP-9 secretion.

Topics: Alanine Transaminase; Anesthetics, Inhalation; Animals; Aspartate Aminotransferases; Disease Models, Animal; Ischemia; Ischemic Preconditioning; Liver; Lung; Male; Malondialdehyde; Peroxidase; Rats; Rats, Wistar; Reperfusion Injury; Sevoflurane; Tumor Necrosis Factor-alpha

The role of neutrophils in the pathogenesis of inflammatory bowel disease (IBD) is still only incompletely understood. Here, we evaluated target-specific fluorescence-mediated tomography (FMT) for visualization of neutrophil infiltration in murine experimental DSS-induced colitis. Colitis was assessed using clinical, endoscopic, and histopathological parameters. Intestinal neutrophil infiltration was determined at day 0, 4, and 10 by targeted FMT after injection of a neutrophil-specific fluorescence-labelled monoclonal antibody (Gr-1). Complementary, immunofluorescence tissue sections with Gr-1 and ELISA-based assessment of tissue myeloperoxidase (MPO) served as the gold standard for the quantification of neutrophil infiltration. Colitic animals showed decreasing body weight, presence of fecal occult blood, and endoscopic signs of inflammation. FMT revealed a significantly increased level of fluorescence only four days after colitis induction as compared to pre-experimental conditions (pmol tracer 73.2 ± 18.1 versus 738.6 ± 80.7;

Topics: Animals; Colitis; Colon; Disease Models, Animal; Female; Fluorescence; Inflammation; Inflammatory Bowel Diseases; Mice; Mice, Inbred C57BL; Neutrophil Infiltration; Neutrophils; Peroxidase; Tomography

Myeloperoxidase (MPO) and eosinophil peroxidase (EPO) are cationic haloperoxidases with potent microbicidal and detoxifying activities. MPO selectively binds to and kills some Gram-positive bacteria (GPB) and all Gram-negative bacteria (GNB) tested. GNB contain endotoxin, i.e., lipopolysaccharide (LPS) comprising a toxic lipid A component. The possibility that MPO and EPO bind and inhibit the endotoxin of GNB was tested by mixing MPO or EPO with LPS or lipid A and measuring for inhibition of endotoxin activity using the chromogenic Limulus amebocyte lysate (LAL) assay. The endotoxin-inhibiting activities of MPO and EPO were also tested

Topics: Animals; Biological Assay; Disease Models, Animal; Dose-Response Relationship, Drug; Endotoxins; Eosinophil Peroxidase; Kaplan-Meier Estimate; Lipopolysaccharides; Mice; Mortality; Peroxidase

Trinitrobenzenesulfonic acid (TNBS) and dextran sodium sulfate (DSS) are commonly used to induce experimental murine ulcerative colitis (UC). Our recent study has demonstrated that a novel andrographolide derivative, AL-1, ameliorated TNBS-induced colitis in mice. However, the effect of AL-1 on DSS-induced murine colitis and the underlying mechanisms are yet unknown. In the present study, we aimed to investigate the therapeutic potential of AL-1 against DSS-induced UC in mice and to define its mechanisms of action. Oral administration of AL-1 attenuated body weight loss, reduced colon length shortening, lowered the disease activity index score, and alleviated colon histological damage. AL-1 significantly inhibited myeloperoxidase activity and suppressed immune inflammatory responses in colonic tissues. Moreover, AL-1 reversed DSS-altered expression of inflammatory cytokines in DSS-induced colitis mice. Importantly, the efficacy of 45 mg/kg of AL-1 was higher than that of 100 mg/kg of the positive control drugs 5-aminosalicylic acid and mesalazine. AL-1 decreased lipopolysaccharide-induced generation of reactive oxygen species and nitric oxide in cultured macrophages in vitro; it also reversed the altered expression of inflammatory cytokines. In both in vivo and in vitro studies, Western blot analysis revealed that AL-1 reduced the expression of phosphorylated NF-

Topics: Animals; Cell Nucleus; Colitis; Cytokines; Dextran Sulfate; Disease Models, Animal; Diterpenes; Female; Inflammation; Inflammation Mediators; Lipopolysaccharides; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Models, Biological; NF-kappa B; Nitric Oxide; Peroxidase; RAW 264.7 Cells; Reactive Oxygen Species

Topics: AMP-Activated Protein Kinase Kinases; Animals; Colitis; Colon; Dextran Sulfate; Disease Models, Animal; Drugs, Chinese Herbal; Humans; Immunity, Cellular; Inflammatory Bowel Diseases; Male; Medicine, Chinese Traditional; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; Oxidative Stress; Peroxidase; Protein Kinases; Signal Transduction; Th1 Cells; Th17 Cells

The literature shows that phenolic compounds possess important antioxidant and anti-inflammatory activities; however, the mechanism underlying these effects is not elucidated yet. The genus

Topics: Animals; Antioxidants; Catalase; Disease Models, Animal; Female; Glutathione Transferase; Interleukin-10; Interleukin-17; Interleukin-1beta; Male; Mice; Neutrophils; Oxidative Stress; Peroxidase; Phenols; Pleurisy; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances

Oxytocin (OT) has been reported to have a protective effect in lipopolysaccharide-induced experimental acute lung injury (ALI). However, its role in heat stroke-related ALI has never been investigated. Herein, we aimed to explore the therapeutic effects and potential mechanism of action of OT on heat-induced ALI. Rats were treated with OT 60 min before the start of heat stress (42 °C for 80 min). Twenty minutes after the termination of heat stress, the effects of OT on lung histopathological changes, edema, acute pleurisy and the bronchoalveolar fluid levels of inflammatory cytokines and indicators of ischemia, cellular damage, and oxidative damage were assessed. We also evaluated the influence of OT pretreatment on heat-induced hypotension, hyperthermia, ALI score, and death in a rat model of heat stroke. The results showed that OT significantly reduced heat-induced lung edema, neutrophil infiltration, hemorrhage score, myeloperoxidase activity, ischemia, and the levels of inflammatory and oxidative damage markers in bronchoalveolar lavage fluid. The survival assessment confirmed the pathophysiological and biochemical results. An OT receptor antagonist (L-368,899) was administered 10 min before the OT injection to further demonstrate the role of OT in heat-induced ALI. The results showed that OT could not protect against the aforementioned heat stroke responses in rats treated with L-368,899. Interestingly, OT treatment 80 min after the start of heat shock did not affect survival. In conclusion, our data indicate that OT pretreatment can reduce the ischemic, inflammatory and oxidative responses related to heat-induced ALI in rats.

Topics: Acute Lung Injury; Animals; Bronchoalveolar Lavage Fluid; Camphanes; Cytokines; Disease Models, Animal; Fever; Heat Stroke; Heat-Shock Response; Hypotension; Lung; Male; Neutrophil Infiltration; Oxytocin; Peroxidase; Piperazines; Protective Agents; Pulmonary Edema; Rats; Rats, Sprague-Dawley; Receptors, Oxytocin; Survival Analysis

Lifestyle factors are important drivers of chronic diseases, including cardiovascular syndromes, with low grade inflammation as a central player. Attenuating myeloperoxidase (MPO) activity, an inflammatory enzyme associated with obesity, hypertension and heart failure, could have protective effects on multiple organs. Herein, the effects of the novel oral available MPO inhibitor AZM198 were studied in an obese/hypertensive mouse model which displays a cardiac phenotype. Eight week old male C57BL6/J mice received 16 weeks of high fat diet (HFD) combined with angiotensin II (AngII) infusion during the last 4 weeks, with low fat diet and saline infusion as control. Treated animals showed therapeutic AZM198 levels (2.1 µM), corresponding to 95% MPO inhibition. AZM198 reduced elevated circulating MPO levels in HFD/AngII mice to normal values. Independent of food intake, bodyweight increase and fat accumulation were attenuated by AZM198, alongside with reduced visceral adipose tissue (VAT) inflammation and attenuated severity of nonalcoholic steatohepatitis. The HFD/AngII perturbation caused impaired cardiac relaxation and contraction, and increased cardiac hypertrophy and fibrosis. AZM198 treatment did, however, not improve these cardiac parameters. Thus, AZM198 had positive effects on the main lipid controlling tissues in the body, namely adipose tissue and liver. This did, however, not directly result in improved cardiac function.

Topics: Angiotensin II; Animals; Diet, High-Fat; Disease Models, Animal; Heart Ventricles; Humans; Hypertension; Hypertrophy, Left Ventricular; Intra-Abdominal Fat; Liver; Male; Mice; Non-alcoholic Fatty Liver Disease; Obesity; Peroxidase; Severity of Illness Index; Thioxanthenes; Ventricular Remodeling

Myeloperoxidase (MPO) has paradoxically been found to be able to both activate matrix metalloproteinases (MMPs) as well as inhibit MMPs. However, these regulatory effects have not yet been observed in vivo, and it is unclear which pathway is relevant in vivo. We aim to track MPO regulation of MMP activity in living animals in neuroinflammation. Mice induced with experimental autoimmune encephalomyelitis (EAE), a mouse model of neuroinflammation and multiple sclerosis, were treated with either the MPO-specific inhibitor 4-aminobenzoic acid hydrazide or saline as control. Mice underwent concurrent magnetic resonance imaging (MRI) with the MPO-specific molecular imaging agent MPO-Gd and fluorescence molecular tomography (FMT) with the MMP-targeting agent MMPsense on day 12 after induction. Biochemical and histopathological correlations were performed. Utilizing concurrent MRI and FMT imaging, we found reduced MMP activity in the brain with MPO inhibition, demonstrating MPO activity positively regulates MMP activity in vivo. In vivo MMPSense activation and MMP-9 activity correlated with MPO-Gd

Topics: Animals; Brain; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Magnetic Resonance Imaging; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Mice; Molecular Imaging; Peroxidase

Crush syndrome (CS), a serious medical condition characterised by damage to the muscle cells due to pressure, is associated with high mortality, even when patients receive fluid therapy during transit to the hospital or admission to the hospital. There is no standard triage approach for earthquake victims with crush injuries due to the scarcity of epidemiologic and quantitative data. We examined whether mortality can be predicted based on the severity of skin damage so that assess the severity and prognosis in crush syndrome by assessment of skin damage in hairless rats because we have previously observed that CS results in oedema and redness of the skin in rats.. Anaesthetised rats were subjected to bilateral hind limb compression [1 kg (mild) and 2 kg (severe) loads] with a rubber tourniquet for 5 h. The rats were then randomly divided into three groups: sham, mild CS, and severe CS.. The mild and severe CS groups had mortality rates of 20 and 90%, respectively. The severe CS group demonstrated higher rates of hyperkalaemia, hypovolemic shock, acidosis, and inflammation. Skin damage was significantly worse in the severe CS group compared to the mild CS group. Skin damage showed good correlation with pathological severity.. Skin damage is a valid measure of transepidermal water loss and severity of CS. We suggest that these models may be useful to professionals who are not experienced in disaster management to identify earthquake victims at high risk of severe CS.

Topics: Animals; Crush Syndrome; Disease Models, Animal; Injury Severity Score; Male; Muscle, Skeletal; Peroxidase; Prognosis; Rats, Hairless; Reactive Oxygen Species; Skin

Severe acute pancreatitis (SAP) is a condition associated with high rates of mortality and lengthy hospital stays. In the current study, SAP mouse models were established in BALB/c wild-type and P21-activated kinase 1 (PAK1) knockdown mice with the objective of determining the expression of microRNA-542-5p (miR-542-5p) and the subsequent elucidation of the mechanism by which it influences acute lung injury (ALI) by mediating mitogen-activated protein kinase (MAPK) signaling and binding to PAK1. The targeting relationship between miR-542-5p and PAK1 was verified using the bioinformatics prediction website and by the means of a dual-luciferase reporter assay. Following the SAP model establishment, the mice were assigned into various groups with the introduction of different mimic and inhibitors in an attempt to investigate the effects involved with miR-542-5p on inflammatory reactions among mice with SAP-associated ALI. Our results indicated that PAK1 was targeted and negatively mediated by miR-542-5p. Mice with SAP-associated ALI exhibited an increased wet-to-dry weight ratio, myeloperoxidase activity, serum amylase activity, TNF-α, interleukin-1 beta (IL-1β), and intercellular adhesion molecule-1 (ICAM-1) contents, p-p38MAPK, p-ERK1/2, and p-JNK protein levels as well as PAK1 positive expression, while decreased miR-542-5p levels were observed. Functionally, overexpression of miR-542-5p improves ALI in mice with SAP via inhibition of the MAPK signaling pathway by binding to PAK1.Based on the evidence from experimental models, miR-542-5p was shown to improve ALI among mice with SAP, while suggesting that the effect may be related to the inactivation of the MAPK signaling pathway and downregulation of PAK1 gene. Thus, miR-542-5p could serve as a promising target for ALI treatment.

Topics: Acute Lung Injury; Amylases; Animals; Disease Models, Animal; Edema; Gene Knockdown Techniques; Intercellular Adhesion Molecule-1; Interleukin-1beta; Male; MAP Kinase Signaling System; Mice; Mice, Inbred BALB C; MicroRNAs; Mitogen-Activated Protein Kinases; NIH 3T3 Cells; p21-Activated Kinases; p38 Mitogen-Activated Protein Kinases; Pancreatitis; Peroxidase; Tumor Necrosis Factor-alpha

Inflammatory bowel diseases [IBD] represent a challenging health issue with a complex aetiology involving genetic and environmental parameters. Although our understanding of the pathophysiology of IBD has improved, much remains to be explored. In this context, bioactive lipids, more specifically oxysterols, i.e. oxygenated derivatives of cholesterol, represent an interesting avenue to investigate. Indeed, oxysterols or their receptors are involved in inflammation and immune regulation. Therefore, we set out to study the oxysterome in IBD.. We used both high-performance liquid chromatograph/mass spectroscopy and molecular biology tools to quantify oxysterol levels and the expression of their metabolic enzymes in several models of murine colitis [both acute and chronic], as well as in colon biopsies from patients with Crohn's disease and ulcerative colitis.. We found that the oxysterome is altered in IBD, in both acute and chronic murine models as well as in human IBD. Two of the oxysterols quantified, 4β-hydroxycholesterol and 25-hydroxycholesterol, were consistently altered in all our models and therefore could be of interest in this context. Hence, we administered them to mice with colitis. While 25-hydroxycholesterol had no effect, 4β-hydroxycholesterol worsened colon inflammation.. Our study addresses the potential involvement of oxysterols in colitis and clearly points towards an active role as well as a clinical relevance for these bioactive lipids.

Topics: Animals; Chromatography, High Pressure Liquid; Colitis; Colitis, Ulcerative; Colon; Crohn Disease; Disease Models, Animal; Humans; Hydroxycholesterols; Liver; Male; Mass Spectrometry; Mice; Mice, Inbred C57BL; Oxysterols; Peroxidase; Real-Time Polymerase Chain Reaction; Transcriptome

Cardiac surgery-associated acute kidney injury (CSA-AKI) is one of the most common postoperative complications in intensive care medicine. Baicalin has been shown to have anti-inflammatory and antioxidant roles in various disorders. We aimed to test the protective effects of baicalin on CSA-AKI using a rat model.. Sprague-Dawley rats underwent 75 min of cardiopulmonary bypass (CPB) with 45 min of cardioplegic arrest (CA) to establish the AKI model. Baicalin was administered at different doses intragastrically 1 h before CPB. The control and treated rats were subjected to the evaluation of different kidney injury index and inflammation biomarkers.. Baicalin significantly attenuated CPB/CA-induced AKI in rats, as evidenced by the lower levels of serum creatinine, serum NGAL, and Kim1. Baicalin remarkably inhibited oxidative stress, reflected in the decreased malondialdehyde and myeloperoxidase activity, and enhanced superoxide dismutase activity and glutathione in renal tissue. Baicalin suppressed the expression of IL-18 and iNOS, and activated the Nrf2/HO-1 pathway.. Our data indicated that baicalin mediated CPB/CA-induced AKI by decreasing the oxidative stress and inflammation in the renal tissues, and that baicalin possesses the potential to be developed as a therapeutic tool in clinical use for CSA-AKI.

Topics: Acute Kidney Injury; Animals; Biomarkers; Cardiac Surgical Procedures; Disease Models, Animal; Enteral Nutrition; Enzyme Inhibitors; Flavones; Flavonoids; Male; Malondialdehyde; Oxidative Stress; Peroxidase; Postoperative Complications; Rats; Rats, Sprague-Dawley

Stroke is devastating with a limited choice of intervention. Many pharmacological entities are available but none of them have evolved successfully in counteracting the multifaceted molecular alterations following stroke. Myeloperoxidase (MPO) has been reported to play an important role in neuroinflammation following neurodegenerative diseases. Therefore, using it as a therapeutic target may be a strategy to confer neuroprotection in stroke. Trigonelline (TG), a plant alkaloid has shown neuroprotective effects in the past. Here we explore its neuroprotective effects and its role in glutathione mediated MPO inhibition in ischemic stroke.. An in silico study was performed to confirm effective TG and MPO interaction. An in vitro evaluation of toxicity with biochemical estimations was performed. Further, in vivo studies were undertaken where rats were treated with 25, 50 and 100 mg/kg TG or standard MPO inhibiting drug4‑Aminobenzoic hydrazide (4‑ABH) at 60 min prior, post immediate and an hour post 90 min of middle cerebral artery occlusion (MCAo) followed by 24 h reperfusion. Rats were evaluated for neurodeficit and motor function tests. Brains were further harvested for infarct size evaluation, biochemical analysis, and western blot experiments.. TG at 100 mg/kg dose i.p. administered immediately post ischemia confers neuroprotection by reducing cerebral infarct with improvement in motor and neurodeficit scores. Furthermore, elevated nitrite and MDA levels were also found to be reduced in brain regions in the treated group. TG also potentiated intrinsic antioxidant status and markedly inhibited reduced glutathione mediated myeloperoxidase expression in the cortical brain region.. TG confers neuroprotection by reduced glutathione mediated myeloperoxidase inhibition in ischemic stroke.

Topics: Alkaloids; Aniline Compounds; Animals; Antioxidants; Blotting, Western; Brain Ischemia; Cerebral Infarction; Disease Models, Animal; Dose-Response Relationship, Drug; Glutathione; Male; Neuroprotective Agents; Peroxidase; Rats; Rats, Sprague-Dawley; Stroke

To test whether sulpiride (SP), an anti-psychotic and prokinetic drug, shows beneficial effects on experimental murine colitis, a colon-targeted prodrug of SP, 5-(aminoethanoylsulfamoyl)-N-[(1-ethylpyrrolidin-2-yl)methyl]-2-methoxybenzamide (glycylsulpiride (GSP)), was synthesized and its colonic delivery and therapeutic activity against 2,4-dinitrobenzenesulfonic acid (DNBS)-induced rat colitis were assessed. Synthesis of GSP was verified by infrared and proton nuclear magnetic resonance spectroscopy. GSP was converted to SP when incubated with the cecal contents but not when incubated with the small intestinal contents. The percent conversion was about 50.5% at 6 h and 67.7% at 10 h. Colonic delivery of GSP was examined by comparison with sulfasalazine (SSZ), a colon-specific prodrug of 5-aminosalicylic acid currently used for the treatment of inflammatory bowel disease. The two prodrugs accumulated similar concentrations of the corresponding parent drugs in the cecum at 2, 4, and 6 h after oral gavage. Although oral gavage of GSP released millimolar level of SP in the large intestine, SP was hardly detected in the blood. GSP improved colonic damage score and reduced myeloperoxidase activity up to 80.5% in the inflamed colon in a dose-dependent manner. Moreover, GSP was able to reduce the levels of inflammatory mediators in the inflamed colon. Overall, the anti-colitic effectiveness of GSP and SSZ was similar. In conclusion, colonic delivery of SP ameliorates DNBS-induced colitis in rats with no significant systemic absorption of SP. Thus, colon-targeted SP may be therapeutically switched to an anti-colitic drug.

Topics: Animals; Benzamides; Colitis; Colon; Dinitrofluorobenzene; Disease Models, Animal; Dose-Response Relationship, Drug; Down-Regulation; Drug Delivery Systems; Male; Peroxidase; Prodrugs; Rats; Rats, Sprague-Dawley; Sulfasalazine; Sulpiride

Probiotic lactobacilli have an unprecedented history of safe use, although some cases of infections have raised concerns about their safety, and hence, a rigorous screening of any new strain even of Lactobacillus is a must in order to study possible adverse interactions with the host, particularly under unhealthy conditions. The present study was, therefore, undertaken to investigate the safety as well as therapeutic efficacy of probiotic Lactobacillus plantarum MTCC 5690 and L. fermentum MTCC 5689 strains in dextran sodium sulfate (DSS)-induced colitis mouse model. Both MTCC 5690 and MTCC 5689 did not induce any detrimental effect on the colitic mice, as was reflected by normal colon and caecum length, blood biochemistry, hematology, and absence of inflammation. Although translocation of both the strains was observed in extraintestinal organs, probiotic-fed mice had significantly improved intestinal permeability and decreased myeloperoxidase (MPO) activity. Probiotic interventions also led to an improved health index and better growth of colitis mice compared to colitis animals with no probiotic intervention. These results point towards the safe use of L. plantarum MTCC 5690 and L. fermentum MTCC 5689 as biotherapeutics for amelioration of inflammatory conditions after establishing their efficacy in human clinical trials.

Topics: Animals; Colitis; Dextran Sulfate; Disease Models, Animal; Drug Evaluation, Preclinical; Humans; Lactobacillus plantarum; Limosilactobacillus fermentum; Male; Mice; Peroxidase; Probiotics

Acute lung injury (ALI) due to chemotherapy occurs frequently. It presents a challenge for clinicians managing therapies for different types of cancers. Carfilzomib (Kyprolis™) is a new proteasome inhibitor that shows promise for the treatment of relapsing multiple myeloma. However, several cases of severe ALI have raised concern about the use of carfilzomib against relapsed multiple myelomas. To improve the efficacy of carfilzomib, a new anti-inflammatory drug for psoriasis treatment, apremilast (Otezla™) was investigated for its protective effects against carfilzomib-induced ALI in rats. RT-PCR analyses revealed that carfilzomib administration in rats markedly increased the levels of tumor necrosis factor-alpha and nuclear factor-kappa B and myeloperoxidase activity with a concomitant increase in lipid peroxidation. The anti-inflammatory cytokine, interleukin-10, was downregulated following carfilzomib administration. Reduction in glutathione levels indicated diminished cellular antioxidant defenses in response to carfilzomib-induced ALI. ALI was confirmed by histopathological observations in lung tissue slices. Apremilast administration reduced lung inflammation in terms of reduction in myeloperoxidase activity and levels of tumor necrosis factor-alpha and alveolar infiltrating cells. Apremilast reversed all observed toxic effects of carfilzomib and prevented ALI in rats.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Disease Models, Animal; Drug-Related Side Effects and Adverse Reactions; Glutathione; Humans; Interleukin-10; Lipid Peroxidation; Male; Multiple Myeloma; NF-kappa B; Oligopeptides; Peroxidase; Rats; Rats, Inbred Strains; Thalidomide; Tumor Necrosis Factor-alpha; Vascular System Injuries

Hyperin, a flavonoid compound found in natural plants, has been reported that it have anti-inflammatory properties. However, the protective effects and mechanisms of hyperin on acute lung injury have not been reported so far. This research was designed to investigate the protective effects of hyperin on lipopolysaccharide-induced acute lung injury (ALI) in mice. The mice were stimulated with LPS in the presence or absence of hyperin and the MPO activity, lung wet/dry ratio, inflammatory cells in BALF, and cytokines, as well as NF-κB expression were assessed in lung tissue. Results showed that hyperin significantly inhibited LPS-induced histological changes, inflammatory cell infiltration, MPO activity and lung wet/dry ratio. Additionally, hyperin distinctly reduced the production of TNF-α, IL-1β and IL-6 and the activation of NF-κB signaling pathways in LPS-induced ALI in mice. In conclusion, hyperin is an effective suppressor of inflammation and may be a promising potential therapeutic reagent for ALI treatment.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; Cytokines; Disease Models, Animal; Leukocytes; Lipopolysaccharides; Lung; Mice; Peroxidase; Quercetin

Fraxin, the effective component of the Chinese traditional medicine Cortex Fraxini, is reported to have anti-inflammatory effects. This study assessed the anti-inflammatory effect of fraxin on the lipopolysaccharide (LPS)-induced inflammatory response in A549 cells and the protective efficacy on LPS-induced acute lung injury (ALI) in mice. Fraxin reduced LPS-induced TNF-α, IL-6 and IL-1β production in A549 cells and alleviated the LPS-induced wet/dry (W/D) weight ratio and the effects observed via histopathological examination of the lung in vivo. Furthermore, fraxin reduced the protein concentrations in the broncho-alveolar lavage (BAL) fluid and cytokine production in the sera. Fraxin also clearly attenuated the oxidation index, including the activity of myeloperoxidase (MPO), malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione (GSH). Immunohistochemistry analysis showed that fraxin suppressed LPS-induced inflammatory damage. The expression of proteins involved in the NF-κB and NLRP3 inflammatory corpuscle signalling pathways was consistent between the lung tissues and cell samples. Overall, fraxin played a protective role in LPS-induced lung injury by inhibiting the NF-κB and NLRP3 signalling pathways.

Topics: A549 Cells; Acute Lung Injury; Animals; Anti-Inflammatory Agents; Coumarins; Cytokines; Disease Models, Animal; Humans; Inflammation Mediators; Lipopolysaccharides; Male; Medicine, Chinese Traditional; Mice; Mice, Inbred Strains; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Oxidation-Reduction; Peroxidase; Respiratory Mucosa; Signal Transduction

Acute pancreatitis (AP) is an aseptic inflammation characterized with an annual incidence rate, and ~20% patients progressing to severe AP (SAP) with a high mortality rate. Although Qingyi decoction has been frequently used for SAP treatment over the past 3 decades in clinic, the actual mechanism of its protective effects remains unknown. As the major active ingredient of Qingyi decoction, emodin was selected in the present study to investigate the effect of emodin against severe acute pancreatitis (SAP) in rats through NOD‑like receptor protein 3 (NLRP3) inflammasomes. The rats were randomly divided into a sham operation group, an SAP model group induced by a standard retrograde infusion of 5.0% sodium taurocholate into the biliopancreatic duct, and low‑dose (30 mg/kg) and high‑dose (60 mg/kg) emodin‑treated groups. At 12 h after the event, the plasma amylase, lipase, interleukin (IL)‑1β, IL‑18 and myeloperoxidase (MPO) activities were examined. Furthermore, the pathological scores of pancreases were evaluated by hematoxylin and eosin staining. The expression levels of P2X ligand‑gated ion channel 7 (P2X7), NLRP3, apoptosis‑associated speck‑like protein containing a C‑terminal caspase recruitment domain and caspase‑1 were also analyzed by western blot analysis. The data demonstrated that, compared with the SAP group, emodin could significantly relieve the pancreatic histopathology and acinar cellular structure injury, and notably downregulate the plasma amylase and lipase levels, as well as the MPO activities in pancreatic tissues, in a dose‑dependent manner. Furthermore, emodin inhibited the P2X7/NLRP3 signaling pathway followed by the decrease of pro‑inflammatory factors, and the latter is beneficial for the recovery of SAP. Collectively, the data indicated that emodin may be an efficient candidate natural product for SAP treatment.

Topics: Animals; Disease Models, Animal; Drugs, Chinese Herbal; Emodin; Humans; Male; NLR Family, Pyrin Domain-Containing 3 Protein; Pancreatitis; Peroxidase; Plant Extracts; Protective Agents; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P2X7; Rheum; Severity of Illness Index; Signal Transduction; Taurocholic Acid; Treatment Outcome

Intestinal inflammation is a mediator of multiorgan failure in trauma. We have previously shown that histone deacetylase (HDAC6) inhibitors, including ACY1083, improve survival and preserve intestinal tight junction integrity in a rodent model of hemorrhagic shock (HS). However, mechanisms leading to this alleviation in intestinal injury remain poorly defined. In this study, we sought to determine whether HDAC6 inhibition by ACY1083 can attenuate intestinal inflammation and apoptosis in rats subjected to HS.. Sprague Dawley rats were subjected to hemorrhage (40% of total blood volume) followed by intravenous injection of either ACY1083 (30 mg/kg) dissolved in cyclodextrin or cyclodextrin only (vehicle group). Three hours after hemorrhage, blood samples were collected, and small bowel was harvested. Histological effects of ACY1083 on small bowel were examined. Myeloperoxidase (MPO) levels were assessed as a marker for neutrophil infiltration. Whole cell lysates were analyzed for acetylated α-tubulin, metalloproteinase (ADAM) 17, TNF-α, IL-6, and cleaved caspase 3 using Western blot. The levels of ADAM17, TNF-α, and IL-6 in serum were also examined using enzyme-linked immunosorbent assay.. ACY1083 treatment significantly attenuated HS-induced intestinal injury and MPO production. Both systemic and intestinal TNF-α and IL-6 levels were attenuated following ACY1083 administration. Increased acetylation of α-tubulin was observed in rats treated with ACY1083, along with a significantly decreased expression of cleaved caspase 3 following hemorrhage.. Inhibition of HDAC6 with ACY1083 provides intestinal protection by attenuating both the inflammatory and apoptotic responses during HS.

Topics: ADAM17 Protein; Animals; Apoptosis; Blotting, Western; Caspase 3; Disease Models, Animal; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Inflammation; Interleukin-6; Intestines; Male; Peroxidase; Pyridazines; Rats; Rats, Sprague-Dawley; Shock, Hemorrhagic; Tumor Necrosis Factor-alpha

Renal fibrosis is the pathological hallmark of chronic kidney disease (CKD) and manifests as glomerulosclerosis and tubulointerstitial fibrosis. Reactive oxygen species contribute significantly to renal inflammation and fibrosis, but most research has focused on superoxide and hydrogen peroxide (H

Topics: Animals; Cell Movement; Disease Models, Animal; Eosinophil Peroxidase; Eosinophils; Extracellular Matrix Proteins; Female; Fibrosis; Kidney; Male; Mice, Inbred C57BL; Mice, Knockout; Nephritis, Interstitial; Peroxidase; Peroxidases; Peroxidasin; Reactive Oxygen Species; Signal Transduction; Ureteral Obstruction

Hydrogen-rich saline (HRS) has antioxidative, anti-inflammatory and anti-apoptotic properties. We investigated the effects of hydrogen on hepatic ischemia-reperfusion (I/R) and laparoscopic hepatectomy in swine.. Twenty-one healthy Bama miniature pigs were randomly divided into the sham group, ischemia-reperfusion injury (IRI) group, HRS-5 (5 mL/kg) group, and HRS-10 (10 mL/kg) group. HRS was injected through the portal vein 10 min before reperfusion and at postoperative day 1, 2 and 3. The roles of HRS on oxidative stress, inflammatory response and liver regeneration were studied.. Compared with the IRI group, HRS treatment attenuated oxidative stress by increasing catalase activity and reducing myeloperoxidase. White blood cells in the HRS-10 group were reduced compared with the IRI group (P < 0.01). In the HRS-10 group, interleukin-1 beta, interleukin-6 and tumor necrosis factor alpha, C-reactive protein and cortisol were downregulated, whereas interleukin-10 was upregulated. In addition, HRS attenuated endothelial cell injury and promoted the secretion of angiogenic cytokines, including vascular endothelial growth factor, angiopoietin-1 and angiopoietin-2. HRS elevated the levels of hepatocyte growth factor, Cyclin D1, proliferating cell nuclear antigen, Ki-67 and reduced the secretion of transforming growth factor-beta.. HRS treatment may exert a protective effect against I/R and hepatectomy-induced hepatic damage by reducing oxidative stress, suppressing the inflammatory response and promoting liver regeneration.

Topics: Angiogenic Proteins; Animals; Anti-Inflammatory Agents; Antioxidants; Catalase; Cell Cycle Proteins; Disease Models, Animal; Hepatectomy; Inflammation Mediators; Laparoscopy; Liver; Liver Diseases; Liver Regeneration; Oxidative Stress; Peroxidase; Reperfusion Injury; Saline Solution; Swine; Swine, Miniature; Time Factors

Platelets store large amounts of serotonin that they release during thrombus formation or acute inflammation. This facilitates hemostasis and modulates the inflammatory response.. Infarct size, heart function, and inflammatory cell composition were analyzed in mouse models of myocardial reperfusion injury with genetic and pharmacological depletion of platelet serotonin. These studies were complemented by in vitro serotonin stimulation assays of platelets and leukocytes in mice and men, and by measuring plasma serotonin levels and leukocyte activation in patients with acute coronary syndrome.. Platelet-derived serotonin induced neutrophil degranulation with release of myeloperoxidase and hydrogen peroxide (H. Taken together, we identify serotonin as a potent therapeutic target in neutrophil-dependent thromboinflammation during myocardial reperfusion injury.

Topics: Acute Coronary Syndrome; Animals; Blood Platelets; Case-Control Studies; CD11b Antigen; Cell Degranulation; Disease Models, Animal; Humans; Hydrogen Peroxide; Mice, Inbred C57BL; Mice, Knockout; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Neutrophils; Peroxidase; Serotonin; Tryptophan Hydroxylase

Vanillin is used in a variety of food, chemical, and pharmaceutical applications, and exhibits anti-inflammatory properties. However, there are no reports about the effects of vanillin on lipopolysaccharide (LPS)-induced mastitis. In this study, we explored the effects of vanillin on the subsequent inflammatory response and blood-milk barrier in LPS-induced mastitis. Results showed that vanillin suppressed the inflammatory response by a) inhibiting myeloperoxidase activity; b) decreasing the production of pro-inflammatory mediators which include tumor necrosis factor alpha (Tnf-α; from 128.5 ± 14.59 to 67.51 ± 10.88,pg/mL, P < 0.01), interleukin-6 (Il-6; from 531.5 ± 196.4 to 109.3 ± 24.14, pg/mL, P < 0.05), interleukin-1β (Il-1β; from 2569 ± 1648 to 731.8 ± 171.7, pg/mL, P < 0.05), inducible nitric oxide synthase (Inos), and cyclooxygenase-2 (Cox-2); and c) repairing the blood-milk barrier by increasing the protein levels of the tight junction proteins, including zona occludens 1 (Zo-1), claudin-3, and occludin. In vitro experiment, Vanillin can inhibit LPS-induced inflammation and enhance the protein levels of tight junction proteins. Further studies have shown that vanillin inhibits inflammation by inhibiting mitogen-activated protein kinases (MAPKs) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathways. Our findings showed that vanillin protects mammary gland from LPS-induced mastitis by enhancing the blood-milk barrier and inhibiting the inflammatory response.

Topics: Animals; Anti-Inflammatory Agents; Benzaldehydes; Cells, Cultured; Cyclooxygenase 2; Cytokines; Disease Models, Animal; Epithelial Cells; Female; Inflammation Mediators; Lactation; Lipopolysaccharides; Mammary Glands, Animal; Mastitis; Mice, Inbred BALB C; Mitogen-Activated Protein Kinases; NF-kappa B; Nitric Oxide Synthase Type II; Peroxidase; Pregnancy; Signal Transduction; Tight Junction Proteins; Tight Junctions

Purpose To investigate the association of inflammation and brain edema in a cerebral malaria (CM) mouse model with a combination of bis-5-hydroxy-tryptamide-diethylenetriaminepentaacetate gadolinium, referred to as MPO-Gd, and cross-linked iron oxide nanoparticle (CLIO-NP) imaging. Materials and Methods Female wild-type (n = 23) and myeloperoxidase (MPO) knock-out (n = 5) mice were infected with the Plasmodium berghei ANKA strain from May 2016 to July 2018. Seven healthy mice served as control animals. At a Rapid Murine Coma and Behavioral Scale (RMCBS) score of less than 15, mice underwent MRI at 9.4 T and received gadodiamide, MPO-Gd, or CLIO-NPs. T1-weighted MRI was used to assess MPO activity, and T2*-weighted MRI was used to track CLIO-NPs. Immunofluorescent staining and flow cytometric analyses characterized CLIO-NPs, MPO, endothelial cells, and leukocytes. An unpaired, two-tailed Student t test was used to compare groups; Spearman correlation analysis was used to determine the relationship of imaging parameters to clinical severity. Results MPO-Gd enhancement occurred in inflammatory CM hotspots (olfactory bulb > rostral migratory stream > brainstem > cortex, P < .05 for all regions compared with control mice; mean olfactory bulb signal intensity ratio: 1.40 ± 0.07 vs 0.96 ± 0.01, P < .01). The enhancement was reduced in MPO knockout mice (mean signal intensity ratio at 60 minutes: 1.13 ± 0.04 vs 1.40 ± 0.07 in CM, P < .05). Blood-brain barrier compromise was suggested by parenchymal gadolinium enhancement, leukocyte recruitment, and endothelial activation. CLIO-NPs accumulated mainly intravascularly and at the vascular endothelium. CLIO-NPs were also found in the choroid plexus, indicating inflammation of the ventricular system. Blood-cerebrospinal fluid barrier breakdown showed correlation with brain swelling (r

Topics: Animals; Brain; Brain Edema; Disease Models, Animal; Encephalitis; Female; Magnetic Resonance Imaging; Magnetite Nanoparticles; Malaria, Cerebral; Mice; Mice, Inbred C57BL; Mice, Knockout; Peroxidase

Calcineurin inhibitor Tacrolimus, is a potent immunosuppressive drug widely used in order to prevent acute graft rejection. Urinary tract infection (UTI) is the most frequent infectious complication in renal transplant patients and long-term use of Tacrolimus might be involved in higher susceptibility to bacterial infections. It remains largely unknown how Tacrolimus affects the host innate immune response against lower and upper UTI. To address this issue, we used experimental UTI model by intravesical inoculation of uropathogenic E.coli in female wild-type mice pre-treated with Tacrolimus or solvent (CTR). We found that Tacrolimus pre-treated mice displayed higher bacterial loads (cystitis, pyelonephritis and bacteremia) than CTR mice. Granulocytes from Tacrolimus pre-treated mice phagocytized less E. coli, released less MPO and expressed decreased levels of CXCR2 receptor upon infection. Moreover, Tacrolimus reduced TLR5 expression in bladder macrophages during UTI. This immunosuppressive state can be explained by the upregulation of TLR-signaling negative regulators (A20, ATF3, IRAK-M and SOCS1) and parallel downregulation of TLR5 as observed in Tacrolimus treated granulocytes and macrophages. We conclude that Tacrolimus impairs host innate immune responses against UTI.

Topics: Animals; Bacterial Load; Calcineurin Inhibitors; Disease Models, Animal; Escherichia coli Infections; Female; Granulocytes; Immunologic Factors; Immunosuppressive Agents; Mice; Peroxidase; Phagocytosis; Tacrolimus; Urinary Tract Infections; Uropathogenic Escherichia coli

Adhesion formation that occurred after alkali-induced injury of the cecum was used as a novel adhesion model in rats, and it was compared with that of a common adhesion model after abrading the cecum. Using the novel adhesion model, inhibition of adhesion formation by a chymase inhibitor, Suc-Val-Pro-PheP(OPh)2, and by sodium hyaluronate/carboxymethylcellulose (Seprafilm) was evaluated, and their mechanisms were assessed. The degree of adhesion formation was more severe and more stable in the alkali-induced injury model than in the abrasion-induced injury model. Both the chymase inhibitor and Seprafilm showed significant attenuation of the degree of adhesion 14 days after alkali-induced injury. Chymase activity in the cecum was significantly increased after alkali-induced injury, but it was significantly attenuated by the chymase inhibitor and Seprafilm. Myeloperoxidase and transforming-growth factor (TGF)-β levels were significantly increased after alkali-induced injury, but they were attenuated by both the chymase inhibitor and Seprafilm. At the level of the adhesions, the numbers of both chymase-positive cells and TGF-β-positive cells were significantly increased, but their numbers were reduced by the chymase inhibitor and Seprafilm. In conclusion, a chymase inhibitor attenuated the degree of adhesions to the same degree as Seprafilm in a novel peritoneal adhesion model that was more severe and more stable than the common adhesion model, and not only the chymase inhibitor, but also Seprafilm reduced the chymase increase at the adhesions.

Topics: Animals; Carboxymethylcellulose Sodium; Cecum; Chymases; Disease Models, Animal; Gene Expression; Hyaluronic Acid; Male; Peritoneal Diseases; Peroxidase; Protease Inhibitors; Rats; Rats, Sprague-Dawley; Tissue Adhesives; Transforming Growth Factor beta

Inflammatory bowel diseases (IBD) are characterized by repetition of flares and remission periods leading to chronic postinflammatory sequelae. Among postinflammatory sequelae, one-third of patients with IBD are suffering from functional symptoms or psychological comorbidities that persist during remission. The aim of our study was to assess functional and behavioral sequelae of chronic colitis in rats with quiescent intestinal inflammation. Chronic colitis was induced by a weekly intrarectal injection of increasing concentrations of trinitrobenzene sulfonic acid (TNBS) for 3 wk (15-45 mg of TNBS) in 30 rats, whereas the control rats (

Topics: Animals; Anxiety; Behavior, Animal; Colitis; Colon; Cytokines; Disease Models, Animal; Gastrointestinal Motility; Inflammation; Inflammatory Bowel Diseases; Male; Permeability; Peroxidase; Rats; Tight Junction Proteins; Visceral Pain

The Tec kinase family is involved in acute and chronic inflammatory diseases, but its relationship with severe acute pancreatitis (SAP) remains unclear.. To investigate whether Tec tyrosine kinase can be used as a target for severe acute pancreatitis-associated acute lung injury (PALI).. A total of 90 mice were randomly assigned into four groups: SAP (n = 15), control (n = 15), SAP + α-cyano-β-hydroxy-β-methyl-N-(2,5-dibromophenyl)propenamide (LFM-A13) (pretreated with Tec kinase inhibitor LFM-A13, n = 15), and SAP + Tec siRNA (pretreated with PBS/negative control siRNA/Tec siRNA, n = 45). SAP was induced by caerulein and lipopolysaccharide. Animals were sacrificed at 0, 3, 24, 48, and 72 h, respectively. Pathological changes and scores of the lung and pancreas were determined using hematoxylin-eosin staining. Expression of Tec and phosphorylated Tec (p-Tec) were examined by real-time polymerase chain reaction, Western blot, and immunoprecipitation. Serum levels of amylase, myeloperoxidase, and pro-inflammatory cytokines were measured by ELISA.. The expression of Tec in lung tissue was significantly higher in the SAP group than in the control group (p < 0.05), and p-Tec expression gradually increased with time. Furthermore, p-Tec expression was significantly lower in the SAP + LFM-A13 group than in the SAP group (p < 0.05); however, Tec expression did not vary. Tec inhibitors, LFM-A13 and Tec siRNA, alleviated pathological damage and release of inflammatory cytokines (p < 0.05).. Tec tyrosine kinase plays a key role in PALI, and is therefore a potential target for clinical treatment.

Topics: Acute Lung Injury; Amides; Amylases; Animals; Anti-Inflammatory Agents; Cytokines; Disease Models, Animal; Inflammation Mediators; Lung; Male; Mice, Inbred C57BL; Neutrophil Infiltration; Nitriles; Pancreatitis; Peroxidase; Phosphorylation; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; RNA Interference; RNA, Small Interfering; Signal Transduction

Aerococcus viridans, a firmicutes bacteria widespread in the environment, is increasingly isolated from humans and animals, especially cows with mastitis. However, its pathogenicity in the bovine mammary gland is unclear. The objective was to explore pathogenic potential of putative virulent and avirulent A. viridans in murine systemic and intramammary infection and mechanistically in cultured bovine mammary epithelial cells (bMECs). Virulence of 9 strains of A. viridans, isolated from subclinical cases of mastitis, was tested for their ability to kill mice when systemically inoculated. Two A. viridans strains, causing highest and lowest survival rate in mice, were selected further as putative avirulent and virulent strains, respectively. Staphylococcus aureus N305 was used as a positive control. After intramammary inoculation, the virulent strain survived and replicated in the murine mammary gland for 9 d, whereas the avirulent strain was eliminated within 3 d. The virulent strain induced a robust inflammatory reaction in the mammary gland, characterized by acute histopathological changes, increased myeloperoxidase activity and higher expression of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) compared to the avirulent strain. The virulent strain produced CAMP factor and exhibited strong cytotoxic effects (LDH release) and adhering and invasive abilities in contact with bMECs. Adhesion and invasion of virulent strain to bMECs was further confirmed by scanning and transmission electron microscopy; there was severe damage, including cytomembrane disruption, swollen mitochondria and loss of organelles. In conclusion, the putative virulent strain of A. viridans activated a strong neutrophil-based inflammatory response in the mammary gland, attributed to its ability to adhere to and invade mammary epithelium.

Topics: Aerococcus; Animals; Bacterial Adhesion; Cattle; Cytokines; Disease Models, Animal; Epithelial Cells; Female; Gram-Positive Bacterial Infections; Inflammation; Mammary Glands, Animal; Mastitis; Mastitis, Bovine; Mice; Mice, Inbred BALB C; Neutrophils; Peroxidase; Specific Pathogen-Free Organisms; Staphylococcal Infections; Virulence

Traumatic brain injury (TBI) leads to neuronal damage and neurological dysfunction. The aim of our study was to investigate the antioxidative effect of honokiol on TBI in rats with biochemical, histopathological and immunohistochemical methods.. Sprague-Dawley rats were subjected to TBI with a weight-drop device using 300 g/1 m weight/height impact. Forty-five rats were divided into three groups as control group, TBI group and TBI + honokiol group (5 mg/kg/day, i.p.). Honokiol (5 mg/kg) dissolved in dimethyl sulfoxide (DMSO) was intraperitoneally administered to rats for 7 days after the trauma. At the end of experiment, blood samples were taken from the animals and analysed with various biochemical markers.. Histopathological examination of the trauma group revealed some degenerated pyramidal cells, dilatation and congestion in blood vessels, hyperplasia in endothelial cells, inflammatory cell infiltration around the vein and disruptions in glial extensions. In TBI + honokiol group, pyramidal neurons showed a decrease in degeneration, slight dilatation in blood vessels, improvement of endothelial cells towards the lumen, and reduction of inflammatory cells in the vessel. In TBI + honokiol group, vascular endothelial growth factor expression was positive in the endothelial and few inflammatory cells of the mildly dilated blood vessels. In the blood brain barrier deteriorated after trauma, it was observed that the glial foot processes were positive expression and extended to the endothelial cells in the TBI + honokiol group.. Glial fibrillary acidic protein expression showed a positive reaction in these processes. Considering the important role of antioxidants and inflammatory responses in cerebral damage induced by traumatic head injury, honokiol is thought to be important in decreasing lipid peroxidation, protecting the membrane structure of blood brain barrier, degeneration of neurons and glial cells.

Topics: Animals; Biphenyl Compounds; Blood-Brain Barrier; Brain Injuries, Traumatic; Disease Models, Animal; Glial Fibrillary Acidic Protein; Glutathione Peroxidase; Immunohistochemistry; Lignans; Male; Malondialdehyde; Permeability; Peroxidase; Rats, Sprague-Dawley; Vascular Endothelial Growth Factor A

To investigate whether phenylephrine (PE) inhibits sepsis-induced cardiac dysfunction, cardiac inflammation, and mitochondrial injury through the PI3K/Akt signaling pathway.. A rat model of sepsis was established by cecal ligation and puncture. PE and/or wortmannin (a PI3K inhibitor) were administered to investigate the role of PI3K/Akt signaling in mediating the effects of PE on inhibiting sepsis-induced cardiac dysfunction, cardiac inflammation, and mitochondrial injury. Hematoxylin-eosin staining, echocardiography, and Langendorff system were used to examine the myocardial injury and function. The concentrations of TNF-α and IL-6 were analyzed by enzyme-linked immunosorbent assay. Intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), myeloperoxidase, mitochondria-related fusion/fission proteins, and PI3K/Akt signaling pathway-associated proteins were analyzed by Western blotting.. PE improved the cardiac function and survival in septic rats. PE decreased TNF-α, IL-6, ICAM-1, VCAM-1, and myeloperoxidase contents in the myocardium of septic rats. Meanwhile, PE increased the fusion-related proteins and decreased the fission-related proteins in the myocardial mitochondria of septic rats. On the other hand, PE activated the PI3K/Akt signaling pathway in the cecal ligation and puncture-treated rats, and all the protective effects of PE were abolished by wortmannin.. PE attenuated sepsis-induced cardiac dysfunction, cardiac inflammation, and mitochondrial injury through the PI3K/Akt signaling pathway.

Topics: Animals; Disease Models, Animal; Inflammation Mediators; Isolated Heart Preparation; Male; Mitochondria, Heart; Mitochondrial Dynamics; Mitochondrial Proteins; Myocarditis; Myocytes, Cardiac; Peroxidase; Phenylephrine; Phosphatidylinositol 3-Kinase; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Sepsis; Signal Transduction; Stroke Volume; Ventricular Function, Left

Topics: Animals; Apoptosis; Cytokines; Disease Models, Animal; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Flavanones; Inflammation; Lung; Male; Mice; Mice, Inbred C57BL; Permeability; Peroxidase; Pneumococcal Infections; Pneumonia, Bacterial; Streptococcus pneumoniae

Neuroinflammation plays a prominent role in the pathophysiology and progression of schizophrenia. Thus, suppression of neuroinflammation may retard the progression of the disease. This study was designed to investigate whether morin, a bioactive compound with antipsychotic-like activity could reduce biomarkers of neuroinflammation and neurodegeneration in lipopolysaccharide (LPS)- and ketamine (KET)-induced schizophrenic-like behavior in mice. Animals were treated once daily intraperitoneally with morin (100 mg/kg), haloperidol (1 mg/kg), risperidone (0.5 mg/kg), or saline (10 mL/kg) in combination with LPS (0.1 mg/kg) for 14 consecutive days. However, from days 8-14, overt schizophrenia-like episode was produced with i.p. injection of KET (20 mg/kg) once daily. Schizophrenic-like behaviors: positive (open-field test), negative (social-interaction and social-memory tests) and cognitive (Y-maze test) symptoms were assessed on day 14. Thereafter, the levels and expressions of biomarkers of neuroinflammation were estimated in the striatum (ST), prefrontal cortex (PFC) and hippocampus (HC) using spectrophotometry, ELISA and immunohistochemistry. The effects of morin on cortical pyramidal neurons were estimated using Golgi-impregnation staining technique. LPS in combination with KET significantly (p < 0.05) induced schizophrenia-like behaviors, which was attenuated by morin. Morin significantly (p < 0.05) decreased tumor necrosis factor-α, interleukine-6 levels and myeloperoxidase activity in the ST, PFC and HC of mice treated with LPS + KET. Moreover, morin reduced regional brain expressions of cyclooxygenase-2, inducible nitric oxide synthase and nuclear factor kappa-B, and also rescued loss of pyramidal neurons in the PFC. Taken together, these findings suggest that morin reduces schizophrenic-like symptoms induced by LPS + KET via mechanisms related to inhibition of the release of pro-inflammatory mediators and suppression of degeneration of cortical pyramidal neurons in mice.

Topics: Animals; Antioxidants; Behavior, Animal; Cerebellar Cortex; Disease Models, Animal; Flavonoids; Humans; Inflammation Mediators; Interleukin-6; Ketamine; Lipopolysaccharides; Male; Mice; Neurogenic Inflammation; Peroxidase; Pyramidal Cells; Schizophrenia; Social Behavior; Spinocerebellar Degenerations; Tumor Necrosis Factor-alpha

Baicalein is one of the main active ingredients of Scutellaria baicalensis Georgi. Baicalein has many good biological activities, such as anti-inflammatory, antioxidant and anti-apoptosis. The protective effect of baicalein on myocardial ischemia and reperfusion injury was studied. The results showed that baicalein could decrease the content of MDA (malondialdehyde) and MPO (myeloperoxidase) in serum of rats and increase the level of SOD (superoxide dismutase), which was significantly different from the model group (P<0.05). The results showed that baicalein could enhance the antioxidant capacity and alleviate neutrophil mediated inflammatory injury. Compared with the model group, the SOD activity of baicalein low concentration group (25mg/kg) increased significantly (3.47±0.28). The content of MDA in myocardium of rats with high concentration of baicalein (50mg/kg) decreased significantly (425.87±19.24), whereas he GSH/GSSG ratio increased significantly (30.28+0.48), P<0.05. High concentration of baicalein preconditioning can significantly reduce the release of CK (creatine kinase) and LDH(lactate dehydrogenase) induced by myocardial ischemia/reperfusion injury, reduce the rate of myocardial infarction and reduce the rate of myocardial apoptosis.

Topics: Animals; Antioxidants; Apoptosis; Disease Models, Animal; Dose-Response Relationship, Drug; Flavanones; Male; Malondialdehyde; Myocardial Reperfusion Injury; Peroxidase; Plant Extracts; Protective Agents; Rats, Sprague-Dawley; Scutellaria baicalensis; Superoxide Dismutase

Kalanchoe brasiliensis and Kalanchoe pinnata are used interchangeably in traditional medicine in the treatment of wound healing. In this context, the objective of the present study was to evaluate the local anti-inflammatory activity of a topical formulation containing aqueous extract of both species. The in vivo model used was ear edema induced by croton oil and paw edema induced by carrageenan. The Swiss mice treatments use formulations containing aqueous extract at different concentrations (1.25%, 2.5%, and 5%) or dexamethasone (1 mg/g), all administered topically and immediately after edema induction. The treatment with formulations containing aqueous extract of both species reduced ear and paw edema, besides that, the decrease in edema was evidenced by reduction of myeloperoxidase activity, IL-1β, and TNF-α levels and increase IL-10 levels. In conclusion, the two species showed local anti-inflammatory activity; however K. brasiliensis showed a better result in both edematogenic models since it had activity in the lowest concentration.

Topics: Administration, Cutaneous; Animals; Anti-Inflammatory Agents; Carrageenan; Croton Oil; Dexamethasone; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Female; Inflammation; Interleukin-1beta; Kalanchoe; Male; Mice; Peroxidase; Plant Extracts; Plant Leaves; Tumor Necrosis Factor-alpha; Water

Reduning injection (RDN), a patented Chinese medicine, is broadly used for common cold and lung infection in clinic, but the mechanism underlying its effects on inflammation-related pulmonary injury remains unclear. Paraquat (PQ, bolus 15 mg/kg dose, ip) was administered for acute lung injury induction in mice, which were orally administered dexamethasone (2 mg/kg) or RDN (50 and 100 mg/kg/day) for 5 days. After treatment, plasma and lung tissue samples from the euthanized animals were obtained and analyzed by histological, biochemical and immunoblot assays. Histological observation demonstrated RDN alleviated PQ-induced lung damage. Meanwhile, RDN suppressed myeloperoxidase (MPO) activity, reduced the wet/dry (W/D) ratio and decreased the amounts of total leukocytes and neutrophils. Treatment also markedly decreased the amounts of malondialdehyde, MPO, and inflammatory cytokines while increasing superoxide dismutase activity in comparison with the PQ group. In immunoblot, RDN blocked the phosphorylation levels of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), JNK, ERK, p38, inhibitor of nuclear factor κB kinase and nuclear factor-κB (NF-κB) in lung tissue specimens in PQ-challenged animals, which was further verified in vitro. The above data indicated protective effects for RDN in PQ-induced lung damage, possibly through inhibition of the AMPK/MAPK/NF-κB pathway.

Topics: A549 Cells; Acute Lung Injury; Administration, Oral; AMP-Activated Protein Kinases; Animals; Dexamethasone; Disease Models, Animal; Drugs, Chinese Herbal; Gene Expression Regulation; Humans; Injections, Intraperitoneal; Male; Mice; Mitogen-Activated Protein Kinases; NF-kappa B; Paraquat; Peroxidase; Phosphorylation; Signal Transduction

Mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitors have failed to show clinical benefit in Kirsten rat sarcoma (

Topics: Animals; Benzamides; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Drug Resistance, Neoplasm; Epithelial Cells; Humans; Lung Neoplasms; MAP Kinase Signaling System; Mesoderm; Mice; MicroRNAs; Mitogen-Activated Protein Kinase Kinases; Mutation; Neoplasms; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); Pyrimidines; Receptors, Interleukin-17; Zinc Finger E-box-Binding Homeobox 1

Elevated serum amyloid A (SAA) levels may promote endothelial dysfunction, which is linked to cardiovascular and renal pathologies. We investigated the effect of SAA on vascular and renal function in apolipoprotein E-deficient (ApoE

Topics: Animals; Aorta; Apolipoproteins E; Biomarkers; Blood Vessels; Cytokines; Disease Models, Animal; Disease Susceptibility; Endothelial Cells; Immunohistochemistry; Inflammation Mediators; Kidney Diseases; Kidney Function Tests; Lipids; Macrophages; Male; Mice; Mice, Knockout; Peroxidase; Serum Amyloid A Protein

During the acute stroke phase, neutrophils from the peripheral blood are first to arrive in the ischemic brain, which then attracts other immune cells that exacerbate neuroinflammation in the ischemic tissue. Myosin1f was reported to specifically mediate neutrophil migration in the peripheral tissues, but whether it plays a critical role in the neuroinflammatory response after ischemic stroke remains unknown. In this study, we aim to test the hypothesis that myosin1f-mediated neutrophil migration is critical in acute neuroinflammation induced by ischemic stroke.. Myosin1f. The myosin1f. Myosin1f determines neutrophil migration into the ischemic hemisphere, which directly affects stroke outcome.

Topics: Animals; Bone Marrow Transplantation; Brain Injuries; CD11b Antigen; Cell Movement; Disease Models, Animal; Encephalitis; Flow Cytometry; Gene Expression Regulation; Infarction, Middle Cerebral Artery; Leukocyte Common Antigens; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myosin Type I; Myosins; Neutrophils; Peroxidase; RNA, Messenger; Severity of Illness Index; Time Factors

Sepsis was induced by Cecal Ligation and Perforation (CLP) surgery. Adult male Wistar rats were divided into three groups of eight animals: Sham; CLP and POMx [consumed POMx (250 mg of pomegranate fruit extract/kg/day) for four weeks before CLP].. Peritoneal neutrophil myeloperoxidase activity was significantly lower in POMx compared with Sham and CLP groups (. High dose POMx consumption prior to sepsis induction, suppressed the vital function of neutrophils in early hours after sepsis initiation, resulting in higher oxidative stress. These findings indicate that caution should be made in using high dose pomegranate products. The main message of current study is that such useful compounds as antioxidants including pomegranate juice which have beneficial effects on general health status may have detrimental effects if misused or used in high doses.

Topics: Animals; Disease Models, Animal; Male; Neutrophils; Oxidative Stress; Peroxidase; Plant Extracts; Pomegranate; Rats; Rats, Wistar; Sepsis

Our study aimed to investigate the effects of the polysaccharide-rich extract of

Topics: Animals; Catalase; Disease Models, Animal; Fatigue; Glutathione; Glutathione Peroxidase; Humans; Male; Mice; Mice, Inbred ICR; Peroxidase; Plant Extracts; Poaceae; Polysaccharides; Rhizome; Stress, Physiological; Superoxide Dismutase; Swimming

Hemorrhagic shock (HS) is a life-threatening condition resulting from rapid and significant loss of intravascular volume, leading to hemodynamic instability and death. Inflammation contributes to the multiple organ injury in HS. Type I interferons (IFNs), such as IFN-α and IFN-β, are a family of cytokines that regulate the inflammatory response through binding to IFN-α receptor (IFNAR) which consists of IFNAR1 and IFNAR2 chains. We hypothesized that type I IFNs provoke inflammation and worsen organ injury in HS.. Male C57BL/6 mice (20-25 g) underwent hemorrhage by controlled bleeding via the femoral artery to maintain a mean arterial pressure of 27 ± 2.5 mm Hg for 90 minutes, followed by resuscitation for 30 minutes with two times shed blood volume of Ringer's lactate solution containing 1 mg/kg body weight of anti-IFNAR1 antibody (Ab) or control isotype-matched IgG (IgG). Blood and tissue samples were collected at 20 hours after the resuscitation for various analyses.. The expression of IFN-α and IFN-β mRNAs was significantly elevated in lungs and liver of the mice after HS. The IFNAR1-Ab treatment significantly decreased serum levels of organ injury markers lactate dehydrogenase and aspartate aminotransferase, as well as improved the integrity of lung and liver morphology, compared to the IgG control. The protein levels of proinflammatory cytokines TNF-α and IL-6, and mRNA expression of proinflammatory chemokines monocyte chemoattractant protein (MCP)-1, MCP-2, macrophage inflammatory protein 2 (MIP-2), and keratinocyte cytokine (KC) in the lungs of the HS mice were significantly decreased after treated with IFNAR1-Ab. Moreover, the myeloperoxidase activity and number of apoptotic cells in the lungs of HS mice treated with IFNAR1-Ab were decreased in comparison to the IgG control.. Administration of IFNAR1-Ab reduces inflammation and tissue injury. Thus, type I IFN signaling may be a potential therapeutic target for mitigating organ dysfunction in patients suffering from HS.. Translational animal model.

Topics: Animals; Aspartate Aminotransferases; Disease Models, Animal; In Situ Nick-End Labeling; Inflammation; Interleukin-6; L-Lactate Dehydrogenase; Liver; Lung; Male; Mice; Mice, Inbred C57BL; Multiple Organ Failure; Peroxidase; Real-Time Polymerase Chain Reaction; Receptor, Interferon alpha-beta; Shock, Hemorrhagic; Tumor Necrosis Factor-alpha

The innate immune response plays an important role in the pathophysiology of acute respiratory distress syndrome (ARDS). Glutamine (Gln) decreases lung inflammation in experimental ARDS, but its impact on the formation of extracellular traps (ETs) in the lung is unknown. In a mouse model of endotoxin-induced pulmonary ARDS, the effects of Gln treatment on leukocyte counts and ET content in bronchoalveolar lavage fluid (BALF), inflammatory profile in lung tissue, and lung morphofunction were evaluated in vivo. Furthermore, ET formation, reactive oxygen species (ROS) production, glutathione peroxidase (GPx), and glutathione reductase (GR) activities were tested in vitro. Our in vivo results demonstrated that Gln treatment reduced ET release (as indicated by cell-free-DNA content and myeloperoxidase activity), decreased lung inflammation (reductions in interferon-γ and increases in interleukin-10 levels), and improved lung morpho-function (decreased static lung elastance and alveolar collapse) in comparison with ARDS animals treated with saline. Moreover, Gln reduced ET and ROS formation in BALF cells stimulated with lipopolysaccharide in vitro, but it did not alter GPx or GR activity. In this model of endotoxin-induced pulmonary ARDS, treatment with Gln reduced pulmonary functional and morphological impairment, inflammation, and ET release in the lung.

Topics: Animals; Disease Models, Animal; DNA; Endotoxins; Extracellular Traps; Female; Glutamine; Glutathione Peroxidase; Glutathione Reductase; Inflammation; Interferon-gamma; Interleukin-10; Leukocyte Count; Lung; Male; Mice, Inbred BALB C; Peroxidase; Pneumonia; Pulmonary Alveoli; Reactive Oxygen Species; Respiratory Distress Syndrome

The purpose of the present study was to investigate the effect of carbon monoxide (CO) released from CO‑releasing molecule 2 (CORM‑2) on mice with acute pancreatitis (AP). To perform the investigation, a mouse AP model was established using caerulein. The mice were treated with or without CORM‑2. The survival rate of the mice in the different groups was analyzed, and serum amylase and lipase levels were measured to assess the degree of pancreatic injury. The severity of AP was also evaluated by histological examination, and histopathological scoring of the pancreatic damage was performed. Pancreatic cell apoptosis was analyzed using a terminal deoxynucleotidyl‑transferase‑mediated dUTP nick end labelling assay. The function of the lung and liver was also assessed in the present study. Furthermore, the role of CORM‑2 on oxidative stress, intercellular adhesion molecule 1 (ICAM‑1) and vascular cell adhesion molecule 1 (VCAM‑1) expression, pro‑inflammatory cytokine production, and nuclear factor (NF)‑κB activation in the pancreas of AP mice was determined. The results demonstrated that CORM‑2 reduced the mortality, pancreatic damage, and lung and liver injury of AP mice. CORM‑2 administration also reduced systemic and localized inflammatory cell factors. Furthermore, treatment with CORM‑2 inhibited the expression of ICAM‑1 and VCAM‑1, and the activation of NF‑κB and phosphorylated inhibitor of NF‑κB subunit α, in the pancreas of AP mice. These results indicated that CO released from CORM‑2 exerted protective effects on AP mice, and the beneficial effects were likely due to inhibition of NF‑κB pathway activation.

Topics: Acute Disease; Amylases; Animals; Carbon Monoxide; Ceruletide; Cytokines; Disease Models, Animal; Intercellular Adhesion Molecule-1; Lipase; Lung; Male; Malondialdehyde; Mice; Mice, Inbred C57BL; NF-kappa B; Organometallic Compounds; Oxidative Stress; Pancreas; Pancreatitis; Peroxidase

Wedelolactone, a chemical compound extracted from Wedelia calendulacea or Eclipta alba, has been reported to regulate key steps in inflammation. However, the effects of wedelolactone on fungal keratitis are not known. Hence, we aimed to characterize the impact of wedelolactone in Aspergillus fumigatus keratitis.. Aspergillus fumigatus was used to establish an in vivo mouse model of fungal keratitis and an in vitro model of THP-1 macrophages. Mice and THP-1 macrophages were pre-treated with wedelolactone. Clinical evaluation, myeloperoxidase (MPO) assay, neutrophil staining, western blot and quantitative polymerase chain reaction (qRT-PCR) were used to assess the effect of wedelolactone on A. fumigatus infection. Therapeutic effect of natamycin treatment with or without wedelolactone was measured via slit lamp microscopy.. We confirmed that wedelolactone attenuated the infiltration of neutrophils and decreased MPO level at earlier time points in mice with A. fumigatus keratitis. Pre-treatment with wedelolactone decreased pro-inflammatory cytokine interleukin 1 beta (IL-1β) maturation by inhibiting caspase-1 activity. Combined with natamycin, wedelolactone protected corneal transparency in mouse with fungal keratitis.. Present findings indicated that wedelolactone reduced host immune responses by attenuating neutrophil recruitment and IL-1β maturation in Aspergillus fumigatus keratitis. Wedelolactone combined with an antifungal medicine could be a potential therapy for reducing lesion severity in fungal keratitis.

Topics: Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Cornea; Coumarins; Disease Models, Animal; Eye Infections, Fungal; Female; Humans; Interleukin-1beta; Keratitis; Mice, Inbred C57BL; Natamycin; Neutrophil Infiltration; Peroxidase; THP-1 Cells

The adenosine A2a receptor agonist CGS21680 has been suggested to act as an anti‑inflammatory agent that protects against cardiopulmonary bypass (CPB)‑induced organ injury. However, the therapeutic effects of CGS21680 for CPB‑induced lung injury have not been comprehensively evaluated. Using a juvenile rat model, the present study was designed to evaluated whether CGS21680 attenuates CPB‑induced lung injury. Our juvenile rat CPB model was established by 60 min CPB with or without CGS21680 pretreatment (100 µg/kg, in the CPB priming solution). Rats in the Sham group only underwent cannulation and heparinization. Serum and pulmonary levels of inflammatory markers and histological features of pulmonary tissues were analyzed. All juvenile rats survived following CPB. Significantly elevated serum levels of tumor necrosis factor‑α (TNF‑α), myeloperoxidase (MPO) and interleukin‑1β (IL‑1β), and decreased glutathione peroxidase (GSH‑PX) levels were observed in the CPB group compared to the Sham group (all P<0.05). TNF‑α, MPO and IL‑1β were significantly decreased, while GSH‑PX was markedly increased in the CGS group when compared to the CPB group. Consistently, pulmonary tissues from rats in the CPB group showed considerable amounts of damaged pneumocytes, severe edema, and increased alveolar macrophages, and significantly higher lung injury scores compared to the controls. Collectively, these changes were all further attenuated by CGS21680. Pretreatment with CGS21680 before CPB attenuated pulmonary injury, which may be related to the anti‑inflammatory effects of CGS21680 downstream of A2a receptor activation.

Topics: Adenosine; Adenosine A2 Receptor Agonists; Animals; Cardiopulmonary Bypass; Disease Models, Animal; Humans; Inflammation; Interleukin-1beta; Lung; Lung Injury; Peroxidase; Phenethylamines; Rats; Rats, Sprague-Dawley; Receptor, Adenosine A2A; Tumor Necrosis Factor-alpha

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal).\ \ This article has been retracted at the request of the Editor-in-Chief and authors.\ \ The authors reported that the paper had been submitted without permission of all authors (specifically Professor Wu). When asked to respond to alleged image manipulation by ‘Hoya camphorifolia’ in Fig. 8B and western blots, they responded that they regret the mistakes in figure 8B and that their technical collaborators could not provide the original images of the Western blots in this paper.\ \ The authors apologise for any misconceptions that this paper may have resulted in.

Topics: Animals; Annexin A1; Apoptosis; Disease Models, Animal; Gene Expression Regulation; Humans; Inflammation; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Neutrophil Infiltration; Neutrophils; Peroxidase; Rats; Reperfusion Injury; Signal Transduction; STAT3 Transcription Factor; Transcriptional Activation; Vascular Endothelial Growth Factor A

In this study, Schiff bases of chitosan (CS) were synthesized using citronellal, citral, and their derivatives containing selenium and sulfur. Organoselenium and organosulfur compounds show attractive biological and pharmaceutical activities, which can be beneficial to CS-based materials. From the characterization analyses, it was found that the CS-derivatives containing organoselenium and organosulfur compounds exhibited the highest conversion degrees (23 and 28%). Biological assays were conducted using films prepared by the blending of CS-derivatives and poly(vinyl alcohol). The antimicrobial evaluation indicated that the film prepared with the sulfur-containing CS was the most active against the tested pathogens (Escherichia coli, Staphylococcus aureus, and Candida albicans) since it reduced considerably their counts (42.5%, 17.4%, and 18.7%). Finally, in vivo assays revealed that this film attenuates atopic dermatitis-like symptoms in mice by suppressing the increase of myeloperoxidase (MPO) activity and reactive species (RS) levels induced by 2,4-dinitrochlorobenzene (DNCB). In summary, CS-derivatives containing chalcogens, mainly organosulfur, are potential candidates for biomedical applications such as for the treatment of chronic skin diseases.

Topics: Animals; Anti-Bacterial Agents; Biocompatible Materials; Candida albicans; Chalcogens; Chitosan; Dermatitis, Atopic; Dinitrochlorobenzene; Disease Models, Animal; Escherichia coli; Mice; Mice, Inbred BALB C; Organoselenium Compounds; Peroxidase; Reactive Oxygen Species; Schiff Bases; Staphylococcus aureus

α-Synuclein (αSyn) is central to the neuropathology of Parkinson's disease (PD) due to its propensity for misfolding and aggregation into neurotoxic oligomers. Nitration/oxidation of αSyn leads to dityrosine crosslinking and aggregation. Myeloperoxidase (MPO) is an oxidant-generating enzyme implicated in neurodegenerative diseases. In the present work we have examined the impact of MPO in PD through analysis of postmortem PD brain and in a novel animal model in which we crossed a transgenic mouse expressing the human MPO (hMPO) gene to a mouse expressing human αSyn-A53T mutant (A53T) (hMPO-A53T). Surprisingly, our results show that in PD substantia nigra, the hMPO gene is expressed in neurons containing aggregates of nitrated αSyn as well as MPO-generated HOCl-modified epitopes. In our hMPO-A53T mouse model, we also saw hMPO expression in neurons but not mouse MPO. In the mouse model, hMPO was expressed in neurons colocalizing with nitrated αSyn, carbamylated lysine, nitrotyrosine, as well as HOCl-modified epitopes/proteins. RNAscope in situ hybridization confirmed hMPO mRNA expression in neurons. Interestingly, the hMPO protein expressed in hMPO-A53T brain is primarily the precursor proMPO, which enters the secretory pathway potentially resulting in interneuronal transmission of MPO and oxidative species. Importantly, the hMPO-A53T mouse model, when compared to the A53T model, exhibited significant exacerbation of motor impairment on rotating rods, balance beams, and wire hang tests. Further, hMPO expression in the A53T model resulted in earlier onset of end stage paralysis. Interestingly, there was a high concentration of αSyn aggregates in the stratum lacunosum moleculare of hippocampal CA2 region, which has been associated in humans with accumulation of αSyn pathology and neural atrophy in dementia with Lewy bodies. This accumulation of αSyn aggregates in CA2 was associated with markers of endoplasmic reticulum (ER) stress and the unfolded protein response with expression of activating transcription factor 4 (ATF4), C/EBP homologous protein (CHOP), MPO, and cleaved caspase-3. Together these findings suggest that MPO plays an important role in nitrative and oxidative damage that contributes to αSyn pathology in synucleinopathies.

Topics: Animals; Carbon; Disease Models, Animal; Epitopes; Female; Humans; Male; Maze Learning; Mice; Mice, Transgenic; Motor Disorders; Motor Skills; Neurons; Nitrogen; Oxidative Stress; Parkinson Disease; Peroxidase; Substantia Nigra

Free jejunal flaps are among the most commonly used flaps for esophageal reconstruction. However, ischemia-reperfusion injury caused by warm ischemia seen during transfer limits their use. Iloprost, a prostacyclin analogue, has been shown to reduce ischemia-reperfusion injury in various organs. The authors investigated tissue damage in jejunal flaps with iloprost and ischemic preconditioning and compared the effectiveness of these two modalities.. Thirty-four Sprague-Dawley rats were randomized into five groups: sham, ischemia-reperfusion (control), ischemic preconditioning, iloprost, and ischemic preconditioning plus iloprost. All flaps, except those in the sham group, underwent ischemia for 60 minutes and reperfusion for 2 hours. Flap perfusion was assessed by laser Doppler perfusion monitoring. Histologic sections were scored using the Chiu scoring system. Superoxide dismutase and myeloperoxidase levels were measured spectrophotometrically.. Animals that were administered iloprost and/or underwent ischemic preconditioning had better postischemic recovery of mesenteric perfusion (ischemic preconditioning, 78 percent; iloprost, 83 percent; ischemic preconditioning plus iloprost, 90 percent; versus ischemia-reperfusion, 50 percent; p < 0.05). All intervention groups showed improved histology of jejunal flaps following ischemia-reperfusion injury (ischemic preconditioning, 3; iloprost, 2.3; ischemic preconditioning plus iloprost, 3.2; versus ischemia-reperfusion, 4.7; p < 0.01, p < 0.001, and p < 0.05, respectively). Superoxide dismutase levels were higher in ischemic preconditioning, iloprost plus ischemic preconditioning, and iloprost groups (ischemic preconditioning, 2.7 ± 0.2; ischemic preconditioning plus iloprost, 2.5 ± 0.3; versus ischemia-reperfusion, 1.2 ± 0.1; p < 0.01; iloprost, 2.4 ± 1.1; versus ischemia-reperfusion, 1.2 ± 0.1; p < 0.05). Myeloperoxidase, a marker for neutrophil infiltration, was lower in the iloprost group (iloprost, 222 ± 5; versus ischemia-reperfusion, 291 ± 25; p < 0.05).. This study showed that both iloprost and ischemic preconditioning reduced reperfusion injury in jejunal flaps. Based on histologic results, iloprost may be a novel treatment alternative to ischemic preconditioning.

Topics: Animals; Antioxidants; Biomarkers; Disease Models, Animal; Esophagus; Free Tissue Flaps; Iloprost; Ischemic Preconditioning; Jejunum; Laser-Doppler Flowmetry; Male; Neutrophil Infiltration; Peroxidase; Platelet Aggregation Inhibitors; Random Allocation; Rats, Sprague-Dawley; Reperfusion Injury; Superoxide Dismutase

Ulcerative Colitis (UC) is an Inflammatory Bowel Disease (IBD) characterized by uncontrolled immune response, diarrhoea, weight loss and bloody stools, where sustained remission is not currently achievable. Dextran Sulphate Sodium (DSS)-induced colitis is an animal model that closely mimics human UC. Ultrasound (US) has been shown to prevent experimental acute kidney injury through vagus nerve (VN) stimulation and activation of the cholinergic anti-inflammatory pathway (CAIP). Since IBD patients may present dysfunctional VN activity, our aim was to determine the effects of therapeutic ultrasound (TUS) in DSS-induced colitis.. Acute colitis was induced by 2% DSS in drinking water for 7 days and TUS was administered to the abdominal area for 7 min/day from days 4-10. Clinical symptoms were analysed, and biological samples were collected for proteomics, macroscopic and microscopic analysis, flow cytometry and immunohistochemistry.. TUS attenuated colitis by reducing clinical scores, colon shortening and histological damage, inducing proteomic tolerogenic response in the gut during the injury phase and early recovery of experimental colitis. TUS did not improve clinical and pathological outcomes in splenectomised mice, while α7nAChR (α7 nicotinic acetylcholine receptor - indicator of CAIP involvement) knockout animals presented with disease worsening. Increased levels of colonic F4/80. These results indicate TUS improved DSS-induced colitis through stimulation of the splenic nerve along with possible contribution by VN with CAIP activation. FUND: Intramural Research Programs of the Clinical Centre, the National Institute of Biomedical Imaging and Bioengineering at the NIH and CAPES/Brazil.

Topics: alpha7 Nicotinic Acetylcholine Receptor; Animals; Colitis; Cytokines; Dextran Sulfate; Disease Models, Animal; Humans; Inflammation; Inflammatory Bowel Diseases; Macrophages; Mice; Mice, Knockout; Peroxidase; Proteomics; Ultrasonic Therapy

Asphyxia of newborns is a severe and frequent challenge of the peri- and postnatal period. The purpose of this study was to study early morphological, immunological and structural alterations in lung tissue after asphyxia and hemorrhage (AH).. 44 neonatal piglets (age 32 hrs) underwent asphyxia and hemorrhage (AH) and were treated according to the international liaison committee of resuscitation (ILCOR) guidelines. For this study, 15 piglets (blood transfusion (RBC) n = 9; NaCl n = 6, mean age 31 hrs) were randomly picked. 4 hours after ROSC (return of spontaneous circulation), lung tissue and blood samples were collected.. An elevation of myeloperoxidase (MPO) activity was observed 4 hrs after AH accompanied by an increase of surfactant D after RBC treatment. After AH tight junction proteins Claudin 18 and junctional adhesion molecule 1 (JAM1) were down-regulated, whereas Occludin was increased. Furthermore, after AH and RBC treatment dephosphorylated active form of Connexin 43 was increased.. AH in neonatal pigs is associated with early lung injury, inflammation and alterations of tight junctions (Claudin, Occludin, JAM-1) and gap junctions (Connexin 43) in lung tissue, which contributes to the development of lung edema and impaired function.

Topics: Animals; Animals, Newborn; Asphyxia; Asphyxia Neonatorum; Cell Adhesion Molecules; Claudins; Connexin 43; Disease Models, Animal; Gap Junctions; Lung; Lung Injury; Occludin; Peroxidase; Pulmonary Surfactant-Associated Protein D; Shock, Hemorrhagic; Swine; Tight Junctions

In the lung, chronic alcohol consumption is a risk factor for acute respiratory distress syndrome (ARDS), a disorder that can be fatal due to airspace flooding. The severity of pulmonary edema is controlled by multiple barriers, and in particular the alveolar epithelial barrier and pulmonary microvasculature. However, to date, the effects of chronic alcohol ingestion on both of these barriers in the lung has not been directly and simultaneously measured. In addition the effects of alcohol on systemic, indirect lung injury versus direct injury have not been compared. In this study, we used tissue morphometry and Evans Blue permeability assays to assess the effects of alcohol and endotoxemia injury on pulmonary barrier function comparing intraperitoneal (IP) administration of lipopolysaccharide (LPS) to intratracheal (IT) administration. Consistent with previous reports, we found that in alcohol-fed mice, the alveolar barrier was impaired, allowing Evans Blue to permeate into the airspaces. Moreover, IT administered LPS caused a significant breach of both the alveolar epithelial and vascular barriers in alcohol-fed mice, whereas the endothelial barrier was less affected in response to IP administered LPS. The alveolar barrier of control mice remained intact for both IP and IT administered LPS. However, both injuries caused significant interstitial edema, independently of whether the mice were fed alcohol or not. These data suggest that in order to properly target pulmonary edema due to alcoholic lung syndrome, both the alveolar and endothelial barriers need to be considered as well as the nature of the "second hit" that initiates ARDS.

Topics: Alcoholism; Animals; Disease Models, Animal; Endotoxins; Ethanol; Lipopolysaccharides; Lung; Lung Diseases; Lung Injury; Male; Mice; Mice, Inbred C57BL; Peroxidase; Syndrome

A low fermentable carbohydrate (FODMAP) diet is used in quiescent inflammatory bowel disease when irritable bowel syndrome-like symptoms occur. There is concern that the diet could exacerbate inflammation by modifying microbiota and short-chain fatty acid (SCFA) production. We examined the effect of altering dietary FODMAP content on inflammation in preclinical inflammatory models.. C57BL/6 mice were given 3% dextran sodium sulfate (DSS) in drinking water for 5 days and recovered for 3 weeks (postinflammatory, n = 12), or 5 days (positive-control, n = 12). Following recovery, DSS-treated or control mice (negative-control, n = 12) were randomized to 2-week low- (0.51 g/100 g total FODMAP) or high-FODMAP (4.10 g) diets. Diets mimicked human consumption containing fructose, sorbitol, galacto-oligosaccharide, and fructan. Colons were assessed for myeloperoxidase (MPO) activity and histological damage. Supernatants were generated for perforated patch-clamp recordings and cytokine measurement. Cecum contents were analyzed for microbiota, SCFA, and branched-chain fatty acids (BCFA). Data were analyzed by two-way ANOVA with Bonferroni.. Inflammatory markers were higher in the positive-control compared with negative-control and postinflammatory groups, but no differences occurred between the two diets within each treatment (MPO P > .99, histological scores P > .99, cytokines P > .05), or the perforated patch-clamp recordings (P > .05). Microbiota clustered mainly based on DSS exposure. No difference in SCFA content occurred. Higher total BCFA occurred with the low-FODMAP diet in positive-control (P < .01) and postinflammatory groups (P < .01).. In this preclinical study, reducing dietary FODMAPs did not exacerbate nor mitigate inflammation. Microbiota profile changes were largely driven by inflammation rather than diet. Low FODMAP intake caused a shift toward proteolytic fermentation following inflammation.

Topics: Animals; Colitis; Cytokines; Dextran Sulfate; Dietary Carbohydrates; Disaccharides; Disease Models, Animal; Fatty Acids; Fatty Acids, Volatile; Fermentation; Gastrointestinal Microbiome; Hemiterpenes; Inflammation; Inflammatory Bowel Diseases; Irritable Bowel Syndrome; Isobutyrates; Mice; Monosaccharides; Nociception; Oligosaccharides; Patch-Clamp Techniques; Pentanoic Acids; Peroxidase; RNA, Ribosomal, 16S

Mechanical ventilation is a well-established therapy for patients with acute respiratory failure. However, up to 35% of mortality in acute respiratory distress syndrome may be attributed to ventilation-induced lung injury (VILI). We previously demonstrated the efficacy of the synthetic tripeptide feG for preventing and ameliorating acute pancreatitis-associated lung injury. However, as the mechanisms of induction of injury during mechanical ventilation may differ, we aimed to investigate the effect of feG in a rodent model of VILI, with or without secondary challenge, as a preventative treatment when administered before injury (prophylactic), or as a therapeutic treatment administered following initiation of injury (therapeutic).. Lung injury was assessed following prophylactic or therapeutic intratracheal feG administration in a rodent model of ventilation-induced lung injury, with or without secondary intratracheal lipopolysaccharide challenge.. Prophylactic feG administration resulted in significant improvements in arterial blood oxygenation and respiratory mechanics, and decreased lung oedema, bronchoalveolar lavage protein concentration, histological tissue injury scores, blood vessel activation, bronchoalveolar lavage cell infiltration and lung myeloperoxidase activity in VILI, both with and without lipopolysaccharide. Therapeutic feG administration similarly ameliorated the severity of tissue damage and encouraged the resolution of injury. feG associated decreases in endothelial adhesion molecules may indicate a mechanism for these effects.. This study supports the potential for feG as a pharmacological agent in the prevention or treatment of lung injury associated with mechanical ventilation.

Topics: Administration, Inhalation; Animals; Disease Models, Animal; Lipopolysaccharides; Lung; Male; Oligopeptides; Peroxidase; Platelet Endothelial Cell Adhesion Molecule-1; Pulmonary Edema; Rats, Sprague-Dawley; Respiration, Artificial; Respiratory Mechanics; Vascular Cell Adhesion Molecule-1; Ventilator-Induced Lung Injury

Topics: Animals; Anti-Inflammatory Agents; Disease Models, Animal; Edema; Female; Foot; Formaldehyde; Peroxidase; Rats, Sprague-Dawley; Tannins

Myeloperoxidase (MPO)-ANCA-associated GN is a significant cause of renal failure. Manipulating autoimmunity by inducing regulatory T cells is potentially a more specific and safer therapeutic option than conventional immunosuppression.. To generate MPO-specific regulatory T cells, we used a modified protein-conjugating compound, 1-ethyl-3-(3'dimethylaminopropyl)-carbodiimide (ECDI), to couple the immunodominant MPO peptide (MPO. MPO-Sp but not OVA-Sp administration increased MPO-specific, peripherally derived CD4. These findings in a mouse model indicate that administering apoptotic splenocytes conjugated with the immunodominant MPO peptide suppresses anti-MPO GN by inducing antigen-specific tolerance.

Topics: Animals; Antibodies, Antineutrophil Cytoplasmic; Apoptosis; Autoimmunity; CD4-Positive T-Lymphocytes; Disease Models, Animal; Female; Glomerulonephritis; Green Fluorescent Proteins; Immune Tolerance; Kidney; Kidney Glomerulus; Mice; Mice, Inbred C57BL; Neutrophils; Peroxidase; Spleen; T-Lymphocytes; T-Lymphocytes, Regulatory; Vasculitis

Oxidative stress is one of the major causes of methotrexate induced lung injury (MILI). Alpha-lipoic acid (ALA), which occurs naturally in human food, has antioxidative and anti-inflammatory activities. The aim of this study was to research the potential protective role of ALA on MILI in rats.. Twenty one rats were randomly subdivided into three groups: control (group I), methotrexate (MTX) treated (group II), and MTX+ALA treated (group III). Lung injury was performed with a single dose of MTX (20 mg/kg) to groups 2 and 3. On the sixth day, animals in all groups were sacrificed by decapitation and lung tissue and blood samples were removed for histological examination and also measurement the levels of interleukin-1-beta (IL-1β), malondialdehyde (MDA), glutathione (GSH), tumour necrosis factor-alpha (TNF-α), myeloperoxidase (MPO), and sodium potassium-adenosine triphosphatase (Na+/K+ATPase).. In MTX group tissue GSH, Na+/K+ATPase activities were lower, tissue MDA, MPO and plasma IL-1?, TNF-? were significantly higher than the other groups. Histopathological examination showed that lung injury was less severe in group 2 according to group 3.. Oxidative damage of MTX in rat lung is partially reduced when combined with ALA.

Topics: Animals; Antioxidants; Disease Models, Animal; Glutathione; Humans; Interleukin-1beta; Lung; Lung Injury; Male; Malondialdehyde; Methotrexate; Oxidative Stress; Peroxidase; Rats; Rats, Wistar; Sodium-Potassium-Exchanging ATPase; Thioctic Acid; Tumor Necrosis Factor-alpha

Overpressure blast-wave induced brain injury (OBI) and its long-term neurological outcome pose significant concerns for military personnel. Our aim is to investigate the mechanism of injury due to OBI.. Rats were divided into 3 groups: (1) Control, (2) OBI (exposed 30psi peak pressure, 2-2.5ms), (3) Repeated OBI (r-OBI) (three exposures over one-week period). Lung and brain (cortex and cerebellum) tissues were collected at 24h post injury.. The neurological examination score was worse in OBI and r-OBI (4.2±0.6 and 3.7±0.5, respectively) versus controls (0.7±0.2). A significant positive correlation between lung and brain edema was found. Malondialdehyde (index for lipid peroxidation), significantly increased in OBI and r-OBI groups in cortex (p<0.05) and cerebellum (p<0.01-0.001). The glutathione (endogenous antioxidant) level decreased in cortex (p<0.01) and cerebellum (p<0.05) of r-OBI group when compared with the controls. Myeloperoxidase activity indicating neutrophil infiltration, was significantly (p<0.01-0.05) elevated in r-OBI. Additionally, tissue thromboplastin activity, a coagulation marker, was elevated, indicating a tendency to bleed. NGF and NF-κB proteins along with Iba-1 and GFAP immunoreactivity significantly augmented in the frontal cortex demonstrating microglial activation. Serum biomarkers of injury, NSE, TNF-alpha and leptin, were also elevated.. OBI triggers both inflammation and oxidative injury in the brain. This data in conjunction with our previous observations suggests that OBI triggers a cascade of events beginning with impaired cerebral vascular function leading to ischemia and chronic neurological consequences.

Topics: Animals; Blast Injuries; Blood-Brain Barrier; Brain Edema; Cerebellum; Disease Models, Animal; Frontal Lobe; Gliosis; Glutathione; Inflammation; Leptin; Lung; Male; Malondialdehyde; Microglia; Oxidative Stress; Peroxidase; Rats, Sprague-Dawley; Thromboplastin

We have developed a novel compound from acetylsalicylic acid (ASA) and 2-amino-2-(hydroxymethyl)-1,3-propanediol (Tris) precursors with ASA-like anti-inflammatory efficacy and reduced the mucosa-damaging side-effects. Our aim was to examine local and remote consequences of ASA-Tris administration in 2-,4-,6-trinitrobenzene-sulfonic acid (TNBS)-induced colitis as compared to ASA or mesalamine (5-aminosalicylate) treatment.. Sprague-Dawley rats were randomized to five groups (n = 6, each), and TNBS enemas were performed. Group 1 was the negative control; group 2 was the untreated colitis group. 12 hour after colitis induction repeated doses of ASA, ASA-Tris (both 0.55 mmol/kg) and mesalamine (0.77 mmol/kg) were given 3 times daily for 3 days to groups 3-5. On day 3 of colitis, the in vivo histology of the colon and stomach was investigated. Tissue xanthine-oxidoreductase, myeloperoxidase, nitrite/nitrate changes, and circulating TNF-alpha levels were measured. In addition, liver mitochondria were examined with high-resolution respirometry to analyze alterations in the electron transport chain.. TNBS enema significantly elevated inflammatory enzyme activities, NO production, TNF-alpha concentration, and induced morphological damage in the colon. ASA-treatment reduced the inflammatory marker levels and mucosal injury in the colon, but gastric tissue damage was present. ASA-Tris- and mesalamine-treatments significantly reduced the cytokine levels, inflammatory enzyme activities, and colonic mucosal damage without inducing gastric injury. Also, ASA significantly reduced the Complex IV-linked respiration of liver mitochondria, which was not observed after ASA-Tris-treatment.. As compared to ASA, ASA-Tris conjugation provides significant protection against the colonic injury and cytokine-mediated progression of inflammatory events in experimental colitis without influencing the gastric epithelial structure.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Colitis; Colon; Disease Models, Animal; Intestinal Mucosa; Male; Mesalamine; Methylamines; Nitrates; Nitrites; Peroxidase; Rats; Rats, Sprague-Dawley; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

The aim of this study was to examine whether administration of valproic acid (VPA), a histone deacetylase inhibitor, inhibits proinflammatory mediators and ameliorate visceral vasopermeability both in a rat model of major burn, and also in rat cultured endothelial cells stimulated with permeability evoking mediators. SD rats were subjected to a 50% TBSA full-thickness scald injury, and treated with either saline or VPA (300 mg/kg) intraperitoneally. Pulmonary vascular endothelial growth factor (VEGF), myeloperoxidase (MPO), pulmonary microvascular permeability, water content, and acetylation of histone H3K9 of lungs were evaluated. In addition, pulmonary microvascular endothelial cells (PMECs) from male SD rats were cultured. With then, MPO, VEGF, histone acetylation, and the permeability of PMECs were investigated. Lethal scald injury resulted in a significant increase in microvascular permeability and water content of lung, accompanied by a significant elevation of the content of VEGF and activity of MPO, and a decrease of histone acetylation. VPA treatment significantly alleviated the microvascular permeability and water content of lung, lowered the levels of VEGF and MPO, and promoted acetylation of histone H3K9 following scald injury. Moreover, VPA reduced permeability of monolayer PMECs subjected to scald serum challenge, reduced the level of MPO and VEGF in supernatants, and promoted acetylation of histone H3K9 in PMECs. These results indicated that VPA can protect pulmonary microvascular endothelial barrier, alleviate proinflammatory mediators-evoked vascular hyperpermeability and tissue edema and improve the survival rate of rats subjected to lethal scald injury.

Topics: Animals; Burns; Capillary Permeability; Cell Culture Techniques; Disease Models, Animal; Endothelial Cells; Enzyme Inhibitors; Histone Acetyltransferases; Male; Peroxidase; Rats; Rats, Sprague-Dawley; Valproic Acid; Vascular Endothelial Growth Factor A

Hemorrhagic shock (HS) after tissue trauma increases the complication and mortality rate of polytrauma (PT) patients. Although several murine trauma models have been introduced, there is a lack of knowledge about the exact impact of an additional HS. We hypothesized that HS significantly contributes to organ injury, which can be reliably monitored by detection of specific organ damage markers. Therefore we established a novel clinically relevant PT plus HS model in C57BL/6 mice which were randomly assigned to control, HS, PT, or PT+HS procedure (n = 8 per group). For induction of PT, anesthetized animals received a blunt chest trauma, head injury, femur fracture, and soft tissue injury. HS was induced by pressure-controlled blood drawing (mean arterial blood pressure of 30 mmHg for 60 min) and mice then resuscitated with ionosterile (4 × volume drawn), monitored, and killed for blood and organ harvesting 4 h after injury. After HS and resuscitation, PT+HS mice required earlier and overall more catecholamine support than HS animals to keep their mean arterial blood pressure. HS significantly contributed to the systemic release of interleukin-6 and high mobility group box 1 protein. Furthermore, the histological lung injury score, pulmonary edema, neutrophil influx, and plasma clara cell protein 16 were all significantly enhanced in PT animals in the presence of an additional HS. Although early morphological changes were minor, HS also contributed functionally to remote acute kidney injury but not to early liver damage. Moreover, PT-induced systemic endothelial injury, as determined by plasma syndecan-1 levels, was significantly aggravated by an additional HS. These results indicate that HS adds to the systemic inflammatory reaction early after PT. Within hours after PT, HS seems to aggravate pulmonary damage and to worsen renal and endothelial function which might overall contribute to the development of early multiple organ dysfunction.

Topics: Animals; Bronchoalveolar Lavage; Creatinine; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; HMGB1 Protein; Interleukin-6; Kidney; Mice; Mice, Inbred C57BL; Multiple Trauma; Peroxidase; Random Allocation; Shock, Hemorrhagic

Colon cancer is thought to develop in a stepwise fashion. In this study, the relationship between aberrant crypt foci (ACF) regional distribution and oxidative stress evolution was studied in a murine model of initial colon carcinogenesis induced by dimethylhydrazine (DMH). Mice were given 2 weekly subcutaneous injections of DMH (20 mg/kg) and killed at the 10th, 12th or 14th week. ACF was scored for number, distribution and crypt multiplicity after methylene-blue coloration and histologically analyzed afterwards. Oxidative stress evaluation was assessed through myeloperoxidase activity (MPO), nitric oxide (NO), L-ornithine and malondialdehyde (MDA) levels as well as antioxidant CAT, SOD and GSH. DMH treatment showed a shift from small to large ACF but also from distal to proximal colon between week 10 and 14 (p < 0.05). This was further illustrated histologically with crypt disruption and mucin depletion. Oxidative stress imbalance was observed in all DMH-treated groups. All markers (MPO, MDA and NO) peaked at week 12 (p < 0.01) and decreased at week 14 (p < 0.05) while L-ornithine decreased through all protocol (p < 0.01). Antioxidants decreased in all points (p < 0.05) but only GSH increased at week 14 (p < 0.05). This work provided insight to response-patterns of oxidative stress between distal and proximal colon, showing for the first time a decreasing implication during the development process and suggesting other inflammatory, immunologic or microbiota implication as factors to be considered during chemotherapy approaches.

Topics: 1,2-Dimethylhydrazine; Aberrant Crypt Foci; Animals; Antioxidants; Biomarkers, Tumor; Carcinogenesis; Colon; Colonic Neoplasms; Disease Models, Animal; Female; Malondialdehyde; Mice; Mucins; Nitric Oxide; Ornithine; Oxidative Stress; Peroxidase

Central nervous system (CNS) infections continue to be an important cause of morbidity and mortality, and microbial invasion of the blood-brain barrier (BBB) is considered a prerequisite for CNS infections, which contribute to behavioural abnormalities and disease pathogenesis. Based on this information, the aim of this study was to evaluate whether Pseudomonas aeruginosa causes disruption of the BBB, and to investigate the involvement of cerebral myeloperoxidase (MPO) activity in this process in experimentally infected silver catfish. The permeability of the BBB to Evans blue dye increased in the infected animals on days three and six post-infection (PI) compared to the control group. Moreover, cerebral MPO activity and reactive oxygen species (ROS) levels also increased in the infected animals on days three and six PI compared to the control group. Based on this evidence, we concluded that P. aaeruginosa causes a disruption of the BBB, which may contribute to disease pathogenesis in the CNS. Moreover, the increase in cerebral MPO activity and ROS levels may be considered a pathway involved in BBB breakdown, allowing the passage of bacteria to the CNS.

Topics: Animals; Blood-Brain Barrier; Catfishes; Disease Models, Animal; Fish Diseases; Fish Proteins; Permeability; Peroxidase; Pseudomonas aeruginosa; Pseudomonas Infections; Up-Regulation

We characterized fetal and placental growth and uterine and placental inflammation in pregnant C3H/HeOuJ and C57BL/6J mice (strains with different sensitivities to metabolic and circulatory pathologies), using different uterine ischemia/reperfusion (I/R) protocols, to establish and refine a murine model of I/R-induced fetal growth restriction (FGR). Pregnant C3H/HeOuJ mice on gestation day 15 were subjected to unilateral uterine I/R by (1) total blood flow restriction (TFR) by occlusion of the right ovarian and uterine arteries for 30 minutes, (2) partial flow restriction (PFR) by occlusion of only the right ovarian artery for 30 minutes, or (3) sham surgery. Pregnant C57BL/6J mice were treated the same, but on gestation day 14 and with TFR for only 5 minutes due to high sensitivity of C57BL/6J mice to I/R. Four days post-I/R, the animals were euthanized to determine fetal and placental weight and fetal loss and to assay placental myeloperoxidase (MPO) activity. In C3H/HeOuJ mice, TFR/30 minutes induced significantly ( P < .05) lower fetal and placental weights and higher placental MPO activity, compared to controls. The PFR/30 minutes produced the same effects except placental weights were not reduced. In contrast, in C57BL/6J mice, TFR for only 5 minutes was sufficient to induce FGR and increase fetal loss; while PFR/30 minutes lowered fetal but not placental weights and increased fetal loss but not placental MPO activity. In summary, we present the first published model of I/R-induced FGR in mice. We find that mice of different strains have differing sensitivities to uterine I/R, therefore differing I/R response mechanisms.

Topics: Animals; Chorioamnionitis; Disease Models, Animal; Female; Fetal Growth Retardation; Fetal Weight; Male; Mice, Inbred C3H; Mice, Inbred C57BL; Organ Size; Peroxidase; Placenta; Pregnancy; Reperfusion Injury; Uterine Cervicitis; Uterus

This study aimed to investigate the chemical characteristics and the effects of an orabase gel with Cashew Gum Polysaccharide (CG-P) from Anacardium occidentale L. on alveolar bone loss and relative mRNA expression of TNF-α, IL-1β, RANK, RANKL, and OPG in the periodontal tissue of Wistar rats (Rattus norvegicus) subjected to ligature-induced periodontitis. Crude cashew gum was collected and purified by chemical processes; then, the CG-P was mixed with orabase gel. Female rats were randomly divided into four groups of six animals each: saline 0.9% (Sal Group); orabase gel (Gel Group); 50mg CG-P/1g orabase gel (CG-P50 Group) and 150mg CG-P/1g orabase gel (CG-P150 Group). Periodontitis was induced in the animals; they were treated for 20days with one daily topical application. The purification process of CG-P presented high yield and resulted in a protein-free product. The treatment with CG-P150 (150mg CG-P/1g orabase gel) significantly reduced alveolar bone loss, decreased the relative mRNA expression of TNF-α, IL-1β, RANKL and the RANKL/OPG ratio, and caused a significant decrease in myeloperoxidase activity of the gingival tissue. Thus, the CG-P in orabase represents a potential adjuvant drug for the treatment of periodontitis and possible source of new biotechnological discoveries.

Topics: Alveolar Bone Loss; Anacardium; Animals; Carboxymethylcellulose Sodium; Disease Models, Animal; Female; Gene Expression Regulation; Humans; Inflammation; Interleukin-1beta; Oxidative Stress; Periodontitis; Peroxidase; Polysaccharides; RANK Ligand; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

Acute lung injury (ALI) is a life-threatening syndrome which causes a high mortality rate worldwide. In traditional medicine, lots of aromatic plants-such as some Thymus species-are used for treatment of various lung diseases including pertussis, bronchitis, and asthma. Thymol, one of the primary active constituent derived from Thymus vulgaris (thyme), has been reported to exhibit potent anti-microbial, anti-oxidant, and anti-inflammatory activities in vivo and in vitro. The present study aims to investigate the protective effects of thymol in lipopolysaccharide (LPS)-induced lung injury mice model. In LPS-challenged mice, treatment with thymol (100 mg/kg) before or after LPS challenge significantly improved pathological changes in lung tissues. Thymol also inhibited the LPS-induced inflammatory cells influx, TNF-α and IL-6 releases, and protein concentration in bronchoalveolar lavage fluid (BALF). Additionally, thymol markedly inhibited LPS-induced elevation of MDA and MPO levels, as well as reduction of SOD activity. Further study demonstrated that thymol effectively inhibited the NF-κB activation in the lung. Taken together, these results suggested that thymol might be useful in the therapy of acute lung injury.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Dose-Response Relationship, Drug; Inflammation Mediators; Interleukin-6; Lipopolysaccharides; Lung; Male; Malondialdehyde; Mice, Inbred BALB C; NF-kappa B; Oxidative Stress; Peroxidase; Superoxide Dismutase; Thymol; Tumor Necrosis Factor-alpha

During chronic limb ischemia, oxidative damage and inflammation are described. Besides oxidative damage, the decrease of tissue oxygen levels is followed by several adaptive responses. The purpose of this study was to determine whether supplementation with N-acetylcysteine (NAC) is effective in an animal model of chronic limb ischemia. Chronic limb ischemia was induced and animals were treated once a day for 30 consecutive days with NAC (30mg/kg). After this time clinical scores were recorded and soleus muscle was isolated and lactate levels, oxidative damage and inflammatory parameters were determined. In addition, several mechanisms associated with hypoxia adaptation were measured (vascular endothelial growth factor - VEGF and hypoxia inducible factor - HIF levels, ex vivo oxygen consumption, markers of autophagy/mitophagy, and mitochondrial biogenesis). The adaptation to chronic ischemia in this model included an increase in muscle VEGF and HIF levels, and NAC was able to decrease VEGF, but not HIF levels. In addition, ex vivo oxygen consumption under hypoxia was increased in muscle from ischemic animals, and NAC was able to decrease this parameter. This effect was not mediated by a direct effect of NAC on oxygen consumption. Ischemia was followed by a significant increase in muscle myeloperoxidase activity, as well as interleukin-6 and thiobarbituric acid reactive substances species levels. Supplementation with NAC was able to attenuate inflammatory and oxidative damage parameters, and improve clinical scores. In conclusion, NAC treatment decreases oxidative damage and inflammation, and modulates oxygen consumption under hypoxic conditions in a model of chronic limb ischemia.

Topics: Acetylcysteine; Animals; Disease Models, Animal; Hindlimb; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Interleukin-6; Ischemia; Lactic Acid; Male; Muscle, Skeletal; Nitrates; Nitrites; Oxidative Stress; Oxygen; Oxygen Consumption; Peroxidase; Rats; Rats, Wistar; Thiobarbituric Acid Reactive Substances; Vascular Endothelial Growth Factor A

The present study was designed to investigate the tumor inhibitory potential of bryostatin 1 in a 12‑O‑tetradecanoylphorbol‑13‑acetate (TPA)‑induced mouse model of skin cancer. The radical inhibition potential of various doses of bryostatin 1 was investigated against 2,2‑diphenyl‑1‑picrylhydrazyl (DPPH) bleach in vitro. The DPPH radical potential was observed compared with treatment with 5, 10, 15, 20, 25 and 30 µM doses of bryostatin 1. In vivo, bryostatin 1 prevented the TPA‑mediated increase in the level of H2O2 and myeloperoxidase in mouse epidermal tissue. Pretreatment of the mice with bryostatin 1 (30 µM) followed by administration of TPA reduced the edema, as demonstrated via punched‑out mouse ear tissue, to 7.2 mg, compared with 14 mg in the TPA‑treated group. Treatment with bryostatin 1 prior to TPA administration markedly prevented the inflammation of the skin by inhibiting hyperplasia in the epidermal layer and the aggregation of inflammatory cells. The results demonstrated that treatment of mice with bryostatin 1 at a 30 µM dose prior to TPA administration significantly (P<0.005) inhibited the TPA‑mediated increase in the level of COX‑2. The activity of ornithine decarboxylase, increased by TPA, was additionally inhibited following pretreatment of the mice with bryostatin 1. In the mice treated with bryostatin 1 at 30 µM doses prior to the administration of TPA, the appearance of papillomas was 20%, compared with 100% in the TPA group. Mice pretreated with bryostatin 1 at 30 µM doses prior to TPA administration exhibited the appearance of 0.4 mean papillomas in each animal, compared with 5.2 in the TPA group. Therefore, the results of the present study demonstrated that bryostatin 1 inhibited the development and progression of tumors of skin in the mice, through the prevention of inflammation‑inducing processes and the quenching of radicals. Therefore, bryostatin 1 maybe considered to be adrug of importance in the treatment of skin tumor.

Topics: Animals; Antineoplastic Agents; Bryostatins; Cyclooxygenase 2; Disease Models, Animal; Edema; Female; Mice; Ornithine Decarboxylase; Peroxidase; Skin Neoplasms; Tetradecanoylphorbol Acetate

Chronic endometritis is a continuous inflammation of uterine endometrium. Recent research has shown that higher asymmetric dimethylarginine (ADMA) levels contribute to endothelial dysfunction. In the present study, we tested whether there is a correlation between endometritis and ADMA in LPS-induced endometritis rat and the mechanisms involved. Thirty-six rats were divided into two groups: blank control group and rat model of endometritis group. The entire infused uterus were removed to observe the changes of histopathology, production of myeloperoxidase (MPO), tumor necrosis factor-α (TNF-α), interleukin (IL)-6, 8-isoprostane, and reactive oxygen species (ROS), and gene expression of dimethylarginine dimethylaminohydrolase 2 (DDAH2), protein-methyl transferase 1 (PRMT1), TNF-α, and IL-6. In endometritis rat group, characteristic histopathologic changes in uteri were observed. The uterine 8-isoprostane, ROS, MPO activity, IL-6 and TNF-α concentrations, PRMT1, IL-6, and TNF-α expressions were significantly elevated, and DDAH2 expression was notably reduced in endometritis group compared with control group. The present findings suggest that elevated levels of ADMA are associated with lower DDAH2 and higher PRMT1 in LPS-induced endometritis rat.

Topics: Amidohydrolases; Animals; Arginine; Dinoprost; Disease Models, Animal; Down-Regulation; Endometriosis; Female; Interleukin-6; Lipopolysaccharides; Peroxidase; Protein-Arginine N-Methyltransferases; Rats, Wistar; Reactive Oxygen Species; Tumor Necrosis Factor-alpha; Up-Regulation; Uterus

This study was aimed to investigate the cardioprotective and antioxidant effect of Vaccinium meridionale Swartz in ischemia-induced male albino Wistar strain rats. Rats were grouped into 5 of 6 numbers each. Group I served as a sham, group II served as control and group III, IV, and V served for 1, 10, and 25 mg/kg/d of an extract of Vaccinium meridionale Swartz for 15 consecutive days of treatment. Serum marker enzymes, lipid peroxidation, and myeloperoxidase were increased, whereas antioxidant enzymes were reduced in control due to injury. Increased phenol and anthocyanin contents and increased free radical scavenging activity was noted following treatment. Serum marker enzymes, necrosis, and lipid peroxidation, were reduced, whereas antioxidant enzymes and reduced glutathione were increased. Nitric oxide synthase and Akt expression were also increased following treatment. Taking all these data together, it is suggested that Vaccinium meridionale Swartz may be a potential therapeutic agent for the treatment of ischemic injury.

Topics: Animals; Antioxidants; Biomarkers; Disease Models, Animal; Glutathione; Lipid Peroxidation; Male; Nitric Oxide Synthase; Peroxidase; Plant Extracts; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Reactive Oxygen Species; Reperfusion Injury; Vaccinium

Baicalin exhibits antibacterial, anti‑viral, anti‑oxidative, antipyretic, analgesic, anti‑inflammatory and anti‑tumor properties. The chemical scavenges oxygen free radicals, protects the cardiovascular system and neurons, protects the liver, and has been used for the prevention and treatment of diabetes‑associated complications. The present study investigated the effect of baicalin on severe burn‑induced remote acute lung injury (ALI). The present study demonstrated that baicalin significantly decreased the lung wet‑to‑dry weight ratio, improved pulmonary histological alterations and reduced the expression of high mobility group protein B1 in the rat model of ALI. In addition, treatment with baicalin decreased tumor necrosis factor‑α, interleukin (IL)‑8, IL‑1β and IL‑18 concentrations in the serum, reduced myeloperoxidase activity and malondialdehyde content, and increased the level of superoxide dismutase in the serum in treated model rats with ALI. As a result, baicalin significantly suppressed nucleotide‑binding oligomerization, NACHT, LRR and PYD domains‑containing protein 3 (NLRP3), caspase‑1, nuclear factor‑κB and matrix metalloproteinase‑9 protein expression in the rat model of ALI. The results of the present study suggested that baicalin may serve a protective role against ALI in rats through the NLRP3 signaling pathway.

Topics: Acute Lung Injury; Animals; Biomarkers; Burns; Disease Models, Animal; Enzyme Activation; Female; Flavonoids; Gene Expression; HMGB1 Protein; Matrix Metalloproteinase 9; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Oxidative Stress; Peroxidase; Protective Agents; Rats

Red cell-derived microparticles (RMPs) are potential mediators of transfusion-related acute lung injury (TRALI). The aim of this study was to investigate the effects of microparticles present in red cell concentrates (RCC) on polymorphonuclear neutrophil (PMN) respiratory burst and acute lung injury (ALI) in mice. Microparticles (MPs) in RCC supernatant were quantified using flow cytometry. The priming activity of either isolated MPs or RCC supernatant toward human PMN was measured in vitro. Mice were injected with lipopolysaccharide (LPS), followed by an infusion of either isolated MPs or heat-treated RCC supernatant. The lungs were harvested to assess myeloperoxidase (MPO) activity, histology and pulmonary edema. Protein content in bronchoalveolar lavage fluid (BALF) was measured. The number of RMPs increased significantly during storage. Both isolated MPs and the supernatants from RCCs that had been stored for 28 and 35days effectively primed the PMN respiratory burst. The infusion of isolated MPs or supernatants that had been stored for >28days into LPS-treated mice caused ALI. The filtered supernatant resulted in significantly ameliorated mouse ALI. MPs that accumulate during RCC storage prime the PMN respiratory burst and cause ALI in a two-event mouse model.

Topics: Acute Lung Injury; Animals; Blood Substitutes; Cell-Derived Microparticles; Disease Models, Animal; Erythrocytes; Flow Cytometry; Humans; Immunization; Lipopolysaccharides; Lung; Male; Mice; Mice, Inbred BALB C; Neutrophils; Peroxidase; Respiratory Burst

The prospects for complement-targeted therapy in ANCA-associated vasculitis have been enhanced by a recent clinical trial in which C5a receptor 1 (C5aR1) inhibition safely replaced glucocorticoids in induction treatment. C5aR1 primes neutrophils for activation by anti-neutrophil cytoplasmic antibody (ANCA) and is therefore required in models of glomerulonephritis induced by anti-myeloperoxidase antibody. Although humoral and cellular autoimmunity play essential roles in ANCA-associated vasculitis, a role for C5aR1 in these responses has not been described. Here, we use murine models to dissect the role of C5aR1 in the generation of anti-myeloperoxidase autoimmunity and the effector responses resulting in renal injury. The genetic absence or pharmacological inhibition of C5aR1 results in reduced autoimmunity to myeloperoxidase with an attenuated Th1 response, increased Foxp3

Topics: Animals; Antibodies, Antineutrophil Cytoplasmic; Autoimmunity; Cells, Cultured; Dendritic Cells; Disease Models, Animal; Glomerulonephritis; Immunity, Cellular; Immunity, Humoral; Kidney Glomerulus; Mice, Inbred C57BL; Mice, Knockout; Neutrophil Activation; Neutrophils; Peroxidase; Reactive Oxygen Species; Receptor, Anaphylatoxin C5a; Respiratory Burst; T-Lymphocytes, Regulatory; Th1 Cells

Recent studies suggest that myeloperoxidase (MPO)-dependent oxidative stress plays a significant role in brain injury in stroke patients. We previously showed that

Topics: Animals; Apoptosis; Brain; Cell Differentiation; Cell Proliferation; Disease Models, Animal; Enzyme Inhibitors; Male; Mice; Mice, Inbred C57BL; Microglia; Neural Stem Cells; Neurons; Neutrophils; Oligopeptides; Oxidative Stress; Peroxidase; Stroke; Wnt Signaling Pathway

A various of pharmacological effects of astaxanthin has been confirmed. However, the mechanism underlying protective effect of astaxanthin on acute pancreatitis (AP) induced by cerulein still unclear. The present study is to investigate the mechanism underlying the effect of astaxanthin on autophagy and apoptosis via the JAK/STAT3 pathway.. Intraperitoneal injection of cerulein at hourly intervals followed by lipopolysaccharide injection were used in Balb/C mice. Vehicle or astaxanthin, which intraperitoneal injected in two doses (20 mg/kg and 40 mg/kg), were injected in mice 1 h before the first cerulein injection. At 3 h after the last injection, when the pathological changes were most severe, pancreatic tissue was analyzed by pathologically scored and hematoxylin and eosin (H&E) staining. The severity of AP was assessed by histological grading, proinflammatory cytokine levels, biochemistry, myeloperoxidase (MPO) activity, and analysis of JAK/STAT3 activity.. Astaxanthin administration markedly reduced serum digestive enzyme activities, pancreatic histological scores, proinflammatory cytokine levels (tumor necrosis factor-α (TNF-α), Interleukin-1β (IL-1β), and Interleukin-6 (IL-6)), MPO and JAK/STAT3 activity.. Collectively, these results indicate that astaxanthin inhibits pancreatic injury in AP by targeting JAK/STAT3-mediated apoptosis and autophagy.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents; Apoptosis; Autophagy; Ceruletide; Cytokines; Disease Models, Animal; Humans; Inflammation Mediators; Janus Kinases; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; Pancreas; Pancreatitis; Peroxidase; STAT3 Transcription Factor; Xanthophylls

Diallyl disulfide (DADS) is the main organosulfur ingredient in garlic, with known antioxidant and anti-inflammatory activities. The aim of the present study was to investigate the effect of DADS on reducing the inflammation and redox imbalance in a rat emphysema model that was induced by intraperitoneal injection of cigarette smoke extract (CSE). Briefly, DADS exerted an anti-inflammation effect on emphysema rats through decreasing cell influx in the bronchoalveolar lavage fluid (BALF) and suppressing pro-inflammation cytokine production including tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) via inhibiting the NF-κB pathway. In addition, levels of oxidative stress markers including malondialdehyde (MDA) and myeloperoxidase (MPO) were reduced, while the activities of glutathione (GSH), glutathione peroxidase (GSH-PX), superoxide dismutase (SOD) and total antioxidant capacity (T-AOC) were markedly enhanced by DADS. Moreover, MMP-9 and TIMP-1 expression were down-regulated by DADS. Furthermore, the regulation effects of DADS on CD4⁺ and CD8⁺ T cells were observed. In conclusion, these encouraging findings suggest that DADS could be considered as a promising anti-inflammation and antioxidative agent for the treatment of emphysema.

Topics: Allyl Compounds; Animals; Anti-Inflammatory Agents; Antioxidants; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Disulfides; Down-Regulation; Emphysema; Garlic; Glutathione; Glutathione Peroxidase; Interleukin-1beta; Interleukin-6; Male; Malondialdehyde; Matrix Metalloproteinase 9; NF-kappa B; Nicotiana; Oxidative Stress; Peroxidase; Rats; Rats, Sprague-Dawley; Smoke; Superoxide Dismutase; Tissue Inhibitor of Metalloproteinase-1; Tumor Necrosis Factor-alpha

Acute lung injury (ALI) is a common complication after intestinal ischemia and reperfusion (I/R) injury that can lead to acute respiratory distress syndrome (ARDS). We have previously demonstrated that females are protected against lung damage induced by intestinal I/R through an estrogen mediated mechanism.. To investigate the effect of obesity on ALI induced by intestinal I/R in female mice.. C57Bl/6 female mice were fed with a standard low-fat diet (SD) or a high-fat diet (HFD) for 9 weeks. Intestinal I/R injury was induced by a 45 min occlusion of the mesenteric artery followed by 2 and 24 h of reperfusion.. Significant increase in lung myeloperoxidase expression (MPO) and neutrophil numbers of SD and HFD mice occurred at 2 h and 24 h of reperfusion. Furthermore, HFD mice presented a significant increase in lung eosinophil peroxidase (EPO) expression and eosinophil numbers compared to SD mice. Lung wet/dry weight ratio was significantly greater in HFD mice at 2 and 24 h of reperfusion, accompanied by a significant increase in the expression of inducible NO in the lung tissue and a significant decrease in arterial oxygen saturation at 24 h of reperfusion relative to SD mice.. Obesity predisposes female mice to increased pulmonary oedema and deterioration in gas exchange, which is accompanied by an increase in iNOS expression in the lung.

Topics: Acute Lung Injury; Animals; Diet, High-Fat; Disease Models, Animal; Female; Intestines; Mice; Mice, Inbred C57BL; Neutrophils; Nitric Oxide Synthase Type II; Obesity; Peroxidase; Pulmonary Edema; Pulmonary Gas Exchange; Reperfusion Injury; Sex Factors

The neurokinin 1 receptor (NK1R) plays an important role in the pathogenesis of acute pancreatitis (AP). Maropitant is an NK1R antagonist that is widely used as an antiemetic in dogs and cats. In the present study, we investigated the anti-inflammatory action of maropitant in a mouse model of AP. AP was induced in BALB/c mice by intraperitoneal administration of cerulein, and maropitant was administered subcutaneously at a dose of 8 mg/kg. We assessed the mRNA expression levels of NK1R and substance P (SP) in the pancreatic tissue via real-time reverse transcription polymerase chain reaction. In addition, the effect of maropitant on plasma amylase, lipase, and interleukin-6 (IL-6) levels was measured in each mouse. Inflammatory cell infiltration in the pancreas was assessed by myeloperoxidase (MPO) staining. Our results showed that AP induction significantly elevated the mRNA expression of SP in the pancreatic tissue. Treatment with maropitant significantly lowered plasma amylase and IL-6 levels. In addition, treatment with maropitant inhibited the infiltration of MPO-positive cells in the pancreas. The present study suggests that maropitant possesses an anti-inflammatory activity, in addition to its antiemetic action.

Topics: Acute Disease; Amylases; Animals; Anti-Inflammatory Agents; Disease Models, Animal; Interleukin-6; Male; Mice; Mice, Inbred BALB C; Neurokinin-1 Receptor Antagonists; Pancreatitis; Peroxidase; Quinuclidines; Receptors, Neurokinin-1; Substance P

This study aimed to investigate the anti-inflammatory effect of 4-methylcyclopentadecanone (4-MCPC) in rats suffering from a cerebral ischemia/reperfusion (I/R) injury. In this study, the focal cerebral ischemia in rats was induced by middle cerebral artery occlusion (MCAO) for 2 h, and the rats were treated with 4-MCPC (8 mg/kg) just 0.5 h before reperfusion. The ischemic infarct volume was recorded 24 h after the MCAO. In addition, myeloperoxidase (MPO) activity and TNF-α and IL-1β levels in the ischemic cerebral cortex were determined by ELISA, while nuclear translocation of NF-κB p65 subunit and expression of p-IκBα were investigated by Western blotting. Our results showed that 4-MCPC treatment decreased infarct volume significantly, compared with I/R group (16.8%±7.5% vs. 39.7%±10.9%); it reduced MPO activity (0.43 ± 0.10 vs. 1.00 ± 0.51 U/g) and expression levels of TNF-α (18.90 ± 3.65 vs. 35.87 ± 4.87 ng/g) and IL-1β (1.68 ± 0.23 vs. 2.67 ± 0.38 ng/g) in ischemic brain tissues of rats. Further study revealed that 4-MCPC treatment markedly reduced nuclear translocation of NF-κB p65 subunit and expression of p-IκBα in ischemic cerebral cortex. Taken together, our results suggest that 4-MCPC protects against cerebral I/R injury and displays anti-inflammatory actions through inhibition of the NF-κB signal pathway.

Topics: Animals; Anti-Inflammatory Agents; Cerebral Cortex; Disease Models, Animal; Infarction, Middle Cerebral Artery; Interleukin-1beta; Ketones; Macrocyclic Compounds; Male; Neuroprotective Agents; NF-KappaB Inhibitor alpha; Peroxidase; Phosphorylation; Rats, Sprague-Dawley; Reperfusion Injury; Transcription Factor RelA; Tumor Necrosis Factor-alpha

Studies have signified that high serum cholesterol plays an intriguing role in amyloid β metabolism and accumulation. Ligand activation of pregnane x receptors (PXRs), up-regulates the expression of P- glycoprotein and has a crucial role in amyloid β efflux. The present study has been undertaken to investigate the effect of forskolin, a PXR agonist in experimental dementia.. Wistar rats were allowed free access to cholesterol-rich High Fat Diet (HFD) for 90days to induce dementia. HFD rats were then treated with forskolin (10mg/kg; 20mg/kg) followed by exposure to Morris water maze (MWM) test to deconvolute the mechanistic of learning and memory. An array of biochemical and histopathological tests were performed to demonstrate the extent of damage induced by HFD.. HFD-treated rats exhibited marked accentuation in brain thiobarbituric acid reactive species, Interleukin-1β, tumor necrosis factor-α levels, myeloperoxidase and acetylcholinestrase activity in addition to attenuation of glutathione levels and superoxide dismutase activity as compared to rats fed on normal chow diet. Consistent rise in serum cholesterol level was also indicated. Histopathological examination of cerebral cortex using hematoxylin and eosin and congo red staining methods demonstrated significant neutrophilic incursion and amyloid deposition. Administration of forskolin to HFD treated rats improved memory functions, biochemical and histopathological alterations. Concomitant administration of ketoconazole, a PXR antagonist with forskolin prevented the observed protective effects.. Our findings signify that forskolin defends HFD induced cognitive deficits. Current plethora of results also defines the potential of PXR in neuroprotective action of forskolin in dementia.

Topics: Acetylcholinesterase; Animals; Behavior, Animal; Biomarkers; Brain; Cholesterol, Dietary; Cognition; Colforsin; Cytokines; Dementia; Diet, High-Fat; Disease Models, Animal; Female; Glutathione; GPI-Linked Proteins; Male; Maze Learning; Memory; Neuroprotective Agents; Oxidative Stress; Peroxidase; Pregnane X Receptor; Rats, Wistar; Receptors, Steroid; Signal Transduction; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances

This study aimed to analyze the effects of quercitrin, which has anti-inflammatory properties, on bacterial translocation in inflammatory bowel diseases by using an experimental colitis model.. Forty male Wistar-Albino rats were used in the study. Rats were divided into 4 groups (control, colitis, treatment 1 and 2 groups). The rats in the control group were given normal drinking water. In the colitis group, colitis was induced by 5% DSS in drinking water. The control and colitis groups underwent operation on Day 7. In the 2 treatment groups, 5% DSS was added to drinking water for the first 7 days and the groups were treated with quercitrin at the doses of 1 and 5 mg/kg/day for the following 10 days. Treatment groups operated on Day 18. Blood samples were taken for blood culture and left colectomy was performed. The inflammation in the colon was macroscopically and microscopically evaluated and graded. Tissue samples were taken (liver, spleen and mesenteric lymph nodes (MLN)) for tissue culturing in order to assess bacterial translocation. Tissue myeloperoxidase (MPO), serum tumor necrosis factor-alpha (TNF-α) and plasma endotoxin levels were measured.. When the control and colitis groups were compared, observed that colitis was induced by DSS (p < 0.05). When the colitis and treatment groups were compared, it was found that quercitrin had a significant therapeutic effect (p < 0.05).. In the experimental colitis model established by using DSS, treatment with quercitrin resulted in a histopathological improvement and reduction in biochemical parameters, inflammation and in bacterial translocation (p < 0.05).

Topics: Animals; Anti-Inflammatory Agents; Bacterial Translocation; Biomarkers; Colitis; Colon; Disease Models, Animal; Endotoxins; Inflammation; Male; Peroxidase; Quercetin; Rats; Tumor Necrosis Factor-alpha

It has been demonstrated that tranexamic acid (TXA), a synthetic derivative of lysine, alleviates lung damage in a trauma-hemorrhagic shock (T/HS) model. Nevertheless, the mechanism of TXA against acute lung injury (ALI) has not deeply elaborated. In this study, we generated a T/HS rat model based on previous research, and TXA (50 mg/kg and 100 mg/kg) was intravenously injected into these rats prior to or post T/HS. The results revealed that the decreased survival rate and impaired lung permeability of the rats caused by T/HS were improved by TXA pretreatment or posttreatment. T/HS-triggered over-generation of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in bronchoalveolar fluid and serum was inhibited by TXA, and the enzymatic activity of myeloperoxidase (MPO) in lung tissues was suppressed by TXA as well. Furthermore, TXA treatment deactivated the poly ADP-ribose polymerase-1 (PARP1)/nuclear factor κB (NF-κB) signaling pathway in the lungs of T/HS rats, as evidenced by increased IκBα expression, and decreased cleaved PARP1, p-p65 (Ser276), p-p65 (Ser529), p-IκBα (ser32/ser36), and intercellular adhesion molecule-1. While the expression level of total p65 did not change after T/HS, its DNA binding activity was strengthened. Both TXA pretreatment and posttreatment suppressed this effect on the DNA binding activity of NF-κB. Taken together, our results reveal that administration of TXA effectively relieves T/HS-induced ALI, at least in part, by attenuating the abnormal pulmonary inflammation.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; Disease Models, Animal; DNA; Infusions, Intravenous; Interleukin-6; Lung; Male; Molecular Targeted Therapy; Neoplasm Proteins; NF-kappa B; Nucleocytoplasmic Transport Proteins; Peroxidase; Poly (ADP-Ribose) Polymerase-1; Protein Binding; Rats, Sprague-Dawley; Shock, Hemorrhagic; Signal Transduction; Tranexamic Acid; Tumor Necrosis Factor-alpha; Wounds and Injuries

To develop a new strategy for inflamed site-specific drug delivery in the colon for the treatment of ulcerative colitis (UC), we leveraged on the interaction between myeloperoxidase (MPO) and human serum albumin (HSA) and prepared nanoparticles (HSA NPs) conjugated with 5-aminosalicylic acid (5-ASA). The 5-ASA-HSA NPs (nine molecules of 5-ASA per HSA molecule) were uniform particles with an average particle size of 190 nm, a zeta potential of --11.8 mV, and a polydispersity index of 0.35. This was considered a suitable particle characteristic to pass through the mucus layer and accumulate into the mucosa. The specific interaction between the 5-ASA-HSA NPs and MPO was observed using quartz crystal microbalance analysis in vitro. In addition, the 5-ASA-HSA NPs group containing one thousandth of the dose of the 5-ASA (75 μg/kg) showed significantly lower disease activity index values and colon weight/length ratios in UC model mice as similar to large amount of neat 5-ASA group (75 mg/kg), indicating that the therapeutic effect of the 5-ASA-HSA NP formulation was confirmed in vivo. Microscopic images of tissue sections of colon extracted from UC model mice demonstrated that HSA NPs and MPO were both localized in the colon, and this specific interaction between HSA NPs and MPO would be involved the in the therapeutic effect in vivo. Furthermore, in the 5-ASA and 5-ASA-HSA NPs groups, some inflammatory damage was observed in the colon, but the degree of damage was mild compared with the control and HSA NPs groups, suggesting mucosal repair and replacement with fibrous granulation tissue had occurred. Therefore, these data demonstrated that an HSA NP formulation has the potential to specifically deliver 5-ASA to an inflamed site where MPO is highly expressed.

Topics: Animals; Colitis; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Delivery Systems; Drug Interactions; Humans; Male; Mice; Mice, Inbred BALB C; Nanoparticles; Peroxidase; Random Allocation; Serum Albumin, Human

Ischemia reperfusion injury (IRI) causes postoperative complications and influences the outcome of the patients undergoing liver surgery and transplantation. Postconditioning (PostC) is a known manual conditioning to decrease the hepatic IRI. Here we aimed to optimize the applicable PostC protocols and investigate the potential protective mechanism.. Thirty Sprague-Dawley rats were randomly divided into 3 groups: the sham group (n = 5), standard orthotopic liver transplantation group (OLT, n = 5), PostC group (OLT followed by clamping and re-opening the portal vein for different time intervals, n = 20). PostC group was then subdivided into 4 groups according to the different time intervals: (10 s × 3, 10 s × 6, 30 s × 3, 60 s × 3, n = 5 in each subgroup). Liver function, histopathology, malondialdehyde (MDA), myeloperoxidase (MPO), expressions of p-Akt and endoplasmic reticulum stress (ERS) related genes were evaluated.. Compared to the OLT group, the grafts subjected to PostC algorithm (without significant prolonging the total ischemic time) especially with short stimulus and more cycles (10 s × 6) showed significant alleviation of morphological damage and graft function. Besides, the production of reactive oxidative agents (MDA) and neutrophil infiltration (MPO) were significantly depressed by PostC algorithm. Most of ERS related genes were down-regulated by PostC (10 s × 6), especially ATF4, Casp12, hspa4, ATF6 and ELF2, while p-Akt was up-regulated.. PostC algorithm, especially 10 s × 6 algorithm, showed to be effective against rat liver graft IRI. These protective effects may be associated with its antioxidant, inhibition of ERS and activation of p-Akt expression of reperfusion injury salvage kinase pathway.

Topics: Algorithms; Animals; Constriction; Disease Models, Animal; Endoplasmic Reticulum Stress; Gene Expression Regulation; Ischemic Postconditioning; Liver; Liver Transplantation; Male; Malondialdehyde; Neutrophil Infiltration; Oxidative Stress; Peroxidase; Phosphorylation; Portal Vein; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Reperfusion Injury; Signal Transduction; Time Factors

Oxidative stress and inflammation may play a key role in the pathogenesis of acute pancreatitis (AP). Lycopene, a natural carotenoid, has antioxidant scavenger capacity and inhibits inflammation in many experimental models.. The study was designed to investigate whether lycopene can ameliorate l-arginine-induced pancreatitis in rats and to elucidate the underlying molecular mechanisms of these effects.. Forty-eight adult male Wistar rats were divided into: control group (vehicle, orally, 10 days), AP group (3 g/kg l-arginine, single i.p. injection, on day 10th of the experiment), lycopene group (50 mg/kg) and methylprednisolone group (30 mg/kg). Lycopene and methylprednisolone were given orally, once daily for 10 days prior to l-arginine injection. Rats were sacrificed 24 h after l-arginine injection. Inflammation/oxidative stress and pancreatic markers were assessed. Pancreatic histopathological studies were done.. Lycopene group showed a significant reduction in tumor necrosis factor alpha (TNF-α), myeloperoxidase activity, and down-regulation of inducible nitric oxide synthase (iNOS) gene expression. Pancreatic nitric oxide concentration was reduced and pancreatic GSH was increased in lycopene group. Serum α-amylase and lipase activities were reduced by lycopene treatment. The histology of pancreas was improved in lycopene group as well as methylprednisolone group.. Lycopene prior treatment proved anti-inflammatory and antioxidant effects against AP rat model via different mechanisms.

Topics: Acute Disease; Amylases; Animals; Anti-Inflammatory Agents; Antioxidants; Carotenoids; Disease Models, Animal; Gene Expression; Lycopene; Male; Methylprednisolone; Nitric Oxide Synthase Type II; Oxidative Stress; Pancreas; Pancreatitis; Peroxidase; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

Acute respiratory distress syndrome (ARDS) is a major cause of mortality in critically ill patients. Patients are currently managed by protective ventilation and alveolar recruitment using positive-end expiratory pressure (PEEP). However, the PEEP's effect on both pulmonary metabolism and regional inflammation is poorly understood. Here, we demonstrate the effect of PEEP on pulmonary anaerobic metabolism in mechanically ventilated injured rats, using hyperpolarized carbon-13 imaging. Pulmonary lactate-to-pyruvate ratio was measured in 21 rats; 14 rats received intratracheal instillation of hydrochloric-acid, while 7 rats received sham saline. 1 hour after acid/saline instillation, PEEP was lowered to 0 cmH

Topics: Acute Lung Injury; Animals; Biomarkers; Carbon Isotopes; Disease Models, Animal; Gene Expression; Humans; Hyalin; Hydrochloric Acid; Intercellular Adhesion Molecule-1; Lactic Acid; Lung; Magnetic Resonance Imaging; Male; Peroxidase; Pneumonia; Positive-Pressure Respiration; Pyruvic Acid; Rats; Rats, Sprague-Dawley; Respiration, Artificial; Respiratory Distress Syndrome

Costunolide is known to possess anti-inflammatory and antitumor activity, but its role in tumor angiogenesis, the key step involved in tumor growth and metastasis, and the involved molecular mechanism is still unknown. We aimed to investigate the effects of costunolide on key components of inflammatory angiogenesis in the murine cannulated sponge implant angiogenesis model. Polyester-polyurethane sponges, used as a framework for fibrovascular tissue growth, were implanted in Swiss albino mice and costunolide (5, 10 and 20 mg/kg/day) was administered for 14 days through installed cannula. The implants collected at day 14 post-implantation were processed for the assessment of hemoglobin (Hb), myeloperoxidase (MPO), N-acetylglucosaminidase (NAG) and collagen, which were used as indices for angiogenesis, neutrophil and macrophage accumulation, and extracellular matrix deposition, respectively. Relevant inflammatory, angiogenic and fibrogenic cytokines were also determined. Costunolide treatment attenuated the main components of the fibrovascular tissue, wet weight, vascularization (Hb content), macrophage recruitment (NAG activity), collagen deposition, and the levels of vascular endothelial growth factor (VEGF), interleukin (IL)-1β, IL-6, IL-17, tumor necrosis factor (TNF)-α and transforming growth factor (TGF-β). Regulatory function of costunolide on multiple parameters of the main components of inflammatory angiogenesis has been revealed giving insight into the potential therapeutic benefit underlying the anti-angiogenic actions of costunolide.

Topics: Acetylglucosaminidase; Angiogenesis Inhibitors; Animals; Collagen; Cytokines; Disease Models, Animal; Hemoglobins; Macrophages; Male; Mice; Neovascularization, Pathologic; Neutrophils; Peroxidase; Polyesters; Polyurethanes; Sesquiterpenes

Topics: Alkaloids; Animals; Anti-Inflammatory Agents; Biomarkers; Colitis; Cytokines; Dextran Sulfate; Disease Models, Animal; I-kappa B Proteins; Inflammation Mediators; Intestinal Mucosa; Mice; Peroxidase; Quinolizines

Recent evidence suggests that adaptive immunity develops during abdominal aortic aneurysm evolution. Uncertainties remain about the antigens implicated and their role in inducing rupture. Because antigens from the extracellular matrix (ECM) have been suspected, the aim of this experimental study was to characterize the role of adaptive immunity directed against antigens from the aortic ECM.. In a first step, an experimental model of abdominal aortic aneurysm rupture based on adaptive immunity against the ECM was developed and characterized. Forty 4-week-old male Lewis rats were divided into two groups. In the ECM group (n = 20), rats were presensitized against the guinea pig aortic ECM before implantation of a decellularized aortic xenograft (DAX). In the control group (n = 20), rats were not presensitized before DAX implantation. In each group, half the rats were sacrificed at day 3 to analyze early mechanisms involved after DAX implantation. In a second step, we aimed to assess which ECM component was most efficient in inducing rupture. For this purpose, the nonfibrillar and fibrillar ECM components were sequentially extracted from the guinea pig aortic wall. Forty Lewis rats were then divided into four groups. Each group was presensitized against one ECM component (structural glycoproteins and proteoglycans, collagen, elastin alone, and elastin-associated glycoproteins) before DAX implantation. Apart from those that experienced rupture, rats were sacrificed at day 21. Xenografts were harvested for histologic, immunofluorescence, and conditioned medium analyses.. In total, early aortic rupture occurred in 80% of the ECM group vs 0% of the control group (P < .001). In the ECM group, major circumferential immunoglobulin deposits were observed in combination with the C3 complement fraction, without cell infiltration. Conditioned medium analysis revealed that matrix metalloproteinase 9 and myeloperoxidase levels and elastase activities were significantly increased in this group. Immunofluorescence analysis demonstrated that myeloperoxidase co-localized with tissue-free DNA and histone H4, highlighting local neutrophil activation and formation of neutrophil extracellular traps. Following differential presensitization, it appeared that rats presensitized against structural glycoproteins and proteoglycans were significantly more susceptible to rupture after DAX implantation.. Stimulating adaptive immunity against the aortic ECM, especially structural glycoproteins and proteoglycans, triggers rupture after DAX implantation. Further studies are needed to assess the precise proteins involved.

Topics: Animals; Antibodies; Antigens; Aorta; Aortic Aneurysm, Abdominal; Aortic Rupture; Complement C3; Disease Models, Animal; Extracellular Matrix; Extracellular Matrix Proteins; Extracellular Traps; Guinea Pigs; Heterografts; Histones; Immunity, Humoral; Male; Matrix Metalloproteinase 9; Neutrophil Activation; Neutrophils; Pancreatic Elastase; Peroxidase; Rats, Inbred Lew

Ulcerative colitis (UC) is a chronic relapsing disease without satisfactory treatments, in which intestinal inflammation and disrupted intestinal epithelial barrier are two main pathogeneses triggering UC. Berberrubine (BB) is deemed as one of the major active metabolite of berberine (BBR), a naturally-occurring isoquinoline alkaloid with appreciable anti-UC effect. This study aimed to comparatively investigate the therapeutic effects of BB and BBR on dextran sodium sulfate (DSS)-induced mouse colitis model, and explore the potential underlying mechanism. Results revealed that BB (20 mg/kg) produced a comparable therapeutic effect as BBR (50 mg/kg) and positive control sulfasalazine (200 mg/kg) by significantly reducing the disease activity index (DAI) with prolonged colon length and increased bodyweight as compared with the DSS group. BB treatment was shown to significantly ameliorate the DSS-induced colonic pathological alternations and decreased histological scores. In addition, BB markedly attenuated colonic inflammation by alleviating inflammatory cell infiltration and inhibiting myeloperoxidase (MPO) and cytokines (TNF-α, IFN-γ, IL-1β, IL-6, IL-4 and IL-10) productions in DSS mice. Furthermore, BB treatment substantially upregulated the expression of tight junction (TJ) proteins (zonula occludens-1, zonula occludens-2, claudin-1, occludin) and mRNA expression of mucins (mucin-1 and mucin-2), and decreased the Bax/Bcl-2 ratio. In summary, BB exerted similar effect to its analogue BBR and positive control in attenuating DSS-induced UC with much lower dosage and similar mechanism. The protective effect observed may be intimately associated with maintaining the integrity of the intestinal mucosal barrier and mitigating intestinal inflammation, which were mediated at least partially, via favorable modulation of TJ proteins and mucins and inhibition of inflammatory mediators productions in the colonic tissue. This is the first report to demonstrate that BB possesses pronounced anti-UC effect similar to BBR and sulfasalazine with much smaller dosage. BB might have the potential to be further developed into a promising therapeutic option in the treatment of UC.

Topics: Animals; Berberine; Colitis; Colon; Cytokines; Dextran Sulfate; Disease Models, Animal; Inflammation; Intestinal Mucosa; Male; Mice; Mice, Inbred BALB C; Peroxidase; Tight Junction Proteins; Tight Junctions

The factors that trigger the pathophysiology of Parkinson's disease (PD) are unknown. However, it is suggested that environmental factors, such as exposure to pesticides, play an important role, in addition to genetic predisposition and aging. Early signs of PD can appear in the gastrointestinal (GI) tract and in the olfactory system, preceding the onset of motor impairments by many years. The present study assessed the effects of oral rotenone administration (30 mg/kg) in inducing GI and olfactory dysfunctions associated with PD in mice. Here we show that rotenone transiently increased myeloperoxidase activity within 24 h of administration. Leucocyte infiltration in the colon, associated with histological damage and disrupted GI motility, were observed following treatment with rotenone for 7 days. Moreover, 7 days of treatment with rotenone disrupted olfactory discrimination in mice without affecting social recognition ability. The presence of specific deficits in olfactory function occurred with a concomitant decrease in tyrosine hydroxylase-positive neurons and an increase in serotonin (5-hydroxytryptamine) turnover in the olfactory bulb. These findings suggest that in Swiss mice, exposure to rotenone induces GI and olfactory dysfunction involving immunological and neurotransmitter alterations, similar to early signs of PD. This provides further evidence for the involvement of the gut-brain axis in PD.

Topics: Animals; Brain; Colon; Disease Models, Animal; Gastrointestinal Tract; Inflammation; Mice; Neurons; Olfactory Bulb; Parkinson Disease; Peroxidase; Rotenone

Visceral pain, observed in inflammatory bowel disease (IBD) patients, is a challenging medical problem and remains poorly understood because the mechanisms underlying it are unclear. Emerging evidence indicates that microRNAs (miRNAs) play a crucial role in the pathogenesis of acute and chronic pain. In this study, we aimed to explore the potential role of miR-146a-5p (the mature form of miR-146a) in a mouse model of colitis induced by intracolonic injection of trinitrobenzene sulfonic acid (TNBS). We found that induction of colitis resulted in visceral hyperalgesia manifested by a decreased pain threshold to colorectal distension and upregulation of miR-146a-5p expression in the lumbosacral spinal cord. In situ hybridization and immunohistochemistry results showed that miR-146a-5p was colocalized with neuronal marker NeuN, but not with astrocytic marker GFAP or microglial marker IBA-1. Dual-luciferase reporter assay showed that miR-146a-5p directly targeted the 3'-untranslated region (UTR) of CCL8, which was previously identified as an important regulator of visceral pain. In cultured Neuro-2a cells, TNF-α-induced CCL8 upregulation was decreased by transfection of miR-146a-5p mimic dose-dependently. In vivo, exogenous supplementation of miR-146a-5p by intrathecal miR-146a-5p agomir significantly alleviated visceral pain and decreased CCL8 expression in colitis mice. Furthermore, inhibition of CCL8 expression by CCL8 siRNA relieved colitis-induced visceral nociception. Finally, in naïve mice intrathecal miR-146a-5p antagomir upregulated CCL8 expression and induced visceral pain hypersensitivity, which could be partially rescued by neutralization of CCL8. Taken together, the present findings indicate that miR-146a-5p may be an endogenous suppressor of visceral pain and exogenous supplementation of miR-146a-5p could exert an analgesic effect at least partly by targeting spinal CCL8 expression. Thus, miR-146a-5p may serve as a novel therapeutic target for visceral pain intervention in the context of colitis.

Topics: Animals; Antagomirs; Antibodies; Cells, Cultured; Chemokine CCL8; Colitis; Disease Models, Animal; Gene Expression Regulation; Humans; Hyperalgesia; Male; Mice; Mice, Inbred C57BL; MicroRNAs; Peroxidase; RNA, Small Interfering; Spinal Cord; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha; Up-Regulation; Visceral Pain

Acute lung injury (ALI) arises from uncontrolled pulmonary inflammation with high mortality rates. Atractylodin (Atr) is a polyethylene alkynes and has been reported to possess anti-inflammation effect. Thus, we aimed to investigate the protective effect of Atr on lipopolysaccharide (LPS)-induced inflammatory responses ALI. The results indicated that Atr treatment not only significantly attenuated LPS-stimulated histopathological changes but also lessened the myeloperoxidase (MPO) activity, the wet-to-dry weight ratio of the lungs, protein leakage and infiltration of inflammatory cells. Moreover, Atr inhibited the tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β and monocyte chemoattractant protein (MCP)-1 secretion in BALF. Further study demonstrated that such inhibitory effects of Atr were due to suppression of nucleotide-binding domain-(NOD-) like receptor protein 3 (NLRP3) inflammasome and toll like receptor 4 (TLR4) activation, likely contributing to its anti-inflammatory effects. Collectively, these findings suggest that Atr may be an effective candidate for alleviating LPS-induced inflammatory responses.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; Cytokines; Disease Models, Animal; Furans; Inflammasomes; Lipopolysaccharides; Male; Mice, Inbred BALB C; NLR Family, Pyrin Domain-Containing 3 Protein; Peroxidase; Phytotherapy; Signal Transduction; Toll-Like Receptor 4

Epidemiological studies indicate that the use of artificial sweeteners doubles the risk for Crohn's disease (CD). Herein, we experimentally quantified the impact of 6-week supplementation with a commercial sweetener (Splenda; ingredients sucralose maltodextrin, 1:99, w/w) on both the severity of CD-like ileitis and the intestinal microbiome alterations using SAMP1/YitFc (SAMP) mice.. Metagenomic shotgun DNA sequencing was first used to characterize the microbiome of ileitis-prone SAMP mice. Then, 16S rRNA microbiome sequencing, quantitative polymerase chain reaction, fluorescent in situ hybridization (FISH), bacterial culture, stereomicroscopy, histology, and myeloperoxidase (MPO) activity analyses were then implemented to compare the microbiome and ileitis phenotype in SAMP with that of control ileitis-free AKR/J mice after Splenda supplementation.. Metagenomics indicated that SAMP mice have a gut microbial phenotype rich in Bacteroidetes, and experiments showed that Helicobacteraceae did not have an exacerbating effect on ileitis. Splenda did not increase the severity of (stereomicroscopic/histological) ileitis; however, biochemically, ileal MPO activity was increased in SAMP treated with Splenda compared with nonsupplemented mice (P < 0.022) and healthy AKR mice. Splenda promoted dysbiosis with expansion of Proteobacteria in all mice, and E. coli overgrowth with increased bacterial infiltration into the ileal lamina propria of SAMP mice. FISH showed increase malX gene-carrying bacterial clusters in the ilea of supplemented SAMP (but not AKR) mice.. Splenda promoted gut Proteobacteria, dysbiosis, and biochemical MPO reactivity in a spontaneous model of (Bacteroidetes-rich) ileal CD. Our results indicate that although Splenda may promote parallel microbiome alterations in CD-prone and healthy hosts, this did not result in elevated MPO levels in healthy mice, only CD-prone mice. The consumption of sucralose/maltodextrin-containing foods might exacerbate MPO intestinal reactivity only in individuals with a pro-inflammatory predisposition, such as CD.

Topics: Animals; Bacteroidetes; Crohn Disease; Disease Models, Animal; Dysbiosis; Female; Humans; Ileitis; In Situ Hybridization, Fluorescence; Intestinal Mucosa; Male; Mice; Mice, Inbred AKR; Microbiota; Peroxidase; Proteobacteria; RNA, Ribosomal, 16S; Sucrose; Sweetening Agents

Traumatic spinal cord injury (SCI) results in upregulation of chondroitin sulfate proteoglycans (CSPGs) by reactive glia that impedes repair and regeneration in the spinal cord. Degradation of CSPGs is known to be beneficial in promoting endogenous repair mechanisms including axonal sprouting/regeneration, oligodendrocyte replacement, and remyelination, and is associated with improvements in functional outcomes after SCI. Recent evidence suggests that CSPGs may regulate secondary injury mechanisms by modulating neuroinflammation after SCI. To date, the role of CSPGs in SCI neuroinflammation remains largely unexplored. The recent discovery of CSPG-specific receptors, leukocyte common antigen-related (LAR) and protein tyrosine phosphatase-sigma (PTPσ), allows unraveling the cellular and molecular mechanisms of CSPGs in SCI. In the present study, we have employed parallel in vivo and in vitro approaches to dissect the role of CSPGs and their receptors LAR and PTPσ in modulating the inflammatory processes in the acute and subacute phases of SCI.. In a clinically relevant model of compressive SCI in female Sprague Dawley rats, we targeted LAR and PTPσ by two intracellular functionally blocking peptides, termed ILP and ISP, respectively. We delivered ILP and ISP treatment intrathecally to the injured spinal cord in a sustainable manner by osmotic mini-pumps for various time-points post-SCI. We employed flow cytometry, Western blotting, and immunohistochemistry in rat SCI, as well as complementary in vitro studies in primary microglia cultures to address our questions.. We provide novel evidence that signifies a key immunomodulatory role for LAR and PTPσ receptors in SCI. We show that blocking LAR and PTPσ reduces the population of classically activated M1 microglia/macrophages, while promoting alternatively activated M2 microglia/macrophages and T regulatory cells. This shift was associated with a remarkable elevation in pro-regenerative immune mediators, interleukin-10 (IL-10), and Arginase-1. Our parallel in vitro studies in microglia identified that while CSPGs do not induce an M1 phenotype per se, they promote a pro-inflammatory phenotype. Interestingly, inhibiting LAR and PTPσ in M1 and M2 microglia positively modulates their inflammatory response in the presence of CSPGs, and harnesses their ability for phagocytosis and mobilization. Interestingly, our findings indicate that CSPGs regulate microglia, at least in part, through the activation of the Rho/ROCK pathway downstream of LAR and PTPσ.. We have unveiled a novel role for LAR and PTPσ in regulating neuroinflammation in traumatic SCI. Our findings provide new insights into the mechanisms by which manipulation of CSPG signaling can promote recovery from SCI. More importantly, this work introduces the potential of ILP/ISP as a viable strategy for modulating the immune response following SCI and other neuroinflammatory conditions of the central nervous system.

Topics: Animals; Animals, Newborn; Cell Movement; Cell Polarity; Cells, Cultured; Chondroitin Sulfate Proteoglycans; Culture Media, Conditioned; Cytokines; Disease Models, Animal; Enzyme Inhibitors; Female; Gene Expression Regulation; Inflammation; Microglia; Neural Stem Cells; Peroxidase; Phagocytosis; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Rats; Rats, Sprague-Dawley; Receptor-Like Protein Tyrosine Phosphatases, Class 2; Spinal Cord Injuries

Tocoyena sellowiana (Cham. & Schltdl.) K.Schum is one of the most important families of Brazilian medicinal plants. This study aimed to evaluate the effect of Tocoyena sellowiana (Cham. & Schltdl.) K.Schum ethanolic extract in a pre-clinical trial of periodontitis and to investigate possible mechanisms underlying such effects. Periodontitis was induced in Wistar rats by placing a nylon thread ligature around second upper left molars for 11 days. Rats received (per os) Tocoyena sellowiana (0.1, 1 or 10?mg?kg) or vehicle 1?h before ligature and daily until day 11. Macroscopic, histopathological, and COX-2 immunohistochemical analyses were performed to evaluate the periodontium. The gingival tissue was used to quantify the myeloperoxidase (MPO) activity and interleukin (IL)-1? levels by ELISA. Blood samples were collected to evaluate bone-specific alkaline phosphatase (BALP), the dosage of creatinine, aspartate and alanine transaminases. The liver, kidneys, spleen, and body mass variations were also evaluated. Tocoyena sellowiana decreased bone loss, reduced MPO, IL-1? levels as well as COX-2 immunostaining, and increased BALP activity. Moreover, Tocoyena sellowiana did not alter organs nor body weight. Tocoyena sellowiana reduced bone loss in rats and its efficacy was at least partially dependent upon both IL-1? and cyclooxygenase-2 inhibition.

Topics: Alkaline Phosphatase; Alveolar Bone Loss; Animals; Cyclooxygenase 2; Dinoprostone; Disease Models, Animal; Female; Gingiva; Interleukin-1beta; Organ Size; Periodontitis; Peroxidase; Phytotherapy; Plant Extracts; Rats, Wistar; Rubiaceae

Increased myeloperoxidase (MPO) levels and activity are associated with increased cardiovascular risk among individuals with chronic kidney disease (CKD). However, a lack of good animal models for examining the presence and catalytic activity of MPO in vascular lesions has impeded mechanistic studies into CKD-associated cardiovascular diseases. Here, we show for the first time that exaggerated atherosclerosis in a pathophysiologically relevant CKD mouse model is associated with increased macrophage-derived MPO activity. Male 7-week-old LDL receptor-deficient mice underwent sham (control mice) or 5/6 nephrectomy and were fed either a low-fat or high-fat, high-cholesterol diet for 24 weeks, and the extents of atherosclerosis and vascular reactivity were assessed. MPO expression and oxidation products-protein-bound oxidized tyrosine moieties 3-chlorotyrosine, 3-nitrotyrosine, and

Topics: Animals; Aorta; Atherosclerosis; Blood Urea Nitrogen; Creatinine; Diet, Fat-Restricted; Diet, High-Fat; Dietary Fats; Disease Models, Animal; Disease Progression; Kidney Failure, Chronic; Kidney Function Tests; Lipids; Lipoproteins; Macrophages; Male; Mice; Mice, Knockout; Muscle Proteins; Nephrectomy; Oxidants; Oxidative Stress; Parathyroid Hormone; Peroxidase; Receptors, LDL; Tyrosine; Vasodilation

Acute pancreatitis (AP) is an inflammatory disease mediated by damage in acinar cells and pancreatic inflammation with infiltration of leukocytes. The pancreatic renin-angiotensin system may play an important role in the pathogenesis of AP.. The present study aimed to investigate the possible protective role of captopril (CAP), an angiotensin-converting enzyme inhibitor, in attenuating L-arginine-induced AP rat model and to elucidate the underlying molecular mechanisms.. Forty-eight adult male Wister rats were divided into four equal groups: control group (vehicle, orally for 10 days), AP group (3 g/kg L-arginine, single i.p.) on 10th day of the experiment, CAP group (50 mg/kg captopril, orally, once daily), and MP group (30 mg/kg methylprednisolone, orally, once daily). CAP and MP were administered for 10 days prior to L-arginine injection. Rats were sacrificed 24 h after arginine injection. Inflammatory biomarkers; tumor necrosis factor alpha (TNF-α) concentration, myeloperoxidase (MPO) activity, and inducible nitric oxide synthase (iNOS) gene expression were determined in pancreas. Oxidative stress biomarkers; pancreatic nitric oxide (NO) and reduced glutathione (GSH) concentrations were measured. Moreover, serum α-amylase and lipase activities were measured and histopathological studies of the pancreas were done.. CAP group showed a significant reduction in pancreatic TNF-α concentration, MPO activity, NO concentration, and downregulation of iNOS gene expression compared to AP group. CAP group also showed a significant increase in GSH concentration with amelioration of histological changes of AP as well as MP group.. Captopril treatment showed a protective and comparable effect with MP treatment in AP rat model.

Topics: Acute Disease; alpha-Amylases; Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Inflammatory Agents; Antioxidants; Arginine; Captopril; Cytoprotection; Disease Models, Animal; Glutathione; Lipase; Male; Methylprednisolone; Nitric Oxide; Nitric Oxide Synthase Type II; Pancreas; Pancreatitis; Peroxidase; Rats, Wistar; Renin-Angiotensin System; Signal Transduction; Tumor Necrosis Factor-alpha

Neutrophil-secreted effector molecules are one of the primary causes of tissue damage during corneal inflammation. In the present study, we have investigated the effect of stromal cells in regulating neutrophil expression of tissue-damaging enzymes, myeloperoxidase (MPO), and N-elastase (ELANE).. Bone marrow-purified nonhematopoietic mesenchymal stromal cells and formyl-methionyl-leucyl-phenylalanine-activated neutrophils were cocultured in the presence or absence of Transwell inserts for 1 hour. Neutrophil effector molecules, MPO and ELANE, were quantified using ELISA. In mice, corneal injury was created by mechanical removal of the corneal epithelium and anterior stroma approximating one third of total corneal thickness, and mesenchymal stromal cells were then intravenously injected 1 hour post injury. Corneas were harvested to evaluate MPO expression and infiltration of CD11b+Ly6G+ neutrophils.. Activated neutrophils cocultured with mesenchymal stromal cells showed a significant 2-fold decrease in secretion of MPO and ELANE compared to neutrophils activated alone (P < 0.05). This suppressive effect was cell-cell contact dependent, as stromal cells cocultured with neutrophils in the presence of Transwell failed to suppress the secretion of neutrophil effector molecules. Following corneal injury, stromal cell-treated mice showed a significant 40% decrease in MPO expression by neutrophils and lower neutrophil frequencies compared to untreated injured controls (P < 0.05). Reduced MPO expression by neutrophils was also accompanied by normalization of corneal tissue structure following stromal cell treatment.. Mesenchymal stromal cells inhibit neutrophil effector functions via direct cell-cell contact interaction during inflammation. The current findings could have implications for the treatment of inflammatory ocular disorders caused by excessive neutrophil activation.

Topics: Animals; CD11b Antigen; Cell Communication; Coculture Techniques; Corneal Injuries; Disease Models, Animal; Inflammation; Leukocyte Elastase; Mesenchymal Stem Cells; Mice; Neutrophils; Peroxidase; Serine Proteases

Bronchiolitis obliterans (BO) is a highly debilitative and fatal syndrome associated with a series of severe lower airway disorders. The pathogenesis of BO is complicated and not entirely understood. An appropriate animal model of BO may aid research into its pathogenesis. Here, we establish a mouse model of BO to provide insight into this disease.. 6-8 week old BABL/c mice were exposed to 5% nitric acid (NA) aerosol through a nebulizer for 3 hours, and controls were exposed to distilled water instead. Symptoms, airway resistance and pathological process were observed dynamically. The levels of matrix metalloproteinase-2 (MMP-2), MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), 8-isoprostane and myeloperoxidase (MPO) in lung tissue and bronchoalveolar lavage fluids (BLAF) were determined by ELISA on day 3, 7, 14, 28 and 56 after the aerosol nebulization.. Typical BO lesions were observed in NA nebulized mice characterized histologically by initial necrotizing bronchiolitis and final airway fibrosis at day 28 after the aerosol nebulization. NA nebulized mice also exhibited labored breathing and significantly increased airway resistance. Expression of MMP-2, MMP-9, TIMP-1, 8-isoprostane and MPO were significantly elevated in NA nebulized mice in different time frame.. A murine BO model was established by NA aerosol inhalation. It provides an easy, economic, and reproducible mice model for BO research.

Topics: Aerosols; Animals; Bronchiolitis Obliterans; Dinoprost; Disease Models, Animal; Inhalation; Metalloendopeptidases; Mice; Mice, Inbred BALB C; Nitric Acid; Peroxidase; Reproducibility of Results; Time Factors; Tissue Inhibitor of Metalloproteinase-1

Topics: Administration, Oral; Animals; Anti-Infective Agents; Biological Availability; Colitis; Colon; Disease Models, Animal; Drug Carriers; Drug Compounding; Gastrointestinal Agents; Hydrogen-Ion Concentration; Intestinal Mucosa; Male; Micelles; Neutrophil Infiltration; ortho-Aminobenzoates; Particle Size; Peroxidase; Rats, Sprague-Dawley; Solubility; Technology, Pharmaceutical; Trinitrobenzenesulfonic Acid

Renal ischemia-reperfusion injury (I/RI) remains a critical clinical situation. Several evidence revealed the potential reno-protective effects of Vitamin D and/or pioglitazone, on renal I/RI. This study addresses the possible involvement of the Wnt4/β-catenin signaling, p-S536NF-κBp65, PPARγ, Ang II/TGF-β, and ACE2 as potential effectors to vitamin D and pioglitazone-mediated renoprotective effects. Two sets of Sprague-Dawley rats (n = 30 rat each), were randomized into sham, I/R, Vit D "alfacalcidol" (5 ng/kg/day), pioglitazone (5 mg/kg/day), and Vit D + pioglitazone groups. In all groups renal biochemical parameters, as well as inflammatory and structural profiles were assessed, besides the expression/contents of Wnt4/β-catenin and pS536-NF-κBp65. All treatments started 7 days before I/RI and animals were killed 24 h after I/RI in the first set, while those in the 2nd set continued their treatments for 14 days. After 24 h, all pre-treatments impeded theI/R effect on neutrophils recruitment, p-S536NF-κBp65, IL-18, NGAL, caspase-3, AngII, ACE-2, PPARγ and TGF-β, besides the expression of Wnt4 and ACE-2 with notable reflection on histological changes. Two weeks after I/RI, except a marked up regulation in Wnt4 expression and a striking elevation in the β-catenin content, the magnitude of the injurious events was relatively less pronounced, an effect that was mostly augmented by the different treatments. The current study pledges a promising and novel reno-protective role of the administration of Vit D and pioglitazone entailing a potential involvement of ICAM-1, MPO, NF-κB, Ang II, ACE2, TGFβ, and a modulation of Wnt4/β-catenin pathway.

Topics: Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; beta Catenin; Cytoprotection; Disease Models, Animal; Hydroxycholecalciferols; Intercellular Adhesion Molecule-1; Interleukin-18; Kidney; Kidney Diseases; Male; Neutrophil Infiltration; NF-kappa B; Peptidyl-Dipeptidase A; Peroxidase; Pioglitazone; Rats, Sprague-Dawley; Reperfusion Injury; Thiazolidinediones; Time Factors; Transforming Growth Factor beta; Wnt Signaling Pathway; Wnt4 Protein

Although it has been recognized that intestinal bacteria play an important role in the pathology of human ulcerative colitis (UC), specific pathogenic bacteria for UC have not been identified. We investigated the influence of Paraclostridium bifermentans PAGU1678 strain on the pathology of a UC mouse model and found it increased UC pathosis scores such as loose and bloody stools, reduced diversity of fecal flora, disappearance of the crypt structure of distal colon tissue, destruction of intestinal epithelial cells, and atrophy of the colon. Furthermore, we observed an increase in COX-2, TNF-α, IL-6, IL-1, and IL-17 expression and a decrease in Foxp3 and SOCS3 expression, as inflammation-related factors and inflammatory cytokines, a decrease in the concentration of short chain fatty acids (acetic acid, propionic acid, and butyric acid) in feces, and an increase of intestinal mucosal myeloperoxidase activity. These results suggest that P. bifermentans PAGU1678 is a pathology-exacerbating factor in a mouse model of UC. This study is the first to demonstrate exacerbation of the pathological condition in a mouse model of UC by a single bacterial strain.

Topics: Animals; Clostridiales; Colitis, Ulcerative; Colon; Cytokines; Dextran Sulfate; Disease Models, Animal; Fatty Acids, Volatile; Female; Gastrointestinal Microbiome; Humans; Inflammation Mediators; Mice; Mice, Inbred C57BL; Peroxidase; RNA, Messenger

We investigated the effect of topotecan on injury and inflammation in a model of ventilator-inducedlunginjury (VILI).. Acute lung injury (ALI) was induced in mice by high-tidal volume ventilation, and the mice were then treated with topotecan or PBS. Lung tissue and bronchoalveolar lavage fluid were collected to assess pulmonary vascular leaks, inflammation, and cell apoptosis.. Compared to PBS treatment, topotecan significantly decreased the ALI score, myeloperoxidase (MPO) content, total protein concentration, and presence of inflammatory cells and inflammatory cytokines in bronchoalveolar lavage fluid. Topotecan also reduced caspase-3 activation and type Ⅱ alveolar epithelial cell apoptosis. Moreover, topotecan inhibited NF-κB expression and activation in the VILI model.. Topotecan alleviates acute lung injury in the model of VILI through the inhibition of the NF-κB pathway.

Topics: Acute Lung Injury; Animals; Apoptosis; Bronchoalveolar Lavage Fluid; Caspase 3; Cytokines; Disease Models, Animal; Epithelial Cells; Inflammation; Lung; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Peroxidase; Topotecan; Ventilator-Induced Lung Injury

Streptococcus pneumoniae is the major bacterial cause of community-acquired pneumonia, and the leading agent of childhood pneumonia deaths worldwide. Nasal colonization is an essential step prior to infection. The cytokine IL-17 protects against such colonization and vaccines that enhance IL-17 responses to pneumococcal colonization are being developed. The role of IL-17 in host defence against pneumonia is not known. To address this issue, we have utilized a murine model of pneumococcal pneumonia in which the gene for the IL-17 cytokine family receptor, Il17ra, has been inactivated. Using this model, we show that IL-17 produced predominantly from γδ T cells protects mice against death from the invasive TIGR4 strain (serotype 4) which expresses a relatively thin capsule. However, in pneumonia produced by two heavily encapsulated strains with low invasive potential (serotypes 3 and 6B), IL-17 significantly enhanced mortality. Neutrophil uptake and killing of the serotype 3 strain was significantly impaired compared to the serotype 4 strain and depletion of neutrophils with antibody enhanced survival of mice infected with the highly encapsulated SRL1 strain. These data strongly suggest that IL-17 mediated neutrophil recruitment to the lungs clears infection from the invasive TIGR4 strain but that lung neutrophils exacerbate disease caused by the highly encapsulated pneumococcal strains. Thus, whilst augmenting IL-17 immune responses against pneumococci may decrease nasal colonization, this may worsen outcome during pneumonia caused by some strains.

Topics: Animals; Bacteremia; Bacterial Capsules; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Interleukin-17; Lung; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Electron, Transmission; Microscopy, Fluorescence; Nasopharynx; Neutrophils; Peroxidase; Phagocytosis; Pneumonia, Pneumococcal; Receptors, Antigen, T-Cell, gamma-delta; Receptors, Interleukin-17; Specific Pathogen-Free Organisms; Streptococcus pneumoniae

Pulmonary arterial hypertension (PAH) remains a disease with limited therapeutic options and dismal prognosis. Despite its etiologic heterogeneity, the underlying unifying pathophysiology is characterized by increased vascular tone and adverse remodeling of the pulmonary circulation. Myeloperoxidase (MPO), an enzyme abundantly expressed in neutrophils, has potent vasoconstrictive and profibrotic properties, thus qualifying as a potential contributor to this disease. Here, we sought to investigate whether MPO is causally linked to the pathophysiology of PAH. Investigation of 2 independent clinical cohorts revealed that MPO plasma levels were elevated in subjects with PAH and predicted adverse outcome. Experimental analyses showed that, upon hypoxia, right ventricular pressure was less increased in Mpo-/- than in WT mice. The hypoxia-induced activation of the Rho-kinase pathway, a critical subcellular signaling pathway yielding vasoconstriction and structural vascular remodeling, was blunted in Mpo-/- mice. Mice subjected to i.v. infusion of MPO revealed activation of Rho-kinase and increased right ventricular pressure, which was prevented by coinfusion of the Rho-kinase inhibitor Y-27632. In the Sugen5416/hypoxia rat model, PAH was attenuated by the MPO inhibitor AZM198. The current data demonstrate a tight mechanistic link between MPO, the activation of Rho-kinase, and adverse pulmonary vascular function, thus pointing toward a potentially novel avenue of treatment.

Topics: Adult; Amides; Animals; Cohort Studies; Disease Models, Animal; Female; Humans; Hypertension, Pulmonary; Hypoxia; Infusions, Intravenous; Kaplan-Meier Estimate; Lung; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Peroxidase; Pulmonary Artery; Pyridines; Rats; Rats, Sprague-Dawley; Recombinant Proteins; rho-Associated Kinases; Vascular Remodeling; Vasoconstriction

Objective- Nbeal2

Topics: Animals; Blood Platelets; Blood Proteins; CD11b Antigen; Disease Models, Animal; Female; Gray Platelet Syndrome; Host-Pathogen Interactions; Klebsiella Infections; Klebsiella pneumoniae; Lipocalin-2; Male; Matrix Metalloproteinase 9; Mice, Inbred C57BL; Mice, Knockout; Monocytes; Multiple Organ Failure; Neutrophils; Pancreatic Elastase; Peroxidase; Platelet Glycoprotein GPIb-IX Complex; Platelet Transfusion; Pneumonia, Bacterial; Sepsis

This study investigated the protective effects of a lipid extract from hard-shelled mussel (HMLE) on intestinal integrity and the underlying mechanisms after a lipopolysaccharide (LPS) challenge in mice by using a 3 × 2 factorial design. Mice received olive oil, fish oil, and HMLE (

Topics: Amine Oxidase (Copper-Containing); Animals; Anti-Inflammatory Agents; Claudin-1; Colon; Cytokines; Disease Models, Animal; Fish Oils; Gene Expression Regulation; Ileum; Inflammation; Interleukin-1 Receptor-Associated Kinases; Lipids; Lipopolysaccharides; Male; Mice, Inbred C57BL; Myeloid Differentiation Factor 88; Mytilus; Occludin; Permeability; Peroxidase; RNA, Messenger; Signal Transduction; Time Factors; TNF Receptor-Associated Factor 6; Toll-Like Receptor 4

Acute liver failure (ALF) is an inflammation-mediated hepatocellular injury process associated with cellular autophagy. However, the mechanism by which autophagy regulates ALF remains undefined. Herein, we demonstrated that Eva1a (eva-1 homolog A)/Tmem166 (transmembrane protein 166), an autophagy-related gene, can protect mice from ALF induced by D-galactosamine (D-GalN)/lipopolysaccharide (LPS) via autophagy. Our findings indicate that a hepatocyte-specific deletion of Eva1a aggravated hepatic injury in ALF mice, as evidenced by increased levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), myeloperoxidase (MPO), and inflammatory cytokines (e.g., TNFα and IL-6), which was associated with disordered liver architecture exhibited by Eva1a

Topics: Alanine Transaminase; Animals; Apoptosis Regulatory Proteins; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Galactosamine; Genotype; Interleukin-6; Lipopolysaccharides; Liver; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Peroxidase; Tumor Necrosis Factor-alpha

In this study, we aimed to histologically and immunologically evaluate the effect of diode laser treatment when applied adjunctive to scaling and root planing (SRP) in an experimental periodontitis model.. We used Wistar-Albino rats (n=60) with average weight of 230 g. Experimental periodontitis was induced by ligature at the right and left first mandibular molar teeth in all rats. After 11 days, the ligature was removed and rats were divided into two groups. The control group (n=30) received only SRP treatment, while the laser group (n=30) received a diode laser (GaAlAs, 810 nm, 1 W, 10 J, 20 s) treatment adjunctive to SRP. Ten rats in each group were sacrificed after 7, 15, and 30 days. Histopathological examination was performed in the left mandible of rats. Myeloperoxidase (MPO) was evaluated by western blot in the gingival specimens from the right mandible.. MPO levels in the laser group were statistically significantly lower compared with the control group (p≤0.05). There was no statistically significance at any time between MPO levels in the control group (p>0.05). MPO levels in the laser group at the 7th day were statistically significantly higher compared to the 15th (p≤0.05) and the 30th day (p≤0.05). Inflammatory cell infiltration decreased over time in both groups and was statistically significantly lower in the laser group than in the control group at all times (p≤0.01).. Within the limits of this study, we suggest that diode laser application is an adjunctive treatment because it reduced inflammation and MPO when applied in addition to SRP. On the other hand, more studies are needed for the assessment of the effects of diode laser application to periodontal tissues.

Topics: Animals; Blotting, Western; Combined Modality Therapy; Dental Scaling; Disease Models, Animal; Lasers, Semiconductor; Ligation; Low-Level Light Therapy; Periodontitis; Peroxidase; Random Allocation; Rats, Wistar; Reproducibility of Results; Time Factors; Treatment Outcome

The aim of the present work was to explore the outcome of combination of Calcineurin (CaN) inhibitor and Protein Kinase A (PKA) activator, in mouse models of experimental dementia.. Cognitive deficits were induced in mice by injecting Streptozotocin (STZ) intracerebroventricularly (i.c.v.); on the other hand aged animals were procured as a natural model of dementia. To assess cognitive function of mice Morris water maze (MWM) test was utilized; various biochemical studies and histopathological studies were also carried out.. STZ injection and aging resulted in significant development of cognitive deficits; along-with enhancement of Myeloperoxidase (MPO) levels, Thiobarbituric Acid Reactive Species (TBARS), Acetylcholinestrase (AChE) activity, and reduced Glutathione (GSH) levels. Histopathological studies demonstrated pathological changes such as amyloid deposition and severe neutrophilic infiltration in brains of these mice. Donepezil /combination of Tacrolimus and Forskolin treatment markedly improve cognitive function, biochemical parameters, and histopathological alterations in STZ treated and aged mice.. The outcome reveals that combination of CaN inhibitor and PKA activator has significantly alleviated memory dysfunction, biochemical alteration and histopathological changes quiet comparable to Donepezil. It has been inferred that combination of CaN and PKA can be served as an important target in dementia.

Topics: Acetylcholinesterase; Aging; Alzheimer Disease; Animals; Brain; Calcineurin; Calcineurin Inhibitors; Cholinesterase Inhibitors; Cognition Disorders; Colforsin; Cyclic AMP-Dependent Protein Kinases; Disease Models, Animal; Donepezil; Drug Therapy, Combination; Female; Glutathione; Male; Maze Learning; Mice; Peroxidase; Streptozocin; Tacrolimus; Thiobarbituric Acid Reactive Substances; Vasodilator Agents

Topics: Animals; Colitis, Ulcerative; Colon; Disease Models, Animal; Insulin-Like Growth Factor Binding Proteins; Interferon-gamma; Interleukin-4; Male; Mice; Mice, Inbred BALB C; Peroxidase; Serine Proteinase Inhibitors; T-Lymphocytes, Regulatory; Th2 Cells; Transcription Factor RelA; Trichinella spiralis; Trinitrobenzenesulfonic Acid

We have previously demonstrated that apigenin promotes the expression of antiangiogenic protein thrombospondin-1 (TSP1) via a mechanism driven by mRNA-binding protein HuR. Here, we generated a novel mouse model with whole-body THBS-1 gene knockout on SKH-1 genetic background, which allows studies of UVB-induced acute skin damage and carcinogenesis and tests TSP1 involvement in apigenin's anticancer effects. Apigenin significantly inhibited UVB-induced carcinogenesis in the wild-type (WT) animals but not in TSP1 KO (TKO) mice, suggesting that TSP1 is a critical component of apigenin's chemopreventive function in UVB-induced skin cancer. Importantly, TKO mice presented with the elevated cutaneous inflammation at baseline, which was manifested by increased inflammatory infiltrates (neutrophils and macrophages) and elevated levels of the two key inflammatory cytokines, IL-6 and IL-12. In agreement, maintaining normal TSP1 expression in the UVB-irradiated skin of WT mice using topical apigenin application caused a marked decrease of circulating inflammatory cytokines. Finally, TKO mice showed an altered population dynamics of the bone marrow myeloid progenitor cells (CD11b

Topics: Animals; Anti-Inflammatory Agents; Apigenin; Cell Line, Tumor; Cell Transformation, Neoplastic; Chemoprevention; Disease Models, Animal; Genotype; Humans; Inflammation; Keratinocytes; Mice; Mice, Knockout; Neutrophils; Peroxidase; Skin; Skin Neoplasms; Sunscreening Agents; Thrombospondin 1; Ultraviolet Rays; Xenograft Model Antitumor Assays

Betulin is a phenolic flavonoid which has been reported to possess a mass of pharmacological properties, especially anti-inflammatory activity. The purpose of this study was to explore the protective effects and possible mechanism of betulin against lipopolysaccharide/D-galactosamine (LPS/D-Gal)-induced acute liver injury. D-Gal and LPS were intraperitoneally injected to develop acute liver injury animal model. Betulin (2, 4 or 8 mg/kg) were given 1 h before LPS/D-Gal instillation. Liver tissues and plasma samples were collected 9 h after LPS/D-Gal were given. The results indicated that betulin dramatically decreased liver pathologic changes, myeloperoxidase (MPO) activity, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Simultaneously, the levels of interleukin (IL-1β) and tumor necrosis factor (TNF-α) in serum and liver tissues were both attenuated by betulin. Besides, betulin suppressed NF-κB pathway activation in a dose-dependently manner. Betulin increased the expression of PPAR-γ in a dose-dependent manner. In conclusion, all these results revealed that betulin could possess potential therapeutic effect for LPS/D-Gal-induced acute liver injury.

Topics: Alanine Transaminase; Animals; Chemical and Drug Induced Liver Injury; Cytoprotection; Disease Models, Animal; Dose-Response Relationship, Drug; Galactosamine; Interleukin-1beta; Lipopolysaccharides; Liver; Male; Mice, Inbred BALB C; NF-kappa B; Peroxidase; PPAR gamma; Signal Transduction; Triterpenes; Tumor Necrosis Factor-alpha

Inflammatory bowel disease (IBD) is a chronically relapsing inflammatory disorder of the gastrointestinal tract. Current IBD treatments are associated with poor tolerability and insufficient therapeutic efficacy, prompting the need for alternative therapeutic approaches. Recent advances suggest promising interventions based on a number of phytochemicals. Herein, we explored the beneficial effects of tussilagone, a major component of Tussilago farfara, in mice subjected to acute colitis induced by dextran sulfate sodium (DSS). Treatment with tussilagone resulted in a significant protective effect against DSS-induced acute colitis in mice via amelioration of weight loss, and attenuation of colonic inflammatory damage. Additionally, the expression of tumor necrosis factor-α and interleukin-6 and the activity of myeloperoxidase in colonic tissues were significantly reduced in tussilagone-treated mice. Furthermore, immunohistochemical analysis revealed that tussilagone treatment reduced the numbers of nuclear factor-kappa B (NF-κB) and increased the numbers of nuclear factor erythroid 2-related factor 2 (Nrf2) in nuclei of colonic tissues. Taken together, tussilagone treatment attenuated DSS-induced colitis in mice through inhibiting the activation of NF-κB and inducing Nrf2 pathways, indicating that tussilagone is a potent therapeutic candidate for treatment of intestinal inflammation.

Topics: Animals; Colitis; Colon; Dextran Sulfate; Disease Models, Animal; Heme Oxygenase-1; Interleukin-6; Mice; Mice, Inbred BALB C; NF-E2-Related Factor 2; NF-kappa B; Nitric Oxide Synthase Type II; Peroxidase; Sesquiterpenes; Tumor Necrosis Factor-alpha; Tussilago

The aim of this study was to evaluate the potential molecular mechanism of resveratrol (RSV) that attenuates brain damage from focal cerebral ischemia.. To investigate whether phosphatidylinositol 3-kinase/Akt (PI3K/Akt) pathway was involved in RSV anti-inflammatory and neuroprotective properties. Middle cerebral artery occlusion (MCAO) animal model was used in this study. Adult male Sprague-Dawley (SD) rats underwent MCAO, and then received treatment with RSV or vehicle after the onset of ischemia. PI3K inhibitor LY294002 was injected intracerebroventricularly to inhibit the PI3K/Akt signaling pathway. Neurological deficit scores and cerebral water content were assessed 24 h after MCAO. The inflammatory factors interleukin (IL)-1β, tumor necrosis factor (TNFα), and cyclooxygenase-2 (COX2) mRNA level were examined by real-time PCR. The enzymatic activity of myeloperoxidase (MPO) was measured 24 h after MCAO. The protein expression of phospho-Akt and COX2 in ischemic brain were determined by western blot.. RSV significantly reduced neurological deficit scores, cerebral water content and the enzymatic activity of MPO, all of which were abolished by LY294002 administration. Real-time PCR showed that RSV significantly suppressed the upregulation of the inflammatory factors IL-1β, TNFα, COX2 mRNA levels. RSV significantly inhibited upregulated the protein expression of COX2 24 h after MCAO, which effect was abolished by LY294002 administration.. RSV attenuated ischemic brain damage induced by cerebral artery occlusion mainly through PI3K/Akt signaling pathway. Abbreviation: MCAO: Middle cerebral artery occlusion; RSV: resveratrol; PI3K/Akt: phosphatidylinositol 3-kinase/Akt; TNF: tumor necrosis factor; COX2: cyclooxygenase-2; MPO: myeloperoxidase; IL: interleukin.

Topics: Analysis of Variance; Animals; Antioxidants; Brain Ischemia; Cyclooxygenase 2; Cytokines; Disease Models, Animal; Enzyme Activation; Hypoxia, Brain; Infarction, Middle Cerebral Artery; Male; Neurologic Examination; Oncogene Protein v-akt; Peroxidase; Phosphatidylinositol 3-Kinase; Rats; Rats, Sprague-Dawley; Resveratrol; RNA, Messenger; Signal Transduction; Stilbenes

Melanoma has a high propensity to metastasize and exhibits a poor response to classical therapies. Dysregulation of the chemokine receptor gene CXCR4 is associated with melanoma progression, and although n-3 polyunsaturated fatty acids (PUFAs) are known to be beneficial for melanoma prevention, the underlying mechanism of this effect is unclear. Here, we used the n-3 fatty acid desaturase (Fat-1) transgenic mouse model of endogenous n-3 PUFA synthesis to investigate the influence of elevated n-3 PUFA levels in a mouse model of metastatic melanoma. We found that relative to wild-type (WT) mice, Fat-1 mice exhibited fewer pulmonary metastatic colonies and improved inflammatory indices, including reduced serum tumor necrosis factor alpha (TNF-α) levels and pulmonary myeloperoxidase activity. Differential PUFA metabolites in serum were considered a key factor to alter cancer cell travelling to lung, and we found that n-6 PUFAs such as arachidonic acid induced CXCR4 protein expression although n-3 PUFAs such as eicosapentaenoic acid (EPA) decreased CXCR4 levels. In addition, serum levels of the bioactive EPA metabolite, 18-HEPE, were elevated in Fat-1 mice relative to WT mice, and 18-HEPE suppressed CXCR4 expression in B16-F0 cells. Moreover, relative to controls, numbers of pulmonary metastatic colonies were reduced in WT mice receiving intravenous injections either of 18-HEPE or 18-HEPE-pretreated melanoma cells. Our results indicate that 18-HEPE is a potential anticancer metabolite that mediates, at least in part, the preventive effect of n-3 PUFA on melanoma metastasis.

Topics: Animals; Arachidonic Acid; Cadherins; Cell Line, Tumor; Chrysenes; Disease Models, Animal; Eicosapentaenoic Acid; Fatty Acids, Omega-3; Female; Hydroxyeicosatetraenoic Acids; Lung Neoplasms; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neoplasm Metastasis; Peroxidase; Receptors, CXCR4; Tumor Necrosis Factor-alpha

Brain damage can cause lung injury. To explore the mechanism underlying the lung injury induced by acute cerebral ischemia (ACI), we established a middle cerebral artery occlusion (MCAO) model in male Sprague-Dawley rats. We focused on glia maturation factor β (GMFB) based on quantitative analysis of the global rat serum proteome. Polymerase chain reaction, western blotting, and immunofluorescence revealed that GMFB was over-expressed in astrocytes in the brains of rats subjected to MCAO. We cultured rat primary astrocytes and confirmed that GMFB was also up-regulated in primary astrocytes after oxygen-glucose deprivation (OGD). We subjected the primary astrocytes to Gmfb RNA interference before OGD and collected the conditioned medium (CM) after OGD. We then used the CM to culture pulmonary microvascular endothelial cells (PMVECs) acquired in advance and assessed their status. The viability of the PMVECs improved significantly when Gmfb was blocked. Moreover, ELISA assays revealed an elevation in GMFB concentration in the medium after OGD. Cell cultures containing recombinant GMFB showed increased levels of reactive oxygen species and a deterioration in the state of the cells. In conclusion, GMFB is up-regulated in astrocytes after ACI, and brain-derived GMFB damages PMVECs by increasing reactive oxygen species. GMFB might thus be an initiator of the lung injury induced by ACI.

Topics: Animals; Brain; Brain Ischemia; Bronchoalveolar Lavage Fluid; Cell Hypoxia; Cells, Cultured; Cerebrovascular Circulation; Chromatography, High Pressure Liquid; Culture Media, Conditioned; Disease Models, Animal; Endothelial Cells; Gene Expression Regulation; Glia Maturation Factor; In Situ Nick-End Labeling; Lung Injury; Male; Neuroglia; Neurologic Examination; Peroxidase; Proteome; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; RNA Interference; RNA, Small Interfering; Tandem Mass Spectrometry

Ulcerative colitis (UC) is the most common inflammatory bowel diseases and there is still a lack of safe and effective treatments. Consumption of L. reuteri F-9-35 may effective in preventing human UC.

Topics: Animals; Colitis; Colon; Dextran Sulfate; Disease Models, Animal; Female; Gastrointestinal Microbiome; Gene Expression Profiling; Gene Expression Regulation; Inflammation; Inflammatory Bowel Diseases; Interleukin-6; Limosilactobacillus reuteri; Mice; Peroxidase; Phenotype; Probiotics; Tumor Necrosis Factor-alpha

As the inflammatory enzyme myeloperoxidase (MPO) is abundant in ruptured human atherosclerotic plaques, we aimed to investigate the role of MPO as a potential diagnostic and therapeutic target for high-risk plaque.. We employed the tandem stenosis model of atherosclerotic plaque instability in apolipoprotein E gene knockout (Apoe-/-) mice. To test the role of MPO, we used Mpo-/-Apoe-/- mice and the 2-thioxanthine MPO inhibitor AZM198. In vivo MPO activity was assessed by liquid chromatography-tandem mass spectrometry detection of 2-chloroethidium generation from hydroethidine and by bis-5HT-DTPA-Gd (MPO-Gd) molecular magnetic resonance imaging (MRI), while plaque phenotype was verified histologically. Myeloperoxidase activity was two-fold greater in plaque with unstable compared with stable phenotype. Genetic deletion of MPO significantly increased fibrous cap thickness, and decreased plaque fibrin and haemosiderin content in plaque with unstable phenotype. AZM198 inhibited MPO activity and it also increased fibrous cap thickness and decreased fibrin and haemosiderin in plaque with unstable phenotype, without affecting lesion monocytes and red blood cell markers or circulating leukocytes and lipids. MPO-Gd MRI demonstrated sustained enhancement of plaque with unstable phenotype on T1-weighted imaging that was two-fold greater than stable plaque and was significantly attenuated by both AZM198 treatment and deletion of the Mpo gene.. Our data implicate MPO in atherosclerotic plaque instability and suggest that non-invasive imaging and pharmacological inhibition of plaque MPO activity hold promise for clinical translation in the management of high-risk coronary artery disease.

Topics: Animals; Atherosclerosis; Disease Models, Animal; Fibrin; Hemosiderin; Magnetic Resonance Imaging; Mass Spectrometry; Mice, Knockout; Molecular Imaging; Peroxidase; Plaque, Atherosclerotic; Thioxanthenes

Lactobacillus plantarum CQPC06 (LP-CQPC06) is a newly discovered lactic acid bacterial strain. Here, the beneficial effects of this strain on C57BL/6J mice with dextran sulfate sodium-induced colitis were investigated. LP-CQPC06 was more resistant to gastric acid and bile salts than L. delbrueckii subsp. bulgaricus (LB). In the DSS-induced colitis mouse model, LP-CQPC06 treatment decreased the colon weight/length ratio and increased the colon length as compared to untreated mice with DSS-induced colitis. LP-CQPC06 also reduced the serum levels of interleukin 8 (IL-8), IL-1, tumor necrosis factor alpha, and macrophage inflammatory protein-1 alpha, as well as reducing levels of myeloperoxidase (MPO) and nitric oxide (NO) in the colon tissues of mice with DSS-induced colitis. In all cases, the effects of LP-CQPC06 were significantly stronger than those of LB. Quantitative polymerase chain reactions and western blots indicated that LP-CQPC06 increased the mRNA and protein expression levels of neuronal nitric oxide synthase, endothelial nitric oxide synthase, and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha, while decreasing the expression levels of inducible nitric oxide synthase, nuclear factor kappa-beta, C-X-C motif chemokine receptor 1 (CXCR1), and CXCR2. Thus, L. plantarum CQPC06 had a good protective effect against colitis in a mouse model via the IL-8 pathway. Therefore, L. plantarum CQPC06 might have potential uses as a probiotic for colonic protection.. In this study, a newly discovered lactic acid bacteria was investigated. This bacterial strain had a good prophylactic effect against colitis in a mouse model, and might have potential utility as a probiotic.

Topics: Animals; Colitis; Colon; Dextran Sulfate; Disease Models, Animal; Interleukin-8; Lactobacillus plantarum; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Nitric Oxide Synthase Type II; Peroxidase; Probiotics; Tumor Necrosis Factor-alpha

Oenothera rosea L´Hér. ex Ait is a species traditionally used in the treatment of inflammation, headache, stomach pain, infections, among others. The aim of this study was evaluating the acute anti-inflammatory activity of the aqueous extract of O. rosea by 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. Rats were randomized into six groups: (I) Sham; (II) EtOH; (III) TNBS; and (IV-VI) 250, 500 and 750 mg/Kg, respectively. The colonic injury was induced (groups III-VI) by intrarectal instillation of 0.25 mL of TNBS (10 mg) in 50% ethanol. Groups I and II received an enema (0.25 mL) of physiological saline solution or 50% ethanol, respectively. Treatments were administered by oral gavage 48, 24 and 1 h prior, and 24 h after the induction. The inflammatory response was assessed considering the macroscopic and microscopic damage, the serum nitric oxide (NO), the colonic IL-1β levels, and the myeloperoxidase (MPO) activity. Moreover, we performed an LC-MS-based metabolite profiling, and a docking on the MPO. Doses of 500 and 750 mg/Kg showed a protective effect in the TNBS-induced colonic damage. This activity was related to the downregulation of evaluated parameters. Also, considering previous reports, 29 metabolites of 91 detected were selected for the docking, of which Isolimonic acid (29) and Kaempferol 3-(2'',4''-diacetylrhamnoside) (10) showed the highest affinity to MPO. The aqueous extract of O. rosea protected the TNBS-induced colonic damage in rats, an effect that could be associated with the presence of polyphenolic compounds, alkaloids, and terpenes; as well as their ability to down-regulate MPO activity.

Topics: Animals; Colitis; Colon; Disease Models, Animal; Down-Regulation; Female; Inflammation; Interleukin-1beta; Intestinal Mucosa; Nitric Oxide; Oenothera; Peroxidase; Plant Extracts; Rats; Rats, Wistar; Trinitrobenzenesulfonic Acid

In this study, the protective effects of a carboxymethyl polysaccharide CMP33 from Poria cocos against inflammatory bowel disease (IBD) were investigated using TNBS-induced colitis in mice. The results showed that CMP33 markedly ameliorated the severity of colitis, including a 2-fold decrease in the mortality rate, a 50% decrease in disease activity index, and a 36%-44% decrease in macro- or microscopic histopathological score, compared with TNBS administration. Moreover, CMP33 decreased the levels of pro-inflammatory cytokines and increased the levels of anti-inflammatory cytokines in the colon tissue and serum of colitic mice. Using iTRAQ-coupled- nano-HPLC-MS/MS-based proteomics, the protein profiles after TNBS, high- or low-dose CMP33 and salazosulfapyridine (SASP) treatments were compared and many differentially expressed proteins were identified. Among them, 7 proteins (Hmgcs2, Fabp2, Hp, B4galnt2, B3gnt6, Sap and Ca1) were proposed to be the common targeting protein group (TPG) of CMP33 and drug SASP. Particularly, some targeting proteins were CMP33-dose-specific: high-dose-specific TPG (Mtco3, Gal-6, Mptx, S100 g and Hpx) and low-dose-specific TPG (Zg16, Hexb, Insl5, Cept1, Hspb6 and Ifi27l2b), suggesting the complex acting mechanism of CMP33. GC-TOF-MS-based metabolomics revealed that oleic acid and dihydrotestosterone could be the common targets of CMP33 and SASP. By integrative analysis of proteomics and metabolomics, key protein-metabolite pathways (PMP) were identified, PMP for high-dose: 2-hydroxybutyric acid - (GPT, GGH) - glutathione - ALB - testosterone - TTR - dihydrotestosterone; PMP for low-dose: (PYY, FABP2, HMGCS2) - oleic acid - TTR - dihydrotestosterone. In total, these results demonstrated the protective effects of CMP33 against IBD in mice through the potential TPG and PMP.

Topics: Animals; Chromatography, High Pressure Liquid; Colon; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Fatty Acid-Binding Proteins; Haptoglobins; Hydroxymethylglutaryl-CoA Synthase; Inflammatory Bowel Diseases; Male; Malondialdehyde; Metabolomics; Mice; N-Acetylgalactosaminyltransferases; Peroxidase; Polysaccharides; Proteomics; Sulfasalazine; Tandem Mass Spectrometry; Trinitrobenzenesulfonic Acid; Wolfiporia

An effective vaccine against Pseudomonas aeruginosa would be hugely beneficial to people who are susceptible to the serious infections it can cause. Vaccination against PcrV of the P. aeruginosa type III secretion system is a potential prophylactic strategy for improving the incidence and prognosis of P. aeruginosa pneumonia. Here, the effect of nasal PcrV adjuvanted with CpG oligodeoxynucleotide (CpG) was compared with a nasal PcrV/aluminum hydroxide gel (alum) vaccine. Seven groups of mice were vaccinated intranasally with one of the following: 1, PcrV-CpG; 2, PcrV-alum; 3, PcrV alone; 4, CpG alone; 5, alum alone; 6 and 7, saline control. Fifty days after the first immunization, anti-PcrV IgG, IgA and IgG isotype titers were measured; significant increases in these titers were detected only in the PcrV-CpG vaccinated mice. The vaccinated mice were then intratracheally infected with a lethal dose of P. aeruginosa and their body temperatures and survival monitored for 24 hr, edema, bacteria, myeloperoxidase activity and lung histology also being evaluated at 24 hr post-infection. It was found that 73% of the PcrV-CpG-vaccinated mice survived, whereas fewer than 30% of the mice vaccinated with PcrV-alum or adjuvant alone survived. Lung edema and other inflammation-related variables were less severe in the PcrV-CpG group. The significant increase in PcrV-specific IgA titers detected following PcrV-CpG vaccination is probably a component of the disease protection mechanism. Overall, our data show that intranasal PcrV-CpG vaccination has potential efficacy for clinical application against P. aeruginosa pneumonia.

Topics: Adjuvants, Immunologic; Animals; Antibodies, Bacterial; Antigens, Bacterial; Bacterial Toxins; Body Temperature; Disease Models, Animal; Edema; Lung; Male; Mice; Oligodeoxyribonucleotides; Peroxidase; Pneumonia; Pore Forming Cytotoxic Proteins; Pseudomonas aeruginosa; Pseudomonas Infections; Pseudomonas Vaccines; Recombinant Fusion Proteins; Survival Rate; Type III Secretion Systems; Vaccination

Mastitis is the inflammation of the mammary glands caused by bacteria. It causes severe economic loss to dairy industry. Curcumin, a polyphenol obtained from turmeric, has considerable anti-inflammatory effect. Since it is rapidly eliminated from the body, its oral bioavailability is low. However, nanoformulation of curcumin significantly enhances its therapeutic efficiency by improving its oral bioavailability. We evaluated whether nanocurcumin could be more effective than normal curcumin against bovine Staphylococcus aureus mastitis in mouse model. Curcumin-loaded PLGA nanoparticles (CUR-NP) were prepared by solid-in-oil-in-water emulsion method. The mouse model of mastitis was induced by inoculation of a field strain of S. aureus (bovine mastitis isolate) on the 9th day of parturition through the duct of the mammary gland. CUR-NP and curcumin were given orally for 7 days (day 2 to day 8 of parturition) prior to S. aureus inoculation. We determined the levels of inflammatory cytokines and the mRNA expression of NF‑κB. S. aureus infection increased the levels of tumor necrosis factor‑α, interleukin‑1β and myeloperoxidase in mammary tissues and C-reactive protein in serum. Both CUR-NP and curcumin significantly attenuated the levels of these cytokines. However, comparatively, the ameliorative efficiency of CUR-NP was better than normal curcumin. S. aureus infection-induced NF‑κB mRNA expression was significantly reduced to the healthy control level by CUR-NP. Our study demonstrates that the nanoformulation of curcumin can reduce pro-inflammatory mediators in S. aureus-infected mammary tissues by improving NF‑κB signaling. Besides, compared to normal curcumin, this nanoformulation appears to be a better alternative against murine mastitis.

Topics: Animals; C-Reactive Protein; Cattle; Curcumin; Disease Models, Animal; Female; Interleukin-1beta; Mammary Glands, Animal; Mastitis; Mice; Nanoparticles; NF-kappa B; Peroxidase; Polylactic Acid-Polyglycolic Acid Copolymer; Signal Transduction; Staphylococcal Infections; Staphylococcus aureus; Tumor Necrosis Factor-alpha

Modulation of the gut microbiota through the use of probiotics has been widely used to treat or prevent several intestinal diseases. However, inconsistent results have compromised the efficacy of this approach, especially in severe conditions such as inflammatory bowel disease (IBD). The purpose of our study was to develop a personalized probiotic strategy and assess its efficacy in a murine model of intestinal inflammation. Commensal bacterial strains were isolated from the feces of healthy mice and then administered back to the host as a personalized treatment in dextran sodium sulfate (DSS)-induced colitis. Colonic tissues were collected for histological analysis and to investigate inflammatory markers such as

Topics: Animals; Bifidobacterium; Biomarkers; Colitis; Colon; Cytokines; Dextran Sulfate; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Gastrointestinal Microbiome; Inflammation; Inflammatory Bowel Diseases; Intestines; Lactobacillus; Male; Malondialdehyde; Mice; Mice, Inbred C57BL; Peroxidase; Probiotics

We aimed to investigate the protective and therapeutic effects of dexpanthenol (DXP) on liver injuries induced by ischemia-reperfusion (IR) in an in vivo rat model.. Thirty-two rats were randomly divided into 4 experimental groups (n = 8 in each group: Sham, IR, DXP, and DXP+IR. DXP (500 mg/kg) was intraperitoneally administered for 30 min before 60 min of ischemia, followed by 60 min of reperfusion to rats in the DXP and DXP+IR groups. All rats were euthanized on day 10 to evaluate immunohistopathological changes as well as tissue levels of oxidants and antioxidants.. IR decreased total glutathione (tGSH) levels in IR group when compared to the Sham group. DXP supplementation to IR group significantly ameliorated tGSH levels (P < .05). IR also elevated myeloperoxidase production compared to the Sham group, whereas DXP treatment prevented these hazardous effects. However, plasma superoxidedismutase, catalase, and malondialdehyde levels did not differ between the DXP+IR than the IR rats. Histologic tissue damage was reduced in the DXP and DXP+IR group.. Liver IR is an inevitable problem during liver surgery. Our results suggested that DXP pretreatment suppressed oxidative stress and increased antioxidant levels in a rat model of liver IR.

Topics: Animals; Antioxidants; Catalase; Disease Models, Animal; Female; Glutathione; Glutathione Peroxidase; Liver; Malondialdehyde; Oxidative Stress; Pantothenic Acid; Peroxidase; Random Allocation; Rats; Rats, Sprague-Dawley; Rats, Wistar; Reperfusion Injury; Vitamin B Complex

P28GST, a 28Kd glutathione S-transferase enzymatic protein derived from a schistosome helminth prevents experimental colitis when administered subcutaneously in the presence of adjuvant by decreasing pro-inflammatory Th1/Th17 response. Given the antioxidant properties of P28GST, we evaluated its anti-inflammatory potential when administered locally after colitis induction in the absence of adjuvant.. Colitis was induced in BALB/c mice by rectal administration of TNBS, followed by two intraperitoneal injections of P28GST at day 1 and day 2. Mice were sacrificed 48h after TNBS administration and evaluated for macroscopic and histological scores, myeloperoxidase (MPO) quantification and cytokine messenger RNA expression in the colonic tissues.. Both clinical and histological scores significantly decreased in mice treated with P28GST at 5 or 50μg/kg when compared to vehicle- treated mice. A significant reduction of MPO was detected in colonic tissues from P28GST-treated mice, similarly to mice treated with methylprednisolone as the reference treatment. Pro-inflammatory cytokines TNF, IL-1β, and IL-6, mRNA as well as serum levels were down-regulated in mice colonic tissues treated with P28GST at 5 or 50μg/kg. In addition, a significant decrease of mRNA expression levels of T-bet, and ROR-γ, respective markers of Th1 and Th17 cells was observed. Whereas no significant effect was detected on Gata3 mRNA, a marker of Th2 cells, the Arg/iNOS mRNA levels significantly increased in P28GST-treated mice, suggesting the induction of M2 macrophages.. These findings provide evidence that P28GST injected locally after colitis induction induces a potent decrease of colitis inflammation in mice, associated to downregulation of Th1/Th17 response, and induction of anti-inflammatory alternatively activated macrophages.

Topics: Animals; Biomarkers; Colitis; Cytokines; Disease Models, Animal; Female; Glutathione Transferase; Helminth Proteins; Inflammation Mediators; Macrophages; Mice; Peroxidase; Severity of Illness Index; Th1 Cells; Th17 Cells

Exposition to environmental factors is one of the major underlying causes in inflammatory bowel diseases (IBD), with several endogenous systems involved. Our aim was to characterize the impact of stress on the colitis development in relation to the endogenous opioid system (EOS) activity in mice. A unique mouse model of high and low activity of EOS (namely high (HA)/low (LA) stress-induced analgesia) was employed. Mice were bred using bidirectional selection and classified as HA or LA line based on the measurement of analgesia. Colitis was induced by instillation of trinitrobenzenesulfonic acid in 30% EtOH/0.9% NaCl. After 4 days, the macroscopic score was assessed and samples for molecular and histological studies were collected. To evaluate the influence of stress on colitis development, chronic mild stress (exposure to stress stimuli for 2 and 5 weeks) and acute stress (short restraint over 3 days) were applied before colitis induction. We observed a difference in the colitis development between non-stressed HA and LA mice, as indicated by macroscopic and ulcer scores. Acute stress improved colitis in HA mice but did not change the inflammation score in LA line as compared to respective non-stressed mice. Chronic mild stress had no influence on colitis in either of mouse lines. Our study supports the hypothesis that the activity of EOS may be crucial in IBD development. We also evidence that acute, but not chronic stress influenced IBD exacerbation, depending on EOS function.

Topics: Analgesia; Animals; Colitis; Disease Models, Animal; Male; Mice; Narcotic Antagonists; Peroxidase; Stress, Psychological; Trinitrobenzenesulfonic Acid

The PARP inhibitor olaparib has recently been approved for human use for the therapy of cancer. Considering the role of PARP in critical illness, we tested the effect of olaparib in a murine model of burn injury, in order to begin exploring the feasibility of repurposing olaparib for the therapy of burn patients.. Mice were subjected to scald burn injury and randomized into vehicle or olaparib (10 mg·kg. Olaparib reduced myeloperoxidase levels in heart and lung homogenates and reduced malondialdehyde levels in all tissues 24 h post-burn. Olaparib also reduced circulating alkaline aminotransferase, amylase and blood urea nitrogen and creatinine levels, indicative of protection against hepatic, pancreatic and renal dysfunction. Pro-inflammatory mediator (TNF-α, IL-1β, IFN-γ, GCSF, GM-CSF, eotaxin, KC, MIP-1-α and IL-3, 6 and 12) levels as well as the levels of several mediators that are generally considered anti-inflammatory (IL-4, 10 and 13) were reduced by olaparib. Plasma troponin-I levels (an indicator of skeletal muscle damage) was also attenuated by olaparib. Finally, olaparib stimulated wound healing.. The clinically approved PARP inhibitor olaparib improves organ function, suppresses inflammatory responses and accelerates wound healing in murine burn injury. The data raise the potential utility of olaparib for severe burn injury.. This article is part of a themed section on Inventing New Therapies Without Reinventing the Wheel: The Power of Drug Repurposing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.2/issuetoc.

Topics: Animals; Burns; Disease Models, Animal; Inflammation; Inflammation Mediators; Lung; Male; Malondialdehyde; Mice; Myocardium; Peroxidase; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors; Troponin T; Wound Healing

Acute lung injury (ALI) is a serious disease with high morbidity and mortality rate. Although there are effective strategies for treatment of ALI; a widely accepted specific pharmacotherapy has not yet established. Zerumbone, the major active phytochemical compound from Zingiber zerumbet Smith, exhibits various beneficial biological and pharmacological activities, such as antioxidation, anti-inflammation, immunomodulation, and anti-cancer. We aimed to study the potential protective effects and mechanisms of zerumbone in mouse model of lipopolysaccharide (LPS)-induced ALI. Pretreatment with zerumbone inhibited the histopatholgical changes such as neutrophils infiltration, increased in alveolar barrier thickness, hemorrhage, and hyaline membrane formation occurred in lungs in LPS-induced ALI. In addition, not only LPS-induced activation of myeloperoxidase (MPO) and metallopeptidase-9 (MMP-9) was suppressed by zerumbone, but also lipid peroxidation in lungs was inhibited as well. Moreover, pretreatment with zerumbone reversed the antioxidative enzymes activities, including superoxide dismutase, catalase, and glutathione peroxidase, decreased by LPS and enhanced the expression of nuclear factor erythroid 2-related factor (Nrf2) and heme oxygenase (HO-1) induced by LPS. These results from present study suggested that the protective mechanisms of zerumbone on LPS-induced ALI were via up-regulation of antioxidative enzymes and Nrf2/HO-1 pathway.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Antioxidants; Cells, Cultured; Disease Models, Animal; Heme Oxygenase-1; Humans; Lipopolysaccharides; Male; Matrix Metalloproteinase 9; Membrane Proteins; Mice; Mice, Inbred ICR; NF-E2-Related Factor 2; Peroxidase; Sesquiterpenes; Signal Transduction; Zingiberaceae

Menthol is an aromatic compound with high antiinflammatory activity. The purpose of the current research is to investigate the effectiveness of menthol on acetic acid induced acute colitis in rats. Animals were injected with menthol (20 and 50 and 80mg/kg, i.p.) 24h prior to induction of colitis for 3 consecutive days. Menthol at medium and higher doses similar to dexamethasone as a reference drug significantly reduced body weight loss, macroscopic damage score, ulcer area, colon weight, colon length and improved hematocrit in rats with colitis. The histopathological examination also confirmed anti-colitic effects of menthol. Menthol also reduced significantly the colonic levels of tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β), interleukin 6 (IL-6) and myeloperoxidase (MPO) activity in inflamed colons. Thus, the findings of the current study provide evidence that menthol may be beneficial in patients suffering from acute ulcerative colitis.

Topics: Acute Disease; Animals; Body Weight; Colitis; Colon; Cytokines; Disease Models, Animal; Hematocrit; Male; Menthol; Peroxidase; Rats; Rats, Wistar

Flaviviruses are a genre of closely related viral pathogens which emerged in the last decades in Brazil and in the world. Saint (St.) Louis encephalitis virus (SLEV) is a neglected flavivirus that can cause a severe neurological disease that may lead to death or sequelae. St. Louis encephalitis pathogenesis is poorly understood, which hinders the development of specific treatment or vaccine.. To address this problem, we developed a model of SLEV infection in mice to study mechanisms involved in the pathogenesis of severe disease. The model consists in the intracranial inoculation of the SLEV strain BeH 355964, a strain isolated from a symptomatic human patient in Brazil, in adult immunocompetent mice.. Inoculated mice presented SLEV replication in the brain, accompanied by tissue damage, disease signs, and mortality approximately 7 days post infection. Infection was characterized by the production of proinflammatory cytokines and interferons and by leukocyte recruitment to the brain, composed mainly by neutrophils and lymphocytes. In vitro experiments indicated that SLEV is able to replicate in both neurons and glia and caused neuronal death and cytokine production, respectively.. Altogether, intracranial SLEV infection leads to meningoencephalitis in mice, recapitulating several aspects of St. Louis encephalitis in humans. Our study indicates that the central nervous system (CNS) inflammation is a major component of SLEV-induced disease. This model may be useful to identify mechanisms of disease pathogenesis or resistance to SLEV infection.

Topics: Analysis of Variance; Animals; Cell Line, Transformed; Cytokines; Disease Models, Animal; Encephalitis Virus, St. Louis; Encephalitis, St. Louis; Eosinophil Peroxidase; Hexosaminidases; Leukocytes; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Peroxidase; Time Factors; Viral Load

Sepsis is a major cause of mortality in Intensive Care Units. Anesthetic dose isoflurane and 100% oxygen were proved to be beneficial in sepsis; however, their application in septic patients is limited because long-term hyperoxia may induce oxygen toxicity and anesthetic dose isoflurane has potential adverse consequences. This study was scheduled to find the optimal combination of isoflurane and oxygen in protecting experimental sepsis and its mechanisms.. The effects of combined therapy with isoflurane and oxygen on lung injury and sepsis were determined in animal models of sepsis induced by cecal ligation and puncture (CLP) or intraperitoneal injection of lipopolysaccharide (LPS) or zymosan. Mouse RAW264.7 cells or human peripheral blood mononuclear cells (PBMCs) were treated by LPS to probe mechanisms. The nuclear factor kappa B (NF-κB) signaling molecules were examined by Western blot and cellular immunohistochemistry.. The 0.5 minimum alveolar concentration (MAC) isoflurane in 60% oxygen was the best combination of oxygen and isoflurane for reducing mortality in experimental sepsis induced by CLP, intraperitoneal injection of LPS, or zymosan. The 0.5 MAC isoflurane in 60% oxygen inhibited proinflammatory cytokines in peritoneal lavage fluids (tumor necrosis factor-alpha [TNF-β]: 149.3 vs. 229.7 pg/ml, interleukin [IL]-1β: 12.5 vs. 20.6 pg/ml, IL-6: 86.1 vs. 116.1 pg/ml, and high-mobility group protein 1 [HMGB1]: 323.7 vs. 449.3 ng/ml; all P< 0.05) and serum (TNF-β: 302.7 vs. 450.7 pg/ml, IL-1β: 51.7 vs. 96.7 pg/ml, IL-6: 390.4 vs. 722.5 pg/ml, and HMGB1: 592.2 vs. 985.4 ng/ml; all P< 0.05) in septic animals. In vitro experiments showed that the 0.5 MAC isoflurane in 60% oxygen reduced inflammatory responses in mouse RAW264.7 cells, after LPS stimulation (all P< 0.05). Suppressed activation of NF-κB pathway was also observed in mouse RAW264.7 macrophages and human PBMCs after LPS stimulation or plasma from septic patients. The 0.5 MAC isoflurane in 60% oxygen also prevented the increases of phospho-IKKβ/β, phospho-IκBβ, and phospho-p65 expressions in RAW264.7 macrophages after LPS stimulation (all P< 0.05).. Combined administration of a sedative dose of isoflurane with 60% oxygen improves survival of septic animals through reducing inflammatory responses.

Topics: Adult; Anesthesia; Animals; Blotting, Western; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Female; Humans; Inflammation; Isoflurane; Leukocytes, Mononuclear; Lipopolysaccharide Receptors; Lipopolysaccharides; Lung Injury; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Oxygen; Peroxidase; Rats, Sprague-Dawley; RAW 264.7 Cells; Sepsis; Tumor Necrosis Factor-alpha

Ulcerative colitis is a relapsing inflammatory disorder of the colon. There is a need to explore the new treatments for this disorder. Theophylline, a competitive inhibitor of phosphodiesterase, is shown to have anti-inflammatory properties. However, the effect of theophylline on ulcerative colitis has not yet been investigated. The present study evaluated the effect of theophylline on acetic acid induced ulcerative colitis in rats.. Colitis was induced by instillation of 2ml of acetic acid solution (3%). Colon samples were evaluated grossly and microscopically and assayed for myeloperoxidase (MPO) activity and proinflammatory cytokine concentrations.. Treatment with theophylline at the doses of 20 and 50mg/kg attenuated acetic acid induced ulcerative colitis as shown by improvement in body weight loss, macroscopic score, ulcer area, hematocrit and histopathological score. Theophylline treatment also reduced MPO activity and tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1 β) and interleukin 6 (IL-6) concentrations in inflamed colon.. Theophylline has a protective effect in acetic acid-induced ulcerative colitis which might be due to its anti-inflammatory activities. Therefore, theophylline has the potential to be used for successful treatment of ulcerative colitis.

Topics: Acetic Acid; Animals; Anti-Inflammatory Agents; Colitis, Ulcerative; Colon; Disease Models, Animal; Interleukin-1beta; Interleukin-6; Male; Peroxidase; Rats; Rats, Wistar; Theophylline; Tumor Necrosis Factor-alpha

Purpose To test whether MPO-Gd, an activatable molecular magnetic resonance (MR) imaging agent specific for myeloperoxidase (MPO) activity, could detect MPO activity in nonalcoholic steatohepatitis (NASH) mouse models and human liver biopsy samples. Materials and Methods In this study, 20 leptin receptor-deficient and three MPO knockout mice were injected with endotoxin (lipopolysaccharide) or fed a methionine and choline-deficient (MCD) diet to induce experimental NASH and underwent MR imaging with MPO-Gd. Saline-injected and control diet-fed leptin receptor-deficient mice were used as respective controls. MPO protein and activity measurements and histologic analyses were performed. Eleven human liver biopsy samples underwent MPO-Gd-enhanced MR imaging ex vivo and subsequent histologic evaluation. Results were compared with Student t test or Mann-Whitney U test. Results With endotoxin, a significantly increased contrast-to-noise ratio (CNR) was found compared with sham (mean CNR, 1.81 [95% confidence interval {CI}: 1.53, 2.10] vs 1.02 [95% CI: 0.89, 1.14]; P = .03) at MPO-Gd MR imaging. In the diet-induced NASH model, an increased CNR was also found compared with sham mice (mean CNR, 1.33 [95% CI: 1.27, 1.40] vs 0.98 [95% CI: 0.83, 1.12]; P = .008). Conversely, CNR remained at baseline in NASH mice imaged with gadopentetate dimeglumine and in MPO knockout NASH mice with MPO-Gd, which proves specificity of MPO-Gd. Ex vivo molecular MR imaging of liver biopsy samples from NASH and control patients confirmed results from animal studies (mean CNR for NASH vs control patients, 2.61 [95% CI: 1.48, 3.74] vs 1.29 [95% CI: 1.06, 1.52]; P = .004). Conclusion MPO-Gd showed elevated MPO activity in NAFLD mouse models and human liver biopsy samples.

Topics: Adult; Animals; Biopsy; Contrast Media; Diagnosis, Differential; Disease Models, Animal; Fatty Liver; Female; Gadolinium DTPA; Humans; Immunoenzyme Techniques; Magnetic Resonance Imaging; Mice; Middle Aged; Molecular Imaging; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Peroxidase

We have recently reported that neutrophils play a pivotal role in innate defense against Streptococcus pneumoniae ( Spn) during mouse acute otitis media (AOM). However, the underlying mechanism remains unclear. By constructing models of pneumococcal AOM in C57BL/6 mice and using a specific inhibitor in vivo, we investigated the role of myeloperoxidase (MPO), one of the most important protein components of neutrophils. Experiment results showed a significant increase in MPO production of the recruited neutrophils in Spn-infected mice. Neutrophils killed Spn in a MPO-dependent manner. MPO facilitated the generation of reactive oxygen species (ROS), and consequently promoted Spn clearance at an early stage and exacerbated tissue damage. Moreover, MPO induced neutrophil apoptosis and necrosis, which, in turn, worsened tissue damage. In summary, our study demonstrates that neutrophil MPO plays a paradoxical role in bacterial clearance and tissue damage in pneumococcal AOM.

Topics: Animals; Apoptosis; Bacteriolysis; Disease Models, Animal; Female; Humans; Immunity, Innate; Male; Mice; Mice, Inbred C57BL; Necrosis; Neutrophils; Otitis Media; Peroxidase; Pneumococcal Infections; Reactive Oxygen Species; Streptococcus pneumoniae

Mangifera indica is widely found in Brazil, and its leaves are used as an anti-inflammatory agent in folk medicine. The aim of this study is to perform composition analysis of essential oils from the M. indica varieties, espada (EOMIL1) and coração de boi (EOMIL2), and confirm their anti-inflammatory properties. Twenty-three volatile compounds were identified via gas chromatography-mass spectrometry (GC-MS) in two essential oils from the leaves. Paw edema and myeloperoxidase (MPO) activity were evaluated using the carrageenan-induced paw model, while leukocyte migration was analyzed using the pleurisy model. At oral doses of 100 and 300 mg/kg, the essential oils significantly reduced edema formation and the increase in MPO activity induced by carrageenan in rat paws. For a dose of 300 mg/kg EOMIL1, 62 ± 8% inhibition of edema was observed, while EOMIL2 led to 51 ± 7% inhibition of edema. At a dose of 100 mg/kg, the inhibition was 54 ± 9% for EOMIL1 and 37 ± 7% for EOMIL2. EOMIL1 and EOMIL2 significantly reduced MPO activity at doses of 100 mg/kg (47 ± 5 and 23 ± 8%, respectively) and 300 mg/kg (50 ± 9 and 31 ± 7%, respectively). In the pleurisy model, inhibitions were also observed for EOMIL1 and EOMIL2 in the leukocyte migration test. The results of the present study show that essential oils from M. indica differ in chemical composition and anti-inflammatory activity in rats.

Topics: Animals; Anti-Inflammatory Agents; Brazil; Carrageenan; Cell Movement; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Gas Chromatography-Mass Spectrometry; Gene Expression Regulation; Leukocytes; Male; Mangifera; Medicine, Traditional; Mice; Oils, Volatile; Peroxidase; Plant Leaves; Plant Oils; Rats

Ulcerative colitis (UC), a type of inflammatory bowel disease (IBD), is a chronic inflammatory disorder of the colon. Although UC is generally treated with anti-inflammatory drugs or immunosuppressants, most of these treatments often prove to be inadequate. Rosmarinic acid (RA) is a phenolic ester included in various medicinal herbs such as Salvia miltiorrhiz and Perilla frutescens. Although RA has many biological and pharmacological activities, the anti-inflammatory effect of RA in colonic tissue remains unclear. In this study, we investigated the anti-inflammatory effects and underlying molecular mechanism of RA in mice with dextran sulphate sodium (DSS)-induced colitis. In the DSS-induced colitis model, RA significantly reduced the severity of colitis, as assessed by disease activity index (DAI) scores, colonic damage, and colon length. In addition, RA resulted in the reduction of the inflammatory-related cytokines, such as IL-6, IL-1β, and IL-22, and protein levels of COX-2 and iNOS in mice with DSS-induced colitis. Furthermore, RA effectively and pleiotropically inhibited nuclear factor-kappa B and signal transducer and activator of transcription 3 activation, and subsequently reduced the activity of pro-survival genes that depend on these transcription factors. These results demonstrate that RA has an ameliorative effect on colonic inflammation and thus a potential therapeutic role in colitis.

Topics: Animals; Cinnamates; Colitis; Colon; Cyclooxygenase 2; Cytokines; Depsides; Dextran Sulfate; Disease Models, Animal; Disease Progression; Gene Expression Regulation; Inflammation; Inflammation Mediators; Male; Mice, Inbred ICR; NF-kappa B; Nitric Oxide Synthase Type II; Peroxidase; Rosmarinic Acid; Spleen; STAT3 Transcription Factor

Neutrophils have crucial antimicrobial functions but are also thought to contribute to tissue injury upon exposure to bacterial products, such as lipopolysaccharide (LPS). To study the role of neutrophils in LPS-induced endotoxemia, we developed a new mouse model,

Topics: Animals; Antibodies; Disease Models, Animal; Endotoxemia; Lipopolysaccharides; Mice; Neutrophils; Peroxidase; Sepsis

The purpose of this study is to investigate the neurological, biochemical, and histopathologic effects of both the acute and maintenance treatment of curcumin on an experimental spinal cord ischemia-reperfusion injury model in rats.. The animals were randomly divided into 4 groups: (1) Sham, (2) ischemia-reperfusion (IR), (3) curcumin, and (4) solvent. Spinal cord ischemia was induced by clamping the aorta with minivascular clamps at a position just below the left renal artery and just proximal to the aortic bifurcation for 45 min. After 72 hr of reperfusion, neurological function was evaluated with a modified Tarlov score. In spinal cords, malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx), and nitric oxide (NO) levels were detected biochemically. Immunohistochemical staining was performed by antibodies against interleukin-6 (IL-6) and myeloperoxidase. Histopathologic changes were examined with hematoxylin and eosin staining.. Although MDA tissue levels were elevated significantly in the IR group compared with the sham group, SOD and GPx levels decreased. After the administration of curcumin, MDA levels in the spinal cord decreased, and SOD and GPx levels increased. Those changes were statistically significant. There was no significance at NO levels. Among all groups, there was no difference in IL-6 and myeloperoxidase immunostaining. Histopathological analysis showed that histopathological changes in the IR group were improved by curcumin treatment. In the curcumin group, neurological outcome scores were significantly better statistically when compared with the IR group.. We believe that curcumin possesses antioxidant, antiproliferative, and anticarcinogenic properties and may be an effective drug for the prevention of spinal cord IR injury in light of the neurologic, biochemical, and histopathological data of this study and published scientific literature.

Topics: Animals; Antioxidants; Curcumin; Disease Models, Animal; Glutathione Peroxidase; Interleukin-6; Malondialdehyde; Neuroprotective Agents; Nitric Oxide; Peroxidase; Rats, Wistar; Reperfusion Injury; Spinal Cord; Spinal Cord Ischemia; Superoxide Dismutase; Time Factors

Resveratrol is a natural polyphenol extracted from mangy plants. It has been reported that resveratrol show multitudinous positive role in biology such as anti-oxidant, anti-nociception and anti-inflammatory effects. Therefore, the present study devotes to test the effect of resveratrol on LPS-induced mastitis in mice. Resveratrol was administered intraperitoneally 1 h before LPS treatment. And the anti-inflammatory effect of resveratrol was measured by histopathological examination, MPO assay, real-time PCR and western blotting analysis. The results showed that resveratrol significantly reduced the LPS-induced mammary histopathological changes. Meanwhile, it sharply attenuated the activity of MPO. The result also indicated that the resveratrol can decrease the expression of pro-inflammatory cytokines TNF-α and IL-1β. From the results of western blotting, resveratrol suppressed the expression of phosphorylation of p65 and IκB from NF-κB signal pathway and phosphorylation of p38 and ERK from MAPK signal pathway. These findings suggested that resveratrol may inhibit the inflammatory response in the mastitis.

Topics: Animals; Anti-Inflammatory Agents; Blotting, Western; Cytokines; Disease Models, Animal; Female; Inflammation; Interleukin-1beta; Lipopolysaccharides; Mammary Glands, Animal; MAP Kinase Signaling System; Mastitis; Mice; Mice, Inbred BALB C; NF-kappa B; Peroxidase; Phosphorylation; Real-Time Polymerase Chain Reaction; Resveratrol; Signal Transduction; Stilbenes; Tumor Necrosis Factor-alpha

Gastrodin (GAS), a phenolic glucoside derived from Gastrodiaelata Blume, has been reported to have anti-inflammatory effect. The aim of this study was to investigate the effects of GAS on LPS-induced acute lung injury in mice. ALI was induced by the intranasal administration of LPS and GAS was given 1 h or 12 h after LPS treatment. The results indicated that GAS treatment markedly attenuated the damage of lung injury induced by LPS. GAS attenuated the activity of myeloperoxidase (MPO) and down-regulated the levels of pro-inflammatory cytokines TNF-α, IL-6 and IL-1β in BALF. LPS-induced lung edema and lung function were also reversed by GAS. Furthermore, GAS was found to inhibit LPS-induced inflammatory cells infiltration. In addition, treatment of GAS inhibited LPS-induced NF-κB activation and up-regulated the expression of Nrf2 and HO-1. In conclusion, our results indicated that GAS had anti-inflammatory effects on LPS-induced acute lung injury. The anti-inflammatory mechanism of GAS was through the inhibition of NF-κB and activation of Nrf2 signaling pathways.

Topics: Acute Lung Injury; Animals; Benzyl Alcohols; Biomarkers; Bronchoalveolar Lavage Fluid; Cytokines; Disease Models, Animal; Glucosides; Heme Oxygenase-1; Inflammation Mediators; Lipopolysaccharides; Mice; NF-E2-Related Factor 2; NF-kappa B; Peroxidase; Protective Agents; Respiratory Function Tests; Signal Transduction

Our study aimed to determine whether antithrombin plays a synergistic role in accentuating the effects of intestinal ischemic preconditioning.. Fifty rats were randomly allocated to 5 groups (10 rats/group) as follows: sham treatment (group 1); ischemia-reperfusion (group 2); ischemic preconditioning followed by ischemia-reperfusion (group 3); antithrombin + ischemia-reperfusion, similar to group 2 but including antithrombin administration (group 4); and antithrombin + ischemic preconditioning, similar to group 3 but including antithrombin administration (group 5). Blood samples and liver specimens were obtained for measurement of cytokines, myeloperoxidase, and malondialdehyde. Liver biopsies were examined by electron microscopy.. Intestinal ischemia-reperfusion induced a remote hepatic inflammatory response as evidenced by the striking increase of proinflammatory cytokines, myeloperoxidase, and malondialdehyde. Tumor necrosis factor-α levels in group 5 (12.48 ± 0.7 pg/mL) were significantly lower than in group 3 (13.64 ± 0.78 pg/mL; P = .014). Mean interleukin 1β was lower in group 5 (9.52 ± 0.67pg/mL) than in group 3 (11.05 ± 1.9 pg/mL; P > .99). Mean interleukin 6 was also significantly lower in group 5 (17.13 ± 0.54 pg/mL) than in group 3 (23.82 ± 1 pg/mL; P ≤ .001). Myeloperoxidase levels were significantly higher in group 3 (20.52 ± 2.26 U/g) than in group 5 (18.59 ± 1.03 U/g; P = .025). However, malondialdehyde levels did not significantly improve in group 5 (4.55 ± 0.46 μmol) versus group 3 (5.17 ± 0.61 μmol; P = .286). Tumor necrosis factor-α, interleukin 6, and myeloperoxidase findings show that antithrombin administration further attenuated the inflammatory response caused by ischemia-reperfusion, suggesting a synergistic effect with ischemic preconditioning. These findings were confirmed by electron microscopy.. The addition of antithrombin to ischemic preconditioning may act to attenuate or prevent damage from ischemia-reperfusion injury by inhibiting the release of cytokines and neutrophil infiltration.

Topics: Animals; Antithrombins; Biomarkers; Combined Modality Therapy; Cytokines; Disease Models, Animal; Hepatitis; Intestinal Diseases; Ischemic Preconditioning; Liver; Malondialdehyde; Mesenteric Artery, Superior; Neutrophil Infiltration; Peroxidase; Rats, Wistar; Reperfusion Injury; Splanchnic Circulation; Time Factors

The aim of this study was to investigate whether experimental periodontitis cause changes to the renal tissues and imbalance in oxidative stress in kidneys.. Twenty-two female Wistar rats were separated into two groups: control and periodontitis. We assessed the following parameters: gingival bleeding index (GBI), tooth mobility, gum malondialdehyde (MDA), myeloperoxidase (MPO) activity, probing pocket depth (PPD), alveolar bone loss (ABL) for periodontal tissues; histomorphometric measures associated with renal corpuscle and histopathological aspects (evaluation of brush border) for kidneys; as also blood and urine biomarkers. Finally, we evaluated renal oxidative stress through glutathione (GSH) and MDA respectively.. With regard to renal histomorphometry, significant differences were observed in all parameters assessed. In relation periodic acid Schiff (PAS) staining, disruption was observed of brush border in the periodontitis group in the renal tubules in comparison with the control group. The periodontitis group presented significantly higher MDA and lower GSH concentrations in the kidneys compared with animals without periodontitis.. The induced periodontitis caused histomorphometric changes in renal tissues as well as disruption of the brush border in renal tubules, alterations associated with increase in oxidative stress in kidneys. However, these alterations were not sufficient to cause differences in the renal function markers.

Topics: Alveolar Bone Loss; Animals; Biomarkers; Disease Models, Animal; Female; Glutathione; Kidney Diseases; Lipid Peroxidation; Malondialdehyde; Oxidative Stress; Periodontal Attachment Loss; Periodontal Index; Periodontal Pocket; Periodontitis; Periodontium; Peroxidase; Rats; Rats, Wistar; Tooth Mobility

The present study aimed to verify the efficacy of tranilast (TL) for treating inflammatory bowel disease (IBD) with the use of an experimental colitis model. The experimental colitis model was prepared by intrarectal instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS; 40mg/kg) dissolved in water containing 25% ethanol. The pharmacological effects of TL after repeated oral administration were evaluated by biomarker and histological analyses, and the pharmacokinetic behavior of TL was also examined after single oral administration. The intrarectal instillation of TNBS solution caused colitis, as evidenced by ca. 2.2-, 5-, and 3-fold increases in myeloperoxidase (MPO) activity, infiltrated cell numbers, and the thickness of the submucosa in the colon, respectively. However, orally-taken TL (10mg/kg, twice a day for 9days) led to a 92% reduction in the increase of the MPO level by TNBS enema, and cellular infiltration and thickened submucosa in the experimental colitis model tended to also be suppressed by repeated oral administration of TL. The oral bioavailability of TL in TNBS-treated rats was calculated to be as low as ca. 6.5%, and the poor oral absorption of TL may be a limitation of the treatment for IBD. TL could attenuate TNBS-induced colitis on the basis of the obtained results, and the anti-inflammatory effects would have clinical relevance to the therapeutic outcomes of TL in IBD patients. Although further improvement in the oral bioavailability of TL might be required for better pharmacological outcomes, TL would be an efficacious agent for treating IBD.

Topics: Animals; Anti-Inflammatory Agents; Colitis; Colon; Disease Models, Animal; Inflammatory Bowel Diseases; Intestinal Mucosa; Male; ortho-Aminobenzoates; Peroxidase; Protective Agents; Rats; Rats, Wistar; Trinitrobenzenesulfonic Acid

Pouchitis occurs in approximately 50% of patients with ulcerative colitis after ileal pouch-anal anastomosis (IPAA) but the pathogenesis remains unclear. We used a rat model of dextran sulfate sodium (DSS)-induced ileal pouchitis to examine whether intestinal barrier disruption plays a role in the development and progression of the disease.. Rats were randomly divided into DSS (underwent IPAA and administered 5% DSS orally), IPAA (underwent IPAA), and Sham groups (underwent switch abdominal surgery). In the DSS group, levofloxacin intervention and nonintervention subgroups were used to determine the influence of antibiotics on intestinal barrier dysfunction. Hematochezia and fecal scores were recorded. Ileum and pouch specimens were obtained for histological assessment. Immunohistochemistry was performed for myeloperoxidase and occludin protein expression. Levels of interleukin-1β (IL-1β), IL-6, IL-10, and tumor necrosis factor α mRNA were detected by real-time PCR. Plasma D-lactate concentrations were determined with colorimetry.. Only rats in the DSS group experienced hematochezia, and their fecal and histological scores significantly increased (P < 0.01). Compared with the IPAA and Sham groups, levels of myeloperoxidase, IL-1β, IL-6, tumor necrosis factor α, and plasma D-lactate significantly increased, whereas occludin and IL-10 reduced in the DSS group (P < 0.01). The levofloxacin subgroup showed increased occludin expression and more balanced inflammatory cytokine levels than the nonintervention subgroup. All differences showed linear correlations.. The intestinal barrier was disrupted in this rat model of pouchitis. Increased proinflammatory and decreased anti-inflammatory factors aggravated the intestinal barrier damage. Antibiotics may ameliorate this process.

Topics: Anastomosis, Surgical; Animals; Colitis, Ulcerative; Colonic Pouches; Cytokines; Dextran Sulfate; Disease Models, Animal; Ileum; Intestinal Mucosa; Male; Occludin; Peroxidase; Pouchitis; Proctocolectomy, Restorative; Rats; Rats, Sprague-Dawley

Trans-chalcone (TC) is a common precursor of flavonoids. However, the pharmacological properties of TC remain to be fully understood. The present study investigated whether topical formulation containing TC (TFcTC) presents therapeutic effect in UVB radiation-induced skin damage using disease, enzyme activity, antioxidant activity, protein and mRNA parameters. Control topical formulation (CTF) and TFcTC were applied in hairless mice before and after exposure to UVB radiation. Dorsal skin samples were collected after UVB exposure to evaluate: i) skin edema (weight) was measured by punch biopsy; ii) spectrophotometric assays were used to measure myeloperoxidase (MPO) and catalase activities, ferric (FRAP) and ABTS cation reducing antioxidant power, superoxide anion production and levels of reduced glutathione (GSH); iii) enzymography was used to measure matrix metalloproteinase-9 (MMP-9) activity; iv) chemiluminescence was used to measure the lipid peroxidation (LPO); v) enzyme-linked immunosorbent assay (ELISA) was used to measure tumor necrosis factor alpha (TNF-α) levels; vi) reverse transcription quantitative PCR (RT-qPCR) was used to measure cyclooxygenase-2 (COX-2), gp91

Topics: Administration, Topical; Animals; Catalase; Chalcone; Cyclooxygenase 2; Disease Models, Animal; Glutathione Peroxidase; Glutathione Peroxidase GPX1; Glutathione Reductase; Heme Oxygenase-1; Inflammation; Isomerism; Lipid Peroxidation; Matrix Metalloproteinase 9; Mice; Mice, Hairless; NF-E2-Related Factor 2; Oxidative Stress; Peroxidase; Skin; Tumor Necrosis Factor-alpha; Ultraviolet Rays

Periodontitis may promote harmful systemic effects such as changes in hepatic tissues. The purpose of this study was to investigate whether the steatosis and oxidative stress caused by experimental periodontitis are reversible in the liver.. Twenty-four rats were divided into three groups: control, periodontitis and P20-20 (20 days with experimental periodontitis and 20 days without experimental periodontitis, to verify the reversibility of hepatic injuries). The following parameters were assessed: gingival bleeding index, probing pocket depth, myeloperoxidase activity, alveolar bone loss for periodontal tissues; liver weights, histopathological scores for steatosis, inflammation and necrosis in liver; glutathione, malondialdehyde, total cholesterol and triglyceride concentrations in hepatic tissues; and blood levels of aspartate aminotransferase, alanine aminotransferase, albumin, gamma-glutaryl transferase, total cholesterol and random glucose.. Gingival bleeding index, probing pocket depth, myeloperoxidase and alveolar bone loss parameters demonstrated the development of periodontitis. There was a significant reduction in the steatosis score of animals from the P20-20 group when compared with the periodontitis group. P20-20 group presented significantly higher glutathione (11 times) and lower malondialdehyde (nearly 23%), total cholesterol (both in blood and hepatic tissue) and triglyceride concentrations compared with the periodontitis group. For levels of aspartate aminotransferase, alanine aminotransferase, albumin, gamma-glutaryl transferase and random glucose, a significant difference between the groups was not observed.. Our results demonstrate that the microvesicular steatosis caused by periodontitis in rats is reversible after removal of the ligature, which is associated with the increase in oxidative stress and lipid peroxidation in the liver.

Topics: Alanine Transaminase; Alveolar Bone Loss; Animals; Aspartate Aminotransferases; Blood Glucose; Cholesterol; Disease Models, Animal; Fatty Liver; Female; gamma-Glutamyltransferase; Gingiva; Glutathione; Inflammation; Ligation; Lipid Peroxidation; Liver; Malondialdehyde; Necrosis; Oxidative Stress; Periodontal Index; Periodontal Pocket; Periodontitis; Peroxidase; Rats; Rats, Wistar; Serum Albumin; Time Factors; Transaminases; Triglycerides

Accounting for high mortality and morbidity rates, intracerebral hemorrhage (ICH) remains one of the most detrimental stroke subtypes lacking a specific therapy. Neuroinflammation contributes to ICH-induced brain injury and is associated with unfavorable outcomes. This study aimed to evaluate whether

Topics: alpha7 Nicotinic Acetylcholine Receptor; Animals; Blood Transfusion, Autologous; Brain Injuries; Bridged Bicyclo Compounds, Heterocyclic; Cerebral Hemorrhage; Collagenases; Disease Models, Animal; Humans; Inflammation; Janus Kinase 2; Mice; Neurons; Peroxidase; Quinuclidines; Rats; STAT3 Transcription Factor; Tumor Necrosis Factor-alpha; Tyrphostins

Pulmonary endothelial injury is a critical process in the pathogenesis of acute lung injury (ALI) during sepsis. Heat shock protein A12B (HSPA12B) is mainly expressed in endothelial cells and protects against several harmful factors. However, the effects of HSPA12B in sepsis-induced ALI and its potential mechanisms of action remain unclear.. For in vivo experiments, C57BL/6 mice were randomly divided into four groups (n=15): a sham operation group, a cecal ligation and puncture (CLP) group, a HSPA12B siRNA-CLP group and a negative control (NC) siRNA-CLP group. The mice were treated by nasal inhalation of 2-OMe-modified HSPA12B siRNA or NC siRNA. Sepsis was induced by CLP. Samples were harvested 24 and 48 hours post-CLP surgery. Pathological changes and scoring of lung tissue samples were monitored using hematoxylin and eosin staining. Levels of pro-inflammatory cytokines (e.g., interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-6) and myeloperoxidase activity in bronchoalveolar lavage fluid were analyzed by ELISA. Pulmonary edema was assessed using a wet-to-dry weight ratio. Neutrophils and alveolar macrophages were counted using flow cytometry. Pulmonary endothelial cell apoptosis was detected by TUNEL staining. Expression levels of MAPK family signaling molecules and caspase-3 were measured by Western blot analysis. In addition, 7-day survival was recorded. For in vitro experiments, human umbilical vein endothelial cells were pre-transfected with HSPA12B siRNA or pIRES2-EGFP-HSPA12B-Flag plasmid and treated with lipopolysaccharide; subsequently, the expression levels of MAPK family signaling molecules and caspase-3 were measured by Western blotting.. Nasal inhalation of nano-polymer-encapsulated HSPA12B siRNA specifically downregulated mRNA and protein expression levels of HSPA12B in lung tissues. The administration of HSPA12B siRNA aggravated lung pathological injury, upregulated pro-inflammatory cytokine (e.g., IL-1β, TNF-α, and IL-6) expression, and increased myeloperoxidase activity, neutrophil infiltration, pulmonary edema, and pulmonary endothelial cell apoptosis. Additionally, HSPA12B knockdown worsened survival after CLP surgery. The potential protective mechanisms of HSPA12B may involve the inhibition of ERK phosphorylation and caspase-3 activation in vivo and in vitro.. HSPA12B protected against sepsis-induced ALI. The potential mechanism may be partly due to the inhibition of ERK phosphorylation and caspase-3 activation. These findings provide a potential therapeutic target for treating sepsis.

Topics: Acute Lung Injury; Animals; Bronchoalveolar Lavage Fluid; Caspase 3; Cells, Cultured; Disease Models, Animal; Endothelial Cells; HSP70 Heat-Shock Proteins; Interleukin-1beta; Interleukin-6; Lung; Male; Mice; Mice, Inbred C57BL; Neutrophils; Peroxidase; RNA Interference; RNA, Small Interfering; Sepsis; Survival Rate; Tumor Necrosis Factor-alpha

Drugs such as mesalamine (5-ASA) are currently recommended for the treatment of inflammatory bowel disease (IBD). To reduce the frequency of their administration and improve their therapeutic effect, this study investigated the adhesion efficacy, wound healing promotion, and decrease in inflammation in ulcers in the colonic tissue of rats with colitis after combined treatment with hyaluronic acid (HA) and 5-ASA (IBD98-M). HA-fluoresceinamine (FL) conjugates successfully adhered to the mucosal layer and were conjugated in the vascular tissue. In addition, macroscopic and microscopic observations indicated that colonic injuries reduced significantly after treatment with IBD98-M. Compared with PBS and 5-ASA treatment alone, treatment with IBD98-M more effectively reduced bowel inflammation and promoted colonic mucosal healing in TNBS-induced colitis. IBD98-M treatment also reduced myeloperoxidase activity and the expression levels of cyclooxygenase 2 and tumor necrosis factor-αin the colitis tissue. In conclusion, IBD98-M treatment strongly promoted wound healing in colonic injuries and significantly inhibited MPO activity in the inflamed colon tissue of rats. Combined treatment with HA and 5-ASA can accelerate wound healing and reduce inflammatory reaction in rat colitis.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase 2; Cytokines; Disease Models, Animal; Hyaluronic Acid; Inflammation Mediators; Inflammatory Bowel Diseases; Intestinal Mucosa; Male; Mesalamine; Peroxidase; Protective Agents; Rats; Trinitrobenzenesulfonic Acid

A strong correlation exists between inflammatory bowel disease (IBD) and oxidative stress involving alterations of several key signaling pathways. It is known that methionine promotes reactive oxygen species (ROS) production; we therefore hypothesize that a methionine restriction diet would reduce ROS production, inflammatory responses, and the course of IBD. We generated a murine colitis model by dextran sodium sulfate (DSS) treatment and tested the effects of the methionine restriction diet. Forty-eight mice were randomly divided into four groups of equal size, which included a control (CON) group, an MR (methionine restriction diet) group, a DSS treated group and an MR-DSS treated group. Mice in the first two groups had unrestricted access to water for one week. Mice in the two DSS-treated groups had unrestricted access to 5% DSS solution supplied in the drinking water for the same period. Mice in the CON and DSS groups were given a basal diet, whereas mice in the MR-DSS and MR groups were fed a 0.14% MR diet. We found that DSS reduced daily weight gain, suppressed antioxidant enzyme expression, increased histopathology scores and activated NF-κB and nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (Nrf2/Keap1) signaling. We also showed that the MR diet upregulated catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) activities, decreased myeloperoxidase (MPO), TNF-α and IL-1β, and reversed activation of the NF-κB signaling pathway in MR-DSS mice. Taken together, our results imply that the MR diet may be considered as an adjuvant in IBD therapeutics.

Topics: Animals; Biomarkers; Catalase; Colitis; Dextran Sulfate; Disease Models, Animal; Immunity; Inflammatory Bowel Diseases; Intestinal Mucosa; Male; Methionine; Mice; NF-kappa B; Oxidative Stress; Peroxidase; Reactive Oxygen Species; Signal Transduction; Superoxide Dismutase

Despite advances in antimicrobial therapy and advanced critical care neonatal bacterial meningitis has a mortality rate of over 10% and induces neurological sequelae in 20-50% of cases. Escherichia coli K1 (E. coli K1) is the most common gram-negative organism causing neonatal meningitis and is the second most common cause behind group B streptococcus. We previously reported that an E. coli K1 experimental meningitis infection in neonatal rats resulted in habituation and aversive memory impairment and a significant increase in cytokine levels in adulthood. In this present study, we investigated the oxidative stress profile including malondialdehyde (MDA) levels, carbonyl protein formation, myeloperoxidase activity (MPO) activity, superoxide dismutase (SOD) activity and catalase (CAT) activity 6, 12, 24, 48, 72 and 96h after E. coli K1 experimental meningitis infection. In addition, sulfhydryl groups, nitrite and nitrate levels and activity of the mitochondrial respiratory chain enzymes were also measured in the frontal cortex and hippocampus of neonatal rats. The results from this study demonstrated a significant increase in MDA, protein carbonyls and MPO activity and a simultaneous decrease in SOD activity in the hippocampus of the neonatal meningitis survivors but the same was not observed in frontal cortex. In addition, we also observed a significant increase in complex IV activity in the hippocampus and frontal cortex of meningitis survivor rats. Thus, the results from this study reaffirmed the possible role of oxidative stress, nitric oxide and its related compounds in the complex pathophysiology of E. coli K1-induced bacterial meningitis.

Topics: Animals; Animals, Newborn; Disease Models, Animal; Escherichia coli; Frontal Lobe; Hippocampus; Male; Malondialdehyde; Meningitis, Escherichia coli; Oxidative Stress; Peroxidase; Rats; Rats, Wistar

Pomegranate (Punica granatum L., Punicaceae) contains varieties of antioxidants and phytochemicals; there are evidences that phytochemicals and antioxidants play a vital role in reducing inflammation. Hence this investigation was planned to assess the outcome of Punica granatum on trinitrobenzene sulfonic acid provoked colitis in rats at 2, 5 and 8ml/kg of the body weight. The effect of P. granatum was assessed in two group i.e. prophylaxis as pre-colitis and therapeutic as post-colitis. After completion of dosing in both the groups, macroscopic and histological examination of colon was carried out along with estimation of serum myeloperoxidase, glutathione, alkaline phosphate, fibrinogen and C-reactive protein. In prophylactic procedure P. granatum revealed significant (P<0.05) changes in biochemical markers of inflammation at 5 and 8ml/kg doses. However in therapeutic procedure significant change was observed only at 8ml/kg. Thus results of the present study suggest that P. granatum have a role in prevention as well as treatment of inflammation.

Topics: Alkaline Phosphatase; Animals; Anti-Inflammatory Agents; Biomarkers; Carrier Proteins; Colitis; Colon; Disease Models, Animal; Dose-Response Relationship, Drug; Fibrinogen; Gastrointestinal Agents; Glutathione; Inflammation Mediators; Lythraceae; Male; Peroxidase; Phytotherapy; Plant Extracts; Plants, Medicinal; Rats, Wistar; Trinitrobenzenesulfonic Acid

Topics: Animals; Autoantibodies; Disease Models, Animal; Glomerulonephritis; Mice; Mice, Transgenic; Monocytes; Peroxidase

Acute pancreatitis (AP) causes morbidity and mortality. The aim of the present study was to investigate the protective effect of tropisetron against AP induced by cerulein. Cerulein (50μg/kg, 5 doses) was used to induce AP in mice. Six hours after final cerulein injection, animals were decapitated. Hepatic/pancreatic enzymes in the serum, pancreatic content of malondialdehyde (MDA), pro-inflammatory cytokines and myeloperoxidase (MPO) activity were measured. Tropisetron significantly attenuated pancreatic injury markers and decreased the amount of elevated serum amylase, lipase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), MPO activities and pro-inflammatory cytokines levels caused by AP in mice. Tropisetron didn't affect the pancreatic levels of MDA. Our results suggest that tropisetron could attenuate cerulein-induced AP by combating inflammatory signaling. Further clinical studies are needed to confirm its efficacy in patients with AP.

Topics: Acute Disease; Animals; Ceruletide; Cytokines; Disease Models, Animal; Indoles; Lipase; Male; Malondialdehyde; Mice; NF-kappa B; Pancreas; Pancreatitis; Peroxidase; Protective Agents; Signal Transduction; Tropisetron

Oxidative stress is an important regulator in the pathogenesis of acute pancreatitis (AP). Reactive oxygen species induce activation of inflammatory cascades, inflammatory cell recruitment, and tissue damage. NF-κB regulates inflammatory cytokine gene expression, which induces an acute, edematous form of pancreatitis. Protein kinase C δ (PKCδ) activates NF-κB as shown in a mouse model of cerulein-induced AP. Docosahexaenoic acid (DHA), an ω-3 fatty acid, exerts anti-inflammatory and antioxidant effects in various cells and tissues. This study investigated whether DHA inhibits cerulein-induced AP in rats by assessing pancreatic edema, myeloperoxidase activity, levels of lipid peroxide and IL-6, activation of NF-κB and PKCδ, and by histologic observation. AP was induced by intraperitoneal injection (i.p.) of cerulein (50 μg/kg) every hour for 7 h. DHA (13 mg/kg) was administered i.p. for three days before AP induction. Pretreatment with DHA reduced cerulein-induced activation of NF-κB, PKCδ, and IL-6 in pancreatic tissues of rats. DHA suppressed pancreatic edema and decreased the abundance of lipid peroxide, myeloperoxidase activity, and inflammatory cell infiltration into the pancreatic tissues of cerulein-stimulated rats. Therefore, DHA may help prevent the development of pancreatitis by suppressing the activation of NF-κB and PKCδ, expression of IL-6, and oxidative damage to the pancreas.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents; Antioxidants; Ceruletide; Disease Models, Animal; Docosahexaenoic Acids; Inflammation; Interleukin-6; Lipid Peroxides; Male; NF-kappa B; Pancreas; Pancreatitis; Peroxidase; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species

Alliin is a garlic organosulfur compound that possesses various pharmacological properties. In the present study, the protective effects and molecular mechanism of alliin on Lipopolysaccharides (LPS)-induced acute lung injury (ALI) were analyzed. LPS-induced ALI was induced in BALB/c mice by intranasal instillation of LPS. Alliin was administered intraperitoneally to mice 1 h after LPS treatment. The results showed that alliin markedly inhibited lung myeloperoxidase (MPO) activity and wet/dry (W/D) ratio induced by LPS. Alliin also inhibited TNF-α and IL-1β in the bronchoalveolar lavage fluid (BALF) induced by LPS. Furthermore, LPS-induced lung pathological injury was attenuated by treatment of alliin. LPS-induced NF-κB activation was significantly inhibited by alliin. In addition, the expression of peroxisome proliferator-activated receptor γ (PPARγ) was up-regulated by treatment of alliin. Taken together, these results suggested that alliin protected against LPS-induced ALI by activating PPARγ, which subsequently inhibited LPS-induced NF-κB activation and inflammatory response. Alliin might be used as an anti-inflammatory agent in the treatment of ALI.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; Cysteine; Cytokines; Disease Models, Animal; Interleukin-1beta; Lipopolysaccharides; Lung; Male; Mice; Mice, Inbred BALB C; NF-kappa B; Peroxidase; PPAR gamma; Signal Transduction; Tumor Necrosis Factor-alpha

β-Patchoulene (β-PAE), a tricyclic sesquiterpene isolated from the essential oil of the leaves and stems of Pogostemon cablin (Blanco) Benth., has been reported to have potent anti-inflammatory activity. The aim of this study was to evaluate the potential protective effect of β-PAE on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice and to illuminate the underlying mechanisms. ALI was induced by intracheal instillation of LPS into lung, and dexamethasone (DEX) was used as a positive control. Results indicated that pretreatment with β-PAE significantly decreased the mortality rate of mice and lung W/D weight ratio, ameliorated lung pathological changes as compared to model group. Meanwhile, β-PAE pretreatment markedly inhibited the increase of TNF-α, IL-6 and IL-1β secretions in the bronchoalveolar lavage fluid, and prevented LPS-induced elevations of MPO activity and MDA level in the lung. Additionally, β-PAE pretreatment significantly elevated miR-146a expression and suppressed the LPS-induced activation of NF-κB and expression of its mediated genes (TNF-α, IL-6 and IL-1β). β-PAE was also observed to markedly upregulate the Nrf2 and HO-1 expression and activate the antioxidant genes (NQO-1, GCLC and HO-1). Taken together, β-PAE possessed protective effect against LPS-induced ALI, which might be associated with its differential regulation of NF-κB and Nrf2 activities and up-regulation of expression of miR-146a. The results rendered β-PAE a promising anti-inflammatory agent worthy of further development into a pharmaceutical drug for the treatment of ALI.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Cytokines; Dexamethasone; Disease Models, Animal; Heme Oxygenase-1; Humans; Inflammation Mediators; Lipopolysaccharides; Lung; Membrane Proteins; Mice; Mice, Inbred Strains; MicroRNAs; NF-E2-Related Factor 2; NF-kappa B; Peroxidase; Pogostemon; Sesquiterpenes; Sesquiterpenes, Guaiane; Signal Transduction

Recent studies have demonstrated the neuroprotective and immunomodulatory effects of 1,25-dihydroxyvitamin D3 (calcitriol), but no previous study has examined these effects on spinal cord ischemia/reperfusion (I/R) injury. Therefore, the present study aimed to evaluate whether calcitriol protects the spinal cord from I/R injury.. Rabbits were randomized into four groups of eight animals: group 1 (laparotomy control), group 2 (ischemia control), group 3 (30mg/kg intraperitoneal methylprednisolone at surgery), and group 4 (0.5μg/kg, intraperitoneal calcitriol for 7 days before I/R injury). The rabbits in the laparotomy control group underwent laparotomy only, whereas all rabbits in the other groups were subject to spinal cord ischemia by aortic occlusion for 20min, just caudal to the renal artery. Malondialdehyde and catalase levels, myeloperoxidase and xanthine oxidase activities, and caspase-3 concentrations were analyzed. Finally, histopathological, ultrastructural, and neurological evaluations were performed.. After I/R injury, increases in malondialdehyde levels, myeloperoxidase and xanthine oxidase activities, and caspase-3 concentrations were found (p<0.001 for all); by contrast, catalase levels decreased (p<0.001). Calcitriol pretreatment was associated with lower malondialdehyde levels (p<0.001), reduced myeloperoxidase (serum, p=0.018; tissue, p<0.001) and xanthine oxidase (p<0.001) activities, and caspase-3 concentrations (p<0.001), but increased catalase levels (p<0.001). Furthermore, calcitriol pretreatment was associated with better histopathological, ultrastructural, and neurological scores.. Calcitriol pretreatment provided significant neuroprotective benefits following spinal cord I/R injury.

Topics: Animals; Caspase 3; Catalase; Disease Models, Animal; Male; Malondialdehyde; Methylprednisolone; Peroxidase; Rabbits; Reperfusion Injury; Spinal Cord Ischemia; Vitamin D; Xanthine Oxidase

This study investigated the mechanisms responsible for the neuroprotective effect of sildenafil citrate (SFC) on ischemia-reperfusion spinal cord (SC) injuries. Balloon occlusion of the thoracic aorta was used to induce SC ischemia. The animals (n=30) were separated into three groups: sham, SC injury with saline, and SC injury with 5mg/kg i.p. SFC treatment (SFC). The Basso, Beattie, and Bresnahan (BBB) score was determined to assess neurological function at different time intervals after reperfusion. After 48h, histopathology of the SC was assessed by triphenyltetrazolium chloride (TTC) and Nissl staining. Myeloperoxidase (MPO) activity was estimated using an MPO assay kit. Western blot and ELISA assays were performed to estimate interleukin 1 & 10 (IL-1 & IL-10), tumour necrosis factor α (TNF-α), and nuclear factor (NF-kB) levels in SC tissue homogenates. The study results suggest that treatment with SFC significantly increased neurological function compared with the SC group. In addition, SFC treatment reduced MPO activity compared with the SC group, which subsequently inhibited the infiltration of neutrophils into the SC. There was a significant (p<0.01) decrease in the expression of IL-1 and TNF-α, and an increase in the expression of IL-10 in SFC tissue homogenates compared with SC tissues. Moreover, SFC treatment inhibited the activation of NF-kB in the SC after injury. This study shows that SFC exerts a neuroprotective effect on the SC after ischemia/reperfusion injury by attenuating inflammatory mediators.

Topics: Animals; Disease Models, Animal; Inflammation Mediators; Interleukin-1; Interleukin-10; Male; Neuroprotective Agents; NF-kappa B; Peroxidase; Phosphodiesterase Inhibitors; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Spinal Cord; Spinal Cord Injuries; Spinal Cord Ischemia; Tumor Necrosis Factor-alpha

Acute otitis media (AOM) is one of the most common bacterial infectious diseases in children aged 2 to 7 years worldwide. We previously demonstrated that interleukin-17A (IL-17A) promotes an acute inflammatory response characterized by the influx of neutrophils into the middle ear cavity during

Topics: Animals; Disease Models, Animal; Ear, Middle; Interleukin-17; MAP Kinase Signaling System; Mice; Mice, Knockout; Neutrophils; Otitis Media; p38 Mitogen-Activated Protein Kinases; Peroxidase; Receptors, Interleukin-17; Streptococcal Infections; Streptococcus pneumoniae

In the present study, we sought to determine the effects of Bacillus subtilis (BAS) and Bacillus licheniformis (BAL) in rats after lipopolysaccharide (LPS)-induced acute intestinal inflammation. We also determined whether the B. subtilis metabolic product (BASM) is as effective as the live-cell probiotic. 60 male SD rats were randomly assigned to five groups and administered a diet containing 0.05% B. licheniformis (BAL group), 0.05% B. subtilis (BAS group), 0.5% B. subtilis metabolic product (BASM group), or a basic diet (PC group and NC group) for 40 days. On day 40, BAL, BAS, BASM, and NC groups were injected with 4 mg/kg body weight LPS. 4 h later, all rats were anesthetized and sacrificed. The results showed that the administration of B. licheniformis and B. subtilis improved intestinal function as evidenced by histology, increased enzyme activity, and mucosal thickness. They also increased the number of intraepithelial lymphocytes and decreased mucosal myeloperoxidase activity and plasma TNF-α. In addition, the cecal content of B. subtilis-treated rats had significantly increased microbial diversity, decreased numbers of Firmicutes, and increased numbers of Bacteroidetes as compared to rats fed basic diets. Similar to BAS group, the cecal content of B. licheniformis-treated rats decreased the number of Firmicutes. Administration of B. subtilis metabolic product had similar effects on intestinal function, inflammation response, and microbial diversity as B. subtilis but these effects were attenuated. In conclusion, administration of probiotic strains B. licheniformis or B. subtilis improved intestinal function, ameliorated the inflammation response, and modulated microflora after LPS-induced acute inflammation in rats. Non-living cells also exerted probiotic properties but live cells tended to function better.

Topics: Animals; Bacillus licheniformis; Bacillus subtilis; Biodiversity; Biological Products; Colony Count, Microbial; Cytokines; Dietary Supplements; Disease Models, Animal; Intestinal Diseases; Intestinal Mucosa; Intestines; Lipopolysaccharides; Peroxidase; Probiotics; Rats

Ulcerative colitis is one of the most common types of inflammatory bowel disease and is multifactorial and relapsing. 6-Gingerol, a component of gingerols extracted from ginger (Zingiber officinale), has been reported to improve ulcerative colitis. The present study aims to investigate the therapeutic efficacy of two analogous forms of 6-gingerol, 8-gingerol, and 10-gingerol, on ulcerative colitis. Colitis was induced in rats through consumption of 5% (w/v) dextran sulfate sodium drinking water for 7 consecutive days. 6-Gingerol, 8-gingerol, and 10-gingerol were then given intraperitoneally at doses of 30 mg kg

Topics: Animals; Catechols; Colitis, Ulcerative; Colon; Dextran Sulfate; Disease Models, Animal; Fatty Alcohols; Interleukin-1beta; Intestinal Mucosa; Male; Malondialdehyde; Oxidative Stress; Peroxidase; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Tumor Necrosis Factor-alpha

The protozoan Entamoeba histolytica is the etiological agent of amoebiasis, which can spread to the liver and form amoebic liver abscesses. Histological studies conducted with resistant and susceptible models of amoebic liver abscesses (ALAs) have established that neutrophils are the first cells to contact invasive amoebae at the lesion site. Myeloperoxidase is the most abundant enzyme secreted by neutrophils. It uses hydrogen peroxide secreted by the same cells to oxidize chloride ions and produce hypochlorous acid, which is the most efficient microbicidal system of neutrophils. In a previous report, our group demonstrated that myeloperoxidase presents amoebicidal activity in vitro. The aim of the current contribution was to analyze in vivo the role of myeloperoxidase in a susceptible (hamsters) and resistant (Balb/c mice) animal models of ALAs. In liver samples of hamsters and mice inoculated intraportally with Entamoeba histolytica trophozoites, the number of neutrophils in ALAs was determined by enzymatic activity. The presence of myeloperoxidase was observed by staining, and its expression and activity were quantified in situ. A significant difference existed between the two animal models in the number of neutrophils and the expression and activity of myeloperoxidase, which may explain the distinct evolution of amoebic liver abscesses. Hamsters and mice were treated with an MPO inhibitor (4-aminobenzoic acid hydrazide). Hamsters treated with ABAH showed no significant differences in the percentage of lesions or in the percentage of amoebae damaged compared with the untreated hamsters. ABAH treated mice versus untreated mice showed larger abscesses and a decreased percentage of damaged amoebae in these lesion at all stages of evolution. Further studies are needed to elucidate the host and amoebic mechanisms involved in the adequate or inadequate activation and modulation of myeloperoxidase.

Topics: Animals; Cricetinae; Disease Models, Animal; Disease Resistance; Entamoeba histolytica; Host-Pathogen Interactions; Leukocyte Elastase; Liver; Liver Abscess, Amebic; Male; Mice, Inbred BALB C; Neutrophils; Peroxidase

Therapeutic effects of continuous intravenous infusions of solvent-free low doses of resveratrol on organ injury and systemic consequences resulting from severe hemorrhagic shock in rats were studied. Hemorrhagic shock was induced by withdrawing arterial blood until a mean arterial blood pressure (MAP) of 25-30 mmHg was reached. Following a shock phase of 60 min, rats were resuscitated with the withdrawn blood plus lactated Ringer's. Resveratrol (20 or 60 μg/kg × h) was continuously infused intravenously starting with the resuscitation phase (30 min) and continued until the end of the experiment (total treatment time 180 min). Animals of the shock control group received 0.9% NaCl solution. After the observation phase (150 min), rats were sacrificed. Resveratrol significantly stabilized the MAP and peripheral oxygen saturation after hemorrhagic shock, decreased the macroscopic injury of the small intestine, significantly attenuated the shock-induced increase in tissue myeloperoxidase activity in the small intestine, liver, kidney and lung, and diminished tissue hemorrhages (particularly in the small intestine and liver) as well as the rate of hemolysis. Already very low doses of resveratrol, continuously infused during resuscitation after severe hemorrhagic shock, can significantly improve impaired systemic parameters and attenuate multiple organ damage in rats.

Topics: Animals; Blood Glucose; Blood Pressure; Disease Models, Animal; Dose-Response Relationship, Drug; Hematocrit; Hemoglobins; Intestine, Small; Isotonic Solutions; Kidney; Lactic Acid; Liver; Lung; Male; Multiple Organ Failure; Peroxidase; Rats; Rats, Wistar; Resuscitation; Resveratrol; Ringer's Lactate; Shock, Hemorrhagic; Sodium Chloride; Stilbenes

This study investigated the anti-inflammatory activity of the extract (LEG) and purified (LPG) lycopene from guava (Psidium guajava L.), as well as some mechanisms possibly involved in this effect. The anti-inflammatory activity was initially assessed using paw edema induced by Carrageenan, Dextran, Compound 48/80, Histamine and Prostaglandin E2 in Swiss mice. A peritonitis model was used to evaluate neutrophil migration, the activity of myeloperoxidase (MPO) and reduced glutathione (GSH) concentration; while the effect on the expression of iNOS, COX-2 and NF-κB, was assessed by immunohistochemistry analysis. Results showed that oral and intraperitoneal administration of LEG and LPG inhibited inflammation caused by carrageenan. LPG (12.5mg/kg p.o.) significantly inhibited the edema formation induced by different phlogistic agents and immunostaining for iNOS, COX-2 and NF-κB. Leukocytes migration in paw tissue and peritoneal cavity was reduced, as well as MPO concentration, whereas GSH levels increased. Thus, lycopene-rich extract from red guava has beneficial effect on acute inflammation, offering protection against the consequences of oxidative stress by downregulating inflammatory mediators and inhibiting gene expression involved in inflammation.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Cyclooxygenase 2; Disease Models, Animal; Edema; Female; Fruit; Glutathione; Inflammation; Inflammation Mediators; Leukocytes; Male; Mice; Neutrophil Infiltration; NF-kappa B; Nitric Oxide Synthase Type II; Oxidative Stress; Peritonitis; Peroxidase; Plant Extracts; Psidium

This study analyzes the sepsis healing therapeutic potential of carnosine against experimentally sepsis-induced male albino rats. Carnosine in 2 different doses, 25 mg/kg and 50 mg/kg, were administered for 30 consecutive days. At the end of the treatment, lipid peroxidation, catalase, superoxide dismutase, glutathione peroxidase and myeloperoxidase activities were measured. Lungs weight and total protein content were determined in the bronchoalveolar fluid (BALF). Cytokines such as macrophage inhibitory factor (MIF), interleukin-8 (IL-8) and tumour necrosis factor-alpha (TNF-α) were determined in the BALF. In addition, the histopathological analysis was also carried out to understand the effect of carnosine in the cellular architecture. Carnosine treatment significantly renormalized the lipid peroxidation and other antioxidant enzymes. IL-β, TNF-α, and MIF were found to be reduced after carnosine treatment. After carnosine treatment, the intensity of sepsis was significantly reduced evidenced by histopathological analysis. In western blot analysis, carnosine treatment causes the upregulation of IκBα together with the downregulation of the expressions of p65 and p-IKKα/β (Ser 180/Ser 181).

Topics: Acute Lung Injury; Animals; Antioxidants; Carnosine; Catalase; Disease Models, Animal; Glutathione; Glutathione Peroxidase; Interleukin-8; Lipid Peroxidation; Lung; Male; Malondialdehyde; Oxidative Stress; Peroxidase; Protective Agents; Rats; Rats, Wistar; Sepsis; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Neutrophils and macrophages are important constituents of the hepatic inflammatory infiltrate in non-alcoholic steatohepatitis. These innate immune cells express CD18, an adhesion molecule that facilitates leukocyte activation. In the context of fatty liver, activation of infiltrated leukocytes is believed to enhance hepatocellular injury. The objective of this study was to determine the degree to which activated innate immune cells promote steatohepatitis by comparing hepatic outcomes in wild-type and CD18-mutant mice fed a methionine-choline-deficient (MCD) diet. After 3 weeks of MCD feeding, hepatocyte injury, based on serum ALT elevation, was 40% lower in CD18-mutant than wild-type mice. Leukocyte infiltration into the liver was not impaired in CD18-mutant mice, but leukocyte activation was markedly reduced, as shown by the lack of evidence of oxidant production. Despite having reduced hepatocellular injury, CD18-mutant mice developed significantly more hepatic steatosis than wild-type mice after MCD feeding. This coincided with greater hepatic induction of pro-inflammatory and lipogenic genes as well as a modest reduction in hepatic expression of adipose triglyceride lipase. Overall, the data indicate that CD18 deficiency curbs MCD-mediated liver injury by limiting the activation of innate immune cells in the liver without compromising intrahepatic cytokine activation. Reduced liver injury occurs at the expense of increased hepatic steatosis, which suggests that in addition to damaging hepatocytes, infiltrating leukocytes may influence lipid homeostasis in the liver.

Topics: Adipose Tissue; Animals; CD18 Antigens; Choline; Cytokines; Disease Models, Animal; Fatty Liver; Hepatocytes; Immunity, Innate; Inflammation; Leukocytes; Lipase; Liver; Male; Methionine; Mice; Mice, Inbred C57BL; Mutation; Oxygen; Peroxidase; Triglycerides

Oxidative stress and inflammatory response are major factors causing several tissue injuries in intestinal ischemia and reperfusion (I/R). Agmatine has been reported to attenuate I/R injury of various organs. The present study aims to analyze the possible protective effects of agmatine on intestinal I/R injury in rats.. Four groups were designed: sham control, agmatine-treated control, I/R control, and agmatine-treated I/R groups. IR injury of small intestine was induced by the occlusion of the superior mesenteric artery for half an hour to be followed by a 3-hour-long reperfusion. Agmatine (10mg/kg) was administered intraperitoneally before reperfusion period. After 180min of reperfusion period, the contractile responses to both carbachol and potassium chloride (KCl) were subsequently examined in an isolated-organ bath. Malondialdehyde (MDA), reduced glutathione (GSH), and the activity of myeloperoxidase (MPO) were measured in intestinal tissue. Plasma cytokine levels were determined. The expression of the intestinal inducible nitric oxide synthase (iNOS) was also assessed by immunohistochemistry.. The treatment with agmatine appeared to be significantly effective in reducing the MDA content and MPO activity besides restoring the content of GSH. The treatment also attenuated the histological injury. The increases in the I/R induced expressions of iNOS, IFN-γ, and IL-1α were brought back to the sham control levels by the treatment as well.. Our findings indicate that the agmatine pretreatment may ameliorate reperfusion induced injury in small intestine mainly due to reducing inflammatory response and oxidative stress.

Topics: Agmatine; Animals; Carbachol; Disease Models, Animal; Inflammation; Intestine, Small; Male; Malondialdehyde; Oxidative Stress; Peroxidase; Potassium Chloride; Rats; Rats, Wistar; Reperfusion Injury

Aucubin, an iridoid glycoside, was isolated from seeds of Eucommia ulmoides Oliver. This study was aimed to evaluate the protective effect of aucubin against ethanol-induced gastric mucosal injury in mice.. Mice were orally administrated with aucubin (20, 40 and 80mg/kg) for 3 consecutive days. On the 3rd day, the mice of gastric mucosal injury were induced with 70% ethanol after the last administration of aucubin. Gastric tissue of mice were submitted for evaluating the severity of gastric mucosal injury. The protective effect of aucubin was evaluated by the gastric ulcer index and histological examinations and determining the levels of inflammatory cytokines, oxidative stress and some gastric mucosal protection factors.. Prophylactic oral administration of aucubin decreased gastric ulcer indexes and histological scores. A significant decrease of myeloperoxidase (MPO) activity and the levels of malondialdehyde (MDA), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were observed in aucubin administrated groups. In addition, mice administrated with aucubin increased glutathione (GSH) and heat shock protein-70 (HSP-70) levels and superoxide dismutase (SOD) activity, as well as normalized the levels of epidermal growth factor (EGF), vascular endothelial growth factor (VEGF) and cyclooxygenase-1 (COX-1) in gastric tissue of mice.. The findings of this study demonstrated that aucubin shows protective effect against ethanol-induced acute gastric mucosal injury through its anti-inflammatory and anti-oxidant effects. Furthermore, aucubin enhanced gastric mucosal protection by up-regulation of HSP-70 level and normalization of EGF, VEGF and COX-1 levels.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Ethanol; Eucommiaceae; Gastric Mucosa; Glutathione; HSP70 Heat-Shock Proteins; Interleukin-6; Iridoid Glucosides; Male; Malondialdehyde; Mice; Oxidative Stress; Peroxidase; Seeds; Stomach Ulcer; Tumor Necrosis Factor-alpha; Up-Regulation

In 2004, a novel mechanism of cellular death, called 'NETosis', was described in neutrophils. This mechanism, different from necrosis and apoptosis, is characterized by the release of chromatin webs admixed with microbicidal granular proteins and peptides (NETs). NETs trap and kill a variety of microorganisms. Diverse microorganisms, including Mycobacterium tuberculosis, are NET inducers in vitro. The aim of this study was to examine whether M. tuberculosis can also induce NETs in vivo and if the NETs are bactericidal to the microorganism. Guinea pigs were intradermally inoculated with M. tuberculosis H37Rv, and the production of NETs was investigated at several time points thereafter. NETs were detected as early as 30 min post-inoculation and were clearly evident by 4 h post-inoculation. NETs produced in vivo contained DNA, myeloperoxidase, elastase, histones, ROS and acid-fast bacilli. Viable and heat-killed M. tuberculosis, as well as Mycobacterium bovis BCG were efficient NET inducers, as were unilamellar liposomes prepared with lipids from M. tuberculosis. In vitro, guinea pig neutrophils also produced NETs in response to M. tuberculosis. However, neither the in vivo nor the in vitro-produced NETs were able to kill M. tuberculosis. Nevertheless, in vivo, neutrophils might propitiate recruitment and activation of more efficient microbicidal cells.

Topics: Animals; Antigens, Bacterial; Disease Models, Animal; Extracellular Traps; Guinea Pigs; Histones; Hot Temperature; Humans; Mycobacterium tuberculosis; Neutrophils; Pancreatic Elastase; Peroxidase; Reactive Oxygen Species; Tuberculosis; Unilamellar Liposomes

Sargentodoxa cuneata, containing syringaresinol and its glycoside liriodendrin as the main bioactive compounds, is a well-known traditional Chinese medicine for treating intestinal inflammation. In our preliminary study, liriodendrin inhibited NF-kB activation in sepsis-induced acute lung injury. The present study was designed to investigate its effect on dextran sulfate sodium (DSS)-induced colitis in a mouse model and to explore the possible related mechanisms. Experimental colitis was established by giving mice drinking water containing 3% (w/v) DSS for 7days. The mice were pretreated with liriodendrin (100mg/kg/day, intragastrically) 3days before DSS treatment. We determined the effects of liriodendrin on disease activity index (DAI), colon length, histopathological examination, antioxidants, and anti-inflammatory activities. Our results showed that liriodendrin greatly decreased MPO and MDA activities and significantly increased SOD and GPx activities in the colon. Moreover, liriodendrin improved DAI, colon length and histological damage in colon and reduced the levels of pro-inflammatory cytokines, such as TNF-a, IL-1β and IL-6. Meanwhile, assessments by western blot revealed that liriodendrin significantly suppressed the activation of Akt and NF-κB pathways and up-regulated the expression of ERβ in the colon. In vitro, liriodendrin down-regulated production of pro-inflammatory cytokines and suppressed NF-κB signalling pathways in LPS-induced RAW 264.7 macrophages in a concentration-dependent manner. In addition, syringaresinol, the hydrolysate of liriodendrin, more potently down-regulated production of pro-inflammatory cytokines and suppressed NF-κB and Akt signalling pathways in LPS-induced RAW 264.7 macrophages,which were abolished by using a pure ER antagonist, ICI182, 780. Taken together, liriodendrin-mediated suppression of inflammatory damage in the colon may be attributable to the in vivo transformation to syringaresinol and liriodendrin may be a promising therapeutic approach preventive agent for colitis treatment.

Topics: Animals; Anti-Inflammatory Agents; Colitis, Ulcerative; Cytokines; Dextran Sulfate; Disease Models, Animal; Disease Progression; Furans; Glucosides; Humans; Inflammation Mediators; Lipopolysaccharides; Macrophages; Male; Medicine, Chinese Traditional; Mice; Mice, Inbred BALB C; Peroxidase; RAW 264.7 Cells

The present study aimed to investigate the potential protective effects of Astragaloside IV (AS-IV) against ethanol-induced gastric mucosal injury in rats. The animals were divided into 7 groups and pretreated with vehicle, various doses of AS-IV (1,2 and 4mg/kg, i.p.) or omeprazole (40mg/kg), 75min later, the gastric mucosal injury was induced by oral administration of ethanol. One hour after ethanol ingestion, the rats were euthanized and gastric tissues were collected to biochemical analyze. Myeloperoxidase (MPO), tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), interleukin 10 (IL-10), nuclear factor kappa B (NF-κB) p65 protein, TNF receptor-associated factor 2 (TRAF2) and nuclear NF-κB (nNF-κB) proteins were estimated by enzyme-linked immunosorbent assay or western blot analysis. The gastric mucosal lesions were assessed by macroscopic and histopathological examinations. The results showed pretreatment with AS-IV attenuated the severity of ethanol gastric mucosal damage as evidenced by lowering of injury scores, histopathologic aberrations and leukocyte invasion. These actions were analogous to the reference omeprazole. AS-IV suppressed gastric inflammation by curbing of MPO, TNF-α levels along with NF-κB p65 and TRAF2 expression. It also augmented the anti-inflammatory IL-10 levels. Meanwhile, AS-IV could inhibit NF-κB transcription by inhibiting the expression of NF-κB p65 and increasing the expression of nNF-κB. It seems that AS-IV as an anti-inflammatory agent may have a protective effect against ethanol-induced mucosal injury by inhibition of neutrophil infiltration and reducing the expression of NF-κB p65, TRAF2 and inflammatory cytokines via regulating TNF-α/NF-κB signal pathway in gastric tissue.

Topics: Animals; Anti-Inflammatory Agents; Cells, Cultured; Cytokines; Disease Models, Animal; Ethanol; Gastritis; Humans; Inflammation Mediators; Intestines; Male; Neutrophils; NF-kappa B; Omeprazole; Peroxidase; Rats; Rats, Sprague-Dawley; Saponins; TNF Receptor-Associated Factor 2; Triterpenes; Tumor Necrosis Factor-alpha

Mango mistletoes Dendrophthoe pentandra (MMDP) extract has attracted interest due to its pharmacological properties, including gastro protective effects. The aim of this study was to investigate whether MMDP extract could increase Foxp3 regulatory T cells and inhibits development of Th17 cells.. Colitis was induced in Balb/c mice by rectal administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS). The mice were randomly divided into five groups comprising group1 receiving vehicle (the negative control), group 2-5 receiving TNBS, group 3-5 orally receiving either MMDP extract 150, 300 and 600 mg/kgBW for 7 days after TNBS administration. On day 8 of the experiment, the colon tissues were removed for histological examination, cytokine and myeloperoxidase (MPO) measurement. T-cells sub-population in mesenteric lymph nodes were analyzed by flow cytometer.. MMDP extract potently suppressed colon shortening and MPO in mice with TNBS-induced colitis. Administration of the extract significantly decreased the severity of TNBS-induced colitis in a dose-dependent manner. The extract significantly attenuated the loss of body weight (p < 0.05). These effects were associated with a remarkable amelioration of the disruption of the colonic architecture, significant reduction of the colonic MPO (p < 0.05). The extract lowered the levels of Th17-associated cytokines but increased the production of Treg-associated cytokines in mesenteric lymph node cells.. Our results suggest that MMDP has the therapeutic potential to ameliorate TNBS-induced colitis symptoms revealed by histological change and inhibit IL-17 production.

Topics: Animals; CD4-Positive T-Lymphocytes; Colitis; Colon; Disease Models, Animal; Female; Interleukin-10; Interleukin-17; Loranthaceae; Lymph Nodes; Mice, Inbred BALB C; Peroxidase; Plant Extracts; Th17 Cells; Trinitrobenzenesulfonic Acid

Oxidative stress plays a fundamental role in abdominal aortic aneurysm (AAA) formation. Activated polymorphonuclear leukocytes (or neutrophils) are associated with AAA and express myeloperoxidase (MPO), which promotes inflammation, matrix degradation, and other pathological features of AAA, including enhanced oxidative stress through generation of reactive oxygen species. Both plasma and aortic MPO levels are elevated in patients with AAA, but the role of MPO in AAA pathogenesis has, heretofore, never been investigated. Here, we show that MPO gene deletion attenuates AAA formation in two animal models: ANG II infusion in apolipoprotein E-deficient mice and elastase perfusion in C57BL/6 mice. Oral administration of taurine [1% or 4% (wt/vol) in drinking water], an amino acid known to react rapidly with MPO-generated oxidants like hypochlorous acid, also prevented AAA formation in the ANG II and elastase models as well as the CaCl

Topics: Angiotensin II; Animals; Antioxidants; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Calcium Chloride; Disease Models, Animal; Gene Deletion; Male; Mice, Inbred C57BL; Mice, Knockout, ApoE; Neutrophils; Oxidative Stress; Pancreatic Elastase; Peroxidase; Reactive Oxygen Species; Serum Amyloid A Protein; Taurine

Cholestasis, which results in hepatic cell death, fibrosis, cirrhosis, and eventually liver failure, is associated with oxidative stress. The aim of this study was to evaluate the effects of milk thistle (MT, Silybum marianum) and ursodeoxycholic acid (UDCA) or their combination on the activation of hepatic stem cells and on the severity of cholestasis liver injury in rats.. Under anesthesia, bile ducts of female Sprague Dawley rats were ligated (BDL) or had sham operation. BDL rats were administered saline, UDCA (15 mg/kg/d), MT (600 mg/kg/d), or UDCA+MT by gavage for 10 days. On the 11th day, rats were sacrificed and blood and liver samples were obtained. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), hepatic malondialdehyde (MDA) levels, and myeloperoxidase (MPO) activity were measured. Hepatic injury, a-smooth muscle actin expression, and stem cell markers c-kit, c-Myc, Oct3/4, and SSEA-1 were histologically determined.. Histological scores, serum ALT, and hepatic MDA levels were higher in BDL group than in the sham rats, while all treatments significantly reduced these levels. The reduction in ALT was significantly greater in UCDA+MT-treated group than in other treatment groups. c-Kit, c-Myc, Oct3/4, and SSEA-1 were increased in saline-treated BDL group with respect to sham-operated control group, and these markers were significantly reduced in all treatment groups.. In addition to a modulatory effect on the stem cell-induced regenerative response of the liver, UDCA, MT, and their combination demonstrated similar anti-inflammatory and antiproliferative effects on cholestasis-induced hepatic injury.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Cholagogues and Choleretics; Cholestasis; Disease Models, Animal; Drug Therapy, Combination; Female; Hepatocytes; Liver; Liver Cirrhosis; Malondialdehyde; Peroxidase; Phytotherapy; Plant Extracts; Rats; Rats, Sprague-Dawley; Silybum marianum; Stem Cells; Ursodeoxycholic Acid

Herbal treatment may have a chondroprotective and therapeutic effect on Osteoarthritis (OA). We investigated the mechanism of action of ginger and curcumin rhizomes cultivated in Egypt in treatment of OA in rat model.. Thirty-five albino rats were intra-articularly injected with Monosodium Iodoacetate in the knee joint. Ginger and curcumin was orally administered at doses of 200 and 400 mg/kg (F200 and F400). Serum levels of cartilage oligomeric matrix protein (COMP), hyaluronic acid (HA), malondialdehyde (MDA), myeloperoxidase (MPO), Interleukin-1 beta (IL-1β) and superoxide dismutase activity (SOD) were measured using ELISA. The composition of the herbal formula hydro-ethanolic extract was characterized using UPLC-ESI-MS. Histopathological changes in injected joints was examined using routine histopathology. Statistical analysis was performed using one-way ANOVA.. Serum levels of COMP, HA, MPO, MDA, and IL-1β were significantly decreased in F 200, F 400 and V groups when compared to OA group (P value <0.0001). On the other hand SOD levels were significantly elevated in treated groups compared to OA groups (P value <0.0001).. The ginger/curcumin at 1:1 had chondroprotective effect via anti-inflammatory and antioxidant effect in rat OA model. Further pharmacological and clinical studies are needed to evaluate this effect.

Topics: Animals; Cartilage Oligomeric Matrix Protein; Curcumin; Disease Models, Animal; Hyaluronic Acid; Interleukin-1beta; Male; Malondialdehyde; Osteoarthritis; Peroxidase; Plant Extracts; Protective Agents; Superoxide Dismutase; Zingiber officinale

Acute lung injury (ALI) remains a severe disease that threatens human life around the world. To decrease the mortality of ALI and improve ALI treatment efficacy, the development of more ALI treatments is urgently needed. Whether fibrocytes directly participate in ALI has not been studied. Therefore, a mouse model of ALI was induced with lipopolysaccharide (LPS).. Fibrocytes were harvested from peripheral blood mononuclear cells of bleomycin mice and identified by using flow cytometry to detect the expression of molecular makers. The fibrocytes were injected for the treatment of acute lung injury mice. The curative effects were evaluated by using ELISA to determine the cytokines (including TNF-α, IL-6 and IFN-γ) concentrations in bronchoalveolar lavage fluid (BALF) supernatant.. The concentrations of cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interferon-γ (IFN-γ) were increased in mice with ALI induced with LPS. The concentrations of TNF-α, IL-6, and IFN-γ as well as their mRNA and protein expression levels were decreased by administration of fibrocytes. The effect of fibrocytes in ameliorating ALI was time dependent. LPS treatment induced an increase in myeloperoxidase (MPO) activity, whereas the fibrocyte treatment caused inhibition of MPO activity as well as expression of the neutrophil-chemoattractant chemokine macrophage inflammatory protein 2 (MIP-2).. Taken together, these data suggest that fibrocytes ameliorated ALI by suppressing inflammatory cytokines and chemokines as well as by decreasing the accumulation of neutrophils in the lung.

Topics: Acute Lung Injury; Animals; Bleomycin; Bronchoalveolar Lavage Fluid; Cells, Cultured; Chemokines; Cytokines; Disease Models, Animal; Fibroblasts; Leukocytes, Mononuclear; Lipopolysaccharides; Lung; Male; Mice; Mice, Inbred BALB C; Neutrophils; Peroxidase

Links between food and inflammatory bowel diseases (IBDs) are often suggested, but the role of food processing has not been extensively studied. Heat treatment is known to cause the loss of nutrients and the appearance of neoformed compounds such as Maillard reaction products. Their involvement in gut inflammation is equivocal, as some may have proinflammatory effects, whereas other seem to be protective. As IBDs are associated with the recruitment of immune cells, including mast cells, we raised the hypothesis that dietary Maillard reaction products generated through heat treatment of food may limit the colitic response and its associated recruitment of mast cells. An experimental model of colitis was used in mice submitted to mildly and highly heated rodent food. Adult male mice were divided in 3 groups and received nonheated, mildly heated, or highly heated chow during 21 days. In the last week of the study, each group was split into 2 subgroups, submitted or not (controls) to dextran sulfate sodium (DSS) colitis. Weight variations, macroscopic lesions, colonic myeloperoxidase activity, and mucosal mast cell number were evaluated at the end of the experiment. Only highly heated chow significantly prevented DSS-induced weight loss, myeloperoxidase activity, and mast cell number increase in the colonic mucosa of DSS-colitic mice. We suggest that Maillard reaction products from highly heated food may limit the occurrence of inflammatory phases in IBD patients.

Topics: Animals; Cell Count; Colitis; Colon; Dextran Sulfate; Disease Models, Animal; Glycation End Products, Advanced; Inflammation; Inflammatory Bowel Diseases; Intestinal Mucosa; Male; Mast Cells; Mice; Mice, Inbred BALB C; Peroxidase; Weight Loss

Myeloperoxidase (MPO) is released from activated neutrophils. The inflammation in preeclampsia was found to be associated with endothelial dysfunction. We hypothesized that cardiac and circulating MPO levels are elevated in hypertensive pregnancy. Systolic and diastolic blood pressure and heart rate were measured on pregnancy days 14, 16, 18 and 20 in normal pregnant and hypertensive pregnant rats. Left and right ventricle weights, the number of viable fetuses, litter size, fetal and placenta weights were recorded on gestational day 21. Circulating and cardiac MPO activities, soluble fms-like tyrosine kinase-1 (sFlt-1) and vascular endothelial growth factor (VEGF) and nitric oxide (NO) were detected. The results showed increases in cardiac (left, but not right ventricle) and circulating MPO activities, and concomitantly lower number of viable fetuses, litter size, and fetal and placenta weights, and decreases in NO in hypertensive pregnant rats. Also, the increases in circulating sFlt-1 and VEGF were found in hypertensive pregnant group. In conclusion, maternal and fetal detrimental changes along with increases in circulating sFlt-1 and VEGF in hypertensive pregnancy may be associated with increases in cardiac and circulating MPO activities, confirming the causative role of inflammatory response in preeclampsia.

Topics: Animals; Disease Models, Animal; Female; Fetus; Gene Expression Regulation; Gestational Age; Heart Ventricles; Humans; Litter Size; Nitric Oxide; Peroxidase; Placenta; Pre-Eclampsia; Pregnancy; Rats; Rats, Inbred SHR; Rats, Wistar; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1

The effect of smokeless tobacco (gutkha) was investigated by treating male and female Swiss Albino mice with an aqueous extract of smokeless tobacco (AEST). AEST was administered at a dose of 25 mg kg-1 body weight per day for different time periods (6, 12, 16, and 24 weeks), and control animals were provided only drinking water without AEST for the same period. Control and AEST-treated mice were observed for different oxidative stress parameters, nitric oxide (NO) release, and myeloperoxidase (MPO) release, and they were evaluated for alterations in tumor suppressor and DNA repair responses in the liver and spleen. Both male and female mice treated with AEST showed significant increase in lipid peroxidation, protein carbonylation, and NO and MPO release in the liver and spleen compared to age- and gender-matched controls. The significant decline in tumor suppressor p53 protein levels, likely mediated by concomitantly upregulated levels of Mdm2, was observed. We also observed a significant decline in the levels of DNA repair proteins Brca2 and Ape-1 compared to the respective controls. Thus, AEST induces oxidative stress, inflammation, and significantly lowers tumor suppressor and DNA repair responses. These factors may work in conjunction to increase the risk for certain diseases, including cancer.

Topics: Animals; Disease Models, Animal; DNA Repair; Female; Male; Mice; Oxidative Stress; Peroxidase; Plant Extracts; Proto-Oncogene Proteins c-mdm2; Tobacco, Smokeless; Tumor Suppressor Protein p53

To evaluate whether NETosis is involved in cytokine-induced ocular inflammation and to track neutrophil extracellular traps (NET) complexes in patients with proliferative diabetic retinopathy (PDR).. For the animal model, the eyes of C57BL/6J mice were intravitreally injected with interleukin-8 (IL-8), tumor necrosis factor alpha (TNF-α), or saline. Histology and immunofluorescence staining for CD11b, neutrophil elastase (NE), myeloperoxidase (MPO), citrullinated histone 3 (H3Cit), and net-like structure were performed. Vitreous samples were collected from patients with PDR; the PDR1 group had no need for repeated surgical intervention, and the PDR2 group had repeated vitreous bleeding or other complication and controls. Levels of MPO, H3Cit-MPO, and NE-MPO complex were measured with enzyme-linked immunosorbent assay (ELISA).. Massive influx of CD11+ inflammatory cells, involving the anterior and posterior chambers, was observed in the murine eyes 24 h after the IL-8 or TNF-α injections. Cells excreted to their surroundings an extracellular net-like structure positive for NE, MPO, and H3Cit. H3Cit staining was abolished with the DNase I treatment, indicating the presence of extracellular DNA in the net-like structures. The vitreous samples of the patients with PDR2 contained statistically significantly higher levels of MPO (173±230) compared to those of the patients with PDR1 (12.0±33.0, p<0.05) or the controls (0.00, p<0.01). The levels of H3Cit-MPO and NE-MPO complexes were also statistically significantly higher in the patients with PDR2 (776.0±1274, 573.0±911.0, respectively) compared to those in the patients with PDR1 (0, p<0.05) and the controls (0, p<0.05).. This study showed the existence of NETosis in cytokine-induced ocular inflammation in a mouse model and human samples. Furthermore, the extent of NET complex formation was higher in a subset of patients who exhibited more complicated PDR.

Topics: Adult; Aged; Animals; Diabetic Retinopathy; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Extracellular Traps; Female; Histones; Humans; Inflammation; Interleukin-8; Leukocyte Elastase; Male; Mice; Mice, Inbred C57BL; Middle Aged; Peroxidase; Tumor Necrosis Factor-alpha; Uveitis, Anterior; Uveitis, Posterior; Vitreous Body

To observe the effects of Xiongshao Capsule (, XSC) on anti-inflflammatory properties of high-density lipoprotein (HDL), myeloperoxidase (MPO) and paraoxonase 1 (PON1) in serum of atherosclerosis (AS) rabbit model and explore the anti-inflflammatory protective effects of XSC on HDL.. Sixty rabbits were randomized into the control, the model, XSC low-, medium- and high-dose (Rhizoma Chuanxiong + Radix Paeoniae rubra: 0.6+0.3, 1.2+0.6, 2.4+1.2g·kg. TC and FC in the model group were significantly higher than those in the control group (P<0.01). Compared with the model group, TC and FC in the XSC groups were signifificantly lower (P<0.05 or P<0.01), so was simvastatin group (P<0.01). There was no signifificant difference in PON1 level between groups (P>0.05), even between model and control groups (P>0.05). The serum MPO level in the model group was signifificantly higher than that in the control group (P<0.05), which was signifificantly lower in XSC groups as well as simvastatin group (P<0.05 or P<0.01), and no difference was found between XSC groups and simvastatin group (P>0.05).. XSC can reduce the serum MPO level in AS rabbits to protect the anti-inflammatory function of HDL, maintaining the normal lipid transport function. TC and FC levels in aorta cells decline, and this process initiated by XSC plays an anti-AS role.

Topics: Animals; Anti-Inflammatory Agents; Aorta; Aryldialkylphosphatase; Atherosclerosis; Capsules; Cardiotonic Agents; Cholesterol; Disease Models, Animal; Drugs, Chinese Herbal; Lipoproteins, HDL; Male; Peroxidase; Rabbits

Curcumin has powerful anti-inflammatory and antioxidant effects and it has been used for treatment of distal ulcerative colitis. The therapeutic effects of curcumin have not yet been evaluated in diversion colitis. The aim of the present study was to evaluate the anti-inflammatory effects of curcumin on colonic mucosa devoid of a faecal stream. Thirty-six rats were subjected to a proximal colostomy and distal colonic fistulation. They were divided into two groups, which were sacrificed two or four weeks after the intervention. Each group was divided into three subgroups treated with the daily application of enemas containing saline or an oily extract of curcumin at 50 mg/kg/day or 200 mg/kg/day. Colitis was diagnosed by histological analysis. Inflammatory grades were assessed using a previously validated scoring system. The infiltration of neutrophils was evaluated based on the tissue expression of myeloperoxidase (MPO), as determined by immunohistochemistry, and a computer-assisted image analysis program. The Mann-Whitney test was used to compare inflammation grades and myeloperoxidase levels among groups, and ANOVA was used to verify the variance over time, with the level of significance set at 5% (p<0.05) for both tests. Enemas containing curcumin improved the inflammation of the mucosa without a faecal stream and reduced the tissue contents of MPO. MPO tissue levels did not vary with time or between the concentrations of curcumin used. Enemas with curcumin improved the inflammation of the colonic mucosa, reduced the inflammatory grade and decreased the tissue content of MPO in colon segments without a faecal stream.

Topics: Animals; Anti-Inflammatory Agents; Colitis; Colon; Curcumin; Disease Models, Animal; Enema; Intestinal Mucosa; Male; Oxidative Stress; Peroxidase; Rats; Rats, Wistar

This study aims to investigate the protective effect of p-chloro-phenyl-selenoesterol [PCS; 0,2 mg/kg; 10 ml/kg i.g.) in colitis induced by 2,4,6-trinitrobenzene sulfonic acid [TNBS; 2 mg/100 µl 50% ethanol; intrarectally) in mice. Several parameters including weight, length, histological analyses determination, thiobarbituric acid reactive species, reactive species levels, superoxide dismutase, catalase, and myeloperoxidase (MPO) activity of colon were evaluated. The serum levels of tumor necrosis factor alpha [TNF-α) and interleukin 6 [IL-6) were also assessed. Treatment with PCS reduced the clinical and histopathologic severity of TNBS-induced colitis, characterized by colon length reduction and increased colon weight and microscopic intestinal inflammation. The therapeutic effects of PCS in this model were associated with significant decrease in proinflammatory cytokines TNF-α and IL-6 and decrease in MPO activity. Furthermore, combined with improvements in inflammatory parameters, treatment with the PCS was able to decrease oxidative stress and to prevent the decrease in antioxidant defenses in animals with TNBS-induced colitis. This finding suggests that PCS can improve experimental colitis in mice and it could be a potential therapeutic agent for the treatment of patients with IBD. J. Cell. Biochem. 118: 709-717, 2017. © 2016 Wiley Periodicals, Inc.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Cytokines; Disease Models, Animal; Female; Inflammation Mediators; Inflammatory Bowel Diseases; Mice; Organoselenium Compounds; Oxidative Stress; Peroxidase; Trinitrobenzenesulfonic Acid

Dobutamine is the currently recommended β-adrenergic inotropic drug for supporting sepsis-induced myocardial dysfunction when cardiac output index remains low after preload correction. Better and safer therapies are nonetheless mandatory because responsiveness to dobutamine is limited with numerous side effects. Apelin-13 is a powerful inotropic candidate that could be considered as an alternative noncatecholaminergic support in the setting of inflammatory cardiovascular dysfunction.. Interventional controlled experimental animal study.. Tertiary care university-based research institute.. One hundred ninety-eight adult male rats.. Using a rat model of "systemic inflammation-induced cardiac dysfunction" induced by intraperitoneal lipopolysaccharide injection (10 mg/kg), hemodynamic efficacy, cardioprotection, and biomechanics were assessed under IV osmotic pump infusions of apelin-13 (0.25 μg/kg/min) or dobutamine (7.5 μg/kg/min).. In this model and in both in vivo and ex vivo studies, apelin-13 compared with dobutamine provoked distinctive effects on cardiac function: 1) optimized cardiac energy-dependent workload with improved cardiac index and lower vascular resistance, 2) upgraded hearts' apelinergic responsiveness, and 3) consecutive downstream advantages, including increased urine output, enhanced plasma volume, reduced weight loss, and substantially improved overall outcomes. In vitro studies confirmed that these apelin-13-driven processes encompassed a significant and rapid reduction in systemic cytokine release with dampening of myocardial inflammation, injury, and apoptosis and resolution of associated molecular pathways.. In this inflammatory cardiovascular dysfunction, apelin-13 infusion delivers distinct and optimized hemodynamic support (including positive fluid balance), along with cardioprotective effects, modulation of circulatory inflammation and extended survival.

Topics: Animals; Body Weight; Cardiac Output; Cardiomyopathies; Cardiotonic Agents; Cytokines; Disease Models, Animal; Dobutamine; Intercellular Signaling Peptides and Proteins; Lipopolysaccharides; Male; Mitogen-Activated Protein Kinases; Myocardium; Nitric Oxide Synthase Type II; Peroxidase; Phosphorylation; Plasma Volume; Rats; Survival Rate; Vascular Resistance; Water-Electrolyte Balance

Erythropoietin is a potent stimulator of erythroid progenitor cells, which is able to inhibit NF-kB activation, due to its pleiotropic properties, thus promoting an anti-inflammatory effect. As inflammatory bowel disease is a chronic disease with reduced quality of life, and the current pharmacotherapy only induces or maintains the patient in remission, there is a crucial need of new pharmacological approaches. The main objective of this study was to evaluate the effect of erythropoietin in the TNBS-induced colitis model in mice with a normal intestinal flora. Mice with TNBS-induced colitis were treated with a daily dose of erythropoietin at 500 IU/kg bw/day and 1000 IU/Kg bw/day IP during 4 days. As to clinical symptoms/signs, erythropoietin attenuated the decreased body-weight and reduced diarrhoea and oedema of the anus registered in the non-treated mice group in a dose-dependent manner. The anti-inflammatory properties of erythropoietin in the TNBS-induced colitis were confirmed by suppression of pro-inflammatory mediators, such as TNF-α, IL-1β and MPO, as well as a significant increase in the anti-inflammatory cytokine, IL-10, was promoted. These treated mice also presented a reduction in haemoglobin faecal and ALP, suggesting a beneficial effect of erythropoietin in the haemorrhagic focus and destruction of the enterocyte associated with the colon injury induced by TNBS, respectively. The histopathological score was reduced after treatment with erythropoietin, decreasing the severity and extension of the colitis. Furthermore, renal and hepatic biomarkers, as well as haematocrit concentration, remained stabilized after treatment. In conclusion, erythropoietin reduces the inflammatory response associated with TNBS-induced colitis in mice.

Topics: Animals; Anti-Inflammatory Agents; Biomarkers; Colitis; Colon; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Epoetin Alfa; Inflammation Mediators; Male; Mice; Peroxidase; Severity of Illness Index; Time Factors; Trinitrobenzenesulfonic Acid

This study evaluated the effects of melatonin on spinal cord injury (SCI)-induced oxidative damage in testes. Adult male C57BL/6 mice were randomly divided into sham-, SCI- or melatonin (10 mg/kg, i.p.)-treated SCI groups. To induce SCI, a standard weight-drop method that induced a contusion injury at T10 was used. After 1 week, testicular blood flow velocity was measured using the Laser Doppler Line Scanner. Malondialdehyde (MDA), glutathione (GSH), oxidised glutathione (GSSG) and myeloperoxidase (MPO) were measured in testis homogenates. Microvascular permeability of the testes to Evan's Blue was examined by spectrophotometric and fluorescence microscopic quantitation. The tight junction protein zonula occludens-1 (ZO-1) and occludin in testes were assessed by immunoblot analysis. Melatonin increased the reduced blood flow and decreased SCI-induced permeability of capillaries. MDA levels and MPO activity were elevated in the SCI group compared with shams, which was reversed by melatonin. In contrast, SCI-induced reductions in GSH/GSSG ratio were restored by melatonin. Decreased expression of ZO-1 and occludin was observed, which was attenuated by melatonin. Overall, melatonin treatment protects the testes against oxidative stress damage caused by SCI.

Topics: Animals; Blood Flow Velocity; Capillary Permeability; Disease Models, Animal; Glutathione; Glutathione Disulfide; Male; Malondialdehyde; Melatonin; Mice; Mice, Inbred C57BL; Occludin; Oxidative Stress; Peroxidase; Spinal Cord Injuries; Testicular Diseases; Testis; Zonula Occludens-1 Protein

The tuber of Amorphophallus paeoniifolius (Dennst.) Nicolson (Araceae), commonly called Suran or Jimmikand, has high medicinal value and is used ethnomedicinally for the treatment of different gastrointestinal and inflammatory disorders.. The present study evaluated the effects of extracts of Amorphophallus paeoniifolius tubers on acetic acid-induced ulcerative colitis (UC) in rats.. Wistar rats were orally administered methanol extract (APME) or aqueous extract (APAE) (250 and 500 mg/kg) or standard drug, prednisolone (PRDS) (4 mg/kg) for 7 days. On 6th day of treatment, UC was induced by transrectal instillation of 4% acetic acid (AA) and after 48 h colitis was assessed by measuring colitis parameters, biochemical estimations and histology of colon.. APME or APAE pretreatment significantly (p < .05-.001) prevented AA-induced reduction in body weight and increase in colitis parameters viz. stool consistency, colon weight/length ratio and ulcer score, area and index. Extracts treatment attenuated (p < .001) increase in alkaline phosphatase and lactate dehydrogenase in serum and myeloperoxidase activity and cytokines in colon tissue due to AA administration. Extracts treatment prevented AA-induced elevation in lipid peroxidation and decline in activities of superoxide dismutase and catalase and reduced-glutathione content (p < .05-.001) along with histopathological alterations. PRDS also showed similar ameliorative effect on colitis.. APME and APAE showed a preventive effect on UC, and ameliorated inflammation and oxidative damage in colon. The effects may be attributed to presence of phytochemicals, betulinic acid, β-sitosterol, and glucomannan. In conclusion, the tuber of Amorphophallus paeoniifolius exhibited an anticolitic effect through anti-inflammatory and antioxidant action.

Topics: Acetic Acid; Alkaline Phosphatase; Amorphophallus; Animals; Anti-Inflammatory Agents; Biomarkers; Catalase; Colitis, Ulcerative; Colon; Cytokines; Cytoprotection; Disease Models, Animal; Gastrointestinal Agents; Glutathione; Inflammation Mediators; L-Lactate Dehydrogenase; Lipid Peroxidation; Male; Oxidative Stress; Peroxidase; Phytotherapy; Plant Extracts; Plant Tubers; Plants, Medicinal; Prednisolone; Rats, Wistar; Solvents; Superoxide Dismutase

Cyclosporine A (CsA) is known as a neuroprotective agent against cerebral ischemia/reperfusion (I/R) in animal models. However, the significant therapeutic effects of CsA have been observed in high systemic doses or manipulating the blood-brain barrier, resulting in systemic side effects and toxicity. As the liposome nanocarriers have been developed for efficient delivery of peptide and proteins, liposomal CsA (Lipo-CsA) could improve cerebral (I/R) injuries. In this study, the liposomal CsA formulation (CsA at dose of 2.5 mg/kg) was prepared to assess the brain injury outcomes in 90 min middle cerebral artery occlusion (MCAO) stroke model followed by 48 h reperfusion in treating rats. Five minutes after induction of cerebral ischemia in rats, intravenous (iv) administration of Lipo-CsA significantly (P < 0.001) recovered the infarct size, the brain edema, and the neurological activities compared to corresponding control groups following 48 h I/R. In addition, after 48 h cerebral I/R, Lipo-CsA potentially (P < 0.001) inhibited the inflammation responses including MPO activity and tumor necrosis factor-alpha level in comparison to other groups. In conclusion, the results indicate that the low dose of CsA in liposomal formulation is more effective compared to higher dose of free form of CsA in treatment of ischemic brain in rats.

Topics: Animals; Brain Ischemia; Cyclosporine; Disease Models, Animal; Infarction, Middle Cerebral Artery; Inflammation; Liposomes; Male; Nanoparticles; Neuroprotective Agents; Peroxidase; Rats; Rats, Wistar; Reperfusion Injury; Stroke; Time Factors; Tumor Necrosis Factor-alpha

Myeloperoxidase (MPO) is an inducible heme peroxidase responsive to some stress situations. It is already known that its activity is stimulated in neurodegenerative disorders and in the animal model of parkinson's disease (PD) induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). By contrast, the role of δ-aminolevulinate dehydratase (δ-ALA-D), an essential enzyme for heme synthesis, has not been investigated in the MPTP model. The aim of this study was to investigate the involvement of striatal δ-ALA-D activity in an acute model of PD, induced by MPTP, in C57Bl/6 mice and its correlation with MPO activity. Animals received four MPTP injections (20 mg/kg, i.p.) or saline (vehicle) to induce a PD model. 7 days after MPTP administration, the motor function was evaluated through rotarod and challenging beam tests in mice. Afterward, mice were killed, and the striata were removed for biochemical analyses. MPTP-treated mice showed impairment in motor skills, such as balance and motor coordination. Furthermore, there was a reduction of tyrosine hydroxylase levels in these animals, which characterizes the dopaminergic lesion. Striatal δ-ALA-D activity was stimulated by MPTP, as well as the MPO activity, and a significant positive correlation between δ-ALA-D and MPO activities was also demonstrated. These data suggest that δ-ALA-D activity could be stimulated due to the requirement of heme groups by peroxidases. Therefore, this study demonstrated for the first time the involvement of striatal δ-ALA-D activity in the MPTP model and its correlation with the MPO activity.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Disease Models, Animal; Male; Mice, Inbred C57BL; Mice, Knockout; Parkinson Disease; Peroxidase; Porphobilinogen Synthase

Damage caused by periodontitis not only affects periodontal tissues, but also increases the severity of various illnesses such as rheumatoid arthritis, diabetes, and liver diseases. The aim of this study is to investigate the association between induced periodontitis and damage caused through its systemic effects on the liver.. Twenty rats were divided into two groups: control and periodontitis. The following parameters were evaluated: gingival bleeding index (GBI), probing depth (PD), myeloperoxidase (MPO) activity, alveolar bone loss (ABL) for periodontal tissues; histopathologic examination of gingival and liver tissues; immunohistochemistry to cells positive for neural/glial antigen 2 (NG2) expressed in hepatic pericytes, glutathione (GSH), and malondialdehyde (MDA) concentrations in liver; and serum levels of alanine aminotransferase and aspartate aminotransferase.. GBI, PD, MPO, ABL, and histopathologic examinations demonstrated the development of periodontitis. There was a significant increase in microvesicular steatosis accompanied by a marked reduction in NG2+ pericytes in the periodontitis group compared with the control group. The periodontitis group had significantly lower GSH and higher MDA concentration in the liver compared with the control group.. The present study results link the systemic effects of induced periodontitis with changes in hepatic tissues such as microvesicular steatosis, likely caused by an increase in oxidative stress and lipid peroxidation. The findings from the present study implicate an association between a decrease of pericytes and liver disease caused by ligature-induced periodontitis in rats.

Topics: Alanine Transaminase; Alveolar Bone Loss; Animals; Antigens; Aspartate Aminotransferases; Biomarkers; Disease Models, Animal; Female; Glutathione; Immunohistochemistry; Liver Diseases; Malondialdehyde; Pericytes; Periodontal Index; Periodontitis; Peroxidase; Proteoglycans; Rats; Rats, Wistar

The transcription factor Nrf2 is a major modulator of the cellular antioxidant response. Oxidative burst of infiltrating macrophages leads to a massive production of reactive oxygen species in inflamed tissue of inflammatory bowel disease patients. This oxidative burst contributes to tissue destruction and epithelial permeability, but it is also an essential part of the antibacterial defence. We therefore investigated the impact of the Nrf2 orchestrated antioxidant response in both acute and chronic intestinal inflammation.. To study the role of Nrf2 overexpression in mucosal inflammation, we used transgenic mice conditionally expressing a constitutively active form of Nrf2 [caNrf2] either in epithelial cells or in the myeloid cell lineage. Acute colitis was induced by dextran sulphate sodium [DSS] in transgenic and control animals, and changes in gene expression were evaluated by genome-wide expression studies. Long-term effects of Nrf2 activation were studied in mice with an IL-10-/- background.. Expression of caNrf2 either in epithelial cells or myeloid cells resulted in aggravation of DSS-induced acute colitis. Aggravation of inflammation by caNrf2 was not observed in the IL-10-/- model of spontaneous chronic colitis, where even a trend towards reduced prolapse rate was observed.. Our findings show that a well-balanced redox homeostasis is as important in epithelial cells as in myeloid cells during induction of colitis. Aggravation of acute DSS colitis in response to constitutive Nrf2 expression emphasises the importance of tight regulation of Nrf2 during the onset of intestinal inflammation.

Topics: Acute Disease; Animals; Chronic Disease; Colitis; Cytokines; Dextran Sulfate; Disease Models, Animal; Female; Interleukin-10; Intestinal Mucosa; Macrophages; Male; Mice; Mice, Transgenic; Myeloid Cells; NF-E2-Related Factor 2; Peroxidase; Respiratory Burst

Purpose/Aim: Oxidative stress plays an important role in the pathogenesis of acute pancreatitis (AP). We compared the therapeutic effects of Ukrain (NSC 631570) and N-acetylcysteine (NAC) in rats with AP.. Forty male Sprague Dawley rats were divided into four groups: controls; AP; AP with NAC; and AP with Ukrain. AP was induced via the ligation of the bile-pancreatic duct; drugs were administered intraperitoneally (i.p.) 30 min and 12 h after AP induction. Twenty-four hours after AP induction, animals were sacrificed and the pancreas was excised. Levels of malondialdehyde (MDA) and nitric oxide (NO), and activity levels of tumor necrosis factor (TNF)-α, and myeloperoxidase (MPO) were measured in tissue samples. Total oxidant status (TOS), total antioxidant status (TAS), and total bilirubin, as well as activity levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), amylase and lipase were measured in serum samples. Pancreatic tissue histopathology was also evaluated.. Test drugs reduced levels of MDA, NO, TNF-α, total bilirubin, AST, ALT, TOS and MPO, amylase and lipase activities (P < 0.001), and increased TAS (P < 0.001). Rats treated with test drugs attenuated AP-induced morphologic changes and decreased pancreatic damage scores compared with the AP group (P < 0.05). Both test drugs attenuated pancreatic damage, but the therapeutic effect was more pronounced in rats that received Ukrain than in those receiving NAC.. These results suggest that treatment with Ukrain or NAC can reduce pancreatic damage via anti-inflammatory and antioxidant effects.

Topics: Acetylcysteine; Alanine Transaminase; Amylases; Animals; Antioxidants; Aspartate Aminotransferases; Berberine Alkaloids; Biliary Tract; Bilirubin; Disease Models, Animal; Humans; Lipase; Male; Malondialdehyde; Nitric Oxide; Oxidants; Oxidative Stress; Pancreas; Pancreatitis; Peroxidase; Phenanthridines; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

In the present study, the role of octreotide (OCT) in pentylenetetrazole (PTZ) kindling as well as in acute convulsion models was evaluated. Mice were allocated in groups as (1) control saline; (2) acute PTZ (PTZ-a; 60 mg/kg, i.p.), as a single convulsive dose; and (3) kindled (PTZ-k) receiving nine subconvulsive doses of PTZ (40 mg/kg, i.p.) for 17 days. Groups 4-7 received either valproic acid (VPA) 50 mg/kg or OCT (50 μg/kg, Sandostatin®) 30 min by oral gavage before PTZ-a or PTZ-k. The median seizure stage, latency onset of first stage 4/5 seizures, and incidence of convulsing animals were recorded. Cortical dopamine (DA), tumor necrosis factor (TNF)-α, interleukin (IL)-10, caspase (Casp)-3, myeloperoxidase (MPO), and nitric oxide (NO) were assessed in addition to inducible nitric oxide synthase (iNOS) that was evaluated immunohistochemically in a different set of groups. OCT halted PTZ-induced epilepsy delaying convulsion latency via modulating MPO and TNF-α and normalizing IL-10 with both treatment regimens. In PTZ-k, it decreased Casp-3 activity, NO level, and iNOS immunoreactivity. OCT in both paradigms decreased DA concentration. The current investigation implicates a crucial role for OCT in modulating PTZ-induced kindling by regulating inflammatory and apoptotic effects.

Topics: Animals; Anti-Inflammatory Agents; Anticonvulsants; Apoptosis; Caspase 3; Cerebral Cortex; Cytoprotection; Disease Models, Animal; Dopamine; Inflammation; Inflammation Mediators; Interleukin-10; Kindling, Neurologic; Male; Mice; Neuroprotective Agents; Nitric Oxide; Nitric Oxide Synthase Type II; Octreotide; Pentylenetetrazole; Peroxidase; Reaction Time; Seizures; Time Factors; Tumor Necrosis Factor-alpha; Valproic Acid

Oxidative and nitrosative stress-induced endothelial cell damage play an essential role in the pathogenesis of hepatic ischemia-reperfusion (IR) injury. IR is associated with reduced eNOS expression and exacerbated by superimposed stress. NOSTRIN induces intracellular endothelial nitric oxide synthase (eNOS) translocation and inducible nitric oxide synthase (iNOS) increases nitric oxide (NO) production. Our aim was to assess hepatic expression of iNOS, eNOS, and NOSTRIN in IR with or without N-acetylcysteine (NAC) or thymoquinone (TQ) pretreatment and to compare their hepatoprotective effects. Surgical induction of IR was performed by occlusion of hepatic pedicle for 30 min with mini-clamp and reperfused for 30 min. The effects of TQ (20 mg/kg/day) or NAC (300 mg/kg/day) administered orally for 10 days were evaluated by serum ALT and AST, oxidative stress parameters, NO production, and histopathological analysis. Also, localization and expression of iNOS, eNOS, and NOSTRIN were assessed by immunofluorescence. TQ or NAC pretreatment significantly decreased elevated serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and myeloperoxidase (MPO) activities, malondialdehyde (MDA) level, and NO production. In addition, they restored the depleted GSH content and alleviated histopathological changes. Furthermore, they up-regulated eNOS and down-regulated iNOS and NOSTRIN expressions. TQ exerts its hepatoprotective effect, at least in part, by nitric oxide signaling pathway through modulation of iNOS, eNOS, and NOSTRIN expressions as well as suppression of oxidative stress.

Topics: Acetylcysteine; Alanine Transaminase; Animals; Antioxidants; Aspartate Aminotransferases; Benzoquinones; Biomarkers; Cytoprotection; Disease Models, Animal; Glutathione; Lipid Peroxidation; Liver; Liver Diseases; Male; Nitric Oxide; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Oxidative Stress; Peroxidase; Rats, Wistar; Reperfusion Injury; Signal Transduction

Several kinds of crystalloid solutions have been used in the treatment of hemorrhagic shock (HS). Clinicians are faced with how to select the resuscitation fluids. The aim of the present study is to compare the effects of 3 crystalloid solutions, such as normal saline (NS), lactated Ringer's (LR), and Plasma-lyte A (PA), on acid-base status and intestine injury in rats subjected to HS.. Thirty Wistar rats were divided into 4 groups. The sham group had no blood withdrawal. The other groups were subjected to severe HS and then injected with NS, LR, or PA. All treatments were followed with an infusion of red blood cell suspension. The mean arterial pressure was monitored throughout the experiment. The arterial blood gas, malonaldehyde, and myeloperoxidase levels in the small intestine were assayed 120 minutes after resuscitation.. Plasma-lyte A treatment could restore the pH, base excess (BE), HCO. Although the 3 crystalloid solutions play different roles, PA is better at correcting the acid-base balance and improving intestine injury during HS than NS and LR.

Topics: Acid-Base Equilibrium; Animals; Blood Pressure; Crystalloid Solutions; Disease Models, Animal; Electrolytes; Fluid Therapy; Intestine, Small; Isotonic Solutions; Male; Malondialdehyde; Neutrophils; Peroxidase; Rats; Rats, Wistar; Resuscitation; Ringer's Lactate; Shock, Hemorrhagic; Sodium Chloride

Psoriatic inflammation has been shown to be associated with cardiovascular dysfunction and systemic inflammation. Recently, psoriasis has also been linked to hepatic disorders, however underlying mechanism connecting the two are unknown. IL-17A being a central pro-inflammatory cytokine in the pathogenesis of psoriasis may be involved in hepatic inflammation through its receptor and downward signaling; however so far no study has investigated IL-17A related signaling in the liver during psoriasis in a murine model. Therefore, this study explored psoriasis-induced hepatic inflammation and concurrent metabolic changes. Mice were applied topically imiquimod (IMQ) to develop psoriatic inflammation. Additionally mice were also treated either with IL-17A or anti-IL17A antibody to explore the role of IL-17 related signaling in liver. Mice were then assessed for hepatic inflammation through assessment of inflammatory/oxidative stress markers (IL-17RC, NFκB, IL-6, MCP-1, IL-1β, GM-CSF, ICAM-1, iNOS, lipid peroxides and myeloperoxidase activity) as well as hepatic injury (alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase) and protein/lipid metabolic biomarkers (total proteins, albumin, total bilirubin, triglycerides, HDL cholesterol, and total cholesterol). IMQ treatment led to hepatic inflammation as evidenced by increased pro-inflammatory cytokines and oxidative stress with concomitant dysregulation in hepatic protein/lipid metabolism. Treatment with IL-17A further aggravated, whereas treatment with anti-IL17A antibody ameliorated IMQ-induced changes in hepatic injury/inflammation and protein/lipid metabolism. Our study shows for the first time that psoriatic inflammation leads to hepatic inflammation which results in dysregulated protein/lipid metabolism through IL-17RC/NFκB signaling. This could result in increased risk of cardiovascular dysfunction in patients with psoriasis.

Topics: Animals; Biomarkers; Cytokines; Disease Models, Animal; Energy Metabolism; Hepatitis; Interleukin-17; Lipid Metabolism; Lipid Peroxidation; Male; Mice; NF-kappa B; Oxidative Stress; Peroxidase; Psoriasis; Receptors, Interleukin-17; Signal Transduction

Children with severe sepsis are known to have altered zinc homeostasis and decreased circulating zinc levels, suggesting a role for zinc supplementation to improve outcomes. We tested the hypothesis that zinc supplementation would improve survival in a juvenile model of polymicrobial sepsis. Juvenile (13-14-d-old) C57BL/6 mice were treated with 10 mg/kg of zinc via i.p. injections (or vehicle) for 3 d prior to induction of polymicrobial sepsis via i.p. cecal slurry injections. Survival after sepsis was followed for 3 d, and bacterial clearance, ex vivo phagocytosis, systemic inflammatory markers and neutrophil extracellular trap (NET) formation were quantified. We found a significant survival benefit and decreased bacterial burden among zinc supplemented mice when compared with the control group. Zinc supplementation also resulted in enhanced phagocytic activity, greater neutrophil recruitment in the peritoneal cavity and NET formation, suggesting a possible mechanism for improved bacterial clearance and survival. We also noted decreased serum cytokine levels and decreased myeloperoxidase activity in lung tissue following zinc supplementation, suggesting attenuation of the systemic inflammatory response. In conclusion, zinc supplementation improves bacterial clearance, and hence survival, in juvenile mice with polymicrobial sepsis.

Topics: Animals; Anti-Inflammatory Agents; Cell Movement; Cells, Cultured; Child; Cytokines; Disease Models, Animal; Extracellular Traps; Humans; Immunomodulation; Inflammation Mediators; Lung; Mice; Mice, Inbred C57BL; Neutrophils; Peritoneal Cavity; Peroxidase; Phagocytosis; Sepsis; Zinc

Interferon-tau (IFN-τ) is a type I interferon and considered as a pregnancy recognition signal in ruminants. Our previous reports have confirmed that IFN-τ has a potential anti-inflammatory effect in macrophage. However, the anti-inflammatory effect of IFN-τ on endometritis has never been reported. Thus, the aim of this study was to investigate the effects of IFN-τ in a mouse model of Staphylococcus aureus-induced endometritis. The histopathological and myeloperoxidase activity results showed that IFN-τ could protect the uterus from S. aureus damage. Enzyme-linked immunosorbent assay and quantitative real-time polymerase chain reaction results revealed that IFN-τ inhibited TNF-α, IL-1β, and IL-6 production. TLR2, involved in the S. aureus infection, was downregulated by IFN-τ and directly activated nuclear transcription factor kappa-B (NF-κB) pathway. Then, we measured the phosphorylation of IκBα and NF-κB p65 by Western blotting. Western blotting results indicated that IFN-τ inhibited the phosphorylation of IκBα and NF-κB p65 in the S. aureus-induced endometritis. Matrix metalloproteinase (MMP)9, which has been reported to be regulated by NF-κB, was also suppressed by IFN-τ, but its inhibitors, tissue inhibitor of metalloproteinases1 level, increased. All of these findings suggested that IFN-τ plays an anti-inflammatory role in S. aureus-induced endometritis by suppressing NF-κB pathway and MMP9 expression.

Topics: Animals; Anti-Inflammatory Agents; Cytokines; Disease Models, Animal; Endometritis; Enzyme Activation; Female; Gene Expression Regulation; Inflammation Mediators; Interferon Type I; Matrix Metalloproteinase 9; Mice; NF-kappa B; Peroxidase; Signal Transduction; Staphylococcus aureus; Toll-Like Receptor 2

The gastroprotective effect of esculin was investigated in a mouse model of ethanol-induced gastric lesion. Administration of esculin at doses of 5, 10, and 20 mg/kg body weight prior to ethanol ingestion led to significant gastroprotection compared with untreated mice. Gastric mucosal lesions were evaluated by macroscopic and histopathological alterations, lesion index, and myeloperoxidase (MPO) activity. Pretreatment with esculin significantly reduced macroscopic and histopathological damage, gastric lesion index, and MPO activity in a dose-dependent manner. Moreover, esculin significantly reduced nitric oxide (NO) production, inducible NO synthase (iNOS) levels, and nuclear factor-kappa B (NF-κB) p65 protein expression in gastric tissues after ethanol challenge. Analysis of inflammatory cytokines indicated that esculin pretreatment markedly suppressed the increased expression of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in ethanol-treated mice. The results demonstrate a protective effect of esculin against gastric injury and suggest that the underlying mechanism might be associated with inhibition of NF-κB activation, which subsequently reduces expression of iNOS, TNF-α, and IL-6.

Topics: Animals; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Esculin; Ethanol; Gastric Mucosa; Interleukin-6; Male; Mice; Nitric Oxide; Peroxidase; Stomach Ulcer; Tumor Necrosis Factor-alpha

Calea uniflora Less. (family Asteraceae), also named "arnica" and "erva-de-lagarto", is a native plant to the South and Southeast of Brazil. This species was used to treat rheumatism, respiratory diseases, and digestive problems in Brazilian folk medicine. In vitro studies have shown the important biological effects of C. uniflora. However no studies have focused on the mechanism of action of anti-inflammatory activity of C. uniflora. The aim of this study was to evaluate the anti-inflammatory effects of the crude extract, its fractions, and isolated compounds obtained from of C. uniflora, using mouse model of carrageenan-induced inflammation. The following inflammatory parameters: leukocyte influx, degree of exudation, myeloperoxidase (MPO) and adenosine deaminase (ADA) activities, nitric oxide metabolites (NOx), proinflammatory cytokines and phosphorylation of the p65 subunit of NF-κB (p-p65 NF-κB), and p38 mitogen-activated protein kinase (p-p38 MAPK) levels were determined. The crude extract of C. uniflora, its fractions and its isolated compounds reduced the leukocyte influx, degree of exudation, MPO and ADA activities, NOx, TNF-α, IFN-γ, MCP-1 and IL-6 levels (p<0.05). The isolated compounds reduced p-p65 NF-κB and p-p38 MAPK levels (p<0.01). This study demonstrated that C. uniflora exhibits a significant anti-inflammatory activity via inhibition of the leukocyte influx and degree of exudation. These effects were associated with a decrease in the levels of several proinflammatory mediators. The mechanism of the anti-inflammatory action of C. uniflora may be, at least in part, via the inhibition of p65 NF-κB and p38 MAPK activation by the isolated compounds.

Topics: Animals; Anti-Inflammatory Agents; Arnica; Carrageenan; Cell Movement; Cytokines; Disease Models, Animal; Female; Humans; Inflammation Mediators; Leukocytes; Mice; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Peroxidase; Phosphorylation; Plant Extracts; Pleurisy

This study evaluated the effect of mycophenolate mofetil (MMF) on uterine tissue preservation following ischaemia/reperfusion (I/R) injury. Uterine I/R injury was induced in rats by clamping the lower abdominal aorta and ovarian arteries for 30 min. Group I/R + V (n = 7) received vehicle alone while Group I/R + M (n = 7) received 20 mg/kg/day MMF. Control groups underwent sham surgery and received vehicle (Group C) or 20 mg/kg/day MMF (Group M) (n = 7 for both). Four hours after detorsion, uterine tissue 8-hydroxy-2'-deoxyguanosine (8-OHdG), glutathione, malondialdehyde (MDA), myeloperoxidase (MPO), superoxide dismutase (SOD) and serum ischaemia modified albumin (IMA) concentrations were measured. Histopathological analyses were performed. The I/R + M group showed significant reduction in serum IMA and uterine tissue 8-OHdG, MDA and MPO and significant increase in SOD concentrations compared with the I/R + V group, indicating a protective effect against I/R oxidative damage (P = 0.009, P = 0.006, P = 0.002, P = 0.003 and P = 0.009, respectively). Histopathological evaluation revealed MMF treatment resulted in significantly less tissue and cellular damage and apoptosis compared with the I/R + V group. These results indicate MMF is effective in attenuating uterine tissue damage and preventing apoptosis following uterine I/R injury, probably via anti-inflammatory and anti-oxidative action.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Albumins; Animals; Antibiotics, Antineoplastic; Antioxidants; Aorta, Abdominal; Arteries; Deoxyguanosine; Disease Models, Animal; Female; Glutathione; Immunosuppressive Agents; Mycophenolic Acid; Ovary; Peroxidase; Rats; Rats, Wistar; Reperfusion Injury; Superoxide Dismutase; Uterus

Ulinastatin (UTI), a serine protease inhibitor, possesses anti-inflammatory properties and has been suggested to modulate lipopolysaccharide (LPS)-induced acute lung injury (ALI). High-mobility group box 1 (HMGB1), a nuclear DNA-binding protein, plays a key role in the development of ALI. The aim of this study was to investigate whether UTI attenuates ALI through the inhibition of HMGB1 expression and to elucidate the underlying molecular mechanisms. ALI was induced in male rats by the intratracheal instillation of LPS (5 mg/kg). UTI was administered intraperitoneally 30 min following exposure to LPS. A549 alveolar epithelial cells were incubated with LPS in the presence or absence of UTI. An enzyme-linked immunosorbent assay was used to detect the levels of inflammatory cytokines. Western blot analysis was performed to detect the changes in the expression levels of Toll-like receptor 2/4 (TLR2/4) and the activation of nuclear factor-κB (NF-κB). The results revealed that UTI significantly protected the animals from LPS-induced ALI, as evidenced by the decrease in the lung wet to dry weight ratio, total cells, neutrophils, macrophages and myeloperoxidase activity, associated with reduced lung histological damage. We also found that UTI post-treatment markedly inhibited the release of HMGB1 and other pro-inflammatory cytokines. Furthermore, UTI significantly inhibited the LPS-induced increase in TLR2/4 protein expression and NF-κB activation in lung tissues. In vitro, UTI markedly inhibited the expression of TLR2/4 and the activation of NF-κB in LPS-stimulated A549 alveolar epithelial cells. The findings of our study indicate that UTI attenuates LPS-induced ALI through the inhibition of HMGB1 expression in rats. These benefits are associated with the inhibition of the activation of the TLR2/4-NF-κB pathway by UTI.

Topics: Acute Lung Injury; Alveolar Epithelial Cells; Animals; Anti-Inflammatory Agents; Biomarkers; Bronchoalveolar Lavage Fluid; Cytokines; Disease Models, Animal; Glycoproteins; HMGB1 Protein; Humans; Lipopolysaccharides; Lung; Male; NF-kappa B; Peroxidase; Protein Binding; Rats; Toll-Like Receptor 2; Toll-Like Receptor 4; Trypsin Inhibitors

During the past era, small molecules derived from various plants have attracted extensive attention for their versatile medicinal benefits. Among these, one organic molecule called mangiferin from certain plant species including mangoes and honey bush tea is widely used in treating inflammation. In this study, a LPS-induced mastitis model in mouse is established to investigate the anti-inflammatory effects and mechanism of mangiferin. The result shows that mangiferin significantly alleviates LPS-induced histopathology, meanwhile, also decreases LPS-induced MPO activity. Furthermore, mangiferin treatment remarkably impeded the expression of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6. In addition, mangiferin was found to inhibit LPS-induced NF-ĸB and NLRP3 inflammasome activation. In conclusion, these results suggested that LPS-induced mastitis can be abated by mangiferin through inhibiting NF-ĸB and NLRP3 signaling pathways.

Topics: Animals; Anti-Inflammatory Agents; Cytokines; Disease Models, Animal; Female; Humans; Inflammasomes; Inflammation Mediators; Lipopolysaccharides; Mammary Glands, Animal; Mastitis; Mice; Mice, Inbred BALB C; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Peroxidase; Signal Transduction; Xanthones

Inflammation is a common symptom of inflammatory bowel disease (IBD). Actually, many experimental models of colitis exist and try to mimic the human situation in order to understand the pathogenesis of Crohn's disease and ulcerative colitis. These experimental models of inflammation can be characterized by specific parameters, which illustrate the proceeding inflammatory process. By use of these models potentially new reagents for improved therapeutic approaches can be analyzed. Here, we describe the TNBS-mediated colitis model and specify different parameters for the detailed characterization of the inflammatory process in experimental colitis models.

Topics: Animals; Antigens, CD; Antigens, Differentiation; Biomarkers; Body Weight; Colitis; Colonoscopy; Cytokines; Disease Models, Animal; Gene Expression; Humans; Immunity, Mucosal; Immunohistochemistry; Mice; Mucous Membrane; Peroxidase; Severity of Illness Index; Trinitrobenzenesulfonic Acid

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Aspartate Aminotransferases; Biomarkers; Colony Count, Microbial; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Flavonoids; Gene Expression; Kaempferols; Leukocyte Count; Liver; Male; Mice; Mice, Inbred ICR; Nitric Oxide; Peroxidase; Sepsis; Survival Analysis; Tumor Necrosis Factor-alpha

Acetaminophen (APAP) overdose causes hepatocytes necrosis and acute liver failure. Baicalin (BA), a major flavonoid of Scutellariae radix, has potent hepatoprotective properties in traditional medicine. In the present study, we investigated the protective effects of BA on a APAP-induced liver injury in a mouse model. The mice received an intraperitoneal hepatotoxic dose of APAP (300[Formula: see text]mg/kg) and after 30[Formula: see text]min, were treated with BA at concentrations of 0, 15, 30, or 60[Formula: see text]mg/kg. After 16[Formula: see text]h of treatment, the mice were sacrificed for further analysis. APAP administration significantly elevated the serum alanine transferase (ALT) enzyme levels and hepatic myeloperoxidase (MPO) activity when compared with control animals. Baicalin treatment significantly attenuated the elevation of liver ALT levels, as well as hepatic MPO activity in a dose- dependent manner (15-60[Formula: see text]mg/kg) in APAP-treated mice. The strongest beneficial effects of BA were seen at a dose of 30[Formula: see text]mg/kg. BA treatment at 30[Formula: see text]mg/kg after APAP overdose reduced elevated hepatic cytokine (TNF-[Formula: see text] and IL-6) levels, and macrophage recruitment around the area of hepatotoxicity in immunohistochemical staining. Significantly, BA treatment can also decrease hepatic phosphorylated extracellular signal-regulated kinase (ERK) expression, which is induced by APAP overdose. Our data suggests that baicalin treatment can effectively attenuate APAP-induced liver injury by down-regulating the ERK signaling pathway and its downstream effectors of inflammatory responses. These results support that baicalin is a potential hepatoprotective agent.

Topics: Acetaminophen; Alanine Transaminase; Analgesics, Non-Narcotic; Animals; Anti-Inflammatory Agents, Non-Steroidal; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Drug Overdose; Flavonoids; Interleukin-6; Liver; MAP Kinase Signaling System; Mice; Peroxidase; Tumor Necrosis Factor-alpha

In addition to neurons, all components of the neurovascular unit (NVU), such as glial, endothelial, and basal membranes, are destroyed during traumatic brain injury (TBI). Previous studies have shown that excessive stimulation of calpain is crucial for cerebral injury after traumatic insult. The objective of this study was to investigate whether calpain activation participated in NVU disruption and edema formation in a mouse model of controlled cortical impact (CCI).. One hundred and eight mice were divided into three groups: the sham group, the control group, and the MDL28170 group. MDL28170 (20 mg/kg), an efficient calpain inhibitor, was administered intraperitoneally at 5 min, 3 h, and 6 h after experimental CCI. We then measured neurobehavioral deficits, calpain activity, inflammatory mediator levels, blood-brain barrier (BBB) disruption, and NVU deficits using electron microscopy and histopathological analysis at 6 h and 24 h after CCI.. The MDL28170 treatment significantly reduced the extent of both cerebral contusion (MDL28170 vs. vehicle group, 16.90 ± 1.01 mm΃ and 17.20 ± 1.17 mm΃ vs. 9.30 ± 1.05 mm΃ and 9.90 ± 1.17 mm΃, both P < 0.001) and edema (MDL28170 vs. vehicle group, 80.76 ± 1.25% and 82.00 ± 1.84% vs. 82.55 ± 1.32% and 83.64 ± 1.25%, both P < 0.05), improved neurological scores (MDL28170 vs. vehicle group, 7.50 ± 0.45 and 6.33 ± 0.38 vs. 12.33 ± 0.48 and 11.67 ± 0.48, both P < 0.001), and attenuated NVU damage resulting (including tight junction (TJ), basement membrane, BBB, and neuron) from CCI at 6 h and 24 h. Moreover, MDL28170 markedly downregulated nuclear factor-κB-related inflammation (tumor necrosis factor-α [TNF-α]: MDL28170 vs. vehicle group, 1.15 ± 0.07 and 1.62 ± 0.08 vs. 1.59 ± 0.10 and 2.18 ± 0.10, both P < 0.001; inducible nitric oxide synthase: MDL28170 vs. vehicle group, 4.51 ± 0.23 vs. 6.23 ± 0.12, P < 0.001 at 24 h; intracellular adhesion molecule-1: MDL28170 vs. vehicle group, 1.45 ± 0.13 vs. 1.70 ± 0.12, P < 0.01 at 24 h) and lessened both myeloperoxidase activity (MDL28170 vs. vehicle group, 0.016 ± 0.001 and 0.016 ± 0.001 vs. 0.024 ± 0.001 and 0.023 ± 0.001, P < 0.001 and 0.01, respectively) and matrix metalloproteinase-9 (MMP-9) levels (MDL28170 vs. vehicle group, 0.87 ± 0.13 and 1.10 ± 0.10 vs. 1.17 ± 0.13 and 1.25 ± 0.12, P < 0.001 and 0.05, respectively) at 6 h and 24 h after CCI.. These findings demonstrate that MDL28170 can protect the structure of the NVU by inhibiting the inflammatory cascade, reducing the expression of MMP-9, and supporting the integrity of TJ during acute TBI.

Topics: Animals; Brain Injuries, Traumatic; Calpain; Dipeptides; Disease Models, Animal; Glycoproteins; Inflammation; Male; Matrix Metalloproteinase 9; Mice; Mice, Inbred BALB C; NF-kappa B; Peroxidase; Tumor Necrosis Factor-alpha

This study investigated the gastroprotective effects of N-acetylcysteine (NAC) against indomethacin-induced gastric ulcer in rats. Ulceration was induced by a single oral administration of indomethacin (30 mg/kg). 50 male albino rats were allocated into 5 equal groups: control group received normal saline orally, indomethacin group rats received normal saline orally for 5 days and indomethacin (50 mg/kg) on the last day, ranitidine group received ranitidine (reference drug) orally for 5 days (50 mg/kg) before receiving indomethacin (50 mg/kg) on the last day, and NAC groups received NAC orally at 300 and 500 mg/kg, respectively, for 5 days before receiving indomethacin (50 mg/kg) on the last day. Gastric tissue interleukin-1β (IL-1β), interferon-γ (IFN-γ), and caspase-3 levels were immunoassayed. Total thiol (T-SH), myeloperoxidase (MPO), and glucose-6-phosphate dehydrogenase (G6PD) were determined by spectrophotometry. Cytokine-induced neutrophil chemoattractant 2α (CINC-2α) gene expression was evaluated in addition to Bcl-2 immunohistochemistry. Pretreatment with NAC improved the inflammatory, apoptotic, and redox status in a dose-dependent manner particularly in NAC 500 mg/kg pretreated group. These results show a role for NAC in improving indomethacin-induced gastric ulceration via antioxidative, antiapoptotic, and anti-inflammatory interactive mechanisms.

Topics: Acetylcysteine; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Antioxidants; Apoptosis; Caspase 3; Chemical and Drug Induced Liver Injury; Chemokines, CXC; Cytoprotection; Disease Models, Animal; Dose-Response Relationship, Drug; Gastric Mucosa; Glucosephosphate Dehydrogenase; Humans; Indomethacin; Interferon-gamma; Interleukin-1beta; Male; Oxidation-Reduction; Pain; Peroxidase; Proto-Oncogene Proteins c-bcl-2; Ranitidine; Rats; Rats, Wistar; Stomach Ulcer

To investigate the protective effect of a recombinant adeno-associated virus carrying thymosin β. AAV-Tβ. Recombinant AAVs efficiently delivered LacZ and Tβ. Tβ

Topics: Animals; Cell Proliferation; Colitis, Ulcerative; Colon; Crohn Disease; Dependovirus; Dextran Sulfate; Disease Models, Animal; DNA, Recombinant; Enterocytes; Enzyme-Linked Immunosorbent Assay; Genetic Vectors; Immunochemistry; Interleukin-10; Interleukin-1beta; Intestinal Mucosa; Male; Malondialdehyde; Mice; Mice, Inbred BALB C; Peroxidase; Superoxide Dismutase; Thymosin; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

The targeting of 5-aminosalicylic acid (5-ASA), a first-line therapeutic agent for mild to moderate active ulcerative colitis (UC), to the site of inflammation has remained a challenge and an unmet requirement in the treatment of UC. However, nanoscale carriers for targeted drug delivery are promising for pharmacotherapy, and nanoparticles improve the pharmacokinetics of the loaded therapeutics based on their physical properties. To design and prepare 5‑ASA‑loaded silicon dioxide nanoparticles (5‑ASA‑SiO2 NPs), a micro‑emulsion method was conducted, and their respective therapeutic effects were validated in a mouse model of UC. Cytotoxicity of 5‑ASA‑SiO2 NPs was detected in vitro using the Cell Counting Kit‑8 method. The therapeutic effect of 5‑ASA‑SiO2 NPs was assessed based on their disease activity index (DAI), colon histopathology, myeloperoxidase (MPO) and levels of tumor necrosis factor‑α (TNF‑α) and interleukin‑6 (IL‑6). SiO2 NPs were successfully prepared, and cytotoxicity of 5‑ASA‑SiO2 NPs was identified as being similar to 5‑ASA and SiO2 NPs. DAI and colonic histopathology scores in the normal dosage, high dosage and the 5‑ASA‑SiO2 NP groups demonstrated a significant improvement when compared with the model group. DAI in the high dosage and 5‑ASA‑SiO2 NP groups also demonstrated a significant improvement when compared with the normal dosage group. However, MPO, serum IL‑6 and TNF‑α levels in normal dosage, high dosage and 5‑ASA‑SiO2 NPs groups were significantly lower than in the model group, and these indexes in the high dosage group and 5‑ASA‑SiO2 NP group were significantly lower than that in the normal dosage group. Expression of IL‑6 and TNF‑α mRNA in colonic mucosa in the normal dosage, high dosage and 5‑ASA‑SiO2 NP group was significantly lower than that in the model group. Colonic mucosal IL‑6 and TNF‑α mRNA expression in the high dosage and 5‑ASA‑SiO2 NP groups was significantly lower than that in the normal dosage group (P<0.05). In conclusion, 5‑ASA‑SiO2 NPs are a selective drug release system that target the inflamed colon, characteristics of UC, and can greatly increase therapeutic efficacy in UC.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Line; Cell Survival; Colitis, Ulcerative; Cytokines; Disease Models, Animal; Drug Delivery Systems; Intestinal Mucosa; Mesalamine; Mice; Nanoparticles; Peroxidase; Severity of Illness Index; Silicon Dioxide

Anti-neutrophil cytoplasmic antibody associated vasculitis (AAV) is a typical disease of the elderly. In AAV, there is an age-specific increase in disease incidence with age being a predictor of disease outcome. In this study, we aimed to determine the contribution of age to the development of AAV employing a mouse model of anti-myeloperoxidase (MPO) antibody-mediated glomerulonephritis.. Anti-MPO IgG and lipopolysaccharide (LPS)-mediated glomerulonephritis was induced in 3- and 18-month-old C57Bl6 mice. Clinical and pathological parameters of disease severity, alterations in the immune system and kidney specific changes in these mice were evaluated.. Eighteen-month-old mice developed increased disease severity upon injection of anti-MPO IgG/LPS compared with 3-month-old mice. This was evidenced by increased albuminuria, more extensive glomerular capillary necrosis and increased glomerular neutrophil accumulation. Glomerular crescent formation was mild in both young and old mice. Old mice displayed higher plasma interleukin-6 levels as well as higher proportions of circulating neutrophils and activated monocytes compared with young mice. In addition, renal mRNA levels of inflammatory genes and endothelial adhesion molecules were higher in 18-month-old mice compared with 3-month-old mice.. In conclusion, our results indicate that aged mice develop more severe clinical and pathological disease upon induction of anti-MPO IgG/LPS-mediated glomerulonephritis. These findings may be attributed to age-related changes in the immune system as well as in the kidney itself.

Topics: Aging; Animals; Autoantibodies; Disease Models, Animal; Female; Glomerulonephritis; Immunoglobulin G; Mice; Mice, Inbred C57BL; Peroxidase; Severity of Illness Index

Astragalus polysaccharide (APS) is a bioactive extract of Astragalus membranaceus (AM), which possess a wide range of medicinal benefits, including anti-inflammatory, anti-oxidative, anti-tumor and anti-diabetic effects. The present work evaluated the therapeutic effect of APS and its potential mechanisms in a mouse model of dextran sulfate sodium (DSS)-induced colitis. The APS treatment led to significant improvements in colitis disease activity index (DAI) and histological scores, as well as significantly increased weight and colon length in mice as compared to the control group. Mechanically, reduced NF-κВ DNA phosphorylation activity and downregulated TNF-α, IL-1β, IL-6, IL-17 expressions and myeloperoxidase (MPO) activity were associated with improvement in colitis observed in APS-treated mice. These findings suggest that APS may represent a natural therapeutic approach for treating inflammatory bowel disease, such as ulcerative colitis.

Topics: Animals; Anti-Inflammatory Agents; Astragalus Plant; Colitis; Dextran Sulfate; Disease Models, Animal; Humans; Interleukin-17; Interleukin-6; Mice; NF-kappa B; Peroxidase; Polysaccharides; Protective Agents; Signal Transduction; Tumor Necrosis Factor-alpha

Nonerosive reflux disease (NERD) is a highly prevalent phenotype of the gastroesophageal reflux disease. In this study, we developed a novel murine model of NERD in mice with microscopic inflammation and impairment in the epithelial esophageal barrier. Female Swiss mice were subjected to the following surgical procedure: the transitional region between the forestomach and the glandular portion of the stomach was ligated, and a nontoxic ring was placed around the duodenum near the pylorus. The control group underwent sham surgery. The animals were euthanized at 1, 3, 7, and 14 days after surgery. Survival and body weight were monitored daily. Esophageal wet weight, macroscopic lesion, histopathological alterations, myeloperoxidase (MPO) activity, cytokine levels, transepithelial electrical resistance (TEER), and mucosal permeability were evaluated. The survival rate was 78% at 14 days, with mild loss in body weight. Surgery did not induce erosive esophagitis but instead induced microscopic inflammation and increased esophageal wet weight, IL-6, keratinocyte-derived cytokine (KC) levels, and MPO activity with maximal peak between 3 and 7 days and resolution at 14 days postsurgery. Epithelial esophageal barrier was evaluated in operated mice at 7 and 14 days postsurgery; a decrease in TEER and increase in the esophageal epithelial permeability were observed compared with the sham-operated group. In addition, the inhibition of acid secretion with omeprazole significantly prevented the esophageal inflammation and impairment of barrier function at 7 days postsurgery. Thus we established a novel experimental model of NERD in mice, which can contribute to understanding the pathophysiological events associated with NERD.

Topics: Animals; Cytokines; Disease Models, Animal; Duodenum; Electric Impedance; Esophageal Mucosa; Esophagitis, Peptic; Female; Gastroesophageal Reflux; Inflammation Mediators; Ligation; Mice; Organ Size; Permeability; Peroxidase; Phenotype; Proton Pump Inhibitors; Stomach; Time Factors

Although it is well established that acute kidney injury (AKI) is a proinflammatory state, little is known about the endogenous counter-inflammatory response. IL-6 is traditionally considered a pro-inflammatory cytokine that is elevated in the serum in both human and murine AKI. However, IL-6 is known to have anti-inflammatory effects. Here we sought to investigate the role of IL-6 in the counter-inflammatory response after AKI, particularly in regard to the anti-inflammatory cytokine IL-10. Ischemic AKI was induced by bilateral renal pedicle clamping. IL-10-deficient mice had increased systemic and lung inflammation after AKI, demonstrating the role of IL-10 in limiting inflammation after AKI. We then sought to determine whether IL-6 mediates IL-10 production. Wild-type mice with AKI had a marked upregulation of splenic IL-10 that was absent in IL-6-deficient mice with AKI. In vitro, addition of IL-6 to splenocytes increased IL-10 production in CD4

Topics: Acute Kidney Injury; Animals; B-Lymphocytes; CD4 Antigens; CD4-Positive T-Lymphocytes; Disease Models, Animal; Humans; Interleukin-10; Interleukin-6; Lung; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Peroxidase; Spleen; Systemic Inflammatory Response Syndrome; Up-Regulation

Previous studies have focused on the effects of propylene glycol alginate sodium sulfate  (PSS)  against  thrombosis,  but  the  anti-inflammatory  potential  is  unknown.  Therefore,  we  specifically focused on the protective effects of PSS on cerulein-induced acute pancreatitis (AP)  using a mouse model, and investigated the mechanism of PSS on autophagy and apoptosis via the  Mitogen-activated  protein  kinase  (MEK)/extracellular  signal-regulated  kinase  (ERK)  pathway.  Cerulein (100 ug/kg) was used to induce AP by ten intraperitoneal injections at hourly intervals in  Balb/C mice. Pretreatment with vehicle or PSS was carried out 1 h before the first cerulein injection  and two doses (25 mg/kg and 50 mg/kg) of PSS were injected intraperitoneally. The severity of AP was  assessed by pathological score, biochemistry, pro-inflammatory cytokine levels, myeloperoxidase  (MPO) activity and MEK/ERK activity. Furthermore, pancreatic histological scores, serum amylase  and lipase activities, tumor necrosis factor-α (TNF-α), interleukin (IL)-1β interleukin (IL)-6 levels, and  MPO activity were significantly reduced by PSS via up-regulated MEK/ERK activity. The representative  molecules of apoptosis and autophagy, such as Bcl-2, Bax, Lc-3, Beclin-1, P62, were remarkably reduced.  Taken together, these results indicate that PSS attenuates pancreas injury by inhibiting autophagy and  apoptosis through a mechanism involving the MEK/ERK signaling pathway.

Topics: Alginates; Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Autophagy; Ceruletide; Disease Models, Animal; Humans; Interleukin-1beta; Interleukin-6; Lipase; Male; MAP Kinase Signaling System; Mice; Mice, Inbred BALB C; Pancreas; Pancreatitis; Peroxidase; Tumor Necrosis Factor-alpha

Methane is part of the gaseous environment of the intestinal lumen. The purpose of this study was to elucidate the bioactivity of exogenous methane on the intestinal barrier function in an antigen-independent model of acute inflammation.. Anesthetized rats underwent sham operation or 45-min occlusion of the superior mesenteric artery. A normoxic methane (2.2%)-air mixture was inhaled for 15 min at the end of ischemia and at the beginning of a 60-min or 180-min reperfusion. The integrity of the epithelial barrier of the ileum was assessed by determining the lumen-to-blood clearance of fluorescent dextran, while microvascular permeability changes were detected by the Evans blue technique. Tissue levels of superoxide, nitrotyrosine, myeloperoxidase, and endothelin-1 were measured, the superficial mucosal damage was visualized and quantified, and the serosal microcirculation and mesenteric flow was recorded. Erythrocyte deformability and aggregation were tested in vitro.. Reperfusion significantly increased epithelial permeability, worsened macro- and microcirculation, increased the production of proinflammatory mediators, and resulted in a rapid loss of the epithelium. Exogenous normoxic methane inhalation maintained the superficial mucosal structure, decreased epithelial permeability, and improved local microcirculation, with a decrease in reactive oxygen and nitrogen species generation. Both the deformability and aggregation of erythrocytes improved with incubation of methane.. Normoxic methane decreases the signs of oxidative and nitrosative stress, improves tissue microcirculation, and thus appears to modulate the ischemia-reperfusion-induced epithelial permeability changes. These findings suggest that the administration of exogenous methane may be a useful strategy for maintaining the integrity of the mucosa sustaining an oxido-reductive attack.

Topics: Administration, Inhalation; Animals; Capillary Permeability; Disease Models, Animal; Endothelin-1; Ileum; Immunohistochemistry; Intestinal Mucosa; Male; Mesenteric Artery, Superior; Methane; Oxidative Stress; Peroxidase; Random Allocation; Rats; Rats, Sprague-Dawley; Reference Values; Reperfusion Injury

To investigate potential effects of poly I:C on mucosal injury and epithelial barrier disruption in dextran sulfate sodium (DSS)-induced acute colitis.. DSS caused significant damage to the colon tissue in the model group. Administration of poly I:C dramatically protected against DSS-induced colitis, as demonstrated by less body weight loss, lower disease activity index score, longer colon length, colonic MPO activity, and improved macroscopic and histological scores. It also ameliorated DSS-induced ultrastructural changes of the colon epithelium, as observed under scanning electron microscopy, as well as FITC-D permeability. The mRNA and protein expressions of TJ protein, zo-1, occludin and claudin-1 were also found to be significantly enhanced in the poly I:C group, as determined by immunohistochemistry/immunofluorescence, Western blot and RT-qPCR. By contrast, poly I:C pretreatment markedly reversed the DSS-induced up-regulated expressions of the inflammatory cytokines TNF-α, IL-17 and IFN-γ.. Our study suggested that poly I:C may protect against DSS-induced colitis through maintaining integrity of the epithelial barrier and regulating innate immune responses, which may shed light on the therapeutic potential of poly I:C in human colitis.

Topics: Animals; Colitis, Ulcerative; Colon; Cytokines; Dextran Sulfate; Disease Models, Animal; Fluorescent Antibody Technique; Immunity, Innate; Immunohistochemistry; Injections, Subcutaneous; Intestinal Mucosa; Male; Mice; Mice, Inbred C57BL; Microscopy, Electron, Scanning; Permeability; Peroxidase; Poly I-C; Real-Time Polymerase Chain Reaction; Severity of Illness Index; Tight Junction Proteins; Toll-Like Receptor 3; Weight Loss

BACKGROUND This study investigated the protective effects of pharmaceutical CD26/dipeptidylpeptidase-4 (CD26/DPP-4) inhibitor in lung transplantation (LTx). Changes in protein expression associated with the treatment were screened and identified to evaluate the role of kininogen-1 in early-term ischemia/reperfusion (I/R) injury after LTx. MATERIAL AND METHODS Orthotopic single LTx was performed in syngeneic C57BL/6 mice, with a pharmaceutical CD26/DPP-4 inhibitor (vildagliptin, subcutaneous injection, 10 mg/kg, every 12 h) administered to the investigational group. All donors were perfused and preserved with low potassium dextran (LPD). Grafts were harvested at 60 h post-transplantation after 8 h of cold ischemia. Myeloperoxidase activity and wet/dry weight ratio were measured, followed by histopathological examination. Proteins were separated, analyzed, and identified using proteomics and database searches. The target proteins were validated by Western blot. Immunohistochemical studies were performed in the same lung specimen locus. RESULTS Investigational group (IN) versus control group (CON) comparison showed decreased myeloperoxidase enzymatic activity, as well as decreased edema and interstitial-alveolar inflammation. Proteomics results revealed 78 spots with significant differences in abundance between the 2 groups. Fifteen proteins were identified. Kininogen-1 was up-regulated in CON and down-regulated in IN, with contrasting results for the heat shock protein 70. Immunohistochemical results revealed significantly different staining with kininogen-1 in alveolar macrophages and inflammatory cells. CONCLUSIONS Combined vildagliptin and LPD significantly ameliorated I/R injury after LTx. This treatment may change local pulmonary protein levels. Moreover, proper application of proteins such as kininogen-1 may enhance the protective effects against I/R injury during transplantation.

Topics: Adamantane; Animals; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Down-Regulation; Immunohistochemistry; Kininogens; Lung; Lung Transplantation; Male; Mice; Nitriles; Peroxidase; Pyrrolidines; Up-Regulation; Vildagliptin

Curcumin (diferuloylmethane), a major component of turmeric is well known for its anti-inflammatory potential. Present study investigates sequential release of inflammatory mediators post LPS challenge (10 mg/kg,i.p.) causing lung inflammation and its modulation by curcumin through different routes (20 mg/kg, i.p and 10 mg/kg, i.n.) in murine model. Dexamethasone (1 mg/kg, i.p) was used as standard drug.. Lung Inflammation was evaluated by histopathological analysis, myeloperoxidase (MPO) activity followed by inflammatory cell count and total protein content measurements in bronchoalveolar fluid (BALF). Reactive oxygen species (ROS), nitrite and TNF-α levels were measured as markers of endotoxin shock at different time points (1-72 h). The mRNA expression of transforming growth factors-β1 (TGF-β1), iNOS and Toll-like receptor-4 (TLR-4) were measured followed by Masson's trichrome staining and hydroxyproline levels as collagen deposition marker leading to fibrotic changes in lungs.. We found that LPS-induced lung inflammation and injury was maximum 24-h post LPS challenge shown by MPO and histological analysis which was further supported by elevated nitrite and ROS levels whereas TNF-α level was highest after 1 h. Endotoxin-induced mortality was significantly reduced in curcumin (i.p) pretreatment groups up to 72-h post LPS challenge. Significant inhibition in mRNA expression of iNOS, TGF-β1 and TNF-α level was noted after curcumin treatment along with lowered MPO activity, inflammatory cell count, ROS, nitrite levels and collagen deposition in lungs.. Our results suggest that higher endotoxin dose causes inflammatory mediator release in chronological order which tend to increase with time and reached maximum after 24-h post-endotoxin (LPS) exposure. Intraperitoneal route of curcumin administration was better in modulating inflammatory mediator release in early phase as compared to intranasal route of administration. It can be used as supplementary therapeutic intervention at early stage of endotoxemia, having fewer side effects.

Topics: Animals; Bronchoalveolar Lavage Fluid; Curcumin; Disease Models, Animal; Endotoxemia; Inflammation Mediators; Lipopolysaccharides; Lung; Mice; Nitric Oxide Synthase Type II; Peroxidase; Pneumonia; Reactive Oxygen Species; RNA, Messenger; Toll-Like Receptor 4; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

(1) Background: The present study aimed to investigate whether beneficial effects of protocatechuic acid (PCA) are associated with inhibition of the SphK/S1P axis and related signaling pathways in a 2,4,6-trinitrobenzenesulfonic acid (TNBS) model of inflammatory bowel disease; (2) Methods: Colitis was induced in male Balb/c mice by intracolonic administration of 2 mg of TNBS. PCA (30 or 60 mg/kg body wt) was given intraperitoneally daily for five days; (3) Results: Administration of PCA prevented the macroscopic and microscopic damage to the colonic mucosa, the decrease in body weight gain and the increase in myeloperoxidase activity induced by TNBS. PCA-treated mice exhibited a lower oxidized/reduced glutathione ratio, increased expression of antioxidant enzymes and Nrf2 and reduced expression of proinflammatory cytokines. Following TNBS treatment mRNA levels, protein concentration and immunohistochemical labelling for SphK1 increased significantly. S1P production and expression of S1P receptor 1 and S1P phosphatase 2 were significantly elevated. However, there was a decreased expression of S1P lyase. Furthermore, TNBS-treated mice exhibited increased phosphorylation of AKT and ERK, and a higher expression of pSTAT3 and the NF-κB p65 subunit. PCA administration significantly prevented those changes; (4) Conclusions: Data obtained suggest a contribution of the SphK/S1P system and related signaling pathways to the anti-inflammatory effect of PCA.

Topics: Animals; Colitis; Colon; Cyclooxygenase 2; Disease Models, Animal; Dose-Response Relationship, Drug; Down-Regulation; Glutathione; Hydroxybenzoates; Interleukin-1beta; Intestinal Mucosa; Male; Mice; Mice, Inbred BALB C; NF-kappa B; Oxidative Stress; Peroxidase; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor); Proprotein Convertases; Serine Endopeptidases; Signal Transduction; STAT3 Transcription Factor; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha; Weight Gain

It has been reported that DOK3 protein negatively regulates LPS responses and endotoxin tolerance in mice. However, the role of DOK3 in the development of acute respiratory distress syndrome (ARDS) remains unknown. In this study, we showed that DOK3 is degraded in the lung tissues of LPS-induced ARDS. Through lentivirus transduction containing DOK3(K27R) via the intranasal route, we created a mice model, in which DOK3 maintains stable expression. We found that the forced DOK3 expression significantly attenuated LPS-induced pulmonary histological alterations, inflammatory cells infiltration, lung edema, as well as the generation of inflammatory cytokines TNFα, IL- 1β and IL-6 in BALF of LPS-induced ARDS mice. In addition, DOK3 expression apparently suppressed LPS-induced NF-κB and ERK activation. These data suggested that DOK3 expression negatively regulates the development of LPS-induced ARDS in mice.

Topics: Adaptor Proteins, Signal Transducing; Animals; Bronchoalveolar Lavage Fluid; Cytokines; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; HEK293 Cells; Humans; Lipopolysaccharides; Lung; Mice, Inbred C57BL; NF-kappa B; Peroxidase; Proteolysis; Pulmonary Edema; Respiratory Distress Syndrome

This study aims to evaluate two proteins derived from the seeds of the plants Cajanus cajan (Leguminosae) and Caesalpinia gilliesii (Leguminosae) for their abilities to ameliorate the toxic effects of chronic doses of acetoaminphen (APAP) through the determination of certain biochemical parameters including liver marker enzymes: alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and total bilirubin. Also, total protein content and hepatic marker enzyme, lactate dehydrogenase were studied. Moreover, liver antioxidants, glutathione (GSH), nitric oxide, and lipid peroxides were determined in this study. Hepatic adenosine triphosphatase (ATPase), adenylate energy charge (ATP, adenosine diphosphate, adenosine monophosphate, and inorganic phosphate), and phosphate potential, serum interleukin-6, tumor necrosis factor-α, and myeloperoxidase were also examined in the present study. On the other hand, histopathological examination of intoxicated and liver treated with both proteins was taken into consideration. The present results show disturbances in all biochemical parameters and hepatic toxicity signs including mild vascular congestion, moderate inflammatory changes with moderate congested sinusoids, moderate nuclear changes (pyknosis), moderate centrilobular necrosis, fatty changes, nuclear pyknosis vascular congestion, and change in fatty centrilobular necrosis liver. Improvement in all biochemical parameters studied was noticed as a result of treatment intoxicated liver with C. gilliesii and C. cajan proteins either paracetamol with or post paracetamol treatment. These results were documented by the amelioration signs in rat's hepatic architecture. Thus, both plant protein extracts can upregulate and counteract the inflammatory process, minimize damage of the liver, delay disease progression, and reduce its complications.

Topics: Acetaminophen; Adenosine Triphosphatases; Alanine Transaminase; Alkaline Phosphatase; Animals; Aspartate Aminotransferases; Bilirubin; Caesalpinia; Cajanus; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Dose-Response Relationship, Drug; Glutathione; Interleukin-6; L-Lactate Dehydrogenase; Liver; Male; Nitric Oxide; Peroxidase; Plant Extracts; Plant Proteins; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

Abdominal aortic aneurysm (AAA) is a particular form of arterial disease characterized by the dilation of the aortic wall and the presence of an intraluminal thrombus linked to a high proteolytic activity. The aim of this study was to investigate the effect of an elastase inhibitor (AZD9668 from AstraZeneca) on aneurysm progression.. For this purpose, we have used a rat model of elastase perfusion followed by repeated injection of Porphyromonas gingivalis (Pg), a weak periodontal pathogen recently reported to enhance AAA thrombus formation. Pg (1.10(7) colony-forming units) was injected through the jugular vein once a week for 4 weeks, and AZD9668, incorporated in the food, was delivered concomitantly.. Our results show a beneficial effect of AZD9668 treatment on AAA progression and composition. The increased AAA diameter induced by Pg was significantly reduced by AZD9668 treatment. Histologic analyses allowed us to observe the persistence of a neutrophil-rich luminal thrombus associated with calcifications in Pg-injected rats and the presence of a healing process in the Pg/AZD9668-treated group. The enhanced concentrations of markers of neutrophil activation, cell-free DNA, and myeloperoxidase and elastase activity in Pg-injected rats were significantly reduced both in the conditioned medium of AAA tissue samples and in plasma of rats injected with Pg and treated with AZD9668.. AZD9668 treatment could therefore constitute a new therapeutic tool for treatment of AAA.

Topics: Animals; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Calcium Phosphates; Dilatation, Pathologic; Disease Models, Animal; Disease Progression; Fibrosis; Matrix Metalloproteinase 9; Neutrophil Activation; Pancreatic Elastase; Peroxidase; Porphyromonas gingivalis; Pyridones; Rats; Serine Proteinase Inhibitors; Sulfones; Tissue Culture Techniques

This study was designed to evaluate the protective effect of water extract of Amaranthus lividus L. (A. lividus) (Amaranthaceae) on carbon tetrachloride (CCl4)-induced toxicity in kidneys of rats. For this purpose, male albino Wistar rats were pretreated with A. lividus (250 and 500 mg/kg body weight (b.w.)) daily for 9 days and a single dose of CCl4 was applied intraperitoneally (50% in olive oil; 1.5 mL/kg b.w.) on the 10th day. All rats were killed 24 h after CCl4 administration, and kidneys were excised and used for determination of histopathological and biochemical parameters. CCl4 administration caused a remarkable increase in lipid peroxidation (LPO) and glutathione levels and glutathione-S-transferase, glutathione peroxidase, glutathione reductase, superoxide dismutase, myeloperoxidase (MPO) activities and a decrease in catalase (CAT) activity when compared to the control group. Pretreatment with A. lividus (250 and 500 mg/kg b.w.) significantly prevented the elevation in LPO level and MPO activity as well as protected the decrease in CAT activity but did not alter other biochemical parameters. The protective effect of A. lividus was further evident through the decreased histological alterations in kidneys. In conclusion, this study has indicated that A. lividus possesses protective and antioxidant effects against CCl4-induced oxidative kidney damage.

Topics: Amaranthus; Animals; Antioxidants; Carbon Tetrachloride; Catalase; Disease Models, Animal; Glutathione; Glutathione Peroxidase; Glutathione Reductase; Glutathione Transferase; Kidney; Kidney Diseases; Lipid Peroxidation; Male; Oxidative Stress; Peroxidase; Plant Extracts; Protective Agents; Rats; Rats, Wistar; Superoxide Dismutase

Accumulating data suggest that platelets not only regulate thrombosis and haemostasis but also inflammatory processes. Platelets contain numerous potent pro-inflammatory compounds, including the chemokines CCL5 and CXCL4, although their role in acute colitis remains elusive. The aim of this study is to examine the role of platelets and platelet-derived chemokines in acute colitis. Acute colitis is induced in female Balb/c mice by administration of 5% dextran sodium sulfate (DSS) for 5 days. Animals receive a platelet-depleting, anti-CCL5, anti-CXCL4, or a control antibody prior to DSS challenge. Colonic tissue is collected for quantification of myeloperoxidase (MPO) activity, CXCL5, CXCL2, interleukin-6 (IL-6), and CCL5 levels as well as morphological analyses. Platelet depletion reduce tissue damage and clinical disease activity index in DSS-exposed animals. Platelet depletion not only reduces levels of CXCL2 and CXCL5 but also levels of CCL5 in the inflamed colon. Immunoneutralization of CCL5 but not CXCL4 reduces tissue damage, CXC chemokine expression, and neutrophil recruitment in DSS-treated animals. These findings show that platelets play a key role in acute colitis by regulating CXC chemokine generation, neutrophil infiltration, and tissue damage in the colon. Moreover, our results suggest that platelet-derived CCL5 is an important link between platelet activation and neutrophil recruitment in acute colitis.

Topics: Acute Disease; Animals; Blood Platelets; Chemokine CCL5; Chemokines, CXC; Colitis; Disease Models, Animal; Female; Mice; Mice, Inbred BALB C; Neutrophil Infiltration; Peroxidase; Platelet Activation; Platelet Factor 4

Fructooligosaccharides (FOS) are used as functional foods due to their prebiotic effects. Intestinal anti-inflammatory activity has been established in most, but not all, studies in animal models of colitis, using mainly chemically induced inflammation. Our goal was to test the effect of FOS (degree of polymerization 2-8) in the chronic, lymphocyte-driven CD4+ CD62L+ T cell transfer model of colitis.. Colitis was induced by transfer of CD4+ CD62L+ T cells to C57BL/6J Rag1(-/-) mice. FOS (75 mg day(-1)) was administered by gavage as a post-treatment. Three groups were established: non-colitic (NC), colitic control (C, CD4+ CD62L+ transferred mice treated with vehicle) and colitic+FOS (C+FOS, similar but treated with FOS). Mice were killed after 13 days.. Treatment of mice with FOS ameliorated colitis, as evidenced by an increase in body weight, a lesser myeloperoxidase and alkaline phosphatase activities, a lower secretion of proinflammatory cytokines by mesenteric lymph node cells ex vivo (IFN-γ, IL-17, and TNF-α), and a higher colonic expression of occludin (C+FOS vs. C, p < 0.05). Increased relative abundance of lactic acid bacteria was observed in FOS-treated mice (p < 0.05).. FOS exert intestinal anti-inflammatory activity in T lymphocyte-dependent colitis, suggesting it may be useful in the management of inflammatory bowel disease in appropriate conditions.

Topics: Alkaline Phosphatase; Animals; Anti-Inflammatory Agents; Calgranulin A; CD4-Positive T-Lymphocytes; Claudin-4; Claudin-5; Colitis; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Gastrointestinal Microbiome; Gene Expression Regulation; Interferon-gamma; Interleukin-10; Interleukin-17; Interleukin-1beta; Intestinal Mucosa; Intestines; L-Selectin; Lactobacillus; Mice; Mice, Inbred C57BL; Occludin; Oligosaccharides; Peroxidase; Tumor Necrosis Factor-alpha

The imbalance of n-6 and n-3 polyunsaturated fatty acids in the maternal diet impairs intestinal barrier development and sensitizes the colon response to inflammatory insults in the young rats. With a view to overcoming this issue, we designed this study to investigate the effect of maternal and neonatal intake of different proportions of n-6/n-3 fatty acids on colon inflammation in the young adult rats.. Female Wistar rats were assigned into four groups, and each group fed one of four semisynthetic diets, namely n-6, low n-3, n-6/n-3 and n-3 fatty acids for 8 weeks prior to mating, during gestation and lactation periods. At weaning, the pups were separated from the dams and fed diet similar to the mothers. Colitis was induced on postnatal day 35, by administering 2 % dextran sulfate sodium in drinking water for 10 days. Colitis was assessed based on the clinical and inflammatory markers in the colon. Fatty acid analysis was done in liver, RBC, colon and spleen.. A balanced n-6/n-3 PUFA diet significantly improved the body weight loss, rectal bleeding and mortality in rats. This was associated with lower myeloperoxidase activity, nitric oxide, prostaglandin E2, TNF-α and IL-6, IL-8, COX-2 and iNOS levels in the colon tissues. Fatty acid analysis has shown that the arachidonic acid/docosahexaenoic acid ratio was significantly lower in liver, RBC, colon and spleen in n-6/n-3 and n-3 diet groups.. We demonstrate that balanced n-6/n-3 PUFA supplementation in maternal and neonatal diet alters systemic AA/DHA ratio and attenuates colon inflammation in the young adult rats.

Topics: Animals; Animals, Newborn; Colitis; Colon; Cyclooxygenase 2; Dextran Sulfate; Diet; Dinoprostone; Disease Models, Animal; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Female; Interleukin-6; Interleukin-8; Maternal Nutritional Physiological Phenomena; Nitric Oxide; Nitric Oxide Synthase Type II; Peroxidase; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

To determine if myeloperoxidase (MPO) is involved in epileptogenesis and if molecular nuclear imaging can be used to noninvasively map inflammatory changes in epileptogenesis.. The animal and human studies were approved by the institutional review boards. Pilocarpine-induced epileptic mice were treated with 4-aminobenzoic acid hydrazide (n = 46), a specific irreversible MPO inhibitor, or saline (n = 42). Indium-111-bis-5-hydroxytryptamide-diethylenetriaminepentaacetate was used to image brain MPO activity (n = 6 in the 4-aminobenzoic acid hydrazide and saline groups; n = 5 in the sham group) by using single photon emission computed tomography/computed tomography. The role of MPO in the development of spontaneous recurrent seizures was assessed by means of clinical symptoms and biochemical and histopathologic data. Human brain specimens from a patient with epilepsy and a patient without epilepsy were stained for MPO. The Student t test, one-way analysis of variance, and Mann-Whitney and Kruskal-Wallis tests were used. Differences were regarded as significant if P was less than .05.. MPO and leukocytes increased in the brain during epileptogenesis (P < .05). Blocking MPO delayed spontaneous recurrent seizures (99.6 vs 142 hours, P = .016), ameliorated the severity of spontaneous recurrent seizures (P < .05), and inhibited mossy fiber sprouting (Timm index, 0.31 vs 0.03; P = .003). Matrix metalloproteinase activity was upregulated during epileptogenesis in an MPO-dependent manner (1.44 vs 0.94 U/mg, P = .049), suggesting that MPO acts upstream of matrix metalloproteinases. MPO activity was mapped during epileptogenesis in vivo in the hippocampal regions. Resected temporal lobe tissue from a human patient with refractory epilepsy but not the temporal lobe tissue from a patient without seizures demonstrated positive MPO immunostaining, suggesting high translational potential for this imaging technology.. The findings of this study highlight an important role for MPO in epileptogenesis and show MPO to be a potential therapeutic target and imaging biomarker for epilepsy.

Topics: 4-Aminobenzoic Acid; Animals; Blotting, Western; Disease Models, Animal; Epilepsy; Flow Cytometry; Mice; Multimodal Imaging; Peroxidase; Pilocarpine; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed

Hydrogen sulphide (H2S) is an endogenous inflammatory mediator produced by cystathionine-γ-lyase (CSE) in monocytes/macrophages. To determine the role of H2S and macrophages in inflammation, we used small interference RNA (siRNA) to target the CSE gene and investigated its effect in a mouse model of acute pancreatitis. Acute pancreatitis is characterised by increased levels of plasma amylase, myeloperoxidase (MPO) activity and pro-inflammatory cytokines and chemokines in the pancreas and lung. SiRNA treatment attenuated inflammation in the pancreas and lungs of mice following caerulein-induced acute pancreatitis. MPO activity increased in caerulein-induced acute pancreatitis (16.21 ± 3.571 SD fold increase over control) and treatment with siRNA significantly reduced this (mean 3.555 ± 2.522 SD fold increase over control) (p < 0.0001). Similarly, lung MPO activity increased following treatment with caerulein (3.56 ± 0.941 SD fold increase over control) while siRNA treatment significantly reduced MPO activity (0.8243 ± 0.4353 SD fold increase over control) (p < 0.0001). Caerulein treatment increased plasma amylase activity (7094 ± 207 U/l) and this significantly decreased following siRNA administration (5895 ± 115 U/l) (p < 0.0001). Cytokine and chemokine levels in caerulein-induced acute pancreatitis reduced following treatment with siRNA. For example, siRNA treatment significantly decreased pancreatic and lung monocyte chemoattractant protein (MCP)-1 (169.8 ± 59.75 SD; 90.01 ± 46.97 SD pg/ml, respectively) compared to caerulein-treated mice (324.7 ± 103.9 SD; 222.8 ± 85.37 SD pg/ml, pancreas and lun,g respectively) (p < 0.0001). These findings show a crucial pro-inflammatory role for H2S synthesised by CSE in macrophages in acute pancreatitis and suggest CSE gene silencing with siRNA as a potential therapeutic approach for this condition.

Topics: Amylases; Animals; Blood Chemical Analysis; Ceruletide; Cystathionine gamma-Lyase; Cytokines; Disease Models, Animal; Gene Silencing; Hydrogen Sulfide; Inflammation Mediators; Lung; Mice; Monocytes; Pancreas; Pancreatitis, Acute Necrotizing; Peroxidase; RNA, Small Interfering

Polyphenols have neuroprotective effects after brain ischemia. It has been demonstrated that rosmarinic acid (RA), a natural phenolic compound, possesses antioxidant and anti-inflammatory properties. To evaluate the effectiveness of RA against memory deficits induced by permanent middle cerebral artery occlusion (pMCAO) mice were treated with RA (0.1, 1, and 20mg/kg/day, i.p. before ischemia and during 5 days). Animals were evaluated for locomotor activity and working memory 72 h after pMCAO, and spatial and recognition memories 96 h after pMCAO. In addition, in another set of experiments brain infarction, neurological deficit score and myeloperoxidase (MPO) activity were evaluates 24h after the pMCAO. Finally, immunohistochemistry, and western blot, and ELISA assay were used to analyze glial fibrillary acidic protein (GFAP), and synaptophysin (SYP) expression, and BDNF level, respectively. The working, spatial, and recognition memory deficits were significantly improved with RA treatment (20mg/kg). RA reduced infarct size and neurological deficits caused by acute ischemia. The mechanism for RA neuroprotection involved, neuronal loss suppression, and increase of synaptophysin expression, and increase of BDNF. Furthermore, the increase of MPO activity and GFAP immunireactivity were prevented in MCAO group treated with RA. These results suggest that RA exerts memory protective effects probably due to synaptogenic activity and anti-inflammatory action.

Topics: Animals; Astrocytes; Brain; Brain Ischemia; Brain-Derived Neurotrophic Factor; Cinnamates; Depsides; Disease Models, Animal; Dose-Response Relationship, Drug; Gliosis; Infarction, Middle Cerebral Artery; Male; Memory Disorders; Memory, Short-Term; Mice; Motor Activity; Neuroprotective Agents; Peroxidase; Recognition, Psychology; Rosmarinic Acid; Spatial Memory; Synapses

We evaluated whether JWH133, a selective cannabinoid type 2 receptor (CB2R) agonist, prevented neurogenic pulmonary edema (NPE) after subarachnoid hemorrhage (SAH) by attenuating inflammation. Adult male rats were assigned to six groups: sham-operated, SAH with vehicle, SAH with JWH133 (0.3, 1.0, or 3.0 mg/kg) treatment 1 h after surgery, and SAH with JWH133 (1.0 mg/kg) at 1 h with a selective CB2R antagonist, SR144528 (3.0 mg/kg). The perforation model of SAH was performed and pulmonary wet-to-dry weight ratio was evaluated 24 and 72 h after surgery. Western blot analyses and immunohistochemistry were evaluated 24 h after surgery. JWH133 (1.0 mg/kg) significantly and most strongly improved lung edema 24 h after SAH. SR144528 administration significantly reversed the effects of JWH133 (1.0 mg/kg). SAH-induced increasing levels of myeloperoxidase (MPO) and decreasing levels of a tight junction (TJ) protein, junctional adhesion molecule (JAM)-A, were ameliorated by JWH133 (1.0 mg/kg) administration 24 h after SAH. Immunohistochemical assessment also confirmed substantial leukocyte infiltration in the outside of vessels in SAH, which were attenuated by JWH133 (1.0 mg/kg) injection. CB2R agonist ameliorated lung permeability by inhibiting leukocyte trafficking and protecting tight junction proteins in the lung of NPE after SAH.

Topics: Animals; Blotting, Western; Camphanes; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Cannabinoids; Cell Movement; Disease Models, Animal; Immunohistochemistry; Junctional Adhesion Molecules; Lung; Male; Neutrophils; Organ Size; Peroxidase; Pulmonary Edema; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB2; Subarachnoid Hemorrhage

Chronic visceral pain is a defining feature of irritable bowel syndrome (IBS). IBS patients often show alterations in innate and adaptive immune function which may contribute to symptoms. Immune mediators are known to modulate the activity of viscero-sensory afferent nerves, but the focus has been on the innate immune system. Interleukin-2 (IL-2) is primarily associated with adaptive immune responses but its effects on colo-rectal afferent function in health or disease are unknown.. Myeloperoxidase (MPO) activity determined the extent of inflammation in health, acute trinitrobenzene-sulfonic acid (TNBS) colitis, and in our post-TNBS colitis model of chronic visceral hypersensitivity (CVH). The functional effects of IL-2 on high-threshold colo-rectal afferents and the expression of IL-2R and NaV 1.7 mRNA in colo-rectal dorsal root ganglia (DRG) neurons were compared between healthy and CVH mice.. MPO activity was increased during acute colitis, but subsided to levels comparable to health in CVH mice. IL-2 caused direct excitation of colo-rectal afferents that was blocked by tetrodotoxin. IL-2 did not affect afferent mechanosensitivity in health or CVH. However, an increased proportion of afferents responded directly to IL-2 in CVH mice compared with controls (73% vs 33%; p < 0.05), and the abundance of IL-2R and NaV 1.7 mRNA was increased 3.5- and 2-fold (p < 0.001 for both) in colo-rectal DRG neurons.. IL-2, an immune mediator from the adaptive arm of the immune response, affects colo-rectal afferent function, indicating these effects are not restricted to innate immune mediators. Colo-rectal afferent sensitivity to IL-2 is increased long after healing from inflammation.

Topics: Adaptive Immunity; Afferent Pathways; Animals; Colitis; Disease Models, Animal; Ganglia, Spinal; Hyperalgesia; Interleukin-2; Irritable Bowel Syndrome; Mice; NAV1.7 Voltage-Gated Sodium Channel; Neurons, Afferent; Peroxidase; Real-Time Polymerase Chain Reaction; Receptors, Interleukin-2; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sodium Channel Blockers; Tetrodotoxin; Trinitrobenzenesulfonic Acid; Visceral Pain

Lippia sidoides Cham (Verbenaceae) is largely distributed in the northeastern region of Brazil. It is popularly known as 'Alecrim-pimenta'. Recent studies have shown that some species of Lippia have interesting pharmacological activities. This study aimed to evaluate the effect of a nanostructured thymol gel (TG) 1.2 mg/g on acute phase of ligature-induced periodontitis model [acute periodontal disease (APD)] in rats. APD was induced in 24 Wistar rats subjected to ligature placement on left molars in maxillae. Animals were treated with TG, immediately after APD induction. Saline-based gel was utilized as negative control and diethylammonium diclofenac gel 10 mg/g was used as positive control. Animals were randomly assigned into the groups. The periodontium and the surrounding gingiva were examined at histopathology, as well as the neutrophil influx into the gingiva was assayed using myeloperoxidase activity levels by ELISA method. TG treatment reduced tissue lesion at histopathology coupled to decreased myeloperoxidase activity production in gingival tissue when compared with the saline gel control group (p < 0.05). The TG gel was able to provide a significant myeloperoxidase decreasing in gingiva tissue confirming to be effective in reducing gingival inflammation in this model.

Topics: Animals; Brazil; Disease Models, Animal; Gas Chromatography-Mass Spectrometry; Gels; Gingiva; Lippia; Male; Nanotechnology; Neutrophils; Oils, Volatile; Periodontitis; Peroxidase; Phytotherapy; Plant Leaves; Plant Oils; Rats; Rats, Wistar; Thymol

We tested our hypothesis that Myc-interacting zinc finger protein 1 (MIZ1), a cell cycle regulator, suppressed inflammation, and therefore, represented a useful prognostic marker in patients with acute necrotizing pancreatitis (ANP) complicated by acute lung injury.. Sprague-Dawley rats were randomly divided into control and ANP groups at different time points. The MIZ1 protein expression was measured by Western blot and ELISA, and confirmed using immunohistochemistry. The severity of pancreatic and lung injury was evaluated by the injury score and wet/dry weight ratio. The severity of disease was evaluated by serum C-reactive protein (CRP). The MPO activity of lung tissue amylase levels and the degree of inflammation were evaluated by serum tumor necrosis factor (TNF)-α and interleukin (IL)-6 expression. The risk due to multiple factors was investigated by relationship analysis.. The serum levels of CRP, amylase, TNF-α, and IL-6 were gradually increased at 6, 24, and 48 h in ANP when compared with the control rats. The MIZ1 expressions were greatly decreased in ANP rats, especially at 24 h. Statistical analysis showed that there were time-dependent differences in ANP rats when compared with control rats (6 vs. 24 or 48 h, P < 0.01). MIZ1 showed close negative correlation with the degree of pancreatic and lung injury, serum amylase, CRP, TNF-α, and IL-6 (P < 0.01, respectively).. The decreasing MIZ1 expression was closely correlated with inflammatory response, and development of ANP. Decreasing MIZ1 levels indicate a risk for ANP.

Topics: Acute Lung Injury; Amylases; Animals; Blotting, Western; C-Reactive Protein; Disease Models, Animal; DNA-Binding Proteins; Enzyme-Linked Immunosorbent Assay; Immunohistochemistry; Inflammation; Interleukin-6; Lung; Nuclear Proteins; Pancreas; Pancreatitis, Acute Necrotizing; Peroxidase; Protein Inhibitors of Activated STAT; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Severity of Illness Index; Tumor Necrosis Factor-alpha; Ubiquitin-Protein Ligases

Ocimum basilicum L has been traditionally used for the treatment of inflammatory bowel disease in Iran. This study investigates the ameliorative effect of Ocimum basilicum essential oil on an acetic acid-induced colitis model in rats. Ocimum basilicum essential oil with 2 doses (200 and 400 μL/kg) significantly ameliorated wet weight/length ratio of colonic tissue compared to the control group. Higher doses of essential oil (200 and 400 μL/kg) significantly reduced ulcer severity, ulcer area, and ulcer index. On the other hand, histological examination revealed the diminution of total colitis index as a marker for inflammatory cell infiltration in the colonic segments of rats treated with Ocimum basilicum essential oil (200 and 400 μL/kg). The increased level of myeloperoxidase was significantly decreased after the treatment with the essential oil (200 and 400 μL/kg). These results suggest that Ocimum basilicum exhibits protective effect against acetic acid-induced colitis.

Topics: Acetic Acid; Animals; Colitis; Colon; Disease Models, Animal; Iran; Male; Ocimum basilicum; Oils, Volatile; Peroxidase; Protective Agents; Rats; Rats, Wistar

Most previous studies of cisplatin-induced acute kidney injury (AKI) have been in models of acute, high-dose cisplatin administration that leads to mortality in non-tumor-bearing mice. The aim of the study was to determine whether CD4 T cell knockout protects against AKI and cancer in a clinically relevant model of low-dose cisplatin-induced AKI in mice with cancer. Kidney function, serum neutrophil gelatinase-associated lipocalin (NGAL), acute tubular necrosis (ATN), and tubular apoptosis score were the same in wild-type and CD4 -/- mice with AKI. The lack of protection against AKI in CD4 -/- mice was associated with an increase in extracellular signal-regulated kinase (ERK), p38, CXCL1, and TNF-α, mediators of AKI and fibrosis, in both cisplatin-treated CD4 -/- mice and wild-type mice. The lack of protection was independent of the presence of cancer or not. Tumor size was double, and cisplatin had an impaired therapeutic effect on the tumors in CD4 -/- vs. wild-type mice. Mice depleted of CD4 T cells using the GK1.5 antibody were not protected against AKI and had larger tumors and lesser response to cisplatin. In summary, in a clinically relevant model of cisplatin-induced AKI in mice with cancer, (1) CD4 -/- mice were not protected against AKI; (2) ERK, p38, CXCL1, and TNF-α, known mediators of AKI, and interstitial fibrosis were increased in CD4 -/- kidneys; and (3) CD4 -/- mice had faster tumor growth and an impaired therapeutic effect of cisplatin on the tumors. The data warns against the use of CD4 T cell inhibition to attenuate cisplatin-induced AKI in patients with cancer.. A clinically relevant low-dose cisplatin model of AKI in mice with cancer was used. CD4 -/- mice were not functionally or histologically protected against AKI. CD4 -/- mice had faster tumor growth. CD4 -/- mice had an impaired therapeutic effect of cisplatin on the tumors. Mice depleted of CD4 T cells were not protected against AKI and had larger tumors.

Topics: Acute Kidney Injury; Animals; Apoptosis; Biomarkers; Caspase 3; CD4-Positive T-Lymphocytes; Cisplatin; Cytokines; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Gene Knockout Techniques; Homozygote; JNK Mitogen-Activated Protein Kinases; Kidney Function Tests; Lymphocyte Depletion; Male; Mice; Neoplasms; p38 Mitogen-Activated Protein Kinases; Peroxidase; Phosphorylation; Signal Transduction; Tumor Burden

Acute pancreatitis is associated with acute lung injury. The aim of the present study is to evaluate alterations of lungs in an experimental model of acute pancreatitis (AP) following both bilio-pancreatic duct obstruction close to the duodenum. Acute pancreatitis is a common disease with significant mortality. This situation makes the need of finding protective factors for the lung parenchyma, imperative. In the present study there is an effort to clarify the role of apigenin, a substance which is well known for its antioxidant and anti-inflammatory effects, on lung injury, following acute pancreatitis in rats.. In the present study, 126 male Wistar-type rats 3-4 months old and 220-350 g weight were used. At time 0 we randomly assigned the following groups: Group Sham: Rats were subjected to virtual surgery. Group Control: Rats were subjected to surgery for induction of acute pancreatitis. Group Apigenin: Rats were subjected to surgery for induction of acute pancreatitis and enteral feeding with apigenin. Immunochemistry for TNF-α and IL-6 as well as MPO activity were measured at predetermined time intervals 6, 12, 24, 48, and 72 h, in order to evaluate architectural disturbances of the lung tissue.. From the pathological reports we realized that comparing the control group with the apigenin group, there is an improvement of lung tissue damage following apigenin administration, with statistical significance. Apigenin reduces most histopathological alterations of the pulmonary tissue, reduces MPO and TNF-α activity at 48 hours and, furthermore, reduces IL-6 activity at 72 hours post-administration.. Oral Apigenin administration in rats, following experimental induced acute pancreatitis, seems to be protective on the lung tissue. Apigenin administration to humans could potentially ameliorate acute lung injuries. However, special caution is required for humans' use, as more detailed studies are needed.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Apigenin; Disease Models, Animal; Humans; Interleukin-6; Male; Pancreas; Pancreatitis; Peroxidase; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

Chlamydia trachomatis causes sexually transmitted diseases with infertility, pelvic inflammatory disease and neonatal pneumonia as complications. The duration of urogenital mouse models with the strict mouse pathogen C. muridarum addressing vaginal shedding, pathological changes of the upper genital tract or infertility is rather long. Moreover, vaginal C. trachomatis application usually does not lead to the complications feared in women. A fast-to-perform mouse model is urgently needed to analyze new antibiotics, vaccine candidates, immune responses (in gene knockout animals) or mutants of C. trachomatis. To complement the valuable urogenital model with a much faster and quantifiable screening method, we established an optimized lung infection model for the human intracellular bacterium C. trachomatis serovar D (and L2) in immunocompetent C57BL/6J mice. We demonstrated its usefulness by sensitive determination of antibiotic effects characterizing advantages and limitations achievable by early or delayed short tetracycline treatment and single-dose azithromycin application. Moreover, we achieved partial acquired protection in reinfection with serovar D indicating usability for vaccine studies, and showed a different course of disease in absence of complement factor C3. Sensitive monitoring parameters were survival rate, body weight, clinical score, bacterial load, histological score, the granulocyte marker myeloperoxidase, IFN-γ, TNF-α, MCP-1 and IL-6.

Topics: Animals; Anti-Bacterial Agents; Bacterial Load; Bacterial Vaccines; Biopsy; Cell Line; Chlamydia trachomatis; Chlamydial Pneumonia; Complement C3; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Host-Pathogen Interactions; Humans; Immunoglobulin G; Lung; Mice; Mice, Knockout; Peroxidase

To examine the effect of 3-[(dodecylthiocarbonyl)-methyl]-glutarimide (DTCM-G), a novel anti-inflammatory agent that inhibits lipopolysaccharide (LPS) activation of RAW264.7 macrophages, on murine models of colitis and RAW264.7 cells.. Colitis was induced by rectally infusing trinitrobenzenesulfonic acid (TNBS) (1.5 mg in 50% ethanol) in BALB/c mice or orally administering 3% dextran sulfate sodium (DSS) for 5 days in C57BL/6 mice. The severity of colitis was assessed after intraperitoneally injecting DTCM-G (40 mg/kg). The anti-inflammatory properties of DTCM-G and its mechanisms were investigated in LPS-stimulated RAW264.7 cells.. DTCM-G significantly ameliorated TNBS-induced colitis, according to the body weight loss, disease activity index, colonic obstruction, macroscopic colonic inflammation score, mucosal myeloperoxidase activity, and histopathology. Immunohistochemistry and isolated lamina propria mononuclear cells showed significantly reduced colonic F4/80(+) and CD11b(+) macrophage infiltration. DTCM-G significantly suppressed tumor necrosis factor (TNF)-α and interleukin (IL)-6 messenger RNA expression in the colon and attenuated DSS-induced colitis, according to the disease activity index and histopathology. In RAW264.7 cells, DTCM-G suppressed LPS-induced TNF-α/IL-6 production and enhanced glycogen synthase kinase-3β phosphorylation.. DTCM-G attenuated murine experimental colitis by inhibiting macrophage infiltration and inflammatory cytokine expression. Thus, DTCM-G may be a promising treatment for inflammatory bowel disease.

Topics: Animals; Anti-Inflammatory Agents; CD4-Positive T-Lymphocytes; Cell Line; Colitis; Colon; Cytokines; Dextran Sulfate; Disease Models, Animal; Macrophages; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Peroxidase; Piperidones; RNA, Messenger; Trinitrobenzenesulfonic Acid

Acute pancreatitis is an inflammatory condition that may lead to multisystemic organ failure with considerable mortality. Recently, resolvin D1 (RvD1) as an endogenous anti-inflammatory lipid mediator has been confirmed to protect against many inflammatory diseases. This study was designed to investigate the effects of RvD1 in acute pancreatitis and associated lung injury. Acute pancreatitis varying from mild to severe was induced by cerulein or cerulein combined with LPS, respectively. Mice were pretreated with RvD1 at a dose of 300 ng/mouse 30 min before the first injection of cerulein. Severity of AP was assessed by biochemical markers and histology. Serum cytokines and myeloperoxidase (MPO) levels in pancreas and lung were determined for assessing the extent of inflammatory response. NF-κB activation was determined by Western blotting. The injection of cerulein or cerulein combined with LPS resulted in local injury in the pancreas and corresponding systemic inflammatory changes with pronounced severity in the cerulein and LPS group. Pretreated RvD1 significantly reduced the degree of amylase, lipase, TNF-α, and IL-6 serum levels; the MPO activities in the pancreas and the lungs; the pancreatic NF-κB activation; and the severity of pancreatic injury and associated lung injury, especially in the severe acute pancreatitis model. These results suggest that RvD1 is capable of improving injury of pancreas and lung and exerting anti-inflammatory effects through the inhibition of NF-κB activation in experimental acute pancreatitis, with more notable protective effect in severe acute pancreatitis. These findings indicate that RvD1 may constitute a novel therapeutic strategy in the management of severe acute pancreatitis.

Topics: Animals; Anti-Inflammatory Agents; Ceruletide; Disease Models, Animal; Docosahexaenoic Acids; Gastrointestinal Agents; Inflammation; Interleukin-6; Lung; Lung Injury; Mice; Mice, Inbred C57BL; NF-kappa B; Pancreas; Pancreatitis, Acute Necrotizing; Peroxidase; Protective Agents; Signal Transduction

Asperuloside, an iridoid glycoside found in Herba Paederiae, is a component from traditional Chinese herbal medicine. In this study, we aimed to investigate the protective effects and potential mechanisms of asperuloside action on inflammatory responses in lipopolysaccharide (LPS)-stimulated Raw 264.7 cells and an LPS-induced lung injury model. The pro-inflammatory cytokines and signaling pathways were measured by enzyme-linked immunosorbent assays (ELISA) and Western blotting to determine the effects of asperuloside. We found that asperuloside can significantly downregulate tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, and IL-6 levels in vitro and in vivo, and treatment with asperuloside significantly reduced the lung wet-to-dry weight, histological alterations and myeloperoxidase activity in a murine model of LPS-induced acute lung injury (ALI). In addition, Western blot analysis that pretreatment with asperuloside remarkably blunted the phosphorylation of inhibitor of nuclear factor kappa-B (IκBα), extracellular signal-related kinases 1 and 2 (ERK1/2), c-Jun. N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38MAPK) in LPS-stimulated inflammation. These results indicate that asperuloside exerts its anti-inflammatory effect in correlation with inhibition of a pro-inflammatory mediator through suppressing nuclear factor kappa-B (NF-κB) nuclear translocation and MAPK phosphorylation in a dose-dependent manner.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Cell Line; Cyclopentane Monoterpenes; Disease Models, Animal; Drugs, Chinese Herbal; Glucosides; Humans; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; Macrophages; Male; Mice; Mice, Inbred BALB C; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Peroxidase; Pyrans; Signal Transduction; Tumor Necrosis Factor-alpha

Context Hamelia patens Jacq. (Rubiaceae) is traditionally used to treat wounds, inflammation and diabetes. However, there is still a lack of scientific evidence to support these applications. Objective The objective of this study is to evaluate the anti-inflammatory, antioxidant and antidiabetic activities of Hamelia patens, and identify its bioactive compounds. Materials and methods Four extracts were obtained by maceration and liquid-liquid extraction: HEX, DCM-EtOAc, MeOH-EtOAc and MeOH-Aq. The anti-inflammatory effect was evaluated orally on rat paw carrageenan-induced oedema over 6 h (50, 200 and 500 mg/kg), and topically in mouse ear oedema induced by 12-tetradecanoylphorbol-13-acetate (TPA) after 4 h (0.5 and 1 mg/ear). We also evaluated myeloperoxidase levels in ear tissue, 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging ability, and in vitro α-glucosidase inhibition. The chemical compounds were separated by column chromatography and identified by spectroscopic analysis. Results We found that the oral administration of the HEX extract at 500 and 200 mg/kg significantly decreased the carrageenan-induced inflammation after 1 and 3 h, respectively. The MeOH-EtOAc extract significantly inhibited myeloperoxidase activity (83.5%), followed by the DCM-EtOAc extract (76%), β-sitosterol/stigmasterol (72.7%) and the HEX extract (55%), which significantly decreased oedema induced by TPA at both doses, giving a similar effect to indomethacin. We also found that the MeOH-EtOAc, MeOH-Aq and DCM-EtOAc extracts showed good DPPH scavenging activity (IC50 values of 18.6, 93.9 and 158.2 μg/mL, respectively). The HEX extract showed the lowest α-glucosidase inhibition (an IC50 value of 26.07 μg/mL), followed by the MeOH-EtOAc extract (an IC50 value of 30.18 μg/mL), β-sitosterol/stigmasterol (IC50 34.6 μg/mL) and compound A ((6E,10E,14E,18E)-2,6,10,14,18,23-hexamethyl-2,6,10,14,18,22-tetracosahexaene, an IC50 value of 114.6 μg/mL), which were isolated for the first time from Hamelia patens. Discussion and conclusion Hamelia patens possesses anti-inflammatory, antioxidant and α-glucosidase inhibitory activities, which support its traditional use. These effects can be attributed to the identified compounds.

Topics: alpha-Glucosidases; Animals; Anti-Inflammatory Agents; Biphenyl Compounds; Carrageenan; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Female; Free Radical Scavengers; Glycoside Hydrolase Inhibitors; Hamelia; Peroxidase; Phytotherapy; Picrates; Plant Leaves; Plants, Medicinal; Rats, Wistar; Saccharomyces cerevisiae Proteins; Solvents; Tetradecanoylphorbol Acetate; Time Factors

The purpose of this study was to assess the effect of an enriched C-glycosyl flavonoids fraction (EFF-Cp) from Cecropia Pachystachya leaves on behavior, mitochondrial chain function, and oxidative balance in the brain of rats subjected to chronic mild stress. Male Wistar rats were divided into experimental groups (saline/no stress, saline/stress, EFF-Cp/no stress, and EFF-Cp/stress). ECM groups were submitted to stress for 40 days. On the 35th ECM day, EFF-Cp (50 mg/kg) or saline was administrated and the treatments lasted until the 42nd day. On the 41st and 42nd days, the animals were submitted to the splash test and the forced swim test. After these behavioral tests, the enzymatic activity of mitochondrial chain complexes and oxidative stress were analyzed. EFF-Cp reversed the depressive-like behavior induced by ECM. It also reversed the increase in thiobarbituric acid reactive species, myeloperoxidase activity, and nitrite/nitrate concentrations in some brain regions. The reduced activities of the antioxidants superoxide dismutase and catalase in some brain regions were also reversed by EFF-Cp. The most pronounced effect of EFF-Cp on mitochondrial complexes was an increase in complex IV activity in all studied regions. Thus, it is can be concluded that EFF-Cp exerts an antidepressant-like effect and that oxidative balance may be an important physiological process underlying these effects.

Topics: Animals; Antidepressive Agents; Chronic Disease; Creatine Kinase; Disease Models, Animal; Exploratory Behavior; Flavonoids; Grooming; Male; Nitrites; Oxidative Stress; Oxidoreductases; Peroxidase; Plant Extracts; Plant Leaves; Protein Carbonylation; Rats; Rats, Wistar; Stress, Psychological; Swimming; Thiobarbituric Acid Reactive Substances

Mice lacking three epidermal barrier proteins-envoplakin, periplakin, and involucrin (EPI-/- mice)-have a defective cornified layer, reduced epidermal γδ T cells, and increased dermal CD4(+) T cells. They are also resistant to developing skin tumors. The tumor-protective mechanism involves signaling between Rae-1 expressing keratinocytes and the natural killer group 2D receptor on immune cells, which also plays a role in host defenses against infection. Given the emerging link between bacteria and cancer, we investigated whether EPI-/- mice have an altered skin microbiota. The bacterial phyla were similar in wild-type and EPI-/- skin. However, bacteria were threefold more abundant in EPI-/- skin and penetrated deeper into the epidermis. The major epithelial defense mechanism against bacteria is production of antimicrobial proteins (AMPs). EPI-/- skin exhibited enhanced expression of antimicrobial peptides. However, reducing the bacterial load by antibiotic treatment or breeding mice under specific pathogen-free conditions did not reduce AMP expression or alleviate the abnormalities in T-cell populations. We conclude that the atopic characteristics of EPI-/- skin are a consequence of the defective barrier rather than a response to the increased bacterial load. It is therefore unlikely that the increase in skin microbiota contributes directly to the observed cancer resistance.

Topics: Analysis of Variance; Animals; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Bacterial Load; Disease Models, Animal; Disease Susceptibility; Enzyme-Linked Immunosorbent Assay; Female; In Situ Hybridization, Fluorescence; Membrane Proteins; Mice; Mice, Inbred C57BL; Microbiota; Peroxidase; Protein Precursors; Real-Time Polymerase Chain Reaction; Skin; Skin Absorption; Skin Neoplasms; Statistics, Nonparametric

An experimental study was performed to evaluate the protective effects of probiotics on gut mucosa in peritonitis through antioxidant mechanisms.. Thirty-two male Wistar albino rats were divided equally into four groups. The rats in Group 1 (control group) underwent laparotomy only. In group 2 (peritonitis group), peritonitis was induced in the rats by the cecal ligation and puncture (CLP) model. In group 3, the rats were treated with probiotics for five days after CLP-induced peritonitis. The last group of rats (group 4) were fed probiotics for five days before the CLP procedure and five days after the surgery. On the fifth day after surgery, all rats were killed, and tissue samples from the terminal ileum were obtained to evaluate the activities of myeloperoxidase (MPO), malondialdehyde (MDA), and glutathione (GSH). Histopathologic examinations were also performed to evaluate the grade of intestinal injury.. Myeloperoxidase and MDA activities were increased, GSH concentrations were decreased in group 2, compared with group 1. Intestinal MPO activities in group 4 were decreased compared with group 1 and group 2, indicating a reduction in oxidant activity. Malondialdehyde decreased in group 3 and decreased even more in group 4, compared with the peritonitis group (group 2). Glutathione concentrations were increased in group 4 compared with group 2 and group 3 (p < 0.05). The Chiu scores of the probiotics groups, groups 3 and 4, were lower than those in group 2, indicating reduced mucosal damage in the probiotically fed groups.. Probiotics have protective effects in peritonitis, which may be related to antioxidant mechanisms. This antioxidant effect of probiotics might occur when pre-conditioning with probiotics before peritonitis because there is sufficient time to prepare the tissues for oxidative damage.

Topics: Animals; Antioxidants; Disease Models, Animal; Glutathione; Histocytochemistry; Ileum; Male; Malondialdehyde; Peritonitis; Peroxidase; Probiotics; Rats, Wistar; Severity of Illness Index

Neutrophil extracellular traps (NETs) are a combination of DNA fibers and granular proteins, such as neutrophil elastase (NE). NETs are released in the extracellular space in response to different stimuli. Carrageenan is a sulfated polysaccharide extracted from Chondrus crispus, a marine algae, used for decades in research for its potential to induce inflammation in different animal models. In this study, we show for the first time that carrageenan injection can induce NET release in a mouse model of acute peritonitis. Carrageenan induced NET release by viable neutrophils with NE and myeloperoxidase (MPO) expressed on DNA fibers. Furthermore, although this polysaccharide was able to stimulate reactive oxygen species (ROS) generation by peritoneal neutrophils, NADPH oxidase derived ROS were dispensable for NET formation by carrageenan. In conclusion, our results show that carrageenan-induced inflammation in the peritoneum of mice can induce NET formation in an ROS-independent manner. These results may add important information to the field of inflammation and potentially lead to novel anti-inflammatory agents targeting the production of NETs.

Topics: Animals; Carrageenan; Disease Models, Animal; DNA; Extracellular Traps; Inflammation; Leukocyte Elastase; Mice; Mice, Inbred BALB C; NADPH Oxidases; Neutrophils; Peritonitis; Peroxidase; Reactive Oxygen Species

Inflammation of the colon in patients with ulcerative colitis (UC) causes pain and altered motility, at least in part through the damage of the myenteric neurons (MNs). Thus, it is important to evaluate new drugs for UC treatment that could also protect myenteric neurons efficiently. As a well-known neural protective and anti-inflammatory agent, melatonin could protect neurons from damage through the activation of the nuclear factor erythroid 2-related factor 2 and antioxidant responsive element (Nrf2-ARE) signaling pathway. Therefore, we investigated the potential protective effect of melatonin against MN damage during colitis induced by 2,4-dinitrobenzene sulfonic acid (DNBS) in rats. Colitis was induced by intracolonic (i.c.) instillation of DNBS and treated with melatonin at a dose of 2.5 mg/kg for 4 days. The damage of MN in the left colon was immunohistochemically evaluated in different groups. Ulcerations and inflammation in the colon were semiquantitatively observed. Myeloperoxidase (MPO), superoxide dismutase (SOD), and malondialdehyde (MDA) levels were detected to evaluate the inflammatory and oxidative stress status. The protein and mRNA expressions of Nrf2 and heme oxygenase-1 (HO-1) in the colon were detected by Western blot and quantitative polymerase chain reaction (qPCR), respectively. Melatonin partially prevented the loss of MN and alleviated the inflammation and oxidative stress induced by DNBS. In addition, melatonin markedly increased the Nrf2 and HO-1 level in the colitis. These results indicate that melatonin protects MN from damage by reducing inflammation and oxidative stress, effects that are partly mediated by the Nrf2-ARE pathway.

Topics: Animals; Colitis; Colon; Dinitrofluorobenzene; Disease Models, Animal; Heme Oxygenase-1; Inflammation; Malondialdehyde; Melatonin; Neurons; Oxidative Stress; Peroxidase; Protective Agents; Rats; Superoxide Dismutase

Ulcerative colitis is an inflammatory condition of the colon in the gastrointestinal system. Currently, the most potent medications used for ulcerative colitis produce no response in 20-30% of cases. There is a need for more efficient and reliable medications. Tyrosine kinase inhibitors have shown efficacy in some inflammatory diseases. Although dasatinib, a tyrosine kinase inhibitor, suppresses proinflammatory cytokines in colonic tissue, there are a few cases of hemorrhagic colitis with dasatinib. There is no study investigating the effect of dasatinib on experimental colitis. We aimed to investigate the effect of dasatinib in a colitis model induced with acetic acid in our study.. In the study, 24 male Sprague-Dawley rats randomly distributed into 4 groups of 6 rats each as control, dasatinib, colitis and dasatinib+colitis groups. For colitis induction, 4% acetic acid was used. Sacrificing of the rats was performed on the seventh day. Disease activity, morphologic and histological injury, superoxide dismutase, myeloperoxidase and malondialdehyde activity, TNFα and CD3 expression were assessed in colonic tissue.. Apart from malondialdehyde, significant difference in all parameters between the control and colitis groups was determined. Difference between the colitis and colitis+dasatinib groups was not significant in only weight loss and biochemical parameters. Though dasatinib does not fully resolve the changes in colitis, there was significant regression.. Dasatinib decreased the inflammation in a rodent model of colitis. It may be provide this effect by the suppression of TNFα. Dasatinib may be one of the treatment options for ulcerative colitis.

Topics: Animals; Colitis; Colon; Dasatinib; Disease Models, Animal; Intestinal Mucosa; Malondialdehyde; Peroxidase; Protein Kinase Inhibitors; Rats, Sprague-Dawley; Superoxide Dismutase; Weight Loss

Metallothioneins (MTs) are a family of low molecular-weight and cysteine-rich metalloproteins that regulate metal metabolism and protect cells from oxygen free radicals. Recent studies suggested that MTs have some anti-inflammatory effects. However, the role of MTs in post-burn inflammation remains unclear. This study is designed to investigate the role of MTs in post-burn inflammation in a mouse burn model. MT-I/II null (-/-) and C57BL/6 wild-type (WT) mice were randomly divided into sham burn, burn, Zn treated, and Zn-MT-2 treated groups. The inflammatory cytokines levels were measured by enzyme-linked immunosorbent assay (ELISA). Myeloperoxidase (MPO) activity was determined by spectrophotometry. In in vitro study, exogenous MT-2 was added to macrophages that were stimulated with burn serum in the presence or absence of a p38 MAPK inhibitor SB203580. The IL-6 and TNF-α messenger RNA (mRNA) expression were detected by quantitative real-time polymerase chain reaction. The levels of p38 expression were determined by Western blot. Burn induced increased inflammatory cytokines such as interleukin (IL)-1β, IL-6, tumor necrosis factors-α, and macrophage chemoattractant protein-1 production in burn wound and serum. The MPO activities in the lung and heart were also increased after burn. These effects were significantly more prominent in MT (-/-) mice than in WT mice. Furthermore, these effects were inhibited by administration of exogenous MT-2 to both WT and MT (-/-) mice. Exogenous MT-2 inhibited the p38 expression and abrogated the increase of IL-6 and TNF-α mRNA expression from macrophages that were stimulated with burn serum. The effect of MT-2 was not further strengthened in the presence of SB203580. MTs may have a protective role against post-burn inflammation and inflammatory organ damage, at least partly through inhibiting the p38 MAPK signaling.

Topics: Animals; Burns; Chemokine CCL2; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Imidazoles; Inflammation; Interleukin-1beta; Interleukin-6; Macrophages; Male; MAP Kinase Signaling System; Metallothionein; Mice; Mice, Inbred C57BL; Mice, Knockout; p38 Mitogen-Activated Protein Kinases; Peroxidase; Pyridines; Real-Time Polymerase Chain Reaction; RNA, Messenger; Tumor Necrosis Factor-alpha

The aim of the study was to investigate the ameliorative effects of curcumin on fibrinogen like protein-2 (fgl-2), some oxido-inflammatory and apoptotic markers in rat-induced acute pancreatitis (AP). Seventy-five albino rats were divided into control group, l-arginine (l-Arg)-induced AP group, curcumin pre-treated group before AP induction, curcumin post-treated group after AP induction, and curcumin injected group only. AP group showed severe necrotizing pancreatitis confirmed by histopathological changes and elevations in serum amylase and lipase activities, levels of epithelial neutrophil-activating peptide 78, tissue content of protein carbonyls, levels of tumor necrosis factor α, and caspase-3 as well as myeloperoxidase activity. Significant elevation in pancreatic fgl-2 mRNA expression was detected in AP group. Improvement of all parameters was detected with increase of caspase-3 in both curcumin-treated groups that confirmed curcumin ameliorative effects against AP through induction of apoptosis and inhibition of micro-thrombosis, inflammation, and oxidative stress.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Arginine; Caspase 3; Curcumin; Disease Models, Animal; Fibrinogen; Gene Expression Regulation; Inflammation; Injections, Intraperitoneal; Male; Oxidative Stress; Pancreatitis, Acute Necrotizing; Peroxidase; Protein Carbonylation; Rats; Rats, Sprague-Dawley; RNA, Messenger; Tumor Necrosis Factor-alpha

To evaluate the anti-inflammatory, anti-oxidant and antifibrotic effects of carvedilol (CARV) in rats with ethanol-induced liver injury.. Liver injury was induced by gavage administration of alcohol (7 g/kg) for 28 consecutive days. Eighty Wistar rats were pretreated with oral CARV at 1, 3, or 5 mg/kg or with saline 1 h before exposure to alcohol. Liver homogenates were assayed for interleukin (IL)-1β, IL-10, and tumor necrosis factor (TNF)-α level as well as for myeloperoxidase (MPO) activity and malonyldialdehyde (MDA) and glutathione (GSH) levels. Serum aspartate aminotransferase (AST) activity and liver triglyceride (TG) levels were also assayed. Immunohistochemical analyses of cyclooxygenase 2 (COX-2), receptor activator of nuclear factor kappa-B/ligand (RANK/RANKL), suppressor of cytokine signalling (SOCS1), the Kupffer cell marker IBA-1 (ionized calcium-binding adaptor molecule 1), intercellular adhesion molecule 1 (ICAM-1), superoxide dismutase (SOD-1), and glutathione peroxidase (GPx-1) expression were performed. Confocal microscopy analysis of IL-1β and NF-κB expression and real-time quantitative PCR analysis for TNFα, PCI, PCIII, and NF-κB were performed.. CARV treatment (5 mg/kg) during the alcohol exposure protocol was associated with reduced steatosis, hepatic cord degeneration, fibrosis and necrosis, as well as reduced levels of AST (p < 0.01), ALT (p < 0.01), TG (p < 0.001), MPO (p < 0.001), MDA (p < 0.05), and proinflammatory cytokines (IL-1β and TNF-α, both p < 0.05), and increased levels of the anti-inflammatory cytokine IL-10 (p < 0.001) and GSH (p < 0.05), compared to the alcohol-only group. Treatment with CARV 5 mg/kg also reduced expression levels of COX-2, RANK, RANKL, IBA-1, and ICAM-1 (all p < 0.05), while increasing expression of SOCS1, SOD-1, and GPx-1 (all p < 0.05) and decreasing expression of IL-1β and NF-κB (both, p < 0.05). Real-time quantitative PCR analysis showed that mRNA production of TNF-α, procollagen type I (PCI), procollagen type III (PCIII), and NF-κB were decreased in the alcohol-CARV 5 mg/kg group relative to the alcohol-only group.. CARV can reduce the stress oxidative, inflammatory response and fibrosis in ethanol-induced liver injury in a rat model by downregulating signalling of Kuppfer cells and hepatic stellate cells (HSCs) through suppression of inflammatory cytokines.

Topics: Animals; Biomarkers; Carbazoles; Carvedilol; Chemical and Drug Induced Liver Injury; Cytokines; Disease Models, Animal; Ethanol; Gene Expression Regulation; Glutathione Peroxidase; Hepatic Stellate Cells; Immunohistochemistry; Kupffer Cells; Liver Cirrhosis; Male; Malondialdehyde; Oxidative Stress; Peroxidase; Propanolamines; Rats; RNA, Messenger; Superoxide Dismutase

Hypertension has been reported to induce cognitive decline and dementia of vascular origin. Serotonin- norepinephrine reuptake transporters take part in the control of inflammation, cognitive functions, motivational acts and deterioration of neurons. This study was carried out to examine the effect of venlafaxine; a specific serotonin-norepinephrine reuptake inhibitor (SNRI), in two-kidney-one-clip-2K1C (renovascular hypertension) provoked vascular dementia (VaD) in albino rats. 2K1C technique was performed to provoke renovascular-hypertension in adult male albino Wistar rats. Learning and memory were assessed by using the elevated plus maze and Morris water maze. Mean arterial blood pressure- MABP, as well as endothelial function, were assessed by means of BIOPAC system. Serum nitrosative stress (nitrite/ nitrate), aortic superoxide anion, brain oxidative stress, inflammation, cholinergic dysfunction and brain damage (2,3,5-triphenylterazolium chloride staining) were also assessed. 2K1C has increased MABP, endothelial dysfunction as well as learning and memory impairments. 2K1C method has increased serum nitrosative stress (reduced nitrite/nitrate level), oxidative stress (increased brain thiobarbituric acid reactive species and aortic superoxide anion content along with decreased levels of brain superoxide dismutase, glutathione, and catalase), brain inflammation (increased myeloperoxidase), cholinergic dysfunction (increased acetylcholinesterase activity) and brain damage. Treatment with venlafaxine considerably attenuated renovascular-hypertension induced cognition impairment, endothelial dysfunction, serum nitrosative stress, brain and aortic oxidative stress, cholinergic function, inflammation as well as cerebral damage. The finding of this study indicates that specific modulation of the serotonin-norepinephrine transporter perhaps regarded as potential interventions for the management of renovascular hypertension provoked VaD.

Topics: Acetylcholinesterase; Animals; Arterial Pressure; Cognition Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Glutathione; Hypertension, Renovascular; Male; Maze Learning; Nitrates; Nitrites; Oxidative Stress; Peroxidase; Rats; Rats, Wistar; Serotonin and Noradrenaline Reuptake Inhibitors; Superoxide Dismutase; Superoxides; Venlafaxine Hydrochloride

Oroxyloside, as a metabolite of oroxylin A, may harbor various beneficial bioactivities which have rarely been reported in the previous studies. Here we established the dextran sulfate sodium (DSS)-induced experimental colitis and evaluated the anti-inflammatory effect of oroxyloside in vivo. As a result, oroxyloside attenuated DSS-induced body weight loss, colon length shortening and colonic pathological damage. Furthermore, oroxyloside inhibited inflammatory cell infiltration and decreased myeloperoxidase (MPO) and inducible nitric oxide synthase (iNOS) activities as well. The production of pro-inflammatory cytokines in serum and colon was also significantly reduced by oroxyloside. We unraveled the underlying mechanisms that oroxyloside inhibited NF-κB pathway by activating Peroxisome Proliferator-Activated Receptor γ (PPARγ) to attenuate DSS-induced colitis. Moreover, we investigated the anti-inflammatory effect and mechanisms of oroxyloside in the mouse macrophage cell line RAW264.7 and bone marrow derived macrophages (BMDM). Oroxyloside decreased several LPS-induced inflammatory cytokines, including IL-1β, IL-6 and TNF-α in RAW264.7 and BMDM. We also found that oroxyloside inhibited LPS-induced activation of NF-κB signaling pathway via activating PPARγ in RAW 264.7 and BMDM. Docking study showed that oroxyloside could bind with PPARγ. GW9662, the inhibitor of PPARγ, and PPARγ siRNA transfection blocked the effect of oroxyloside on PPARγ activation. Our study suggested that oroxyloside prevented DSS-induced colitis by inhibiting NF-κB pathway through PPARγ activation. Therefore, oroxyloside may be a promising and effective agent for inflammatory bowel disease (IBD).

Topics: Anilides; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Line; Colitis; Dextran Sulfate; Disease Models, Animal; Female; Flavones; Gene Expression Regulation; Glucuronides; Interleukin-1beta; Interleukin-6; Macrophages; Mice; Mice, Inbred C57BL; Molecular Docking Simulation; NF-kappa B; Nitric Oxide Synthase Type II; Peroxidase; PPAR gamma; RNA, Small Interfering; Signal Transduction; Tumor Necrosis Factor-alpha

Hydrogen sulphide is an endogenous inflammatory mediator produced by cystathionine-γ-lyase (CSE) in macrophages. To determine the role of H2S and macrophages in sepsis, we used small interference RNA (siRNA) to target the CSE gene and investigated its effect in a mouse model of sepsis. Cecal ligation puncture (CLP)-induced sepsis is characterized by increased levels of myeloperoxidase (MPO) activity, morphological changes in liver and pro-inflammatory cytokines and chemokines in the liver and lung. SiRNA treatment attenuated inflammation in the liver and lungs of mice following CLP-induced sepsis. Liver MPO activity increased in CLP-induced sepsis and treatment with siRNA significantly reduced this. Similarly, lung MPO activity increased following induction of sepsis with CLP while siRNA treatment significantly reduced MPO activity. Liver and lung cytokine and chemokine levels in CLP-induced sepsis reduced following treatment with siRNA. These findings show a crucial pro-inflammatory role for H2S synthesized by CSE in macrophages in sepsis and suggest CSE gene silencing with siRNA as a potential therapeutic approach for this condition.

Topics: Animals; Cystathionine gamma-Lyase; Disease Models, Animal; Gene Silencing; Humans; Hydrogen Sulfide; Inflammation; Macrophages; Mice; Monocytes; Peroxidase; Punctures; Sepsis

To investigate the effects of medical ozone theraphy on the colon anastomosis of peritonitis model in rats.. Eighteen rats were randomly assigned into three equal groups; control, cecal punctuation and colon anastomosis and ozone theraphy. Sepsis was performed with a cecal punctuation in groups 2 and 3. The medical ozone theraphy was administered intraperitonealy for three weeks in group 3 while the other rats received saline injection. At the twenty second day serum were obtained for TNF-α and IL-1β, the colonic burst pressures were measured and colonic tissue samples were obtained for MDA and MPO levels. Histolopatological examination was evaluated with H&E stain, and Ki-67, IL-1β and the VEGF immunostaining densities were also compared.. Intraperitoneal ozone administration reversed TNF-α, IL-1β, MDA and MPO levels and the colonic burst pressures. There was also a significant difference at immunostaining densities of histopathological examination.. Medical ozone therapy may contribute to tissue healing by affecting the proliferation and the vascularization thus has benefits on colonic anastomosis at peritonitis in rats.

Topics: Anastomosis, Surgical; Animals; Colon; Disease Models, Animal; Interleukin-1beta; Male; Malondialdehyde; Ozone; Peritonitis; Peroxidase; Random Allocation; Rats, Wistar; Tumor Necrosis Factor-alpha; Wound Healing

To examine the therapeutic effects of tocilizumab, an antibody against interleukin-6 receptor, on experimental severe acute pancreatitis and associated acute lung injury. The optimal dose of tocilizumab and the activation of interleukin-6 inflammatory signaling were also investigated.. Randomized experiment.. Research laboratory at a university hospital.. Experimental severe acute pancreatitis in rats.. Severe acute pancreatitis was induced by retrograde injection of sodium taurocholate (50 mg/kg) into the biliopancreatic duct. In dose-study, rats were administered with different doses of tocilizumab (1, 2, 4, 8, and 16 mg/kg) through the tail vein after severe acute pancreatitis induction. In safety-study, rats without severe acute pancreatitis induction were treated with high doses of tocilizumab (8, 16, 32, and 64 mg/kg). Serum and tissue samples of rats in time-study were collected for biomolecular and histologic evaluations at different time points (2, 6, 12, 18, and 24 hr).. 1) Under the administration of tocilizumab, histopathological scores of pancreas and lung were decreased, and severity parameters related to severe acute pancreatitis and associated lung injury, including serum amylase, C-reactive protein, lung surfactant protein level, and myeloperoxidase activity, were all significant alleviated in rat models. 2) Dose-study demonstrated that 2 mg/kg tocilizumab was the optimal treatment dose. 3) Basing on multi-organ pathologic evaluation, physiological and biochemical data, no adverse effect and toxicity of tocilizumab were observed in safety-study. 4) Pancreatic nuclear factor-κB and signal transducer and activator of transcription 3 were deactivated, and the serum chemokine (C-X-C motif) ligand 1 was down-regulated after tocilizumab administration.. Our study demonstrated tocilizumab, as a marketed drug commonly used for immune-mediated diseases, was safe and effective for the treatment of experimental severe acute pancreatitis and associated acute lung injury. Our findings provide experimental evidences for potential clinical application of tocilizumab in severe acute pancreatitis and associated complications.

Topics: Acute Disease; Acute Lung Injury; Amylases; Animals; Antibodies, Monoclonal, Humanized; C-Reactive Protein; Chemokine CXCL1; Disease Models, Animal; Dose-Response Relationship, Drug; Interleukin-6; NF-kappa B; Pancreatitis; Peroxidase; Pulmonary Surfactant-Associated Proteins; Random Allocation; Rats; Severity of Illness Index; Signal Transduction; Transcription Factors

Green tea-derived polyphenol (-)-epigallocatechin-3-gallate (EGCG) has been extensively studied for its antioxidant and anti-inflammatory properties in models of inflammatory bowel disease, yet the underlying molecular mechanism is not completely understood. Herein, we demonstrate that EGCG can potently inhibit the proinflammatory enzyme myeloperoxidase in vitro in a dose-dependent manner over a range of physiologic temperatures and pH values. The ability of EGCG to mediate its inhibitory activity is counter-regulated by the presence of iron and lipocalin 2. Spectral analysis indicated that EGCG prevents the peroxidase-catalyzed reaction by reverting the reactive peroxidase heme (compound I:oxoiron) back to its native inactive ferric state, possibly via the exchange of electrons. Further, administration of EGCG to dextran sodium sulfate-induced colitic mice significantly reduced the colonic myeloperoxidase activity and alleviated proinflammatory mediators associated with gut inflammation. However, the efficacy of EGCG against gut inflammation is diminished when orally coadministered with iron. These findings indicate that the ability of EGCG to inhibit myeloperoxidase activity is one of the mechanisms by which it exerts mucoprotective effects and that counter-regulatory factors such as dietary iron and luminal lipocalin 2 should be taken into consideration for optimizing clinical management strategies for inflammatory bowel disease with the use of EGCG treatment.

Topics: Acute-Phase Proteins; Animals; Antioxidants; Catechin; Dextran Sulfate; Disease Models, Animal; Humans; Inflammation; Iron, Dietary; Lipocalin-2; Lipocalins; Mice, Inbred C57BL; Oncogene Proteins; Peroxidase; Proto-Oncogene Proteins; Tea

Cyclosporine A (CsA) is a well-known immunosuppressive agent used as rescue therapy in severe steroid-refractory ulcerative colitis (UC). However, toxicity issues associated with CsA when administered in its commercially available formulations have been reported in clinical practice. Since nanotechnology has been proposed as a promising strategy to improve safety and efficacy in the treatment of inflammatory bowel disease (IBD), the main purpose of this study was to evaluate the effect of oral administration of CsA-loaded lipid nanoparticles (LN) in the dextran sodium sulfate (DSS)-induced colitis mouse model using Sandimmune Neoral(®) as reference. The results showed that the formulations used did not decrease colon inflammation in terms of myeloperoxidase activity (MPO), tumor necrosis factor (TNF)-α expression, or histological scoring in the acute stage of the disease. However, further studies are needed in order to corroborate the efficacy of these formulations in the chronic phase of the disease.

Topics: Animals; Colitis; Colon; Cyclosporine; Dextran Sulfate; Disease Models, Animal; Female; Immunosuppressive Agents; Mice, Inbred C57BL; Nanoparticles; Peroxidase; Tumor Necrosis Factor-alpha

This study evaluated the effects of Pistacia atlantica (P. atlantica), butyrate, Lactobacillus casei (L. casei) and especially their combination therapy on 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced rat colitis model. Rats were divided into seven groups. Four groups received oral P. atlantica, butyrate, L. casei and the combination of three agents for 10 consecutive days. The remaining groups were negative and positive controls and a sham group. Macroscopic and histopathological examinations were carried out along with determination of the specific biomarker of colonic oxidative stress, the myeloperoxidase (MPO). Compared with controls, the combination therapy exhibited a significant alleviation of colitis in terms of pathological scores and reduction of MPO activity (55%, p=0.0009). Meanwhile, the macroscopic appearance such as stool consistency, tissue and histopathological scores (edema, necrosis and neutrophil infiltration) were improved. Although single therapy by each P. atlantica, butyrate, and L. casei was partially beneficial in reduction of colon oxidative stress markers, the combination therapy was much more effective. In conclusion, the combination therapy was able to reduce the severity of colitis that is clear from biochemical markers. Future studies have to focus on clinical effects of this combination in management of human ulcerative colitis. Further molecular and signaling pathway studies will help to understand the mechanisms involved in the treatment of colitis and inflammatory diseases.

Topics: Animals; Butyrates; Colitis; Colon; Disease Models, Animal; Drug Therapy, Combination; Lacticaseibacillus casei; Male; Oxidative Stress; Peroxidase; Pistacia; Plant Extracts; Probiotics; Rats; Rats, Wistar; Treatment Outcome; Trinitrobenzenesulfonic Acid

Previously, a respirable powder (RP) formulation of pirfenidone (PFD) was developed for reducing phototoxic risk; however, PFD-RP demonstrated unacceptable in vitro inhalation performance. The present study aimed to develop a new RP system of PFD with favorable inhalation properties by spray-drying method.. Spray-dried PFD (SD/PFD) was prepared by spray-drying with L-leucine, and the physicochemical properties and efficacy in an antigen-sensitized airway inflammation model were assessed. A pharmacokinetic study was also conducted after intratracheal and oral administration of PFD formulations.. Regarding powder characterization, SD/PFD had dimpled surface with the mean diameter of 1.793 μm. In next generation impactor analysis, SD/PFD demonstrated high in vitro inhalation performance without the need of carrier particles, and the fine particle fraction of SD/PFD was calculated to be 62.4%. Insufflated SD/PFD (0.3 mg-PFD/rat) attenuated antigen-evoked inflammatory events in the lung, including infiltration of inflammatory cells and myeloperoxidase activity. Systemic exposure level of PFD after insufflation of SD/PFD at the pharmacologically effective dose was 600-fold lower than that after oral administration of PFD at the phototoxic dose.. SD/PFD would be suitable for inhalation, and the utilization of an RP system with SD/PFD would provide a safer medication compared with oral administration of PFD.

Topics: Administration, Inhalation; Administration, Oral; Aerosols; Animals; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; Chromatography, Liquid; Desiccation; Disease Models, Animal; Drug Compounding; Male; Ovalbumin; Particle Size; Peroxidase; Pneumonia; Powders; Pyridones; Rats, Sprague-Dawley; Spectrometry, Mass, Electrospray Ionization; Technology, Pharmaceutical

Mortality is significantly higher in septic patients with cancer than in septic patients without a history of cancer. We have previously described a model of pancreatic cancer followed by sepsis from Pseudomonas aeruginosa pneumonia in which cancer septic mice have higher mortality than previously healthy septic mice, associated with increased gut epithelial apoptosis and decreased T cell apoptosis. The purpose of this study was to determine whether this represents a common host response by creating a new model in which both the type of cancer and the model of sepsis are altered.. C57Bl/6 mice received an injection of 250,000 cells of the lung cancer line LLC-1 into their right thigh and were followed three weeks for development of palpable tumors. Mice with cancer and mice without cancer were then subjected to cecal ligation and puncture and sacrificed 24 hours after the onset of sepsis or followed 7 days for survival.. Cancer septic mice had a higher mortality than previously healthy septic mice (60% vs. 18%, p = 0.003). Cancer septic mice had decreased number and frequency of splenic CD4+ lymphocytes secondary to increased apoptosis without changes in splenic CD8+ numbers. Intestinal proliferation was also decreased in cancer septic mice. Cancer septic mice had a higher bacterial burden in the peritoneal cavity, but this was not associated with alterations in local cytokine, neutrophil or dendritic cell responses. Cancer septic mice had biochemical evidence of worsened renal function, but there was no histologic evidence of renal injury.. Animals with cancer have a significantly higher mortality than previously healthy animals following sepsis. The potential mechanisms associated with this elevated mortality differ significantly based upon the model of cancer and sepsis utilized. While lymphocyte apoptosis and intestinal integrity are both altered by the combination of cancer and sepsis, the patterns of these alterations vary greatly depending on the models used.

Topics: Animals; Apoptosis; Bronchoalveolar Lavage Fluid; CD4-Positive T-Lymphocytes; Cell Line, Tumor; Cytokines; Disease Models, Animal; Female; Intestinal Mucosa; Liver; Lung; Lung Neoplasms; Male; Mice; Mice, Inbred C57BL; Peroxidase; Receptors, CXCR3; Sepsis; Survival Rate; Transplantation, Homologous

In a previous study, we performed the chemical characterization of a polyvinyl alcohol (PVA) membrane supplemented with latex proteins (LP) displaying wound healing activity, and its efficacy as a delivery system was demonstrated. Here, we report on aspects of the mechanism underlying the performance of the PVA-latex protein biomembrane on wound healing. LP-PVA, but not PVA, induced more intense leukocyte (neutrophil) migration and mast cell degranulation during the inflammatory phase of the cicatricial process. Likewise, LP-PVA induced an increase in key markers and mediators of the inflammatory response (myeloperoxidase activity, nitric oxide, TNF, and IL-1β). These results demonstrated that LP-PVA significantly accelerates the early phase of the inflammatory process by upregulating cytokine release. This remarkable effect improves the subsequent phases of the healing process. The polyvinyl alcohol membrane was fully absorbed as an inert support while LP was shown to be active. It is therefore concluded that the LP-PVA is a suitable bioresource for biomedical engineering.

Topics: Administration, Cutaneous; Animals; Calotropis; Cell Degranulation; Disease Models, Animal; Drug Carriers; Drug Compounding; Inflammation Mediators; Interleukin-1beta; Latex; Macrophage Activation; Mast Cells; Membranes, Artificial; Mice; Neutrophil Infiltration; Nitric Oxide; Peroxidase; Phytotherapy; Plant Proteins; Plants, Medicinal; Polyvinyl Alcohol; Skin; Time Factors; Tumor Necrosis Factor-alpha; Wound Healing; Wounds, Penetrating

Blast-related ocular injuries sustained by military personnel have led to rigorous efforts to elucidate the effects of blast exposure on neurosensory function. Recent studies have provided some insight into cognitive and visual deficits sustained following blast exposure; however, limited data are available on the effects of blast on pain and inflammatory processes. Investigation of these secondary effects of blast exposure is necessary to fully comprehend the complex pathophysiology of blast-related injuries. The overall purpose of this study is to determine the effects of single and repeated blast exposure on pain and inflammatory mediators in ocular tissues.. A compressed air shock tube was used to deliver a single or repeated blast (68.0 ± 2.7 kPa) to anesthetized rats daily for 5 days. Immunohistochemistry was performed on ocular tissues to determine the expression of the transient receptor potential vanilloid 1 (TRPV1) channel, calcitonin gene-related peptide (CGRP), substance P (SP), and endothelin-1 (ET-1) following single and repeated blast exposure. Neutrophil infiltration and myeloperoxidase (MPO) expression were also assessed in blast tissues via immunohistochemistry and enzyme-linked immunosorbent assay (ELISA) analysis, respectively.. TRPV1 expression was increased in rat corneas exposed to both single and repeated blast. Increased secretion of CGRP, SP, and ET-1 was also detected in rat corneas as compared to control. Moreover, repeated blast exposure resulted in neutrophil infiltration in the cornea and stromal layer as compared to control animals.. Single and repeated blast exposure resulted in increased expression of TRPV1, CGRP, SP, and ET-1 as well as neutrophil infiltration. Collectively, these findings provide novel insight into the activation of pain and inflammation signaling mediators following blast exposure.

Topics: Animals; Biomarkers; Blast Injuries; Cornea; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Eye Injuries; Immunohistochemistry; Male; Neutrophils; Peroxidase; Rats; Rats, Long-Evans; TRPV Cation Channels

To investigate the potential effects of pretreatment with allopurinol on renal ischemia/reperfusion injury (IRI) in a rat model.. Twenty four rats were subjected to right kidney uninephrectomy were randomly distributed into the following three groups (n=8): Group A (sham-operated group); Group B (ischemic group) with 30 min of renal ischemia after surgery; and Group C (allopurinol + ischemia group) pretreated with allopurinol at 50 mg/kg for 14 days. At 72 h after renal reperfusion, the kidney was harvested to assess inflammation and apoptosis.. Pretreatment with allopurinol significantly improved renal functional and histological grade scores following I/R injury (p<0.05). Compared with Group B, the expression levels of caspase-3 and Bax were markedly reduced in Group C, meanwhile, whereas expression of bcl-2 was clearly increased (p<0.05). A newly described marker of inflammation, High Mobility Group Box 1(HMGB1), showed reduced expression in Group C (p<0.05).. Pretreatment with allopurinol had a protective effect on kidney ischemia/reperfusion injury, which might be related to the inhibition of HMGB1 expression.

Topics: Allopurinol; Animals; Apoptosis; Blood Urea Nitrogen; Disease Models, Animal; HMGB1 Protein; Inflammation; Ischemic Preconditioning; Kidney; Male; Peroxidase; Protective Agents; Random Allocation; Rats, Sprague-Dawley; Reperfusion Injury; Superoxide Dismutase

PepT1 transports dietary and bacterial peptides in the gut. We hypothesized that cysteinyl-glycine would ameliorate the inflammatory effect of a bacterial peptide, formyl-methionyl-leucyl-phenylalanine (fMLP), in both sow-fed and parenterally-fed piglets.. An intestinal perfusion experiment was performed in piglets (N = 12) that were sow-reared or provided with parenteral nutrition (PN) for 4 d. In each piglet, five segments of isolated intestine were perfused with five treatments including cysteine and glycine, cysteinyl-glycine, fMLP, free cysteine and glycine with fMLP, or cysteinyl-glycine with fMLP. Mucosal cytokine responses and intestinal morphology was assessed in each gut segment.. PN piglets had lower mucosal IL-10 by approximately 20% (P < 0.01). Cysteinyl-glycine lowered TNF-α response to fMLP in PN-fed animals and IFN-γ response to fMLP in both groups (P < 0.05). The free cysteine and glycine treatment reduced TNF-α in sow-fed animals (P < 0.05). fMLP affected villus height in parenterally (P < 0.05), but not sow-fed animals.. Parenteral feeding conferred a susceptibility to mucosal damage by fMLP. The dipeptide was more effective at attenuating the inflammatory response to a bacterial peptide than free amino acids. This may be due to competitive inhibition of fMLP transport or a greater efficiency of transport of dipeptides.

Topics: Animals; Cysteine; Cytokines; Dipeptides; Disease Models, Animal; Genetic Predisposition to Disease; Glycine; Inflammation; Interleukin-10; Intestinal Mucosa; Mannitol; Mucous Membrane; N-Formylmethionine Leucyl-Phenylalanine; Parenteral Nutrition; Perfusion; Peroxidase; Random Allocation; Swine; Time Factors

Reactive oxygen species (ROS) protect the host against a large number of pathogenic microorganisms. ROS have different effects on parasites of the genus Leishmania: some parasites are susceptible to their action, while others seem to be resistant. The role of ROS in L. amazonensis infection in vivo has not been addressed to date.. In this study, C57BL/6 wild-type mice (WT) and mice genetically deficient in ROS production by phagocytes (gp91(phox-/-)) were infected with metacyclic promastigotes of L. amazonensis to address the effect of ROS in parasite control. Inflammatory cytokines, parasite loads and myeloperoxidase (MPO) activity were evaluated. In parallel, in vitro infection of peritoneal macrophages was assessed to determine parasite killing, cytokine, NO and ROS production.. In vitro results show induction of ROS production by infected peritoneal macrophages, but no effect in parasite killing. Also, ROS do not seem to be important to parasite killing in vivo, but they control lesion sizes at early stages of infection. IFN-γ, TNF-α and IL-10 production did not differ among mouse strains. Myeloperoxidase assay showed augmented neutrophils influx 6 h and 72 h post - infection in gp91(phox-/-) mice, indicating a larger inflammatory response in gp91(phox-/-) even at early time points. At later time points, neutrophil numbers in lesions correlated with lesion size: larger lesions in gp91(phox-/-) at earlier times of infection corresponded to larger neutrophil infiltrates, while larger lesions in WT mice at the later points of infection also displayed larger numbers of neutrophils.. ROS do not seem to be important in L. amazonensis killing, but they regulate the inflammatory response probably by controlling neutrophils numbers in lesions.

Topics: Animals; Cytokines; Disease Models, Animal; Inflammation; Leishmania mexicana; Leishmaniasis; Mice; Mice, Inbred C57BL; Parasite Load; Peroxidase; Reactive Oxygen Species

N-acylethanolamines (NAEs) comprise a family of bioactive lipid molecules present in animal and plant tissues, with N-palmitoylethanolamine (PEA) having received much attention owing to its anti-inflammatory, analgesic and neuroprotective activities. 2-Pentadecyl-2-oxazoline (PEA-OXA), the oxazoline of PEA, reportedly modulates activity of N-acylethanolamine-hydrolyzing acid amidase (NAAA), which catabolizes PEA. Because PEA is produced on demand and exerts pleiotropic effects on non-neuronal cells implicated in neuroinflammation, modulating the specific amidases for NAEs (NAAA in particular) could be a way to preserve PEA role in maintaining cellular homeostasis through its rapid on-demand synthesis and equally rapid degradation. This study provides the first description of PEA-OXA in both green and roasted coffee beans and Moka infusions, and its synthesis. In an established model of carrageenan (CAR)-induced rat paw inflammation, PEA-OXA was orally active in limiting histological damage and thermal hyperalgesia 6h after CAR intraplantar injection in the right hindpaw and the accumulation of infiltrating inflammatory cells. PEA-OXA appeared to be more potent compared to ultramicronized PEA given orally at the same dose (10mg/kg). PEA-OXA markedly reduced also the increase in hindpaw myeloperoxidase activity, an index of polymorphonuclear cell accumulation in inflammatory tissues. NAAA modulators like PEA-OXA may serve to maximize availability of NAEs (e.g. PEA) while providing for recycling of the NAE components for further resynthesis.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Carrageenan; Coffee; Disease Models, Animal; Hyperalgesia; Inflammation; Male; Oxazoles; Peroxidase; Rats; Rats, Sprague-Dawley

Tumor necrosis factor (TNF) receptor-associated factor 5 (TRAF5) is a key mediator of TNF receptor superfamily members and is important in both T helper (Th) cell immunity and the regulation of multiple signaling pathways. To clarify TRAF5's influence on inflammatory bowel diseases (IBDs), we investigated TRAF5 deficiency's effect on dextran sulfate sodium- (DSS-) induced colitis. Colitis was induced in TRAF5 knockout (KO) mice and their wild-type (WT) littermates by administering 3% DSS orally for 7 days. The mice were then sacrificed, and their colons were removed. Our data suggested that KO mice were more susceptible to DSS-induced colitis. TRAF5 deficiency significantly enhanced IFN-γ, IL-4, and IL-17a mRNA and protein levels in the colons of DSS-fed mice, and the mRNA expression of T-bet and GATA-3 was also markedly elevated. However, ROR-α and ROR-γt mRNA levels did not differ between DSS-induced KO and WT mice. Flow cytometry showed increased frequencies of Th2 and IFN-γ/IL-17a-coproducing CD4(+) T cells in the colons of DSS-induced KO mice. Additionally, TRAF5 deficiency significantly enhanced the activation of NF-κB in CD4(+) T cells after DSS administration. These results indicated that TRAF5 deficiency significantly aggravated DSS-induced colitis, most likely by regulating Th cell-mediated inflammation.

Topics: Animals; Blotting, Western; CD4-Positive T-Lymphocytes; Colitis; Dextran Sulfate; Disease Models, Animal; Electrophoresis, Polyacrylamide Gel; Female; Flow Cytometry; Inflammation; Interleukin-17; Male; Mice; Mice, Knockout; Peroxidase; Real-Time Polymerase Chain Reaction; RNA, Messenger; T-Lymphocytes, Helper-Inducer; TNF Receptor-Associated Factor 5

The present study aimed to identify biomarkers for peroxidasin (Pxdn) mutation-induced eye disorders and study the underlying mechanisms involved in this process. The microarray dataset GSE49704 was used, which encompasses 4 mouse samples from embryos with Pxdn mutation and 4 samples from normal tissues. After data preprocessing, the differentially expressed genes (DEGs) between Pxdn mutation and normal tissues were identified using the t-test in the limma package, followed by functional enrichment analysis. The protein-protein interaction (PPI) network was constructed based on the STRING database, and the transcriptional regulatory (TR) network was established using the GeneCodis database. Subsequently, the overlapping DEGs with high degrees in two networks were identified, as well as the sub-network extracted from the TR network. In total, 121 (75 upregulated and 46 downregulated) DEGs were identified, and these DEGs play important roles in biological processes (BPs), including neuron development and differentiation. A PPI network containing 25 nodes such as actin, alpha 1, skeletal muscle (Acta1) and troponin C type 2 (fast) (Tnnc2), and a TR network including 120 nodes were built. By comparing the two networks, seven crucial genes which overlapped were identified, including cyclin‑dependent kinase inhibitor 1B (Cdkn1b), Acta1 and troponin T type 3 (Tnnt3). In the sub-network, Cdkn1b was predicted as the target of miRNAs such as mmu-miR-24 and transcription factors (TFs) including forkhead box O4 (FOXO4) and activating enhancer binding protein 4 (AP4). Thus, we suggest that seven crucial genes, including Cdkn1b, Acta1 and Tnnt3, play important roles in the progression of eye disorders such as glaucoma. We suggest that Cdkn1b exert its effects via the inhibition of proliferation and is mediated by mmu-miR-24 and targeted by the TFs FOXO4 and AP4.

Topics: Animals; Cell Cycle Proteins; Cyclin-Dependent Kinase Inhibitor p27; Disease Models, Animal; Embryo, Mammalian; Extracellular Matrix Proteins; Eye; Forkhead Transcription Factors; Gene Expression Profiling; Gene Expression Regulation, Developmental; Gene Regulatory Networks; Glaucoma; Humans; Mice; Microarray Analysis; MicroRNAs; Mutation; Peroxidase; Peroxidasin; Protein Interaction Mapping; Transcription Factors

A lot of evidence for the importance of CD26/dipeptidyl peptidase IV (CD26/DPP IV) in immunoactivation has been reported; however, its involvement in colitis remains unclear. The aim of this study was to investigate the influence of CD26/DPP IV deficiency on immunophenotypic changes associated with dextran sulfate sodium (DSS)-induced colitis in wild-type (WT) and CD26-deficient mice. Development of clinical symptoms of colitis and animal health status parameters were assessed; the expression of the nuclear factor (NF)-κB p65 subunit was measured by quantitative real-time PCR, while cell characterization was determined by flow cytometry and immunohistochemical staining. DSS treatment induced loss of body weight and colon length shortening in both mouse strains. An increase of myeloperoxidase activity in CD26-deficient mice was more intensive than in WT mice, in spite of similar histopathological changes. Furthermore, a significant increase in the expression of NF-κB p65 subunit in the colon of CD26-deficient mice was determined. The percentage of splenic CD4(+) and CD8(+) cells in the acute phase of colitis was significantly decreased in WT mice, while in the same period, an increase in the percentage of splenic CD8(+) cells was present in CD26-deficient mice. Development of colitis was accompanied by a significant increase in the percentage of intrahepatic NKT cells in both mouse strains, but their percentage in spleen was increased only in CD26-deficient mice. CD26 deficiency was associated with a heightened response to DSS accompanied by increased expression of NF-κB p65 subunit and distinct changes in leukocyte trafficking. These results provide new insights into the role of CD26/DPP IV during the development of colitis.

Topics: Animals; Biomarkers; Colitis, Ulcerative; Colon; Dextran Sulfate; Dipeptidyl Peptidase 4; Disease Models, Animal; Disease Progression; Female; Gene Expression Regulation; Intestinal Mucosa; Liver; Male; Mice, Inbred C57BL; Mice, Knockout; Neutrophil Infiltration; Organ Size; Peroxidase; Remission, Spontaneous; Specific Pathogen-Free Organisms; Spleen; Transcription Factor RelA

Citrus bioflavonoids embrace a wide group of phenolic compounds effecting the production and scavenging of reactive oxygen species and the processes relating free radical-mediated injury. Keeping in view of the antioxidant and anti-inflammatory properties of Citrus sinensis and Citrus paradisi, present study was undertaken to explore the effects of C. sinensis (orange juice) and C. paradisi (grapefruit juice) at three different doses alone and their two combinations with the objective to examine the effects of these compounds in an experimental model of rat colitis induced by trinitrobenzenesulphonic acid (TNBS). Hence biochemical parameters e.g. myeloperoxidase, alkaline phosphatase, C-reactive protein (CRP) and glutathione were assessed. Data entry and analysis was accomplished by Statistical Package for the Social Sciences version 17 and was presented as mean ± S.E.M with 95% confidence interval. Present result shows that these juices, mainly C. paradisi, may be efficacious for the management of inflammatory bowel disease. In acute colitis model, C. paradise encouraged a decrease in the extension of the lesion escorted by a decrease in the occurrence of diarrhea and reinstatement of the glutathione content. Related effects were produced by the administration of C. sinensis, which also prevented the myeloperoxidase and alkaline phosphatase actions in acute intestinal inflammatory process. The effect of the citrus juices on the inflammatory process may be associated to their antioxidant and anti-inflammatory properties, as revealed in present investigation. The favorable effects exerted were demonstrated both by histological and biochemical changes and were related with a progress in the colonic oxidative status.

Topics: Alkaline Phosphatase; Animals; Anti-Inflammatory Agents; Antioxidants; Biomarkers; C-Reactive Protein; Citrus paradisi; Citrus sinensis; Colitis; Colon; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Fruit; Fruit and Vegetable Juices; Glutathione; Inflammation Mediators; Male; Oxidative Stress; Peroxidase; Phytotherapy; Plant Extracts; Plants, Medicinal; Rats, Wistar; Trinitrobenzenesulfonic Acid

To investigate the effect of medical ozone treatment on the experimental acute distal colitis in rats.. Eighteen rats were randomly distributed into three equal groups; control, acute distal colitis (ADC) without and with medical ozone treatment. Rats in the control group were taken saline. ADC was performed by rectal way with 4% acetic acid in groups 2 and 3, and the group 3 was treated with medical ozone for three weeks both rectally and intraperitoneally. At the twenty second day the distal colons samples were obtained for malondialdehyde and myeloperoxidase, blood samples were obtained to measure the levels of TNF-α and IL-1β levels. Histolopatological examination was evaluated with Ki-67, IL-1β and VEGF immunostaining densities.. There was significant increase in tissue MDA, MPO activity, TNF-α and IL-1β after ozone administration. There was also a significant difference at immunostaining densities of histopathological examination.. Medical ozone treatment ameliorated the experimental acute distal colitis induced by acetic acid in rats. Its possible effect is by means of decreasing inflammation, edema, and affecting the proliferation and the vascularization.

Topics: Acetic Acid; Acute Disease; Animals; Colitis, Ulcerative; Colon; Disease Models, Animal; Immunohistochemistry; Interleukin-1beta; Male; Malondialdehyde; Oxidants, Photochemical; Ozone; Peroxidase; Random Allocation; Rats, Wistar; Reproducibility of Results; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

Ulcerative colitis is a chronic nonspecific inflammatory disease of unknown cause. The aim of this study was to evaluate the anti-inflammatory effect of tauroursodeoxycholate in 2, 4, 6-trinitrobenzenesulfonic acid-induced experimental colitis in mice. After the induction of colitis for 24h, the mice were administrated orally with tauroursodeoxycholate (20, 40 and 60mg/kg) and sulfasalazine (500mg/kg) by gavage for 7 consecutive days. The inhibition effects were evaluated by the body of weight change, survival rate, macroscopical and histological evaluations. Besides, myeloperoxidase (MPO) activity, interleukin (IL)-1β, interferon (IFN)-γ and tumour necrosis factor-α (TNF-α) in colon tissue were also determined by enzyme-linked immunosorbent assay. Treatment with different doses of tauroursodeoxycholate (20, 40 and 60mg/kg) significantly improved the body weight change, decreased the macroscopic and histopathological scores. Compared with the model group, the accumulation of MPO activity, the colonic tissue levels of IL-1β, IFN-γ and TNF-α were significantly reduced in the tauroursodeoxycholate treated groups. Moreover, tauroursodeoxycholate assuaged the symptoms of colitis. These results suggested that tauroursodeoxycholate has an anti-inflammatory effect in TNBS-induced ulcerative colitis in mice.

Topics: Acute Disease; Administration, Oral; Animals; Anti-Inflammatory Agents; Body Weight; Colitis, Ulcerative; Colon; Disease Models, Animal; Humans; Interferon-gamma; Interleukin-1beta; Male; Mice; Mice, Inbred BALB C; Peroxidase; Taurochenodeoxycholic Acid; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

Myeloperoxidase (MPO) activity contributes to arterial inflammation, vascular dysfunction and disease, including atherosclerosis. Current assessment of MPO activity in biological systems in vivo utilizes 3-chlorotyrosine (3-Cl-Tyr) as a biomarker of hypochlorous acid (HOCl) and other chlorinating species. However, 3-Cl-Tyr is formed in low yield and is subject to further metabolism. Recently, we reported a method to selectively assess MPO-activity in vivo by measuring the conversion of hydroethidine to 2-chloroethidium (2-Cl-E(+)) by liquid chromatography with tandem mass spectrometry (LC-MS/MS) (J. Biol. Chem., 289, 2014, pp. 5580-5595). The hydroethidine-based method has greater sensitivity for MPO activity than measurement of 3-Cl-Tyr. The current methods paper provides a detailed protocol to determine in vivo and ex vivo MPO activity in arteries from mouse models of vascular inflammation and disease by utilizing the conversion of hydroethidine to 2-Cl-E(+). Procedures for the synthesis of standards, preparation of tissue homogenates and the generation of 2-Cl-E(+) are also provided in detail, as are the conditions for LC-MS/MS detection of 2-Cl-E(+).

Topics: Animals; Biomarkers; Chromatography, Liquid; Disease Models, Animal; Halogenation; Humans; Hydrogen Peroxide; Hypochlorous Acid; Inflammation; Mice; Oxidation-Reduction; Peroxidase; Phenanthridines; Tandem Mass Spectrometry; Tyrosine; Vascular Diseases

Necrosis amplifies inflammation and plays important roles in acute respiratory distress syndrome (ARDS). Necroptosis is a newly identified programmed necrosis that is mediated by receptor interacting protein 3 (RIP3). However, the potential involvement and impact of necroptosis in lipopolysaccharide (LPS)-induced ARDS remains unknown. We therefore explored the role and mechanism of RIP3-mediated necroptosis in LPS-induced ARDS. Mice were instilled with increasing doses of LPS intratracheally to induce different degrees of ARDS. Lung tissues were harvested for histological and TUNEL staining and western blot for RIP3, p-RIP3, X-linked inhibitor of apoptosis protein (XIAP), mixed lineage kinase domain-like protein (MLKL), total and cleaved caspases-3/8. Then, wild-type and RIP3 knock-out mice were induced ARDS with 30 mg/kg LPS. Pulmonary cellular necrosis was labeled by the propidium Iodide (PI) staining. Levels of TNF-a, Interleukin (IL)-1β, IL-6, IL-1α, IL-10 and HMGB1, tissue myeloperoxidase (MPO) activity, neutrophil counts and total protein concentration were measured. Results showed that in high dose LPS (30mg/kg and 40mg/kg) -induced severe ARDS, RIP3 protein was increased significantly, accompanied by increases of p-RIP3 and MLKL, while in low dose LPS (10mg/kg and 20mg/kg) -induced mild ARDS, apoptosis was remarkably increased. In LPS-induced severe ARDS, RIP3 knock-out alleviated the hypothermia symptom, increased survival rate and ameliorated the lung tissue injury RIP3 depletion also attenuated LPS-induced increase in IL-1α/β, IL-6 and HMGB1 release, decreased tissue MPO activity, and reduced neutrophil influx and total protein concentration in BALF in severe ARDS. Further, RIP3 depletion reduced the necrotic cells in the lung and decreased the expression of MLKL, but had no impact on cleaved caspase-3 in LPS-induced ARDS. It is concluded that RIP3-mediated necroptosis is a major mechanism of enhanced inflammation and lung tissue injury in high dose LPS- induced severe ARDS in mice.

Topics: Animals; Apoptosis; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Inflammation; Inhibitor of Apoptosis Proteins; Lipopolysaccharides; Lung; Lung Injury; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Necrosis; Neutrophils; Peroxidase; Receptor-Interacting Protein Serine-Threonine Kinases; Respiratory Distress Syndrome

Hypoxia and inflammation have been identified as the hallmarks of colitis, intertwined with metabolism. Here, we report that halofuginone (HF), an antiparasitic drug, attenuates dextran sulfate sodium (DSS)-induced colitis in mice, as represented by attenuating the disease activity index, inhibiting colonic shortening, ameliorating colonic lesions and histological signs of damage, reducing colonic myeloperoxidase activity, and suppressing the production of pro-inflammatory cytokines in colon tissue. Intriguingly, the hypoxia-inducible factor 1alpha (HIF-1α) and tumor necrosis factor alpha were also suppressed by HF treatment in colon tissues, exhibiting a tissue-specific effect. To further reveal the metabolic signatures upon HF treatment, mass spectrometry-based metabolomic analysis of the small molecular metabolites in liver, spleen and colon tissues was performed. As a result, we found that HF treatment counteracted the levels of acylcarnitines, including palmitoyl-l-carnitine, isobutyrylcarnitine, vaccenylcarnitine, and myristoylcarnitine, in colon tissues with DSS induction, but no significant change in the levels of acylcarnitines was observed in liver or spleen tissues. The metabolic signatures may indicate that incomplete fatty acid oxidation (FAO) in the colon could be restored upon HF treatment as the tissue-specific metabolic characterization. Taken together, our findings uncovered that the HF potentiated anti-inflammatory effect in DSS-induced colitis in mice and its underlying mechanisms could be associated with the inhibition of HIF-1α and reduced levels of acylcarnitines, suggesting that both the inhibition of HIF-1α and the counteraction of incomplete FAO might be useful in the prevention and treatment of inflammatory bowel disease.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biomarkers; Body Weight; Colitis; Cytokines; Dextran Sulfate; Disease Models, Animal; Energy Metabolism; Enzyme Activation; Fatty Acids; Gene Expression; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation Mediators; Liver; Male; Metabolic Networks and Pathways; Mice; Models, Biological; Oxidation-Reduction; Peroxidase; Phenotype; Piperidines; Quinazolinones; RNA, Messenger; Spleen

Oxidative stress plays an important and causal role in the mechanisms by which ischemia/reperfusion (I/R) injury increases brain damage after stroke. Accordingly, reducing oxidative stress has been proposed as a therapeutic strategy for limiting damage in the brain after stroke. Myeloperoxidase (MPO) is a highly potent oxidative enzyme that is capable of inducing both oxidative and nitrosative stress in vivo.. To determine if and the extent to which MPO-generated oxidants contribute to brain I/R injury, we treated mice subjected to middle cerebral artery occlusion (MCAO) with N-acetyl lysyltyrosylcysteine amide (KYC), a novel, specific and non-toxic inhibitor of MPO. Behavioral testing, ischemic damage, blood-brain-barrier disruption, apoptosis, neutrophils infiltration, microglia/macrophage activation, and MPO oxidation were analyzed within a 7-day period after MCAO.. Our studies show that KYC treatment significantly reduces neurological severity scores, infarct size, IgG extravasation, neutrophil infiltration, loss of neurons, apoptosis, and microglia/macrophage activation in the brains of MCAO mice. Immunofluorescence studies show that KYC treatment reduces the formation of chlorotyrosine (ClTyr), a fingerprint biomarker of MPO oxidation, nitrotyrosine (NO2Tyr), and 4-hydroxynonenal (4HNE) in MCAO mice. All oxidative products colocalized with MPO in the infarcted brains, suggesting that MPO-generated oxidants are involved in forming the oxidative products.. MPO-generated oxidants play detrimental roles in causing brain damage after stroke which is effectively reduced by KYC.

Topics: Animals; Apoptosis; Blood-Brain Barrier; Brain Infarction; Brain Injuries; Calcium-Binding Proteins; Disease Models, Animal; Gene Expression Regulation; Infarction, Middle Cerebral Artery; Macrophages; Mice; Mice, Inbred C57BL; Microfilament Proteins; Microglia; Motor Activity; Neuroprotective Agents; Neutrophil Infiltration; Nitric Oxide Synthase Type I; Oligopeptides; Oxidants; Peroxidase; Tumor Suppressor Protein p53

Anti-neutrophil cytoplasmic antibody vasculitis is a systemic autoimmune disease with glomerulonephritis and pulmonary haemorrhage as major clinical manifestations. The name reflects the presence of autoantibodies to myeloperoxidase and proteinase-3, which bind to both neutrophils and monocytes. Evidence of the pathogenicity of these autoantibodies is provided by the observation that injection of anti-myeloperoxidase antibodies into mice causes a pauci-immune focal segmental necrotizing glomerulonephritis which is histologically similar to the changes seen on renal biopsy in patients. Previous studies in this model have implicated the alternative pathway of complement activation and the anaphylatoxin C5a. Despite this progress, the factors that initiate complement activation have not been defined. In addition, the relative importance of bone marrow-derived and circulating C5 is not known. This is of interest given the recently identified roles for complement within leukocytes. We induced anti-myeloperoxidase vasculitis in mice and confirmed a role for complement activation by demonstrating protection in C3-deficient mice. We showed that neither MASP-2- nor properdin-deficient mice were protected, suggesting that alternative pathway activation does not require properdin or the lectin pathway. We induced disease in bone marrow chimaeric mice and found that circulating and not bone marrow-derived C5 was required for disease. We have therefore excluded properdin and the lectin pathway as initiators of complement activation and this means that future work should be directed at other potential factors within diseased tissue. In addition, in view of our finding that circulating and not bone marrow-derived C5 mediates disease, therapies that decrease hepatic C5 secretion may be considered as an alternative to those that target C5 and C5a. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Bone Marrow; Complement C3; Complement C5; Disease Models, Animal; Mannose-Binding Protein-Associated Serine Proteases; Mice; Mice, Knockout; Peroxidase; Properdin

Plants from genus Lavandula have been used as anti-inflammatory drugs in Mediterranean traditional medicine. Nowadays, there is a growing interest for complementary medicine, including herbal remedies, to treat inflammatory bowel disease (IBD).. To test the anti-inflammatory properties of Lavandula dentata and Lavandula stoechas extracts in two inflammatory experimental models: TNBS model of rat colitis and the carrageenan-induced paw edema in mice, in order to mimic the intestinal conditions and the extra-intestinal manifestations of human IBD, respectively.. The extracts were characterized through the qualitative HPLC analysis. Then, they were assayed in vitro and in vivo. In vitro studies were performed in BMDMs and CMT-93 epithelial cells with different concentrations of the extracts (ranging from 0.1 to 100µg/ml). The extracts were tested in vivo in the TNBS model of rat colitis (10 and 25mg/kg) and in the carrageenan-induced paw edema in mice (10, 25 and 100mg/kg).. L. dentata and L. stoechas extracts displayed immunomodulatory properties in vitro down-regulating different mediators of inflammation like cytokines and nitric oxide. They also showed anti-inflammatory effects in the TNBS model of colitis as evidenced by reduced myeloperoxidase activity and increased total glutathione content, indicating a decrease of neutrophil infiltration and an improvement of the oxidative state. Besides, both extracts modulated the expression of pro-inflammatory cytokines and chemokines, and ameliorated the altered epithelial barrier function. They also displayed anti-inflammatory effects in the carrageenan-induced paw edema in mice, since a significant reduction of the paw thickness was observed. This was associated with a down-regulation of the expression of different inducible enzymes like MMP-9, iNOS and COX-2 and pro-inflammatory cytokines, all involved in the maintenance of the inflammatory condition.. L. dentata and L. stoechas extracts showed intestinal anti-inflammatory effect, confirming their potential use as herbal remedies in gastrointestinal disorders. In addition, their anti-inflammatory effect was also observed in other locations, thus suggesting a possible use for the treatment of the extra-intestinal symptoms of IBD.

Topics: Animals; Anti-Inflammatory Agents; Carrageenan; Cell Line; Chromatography, High Pressure Liquid; Chromatography, Reverse-Phase; Colitis; Cyclooxygenase 2; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Down-Regulation; Edema; Female; Glutathione; Inflammation Mediators; Lavandula; Matrix Metalloproteinase 9; Methanol; Mice, Inbred BALB C; Neutrophil Infiltration; Nitric Oxide; Nitric Oxide Synthase Type II; Oxidative Stress; Peroxidase; Phytotherapy; Plant Components, Aerial; Plant Extracts; Plants, Medicinal; Rats, Wistar; Solvents; Trinitrobenzenesulfonic Acid

To investigate the side effects of phosalone on intestinal cells and to evaluate benefits of ellagic acid (EA) as a remedy.. In order to conduct an in vivo study, a rat model was used. The rats were divided into ten groups based on the materials used in the experiment and their dosage. The first group was fed normally. The second group was administered EA through gavage. Next Four groups were given (1/3, 1/5, 1/10, 1/20) LD50 phosalone; an organophosphorus compound. The last four groups received (1/3, 1/5, 1/10, 1/20) LD50 phosalone and of EA. After one month, the rats were sacrificed and their colon cells were examined to evaluate the level of inflammation, proteins and oxidative stress markers.. The results of this research show that phosalone elevates oxidative stress and changes the level of tumor necrosis factor-a (TNF-α), interlukin-6β (IL-6β) and nuclear factor (NF)-κB proteins. EA administration reduced phosalone toxicity and changed oxidative stress and inflammatory markers for all phosalone doses. Overall changes in reduction of TNF-α (230.47 ± 16.55 pg/mg protein vs 546.43 ± 45.24 pg/mg protein, P < 0.001), IL-6β (15.85 ± 1.03 pg/mg protein vs 21.55 ± 1.3 pg/mg protein, P < 0.05), and NF-κB (32.47 ± 4.85 pg/mg protein vs 51.41 ± 0.71 pg/mg protein, P < 0.05) manifest that the efficacy of EA is more viable for 1/3 LD50 dose of phosalone. Furthermore, EA is effective to counteract the negative outcomes of oxidative stress. When EA was used to treat 1/3 LD50 of phosalone's side effects, it improved the level of AChE activity (48.5% ± 6% vs 25% ± 7%, P < 0.05), TTM (0.391 ± 0.008 mmol/L vs 0.249 ± 0.032 mmol/L, P < 0.05), FRAP (46.04 ± 5.005 μmol/L vs 18.22 ± 1.9 μmol/L, P < 0.01) and MPO (0.222 ± 0.019 U/mg protein vs 0.387 ± 0.04 U/mg protein, P < 0.05).. This research highlights that EA is effective to alleviate the side effects of phosalone by reducing the level of oxidative stress and inflammatory proteins.

Topics: Acetylcholinesterase; Animals; Anti-Inflammatory Agents; Antioxidants; Biomarkers; Colitis; Colon; Cytokines; Cytoprotection; Disease Models, Animal; Ellagic Acid; GPI-Linked Proteins; Inflammation Mediators; Lipid Peroxidation; Male; NF-kappa B; Organothiophosphorus Compounds; Oxidative Stress; Peroxidase; Rats, Wistar; Sulfhydryl Compounds; Thiobarbituric Acid Reactive Substances

To investigate the potential protective effect of exogenous recombinant interleukin-22 (rIL-22) on L-arginine-induced acute severe pancreatitis (SAP)-associated lung injury and the possible signaling pathway involved.. Balb/c mice were injected intraperitoneally with L-arginine to induce SAP. Recombinant mouse IL-22 was then administered subcutaneously to mice. Serum amylase levels and myeloperoxidase (MPO) activity in the lung tissue were measured after the L-arginine administration. Histopathology of the pancreas and lung was evaluated by hematoxylin and eosin (HE) staining. Expression of B cell lymphoma/leukemia-2 (Bcl-2), Bcl-xL and IL-22RA1 mRNAs in the lung tissue was detected by real-time PCR. Expression and phosphorylation of STAT3 were analyzed by Western blot.. Serum amylase levels and MPO activity in the lung tissue in the SAP group were significantly higher than those in the normal control group (P < 0.05). In addition, the animals in the SAP group showed significant pancreatic and lung injuries. The expression of Bcl-2 and Bcl-xL mRNAs in the SAP group was decreased markedly, while the IL-22RA1 mRNA expression was increased significantly relative to the normal control group (P < 0.05). Pretreatment with PBS did not significantly affect the serum amylase levels, MPO activity or expression of Bcl-2, Bcl-xL or IL-22RA1 mRNA (P > 0.05). Moreover, no significant differences in the degrees of pancreatic and lung injuries were observed between the PBS and SAP groups. However, the serum amylase levels and lung tissue MPO activity in the rIL-22 group were significantly lower than those in the SAP group (P < 0.05), and the injuries in the pancreas and lung were also improved. Compared with the PBS group, rIL-22 stimulated the expression of Bcl-2, Bcl-xL and IL-22RA1 mRNAs in the lung (P < 0.05). In addition, the ratio of p-STAT3 to STAT3 protein in the rIL-22 group was significantly higher than that in the PBS group (P < 0.05).. Exogenous recombinant IL-22 protects mice against L-arginine-induced SAP-associated lung injury by enhancing the expression of anti-apoptosis genes through the STAT3 signaling pathway.

Topics: Acute Disease; Acute Lung Injury; Amylases; Animals; Arginine; bcl-X Protein; Biomarkers; Blotting, Western; Disease Models, Animal; Gene Expression Regulation; Interleukin-22; Interleukins; Lung; Male; Mice, Inbred BALB C; Pancreas; Pancreatitis; Peroxidase; Phosphorylation; Proto-Oncogene Proteins c-bcl-2; Real-Time Polymerase Chain Reaction; Receptors, Interleukin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Severity of Illness Index; Signal Transduction; STAT3 Transcription Factor; Time Factors

Mentha longifolia L (Wild Mint or Habak) (ML) is used in traditional medicine in treatment of many gastrointestinal disorders.. This study aimed to evaluate potential protecting effect of ML and its major constituent, eucalyptol, against acetic acid-induced colitis in rats, a model of human inflammatory bowel disease (IBD).. Rats were divided into ten groups (n=8) given orally for three days (mg/kg/day) the following: normal control, acetic acid-induced colitis (un-treated, positive control), vehicle (DMSO), sulfasalazine (500), ML extract (100, 500, 1000), and eucalyptol (100, 200, 400). After 24h-fasting, two ML of acetic acid (3%) was administered intrarectally. On the fifth day, serum and colonic biochemical markers, and histopathological changes were evaluated.. Colitis significantly increased colonic myeloperoxidase activity and malonaldehyde level, and serum tumor necrosis factor-α, interleukin-6, and malonaldehyde levels while significantly decreased colonic and serum glutathione levels. All treatments (except ML 100, ML 1000, and eucalyptol 100) significantly reversed these changes where eucalyptol (400) showed the highest activity in a dose-dependent manner. The colitis-induced histopathological changes were mild in sulfasalazine and eucalyptol 400 groups, moderate in ML 500 and eucalyptol 200 groups, and severe in ML 100, ML 1000, and eucalyptol 100 groups nearly similar to colitis-untreated rats.. ML (in moderate doses) and eucalyptol (dose-dependently) exerted protective effects against acetic acid-induced colitis in rats possibly through antioxidant and antiinflammatory properties suggesting a potential benefit in treatments of IBD. To our knowledge this is the first report addressing this point.

Topics: Acetic Acid; Animals; Anti-Inflammatory Agents; Antioxidants; Biomarkers; Colitis; Colon; Cyclohexanols; Cytoprotection; Disease Models, Animal; Dose-Response Relationship, Drug; Eucalyptol; Gastrointestinal Agents; Glutathione; Interleukin-6; Male; Malondialdehyde; Mentha; Monoterpenes; Peroxidase; Phytotherapy; Plant Components, Aerial; Plant Extracts; Plants, Medicinal; Rats, Sprague-Dawley; Sulfasalazine; Time Factors; Tumor Necrosis Factor-alpha

The hamster has been shown to share a variety of metabolic similarities with humans. To replicate human acute pancreatitis with hamsters, we comparatively studied the efficacy of common methods, such as the peritoneal injections of caerulein, L-arginine, the retrograde infusion of sodium taurocholate, and another novel model with concomitant administration of ethanol and fatty acid. The severity of pancreatitis was evaluated by serum amylase activity, pathological scores, myeloperoxidase activity, and the expression of inflammation factors in pancreas. The results support that the severity of pathological injury is consistent with the pancreatitis induced in mice and rat using the same methods. Specifically, caerulein induced mild edematous pancreatitis accompanied by minimal lung injury, while L-arginine induced extremely severe pancreatic injury including necrosis and neutrophil infiltration. Infusion of Na-taurocholate into the pancreatic duct induced necrotizing pancreatitis in the head of pancreas and lighter inflammation in the distal region. The severity of acute pancreatitis induced by combination of ethanol and fatty acids was between the extent of caerulein and L-arginine induction, with obvious inflammatory cells infiltration. In view of the advantages in lipid metabolism features, hamster models are ideally suited for the studies of pancreatitis associated with altered metabolism in humans.

Topics: Amylases; Animals; Arginine; Ceruletide; Disease Models, Animal; Ethanol; Fatty Acids; Humans; Injections; Mesocricetus; Pancreatitis; Peroxidase; Severity of Illness Index; Taurocholic Acid

Caryocar coriaceum Wittm. (Pequi) is found in southern Ceará, where the fruit is used as food and in folk medicine as an anti-inflammatory, and to promote healing. However, little is known about the effects of repeated administration of its oil on the biochemical parameters of the blood. This work aimed to evaluate the effects Caryocar coriaceum fixed oil (OFCC); on the lipid profiles of healthy mice, on dyslipidemia induced by tyloxapol, and to study its anti-inflammatory effect both in vivo and in vitro. The results revealed significant reduction in total serum cholesterol and triglycerides, and an increase in HDL-C. The paw edema (induced by carrageenan) and myeloperoxidase (MPO), in polymorphonuclear culture cells, was reduced at all dose levels. Results demonstrated that Caryocar coriaceum's fix oil present anti-inflammatory activity and, for the first time describe the hypolipidemic effects, supporting its traditional use and suggest that present a potential cardioprotective effect.

Topics: Animals; Anti-Inflammatory Agents; Biomarkers; Carrageenan; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Dyslipidemias; Ericales; Fruit; Humans; Hypolipidemic Agents; Inflammation; Lipids; Neutrophils; Peroxidase; Phytotherapy; Plant Extracts; Plant Oils; Plants, Medicinal; Polyethylene Glycols; Rats, Wistar; Time Factors

Accumulating evidence suggests that myeloperoxidase (MPO) is involved in atrial remodeling of atrial fibrillation (AF). Statins could reduce the MPO levels in patients with cardiovascular diseases. This study evaluated the effects of atorvastatin on MPO level and atrial remodeling in a rabbit model of pacing-induced AF.. Eighteen rabbits were randomly divided into sham, control and atorvastatin groups. Rabbits in the control and atorvastatin groups were subjected to rapid atrial pacing (RAP) at 600 bpm for 3 weeks, and treated with placebo or atorvastatin (2.5 mg/kg/d), respectively. Rabbits in the sham group did not receive RAP. After 3 weeks of pacing, atrial structural and functional changes were assessed by echocardiography, atrial effective refractory period (AERP) and AF inducibility were measured by atrial electrophysiological examination, and histological changes were evaluated by Masson trichrome-staining. The L-type calcium channel α1c (Cav1.2), collagen I and III, MPO, matrix metalloproteinase (MMP)-2 and MMP-9 were analyzed by real time polymerase chain reaction and/or western blot.. All rabbits were found to have maintained sinus rhythm after 3 weeks of RAP. Atrial burst stimulation induced sustained AF (>30 min) in 5, 4, and no rabbits in the control, atorvastatin, and sham groups, respectively. The AERP shortened and Cav1.2 mRNA level decreased in the control group, but these changes were suppressed in the atorvastatin group. Obvious left atrial enlargement and dysfunction was found in both control and atorvastatin groups. Compared with the control group, these echocardiograhic indices of left atrium did not differ in the atorvastatin group. Prominent atrial fibrosis and increased levels of collagen I and III were observed in the control group but not in the atorvastatin group. The mRNA and protein levels of MPO, MMP-2 and MMP-9 significantly increased in the control group, but these changes were prevented in the atorvastatin group.. Treatment with atorvastatin prevented atrial remodeling in a rabbit model of RAP-induced AF. The reduction of levels of atrial MPO, MMP-2 and MMP-9 may contribute to the prevention of atorvastatin on atrial remodeling.

Topics: Animals; Atorvastatin; Atrial Fibrillation; Atrial Function, Right; Atrial Remodeling; Blotting, Western; Cardiac Pacing, Artificial; Disease Models, Animal; DNA; Echocardiography; Electrocardiography; Heart Atria; Heart Rate; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Peroxidase; Rabbits; Real-Time Polymerase Chain Reaction

We investigated the anti-inflammatory and anti-colitis effects of Rosmarinus officinalis L. extract (RE) by using both in vitro LPS-activated mouse RAW 264.7 macrophages and in vivo dextran sulfate sodium (DSS)-induced experimental murine colitis and suggested the underlying possible mechanisms. Liquid Chromatography-Mass Spectrometry (LC-MS) analysis was performed to identify the major components present in the RE. The clinical signs, biochemistry, immunoblot, ELISA and histology in colon tissues were assessed in order to elucidate the beneficial effect of RE. RE suppressed the LPS-induced pro-inflammatory cytokine production and the expressions of inflammatory proteins in macrophages. Administration of RE (50 and 100 mg kg(-1)) also significantly reduced the severity of DSS-induced murine colitis, as assessed by the clinical symptoms, colon length and histology. RE administration prevented the DSS-induced activation of p38, ERK and JNK MAPKs, attenuated IκBα phosphorylation and subsequent nuclear translocation and DNA binding of NF-κB (p65). RE also suppressed the COX-2 and iNOS expressions, decreased the levels of TNF-α and IL-6 cytokines and the myeloperoxidase activity in the colon tissue. Histological observation revealed that RE administration alleviated mucosal damage and inflammatory cell infiltration induced by DSS in the colon tissue. Hence, RE could be used as a new preventive and therapeutic food ingredient or as a dietary supplement for inflammatory bowel disease.

Topics: Acute Disease; Animals; Colitis; Colon; Cyclooxygenase 2; Dextran Sulfate; Disease Models, Animal; DNA-Binding Proteins; Interleukin-6; Male; Mice; Mice, Inbred BALB C; NF-kappa B; Nitric Oxide Synthase Type II; Peroxidase; Phosphorylation; Plant Extracts; RAW 264.7 Cells; Rosmarinus; Signal Transduction; Tumor Necrosis Factor-alpha

Cerebral ischemia is a common disease and one of the most common causes of death and disability worldwide. The lack of glucose and oxygen in neuronal tissue leads to a series of inflammatory events, culminating in neuronal death. Eriodictyol is a flavonoid isolated from the Chinese herb Dracocephalum rupestre that has been proven to have anti-inflammatory properties.. Thus, the present study was designed to explore whether eriodictyol has neuroprotective effects against the neuronal damage, motor and memory deficits induced by permanent middle cerebral artery occlusion (pMCAO) in mice.. Animals were orally treated with eriodictyol (1, 2 and 4mg/kg) or vehicle (saline) 30min before pMCAO, 2h after, and then once daily for the following five days.. The parameters studied were neuronal viability, brain infarcted area; sensorimotor deficits; exploratory activity; working and aversive memory; myeloperoxidase (MPO) activity; TNFα, iNOS and GFAP immunoreactivity.. The treatment with eriodictyol prevented neuronal death, reduced infarct area and improved neurological and memory deficits induced by brain ischemia. The increase of MPO activity and TNF-α, iNOS and GFAP expression were also reduced by eriodictyol treatment.. These findings demonstrate that eriodictyol exhibit promising neuroprotection effects against the permanent focal ischemia cerebral injury in the mice experimental model and the underlying mechanisms might be mediated through inhibition of neuroinflammation.

Topics: Animals; Astrocytes; Brain; Brain Ischemia; Cell Survival; Disease Models, Animal; Encephalitis; Exploratory Behavior; Flavanones; Locomotion; Male; Memory, Short-Term; Mice; Neurons; Neuroprotective Agents; Nitric Oxide Synthase Type II; Peroxidase; Stroke; Tumor Necrosis Factor-alpha

This study was conducted to assess the anti-inflammatory effect of a novel synthesized phenanthridine alkaloid (PHE-4i) and to examine the possible involvement of hydrogen sulfide (H2S) in anti-inflammatory mechanism. The synthesized phenanthridine derivative PHE-4i (2, 5, and 10 mg/kg) was administered intraperitoneally to rats. One hour following treatment, inflammation was induced by intraplantar injection of carrageenan (1 %), in the hind paw. Paw volume as the index of inflammation was measured before and after carrageenan injection. Neutrophil sequestration into the hind paw was quantified by measuring tissue myeloperoxidase (MPO) activity and was compared for the inhibition of H2S production. Pretreatment with PHE-4i significantly reduced carrageenan-induced hind paw weight, MPO activity, leukocyte infiltration, and H2S production in a dose-dependent manner (p < 0.001). These results indicate that the anti-inflammatory effect of PHE-4i on carrageenan-induced rat paw oedema could be via the inhibition of the gaseous mediator H2S.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Disease Models, Animal; Edema; Hydrogen Sulfide; Male; Molecular Structure; Neutrophil Infiltration; Peroxidase; Phenanthridines; Rats, Wistar

Severe burn results in systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction (MOD). Currently, large-animal models of burn-induced SIRS/MOD mostly use secondary insults resulting in a paucity of knowledge on the effect of burn alone on different organ systems. The objective of the current study was to develop and characterize a large animal model of burn-induced SIRS over the course of 2 weeks. Yorkshire swine (n = 16) were randomized to sham controls (n = 4) or 40% total body surface area contact burns (n = 6 at 2 and 14 days post-burn). Blood chemistry and complete blood count analyses were performed at baseline and post-burn days 1, 2, 3, 7, 10, and 14. Upon euthanasia, tissue samples were taken for histopathology. Burns were found to be full thickness and did not re-epithelialize. SIRS was evidenced by increased body temperature, respiration rate, pulse, and white blood cell count for the duration of the experiment. Both acute liver injury and acute kidney injury were induced as determined biochemically and histologically. Histology also revealed atelectasis of the lungs which was associated with increased myeloperoxidase activity. Intestinal structure as well as enterocyte homeostasis was also disrupted. All of these organ abnormalities recovered to varying degrees by 14 days post-burn. We report a unique reproducible large animal model of burn-induced SIRS that can be tailored to specific organ systems for investigation into potential immunomodulatory interventions that prevent organ failure or promote organ recovery after burn injury.

Topics: Animals; Body Temperature; Burns; Disease Models, Animal; Female; Multiple Organ Failure; Peroxidase; Swine; Systemic Inflammatory Response Syndrome

We examined the influence of adrenalectomy on NSAID-induced small intestinal damage in rats and investigated the possible involvement of adrenal glucocorticoids in the protective effects of urocortin I, a corticotropin-releasing factor (CRF) agonist. Male SD rats without fasting were administered indomethacin s.c. and killed 24 h later in order to examine the hemorrhagic lesions that developed in the small intestine. Urocortin I (20 μg/kg) was given i.v. 10 min before the administration of indomethacin. Bilateral adrenalectomy was performed a week before the experiment. Indomethacin (10 mg/kg) caused multiple hemorrhagic lesions in the small intestine, which were accompanied by a decrease in mucus secretion and increases in intestinal motility, enterobacterial invasion, and iNOS expression. Adrenalectomy markedly increased the ulcerogenic and motility responses caused by indomethacin, with further enhancements in bacterial invasion and iNOS expression; severe lesions occurred at 3 mg/kg, a dose that did not induce any damage in sham-operated rats. This worsening effect was also observed by the pretreatment with mifepristone (a glucocorticoid receptor antagonist). Urocortin I prevented indomethacin-induced enteropathy, and this effect was completely abrogated by the pretreatment with astressin 2B, a CRF2 receptor antagonist, but was not significantly affected by either adrenalectomy or the mifepristone pretreatment. These results suggested that adrenalectomy aggravated the intestinal ulcerogenic response to indomethacin, the intestinal hypermotility response may be a key element in the mechanism for this aggravation, and endogenous glucocorticoids played a role in intestinal mucosal defense against indomethacin-induced enteropathy, but did not account for the protective effects of urocortin I, which were mediated by the activation of peripheral CRF2 receptors.

Topics: Adrenalectomy; Animals; Anti-Inflammatory Agents, Non-Steroidal; Disease Models, Animal; Dose-Response Relationship, Drug; Enterobacteriaceae; Gastrointestinal Agents; Gastrointestinal Motility; Hormone Antagonists; Indomethacin; Intestinal Diseases; Intestine, Small; Male; Mifepristone; Nitric Oxide Synthase Type II; Peroxidase; Rats, Sprague-Dawley; Urocortins

Proprotein convertase subtilisin/kexin type 9 (PCSK9) targets lipoprotein receptors for degradation, thereby reducing hepatic lipid clearance. PCSK9 inhibition reduces mortality in septic mice, presumably through increased hepatic clearance of pathogen lipids due to increased lipoprotein receptor concentrations. However, PCSK9 overexpression in vivo has not been studied in sepsis. Therefore, this study aimed to evaluate the effects of differential PCSK9 expression on systemic infection, inflammation, and coagulation in sepsis.. Wild-type, PCSK9 knockout (KO), and transgenic (Tg) mice that overexpress PCSK9 were subjected to sham surgery or cecal ligation and puncture (CLP). Bacterial loads were measured in lungs, peritoneal cavity fluid, and blood. Organ pathology was assessed in lungs, liver, and kidneys. Lung myeloperoxidase activity, and plasma concentrations of alanine aminotransferase (ALT), creatinine, cell-free DNA (cfDNA), protein C, thrombin-antithrombin (TAT) complexes, interleukin (IL)-6, and IL-10 were also measured 6 h postoperatively. Morbidity was assessed for 16 h following CLP.. Overexpression of PCSK9 in mice increased liver and kidney pathology, plasma IL-6, ALT, and TAT concentrations during sepsis, whereas PCSK9 KO mice exhibited reduced bacterial loads, lung and liver pathology, myeloperoxidase activity, plasma IL-10, and cfDNA during CLP-induced sepsis. All septic mice had reduced plasma levels of protein C, but the protein C ratio relative to normal was significantly decreased in PCSK9 Tg mice. Dyspnea, cyanosis, and overall grimace scores were greatest in septic mice overexpressing PCSK9, whereas PCSK9 KO mice retained core body temperature during sepsis.. These findings demonstrate that PCSK9 deficiency confers protection against systemic bacterial dissemination, organ pathology, and tissue inflammation, particularly in the lungs and liver, while PCSK9 overexpression exacerbates multi-organ pathology as well as the hypercoagulable and pro-inflammatory states in early sepsis.

Topics: Alanine Transaminase; Animals; Blood Coagulation; Disease Models, Animal; Female; Inflammation; Interleukin-10; Interleukin-6; Kidney; Liver; Lung; Male; Mice; Mice, Knockout; Peroxidase; Proprotein Convertase 9; Protein C; Sepsis

Ursolic acid (UA; 3b-hydroxy-12-urs-12-en-28-oic acid), a natural pentacyclic triterpenoid carboxylic acid, has been known to possess potent anti-inflammatory, antioxidant, and antinociceptive effects in various animal models. Therefore, this study was designed to investigate the antihyperalgesic, anti-inflammatory, and antioxidant effects of UA at 5, 10, and 20 mg/kg of doses via per os (p.o.) route for 14 days in chronic constriction injury (CCI)-induced neuropathic pain in rats. Pain behavior in rats was evaluated before and after UA administration via mechanical and heat hyperalgesia. CCI caused significant increase in levels of pro-inflammatory cytokines and oxido-nitrosative stress. In addition, significant increase in myeloperoxidase, malondialdehyde, protein carbonyl, nitric oxide (NO), and total oxidant status (TOS) levels in sciatic nerve and spinal cord concomitant with mechanical and heat hyperalgesia is also noted for CCI-induced neuropathic pain. Administration of UA significantly reduced the increased levels of pro-inflammatory cytokines and TOS. Further, reduced glutathione is also restored by UA. UA also showed in vitro NO and superoxide radical scavenging activity. UA has a potential in attenuating neuropathic pain behavior in CCI model which may possibly be attributed to its anti-inflammatory and antioxidant properties.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Constriction; Cytokines; Disease Models, Animal; Hyperalgesia; Inflammation; Male; Malondialdehyde; Neuralgia; Nitric Oxide; Oxidative Stress; Peroxidase; Protein Carbonylation; Rats; Sciatic Nerve; Spinal Cord; Superoxides; Triterpenes; Ursolic Acid

To investigate the effects of a defined bacterial consortium on trinitrobenzenesulfonic acid (TNBS)-induced colitis and intestinal dysbiosis in rats.. Rats with TNBS-induced colitis were treated with ceftriaxone and/or a mixture of ten bacterial strains isolated from mouse feces for continuous 24 days. Macroscopic and histopathological parameters in colonic tissue were compared, as were myeloperoxidase enzyme activity and cytokine levels. Patterns of intestinal microbiota were assessed by PCR-denaturing gradient gel electrophoresis, the abundance of selected microbial groups was evaluated by qPCR.. Transplantation of the bacterial consortium showed anti-inflammatory activity in the intestines of rats with TNBS-induced colitis and contributed to the rapid re-establishment of intestinal microbial equilibrium. A defined bacterial consortium may be a viable therapeutic option for the treatment inflammatory bowel disease.

Topics: Animals; Colitis; Colon; Cytokines; Disease Models, Animal; Dysbiosis; Fecal Microbiota Transplantation; Feces; Gastrointestinal Microbiome; Inflammatory Bowel Diseases; Intestines; Mice; Microbial Consortia; Peroxidase; Rats; Trinitrobenzenesulfonic Acid

Amorphophallus paeoniifolius (Dennst.) Nicolson (Family- Araceae) is a crop of south East Asian origin. In India, its tuber is widely used in ethnomedicinal practices by different tribes for the treatment of piles (hemorrhoids).. The present study evaluated the effect of methanolic and aqueous extract of Amorphophallus paeoniifolius tuber on croton oil induced hemorrhoids in rats.. The methanolic extract was standardized with the major phenolic compound, betulinic acid, by HPLC. The hemorrhoids were induced by applying 6% croton oil preparation in the ano-rectal region. Rats were orally administered methanolic and aqueous extract at doses of 250 and 500mg/kg, each for 7 days. Pilex (200mg/kg) was used as reference anti-hemorrhoidal drug. Hemorrhoids were assessed on eighth day by measuring hemorrhoidal and biochemical parameters along with histology of ano-rectal tissue.. Croton oil application caused induction of hemorrhoids as indicated by significant (p<0.001) increase in plasma exudation of Evans blue in ano-rectal tissue, macroscopic severity score and ano-rectal coefficient as compared to normal rats. It significantly (p<0.001) elevated lactate dehydrogenase and cytokines (TNF-α and IL-6) levels in serum and increased myeloperoxidase activity and lipid peroxidation in ano-rectal tissue along with marked histological damage as compared to normal rats. Treatment with tuber extracts and pilex significantly (p<0.05-p<0.001) ameliorated Evans blue exudation, hemorrhoidal parameters and other biochemical parameters with attenuation of tissue damage compared to hemorrhoid control rats. The results indicate that tuber extracts exhibited curative action on hemorrhoids. The aqueous extract showed more pronounced effect than methanolic extract. The effects may be attributed to anti-inflammatory and antioxidant properties.. Results indicate that tuber of Amorphophallus paeoniifolius exhibited curative action on hemorrhoids through anti-inflammatory and antioxidant properties. The study validates the ethnomedicinal use of tuber in hemorrhoids and implicates its therapeutic potential as an anti-hemorrhoidal agent.

Topics: Amorphophallus; Anal Canal; Animals; Anti-Inflammatory Agents; Antioxidants; Betulinic Acid; Biomarkers; Chromatography, High Pressure Liquid; Croton Oil; Disease Models, Animal; Hemorrhoids; Inflammation Mediators; Interleukin-6; L-Lactate Dehydrogenase; Lipid Peroxidation; Male; Methanol; Pentacyclic Triterpenes; Peroxidase; Plant Extracts; Plant Tubers; Rats, Wistar; Rectum; Remission Induction; Severity of Illness Index; Solvents; Triterpenes; Tumor Necrosis Factor-alpha; Water

Chemotherapy-induced intestinal mucositis is characterized by pain and a pro-inflammatory tissue response. Rat models are frequently used in mucositis disease investigations yet little is known about the presence of pain in these animals, the ability of analgesics to ameliorate the condition, or the effect that analgesic administration may have on study outcomes. This study investigated different classes of analgesics with the aim of determining their analgesic effects and impact on research outcomes of interest in a rat model of mucositis. Female DA rats were allocated to 8 groups to include saline and chemotherapy controls (n = 8). Analgesics included opioid derivatives (buprenorphine; 0.05mg/kg and tramadol 12.5mg/kg) and NSAID (carprofen; 15mg/kg) in combination with either saline or 5-Fluorouracil (5-FU; 150mg/kg). Research outcome measures included daily clinical parameters, pain score and gut histology. Myeloperoxidase assay was performed to determine gut inflammation. At the dosages employed, all agents had an analgesic effect based on behavioural pain scores. Jejunal myeloperoxidase activity was significantly reduced by buprenorphine and tramadol in comparison to 5-FU control animals (53%, p = 0.0004 and 58%, p = 0.0001). Carprofen had no ameliorating effect on myeloperoxidase levels. None of the agents reduced the histological damage caused by 5-FU administration although tramadol tended to increase villus length even when administered to healthy animals. These data provide evidence that carprofen offers potential as an analgesic in this animal model due to its pain-relieving efficacy and minimal effect on measured parameters. This study also supports further investigation into the mechanism and utility of opioid agents in the treatment of chemotherapy-induced mucositis.

Topics: Analgesics; Animals; Antineoplastic Agents; Behavior, Animal; Disease Models, Animal; Female; Intestinal Mucosa; Mucositis; Peroxidase; Rats

This study aimed to investigate the role of ligustrazine on apoptosis and inflammatory reaction in acute pancreatitis.. Rats and acinar cells were treated with caerulein to induce acute pancreatitis models. Cell models were treated with saline, p38 inhibitor, Erk inhibitor and ligustrazine. Then, the levels of TNF-α, IL-1β and IL-6 were determined by ELISA assay, the protein levels of p38, Erk1/2, p53 and cleaved caspase3 were determined by western blotting, and apoptosis were measured by flow cytometry. Rat models were treated with saline and ligustrazine. Plasma amylase and pancreatic myeloperoxidase activity and the levels of TNF-α, IL-1β and IL-6 in rats were determined. The protein levels of p38, Erk1/2, p53 and cleaved caspase3 in pancreas tissues were determined by western blotting, and pancreas tissues were also performed TUNEL staining to observe apoptosis status.. Ligustrazine downregulated the levels of TNF-α, IL-1β, IL-6. The protein levels of p38 and Erk were reduced by p38 inhibitor, Erk inhibitor and ligustrazine, while the levels of p53 and cleaved caspase 3 were upregulated. Apoptosis of AP acinar cells and cells in AP rat models was promoted after treated with ligustrazine. Plasma amylase and pancreatic myeloperoxidase activity in AP rat models were reduced by ligustrazine.. Ligustrazine alleviates acute pancreatitis by accelerating acinar cell apoptosis at early phase via the suppression on p38 and Erk MAPK pathways. It is capable of attenuating the severity of acute pancreatitis and may have a therapeutic effect on patients with acute pancreatitis.

Topics: Acinar Cells; Acute Disease; Amylases; Animals; Apoptosis; Cell Line; Cytokines; Disease Models, Animal; Down-Regulation; Inflammation Mediators; MAP Kinase Signaling System; p38 Mitogen-Activated Protein Kinases; Pancreatitis; Peroxidase; Phosphorylation; Pyrazines; Rats, Sprague-Dawley

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by the development of autoantibodies that recognize components of the cell nucleus. The vast majority of lupus research has focused on either the contributions of immune cell dysfunction or the genetics of the disease. Because granulocytes isolated from human SLE patients had alterations in neutrophil nuclear morphology that resembled the Pelger-Huet anomaly, and had prominent mis-splicing of mRNA encoding the nuclear membrane protein lamin B receptor (LBR), consistent with their Pelger-Huet-like nuclear morphology, we used a novel mouse model system to test the hypothesis that a disruption in the structure of the nucleus itself also contributes to the development of lupus autoimmunity. The lupus-prone mouse strain New Zealand White (NZW) was crossed with c57Bl/6 mice harboring a heterozygous autosomal dominant mutation in Lbr (B6.Lbr(ic/+)), and the (NZW×B6.Lbr(ic))F1 offspring were evaluated for induction of lupus autoimmunity. Only female (NZW×B6.Lbr(ic))F1 mice developed lupus autoimmunity, which included splenomegaly, kidney damage and autoantibodies. Kidney damage was accompanied by immune complex deposition, and perivascular and tubule infiltration of mononuclear cells. The titers of anti-chromatin antibodies exceeded those of aged female MRL-Fas(lpr) mice, and were predominantly of the IgG2 subclasses. The anti-nuclear antibody staining profile of female (NZW×B6.Lbr(ic))F1 sera was complex, and consisted of an anti-nuclear membrane reactivity that colocalized with the A-type lamina, in combination with a homogeneous pattern that was related to the recognition of histones with covalent modifications that are associated with gene activation. An anti-neutrophil IgM recognizing calreticulin, but not myeloperoxidase (MPO) or proteinase 3 (PR3), was also identified. Thus, alterations in nuclear structure contribute to lupus autoimmunity when expressed in the context of a lupus-prone genetic background, suggesting a mechanism for the development of lupus autoimmunity in genetically predisposed individuals that is induced by the disruption of nuclear architecture.

Topics: Animals; Autoantibodies; Autoantigens; Autoimmunity; Calreticulin; Cell Nucleus; Cell Separation; Crosses, Genetic; Disease Models, Animal; Female; Granulocytes; Histones; Humans; Immunoglobulin M; Kidney; Lamin B Receptor; Lamin Type A; Lupus Erythematosus, Systemic; Male; Mice, Inbred C57BL; Myeloblastin; Peroxidase; Receptors, Cytoplasmic and Nuclear; RNA Splicing; RNA, Messenger; Splenomegaly; Transcriptional Activation

Dysbiosis of intestinal microbiota and hyperactive immune responses seem to be crucial for the uncontrolled inflammation in inflammatory bowel diseases (IBD). Modulation of the microbiome and immune stimulation of the intestinal epithelium were suggested as therapeutic approaches. In this study, live attenuated and dead bacterial cells of Salmonella Typhimurium SL7207 - a widely used bacterial vector for gene therapy were administered in DSS-induced colitis in mice. C57BL/6 mice were divided into four groups. The first group received pure water (CTRL). The other three groups received 2% dextran sulphate sodium (DSS) to induce colitis. Two DSS groups were treated with live attenuated (DSS live) or inactivated (DSS dead) Salmonella by gastric gavage. Intake of 2% DSS caused weight loss in all DSS groups compared to control mice with some improvement in DSS live group on the last day of the experiment. Significantly longer colon and improved stool consistency were reported in DSS live group, but not DSS dead group, when compared with DSS. Significant enlargement of spleens was observed only in DSS and DSS dead groups compared to control. Significant differences in stool consistency, colon length and spleen enlargement were observed between DSS live and DSS dead groups with beneficial effects of live bacteria. Interestingly, significant decrease in myeloperoxidase activity was detected in both, DSS live and DSS dead groups compared to the DSS group. On the basis of these results, progression of colitis seems to be beneficially influenced not only by live attenuated but to some extent also by inactivated Salmonella Typhimurium SL7207. Our results provide evidence that Salmonella-based gene therapy vectors are able to positively alter gut homeostasis during DSS-induced colitis.. Restoration of gut homeostasis has a great importance in IBD. Here, we tested the nonspecific effect of the strain Salmonella Typhimurium SL7207 on the course of colitis to find out whether the potential effect would be mediated by activity of live bacterial cells or by bacterial structures that are also present in dead bacteria. Live bacterial therapy of colitis showed a beneficial effect on clinical signs as well as on macroscopic and inflammatory markers of colitis. On the other hand, therapy with dead bacteria showed inconsistent effects, negative in most clinical outcomes, positive especially in myeloperoxidase activity. Our data indicate that the beneficial effect of bacterial gene therapy vectors carrying therapeutic genes might be, at least partially, caused by the bacterial vector instead of the therapeutic gene.

Topics: Animals; Colon; Dextran Sulfate; Disease Models, Animal; Dysbiosis; Gastrointestinal Microbiome; Genetic Therapy; Inflammatory Bowel Diseases; Intestinal Mucosa; Male; Mice; Mice, Inbred C57BL; Peroxidase; Salmonella typhimurium; Spleen

Inflammatory bowel disease (IBD) is a complex class of immune disorders. Unfortunately, a treatment for total remission has not yet been found, while the use of natural product-based therapies has emerged as a promising intervention. The present study was aimed to investigate the anti-inflammatory effects of the algal meroterpene 11-hydroxy-1'-O-methylamentadione (AMT-E) in a murine model of dextran sodium sulphate (DSS)-induced colitis. AMT-E was orally administered daily (1, 10, and 20 mg/kg animal) to DSS treated mice (3% w/v) for 7 days. AMT-E prevented body weight loss and colon shortening and effectively attenuated the extent of the colonic damage. Similarly, AMT-E increased mucus production and reduced myeloperoxidase activity (marker for anti-inflammatory activity). Moreover, the algal meroterpene decreased the tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-10 levels, and caused a significant reduction of the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Our results demonstrate the protective effects of AMT-E on experimental colitis, provide an insight of the underlying mechanisms of this compound, and suggest that this class of marine natural products might be an interesting candidate for further studies on the prevention/treatment of IBD.

Topics: Animals; Anti-Inflammatory Agents; Colitis, Ulcerative; Colon; Cyclooxygenase 2; Dextran Sulfate; Disease Models, Animal; Down-Regulation; Female; Interleukin-10; Interleukin-1beta; Intestinal Mucosa; Mice; Mice, Inbred C57BL; Nitric Oxide Synthase Type II; Peroxidase; Phaeophyceae; Terpenes; Tumor Necrosis Factor-alpha; Weight Loss

To investigate the effect of Kineret® on ischemia reperfusion (IR) injury in rat ovaries.. Rats were divided into four groups: ovarian IR (IRG); 50 mg/kg Kineret® + ovarian IR (KIR-50); 100 mg/kg Kineret® + ovarian IR (KIR-100); and sham operation (SOC). KIR-50 (n = 10) and KIR-100 (n = 10) groups received an intraperitoneal injection of Kineret® at doses of 50 and 100 mg/kg, respectively. IRG and SOC (n = 10) rat groups were given distilled water as solvent using the same method. The results were compared between the groups.. In rats in which IR occurred, oxidant parameters, such as malondialdehyde (MDA) and myeloperoxidase (MPO), were increased, the level of proinflammatory interleukin 1 beta (IL-1β) was elevated and total glutathione (tGSH) as an antioxidant was decreased in the ovarian tissues. Administration of Kineret® at a dose of 100 mg/kg inhibited the increase of MDA, MOP and IL-1β and a decrease in tGSH caused by IR more significantly than administration of Kineret® at a dose of 50 mg/kg. In addition, 100 mg/kg Kineret® significantly decreased severe hemorrhage, degeneration and inflammatory signs in the follicular cells, caused by IR. Kineret® at 100 mg/kg markedly ameliorated increased apoptosis in ovarian tissue with IR more significantly than 50 mg/kg kineret.. Our findings indicate that Kineret® might be useful in clinical practice for the treatment of damage that may occur as a result of ovarian torsion.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Caspase 3; Disease Models, Animal; Female; Gene Expression; Glutathione; Interleukin 1 Receptor Antagonist Protein; Interleukin-1beta; Malondialdehyde; Ovary; Peroxidase; Rats; Rats, Wistar; Reperfusion Injury

Short-term cigarette smoke (CS) exposure does not cause emphysema; however, some pathogenesis hallmarks are maintained, such as oxidative stress and inflammation. This study aimed to test the efficacy of eucalyptol against short-term CS exposure in mice. C57BL/6 mice were exposed to 12 cigarettes per day for 5 days (CS group). The control group was exposed to sham smoking. Three groups of mice exposed to CS were treated to different concentrations of eucalyptol (1, 3, 10 mg/mL) via inhalation (15 min/daily) for 5 days (CS + 1 mg, CS+3 mg and CS+10 mg groups). CS group and control one were sham treated by using vehicle. The anti-inflammatory and antioxidant effects of eucalyptol were assessed 24 h after the last CS exposure by determining cell counts, measuring cytokine production and performing western blotting, biochemical and histological analyses. Eucalyptol at 3 mg/mL and 10 mg/mL concentrations reduced total leukocyte numbers compared to the CS group (p < 0.001), while macrophage numbers were reduced at all concentrations (p < 0.001). Myeloperoxidase, used as neutrophil marker, was reduced at 3 mg/mL (p < 0.01) and 10 mg/mL (p < 0.05) concentrations. Eucalyptol reduced cytokine levels (IL-1β, IL-6 and KC) at 3 mg/mL and 10 mg/mL concentrations (p < 0.01) compared to the CS group. The exception was TNF-α, with a reduction only at 10 mg/mL of eucalyptol compared to the CS group (p < 0.001). Additionally, eucalyptol decreased the NF-kappa B p65 subunit at 3 mg/mL and 10 mg/mL compared to the CS group (p < 0.01). Regarding oxidative stress, eucalyptol reduced reactive oxygen species, superoxide dismutase, catalase and malondialdehyde, mainly at 3 mg/mL and 10 mg/mL concentrations compared to the CS group (at least p < 0.05), parallel to reduced glutathione levels at the same concentrations (p < 0.001). Furthermore, treatment with eucalyptol attenuated CS-induced histopathological alterations. Collectively, these results indicate that eucalyptol acts through a mechanism involving decreased oxidative stress, inflammation and the NF-kappa B p65 subunit against CS-induced acute lung inflammation. Thus, eucalyptol may be a potential agent in the treatment of pulmonary inflammation caused by CS in humans.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Cyclohexanols; Disease Models, Animal; Dose-Response Relationship, Drug; Eucalyptol; Inflammation; Macrophages; Male; Mice; Mice, Inbred C57BL; Monoterpenes; Neutrophils; Oxidative Stress; Peroxidase; Pneumonia; Reactive Oxygen Species; Smoke; Smoking; Transcription Factor RelA; Tumor Necrosis Factor-alpha

Partially hydrolysed guar gum (PHGG), a water-soluble dietary fibre produced by the controlled partial enzymatic hydrolysis of guar gum beans, has various physiological roles. This study aimed to elucidate the beneficial effects of PHGG on colonic mucosal damage in a murine 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis model. Acute colitis was induced in male C57BL/6 mice with TNBS after 2 weeks of pre-feeding with PHGG (5 %). The colonic mucosal inflammation was evaluated using macroscopic damage scores, and neutrophil infiltration was assessed by measuring tissue-associated myeloperoxidase (MPO) activity in the colonic mucosa. TNF-α expression in the colonic mucosa was measured by ELISA and real-time PCR. Moreover, the intestinal microbiota and production of SCFA were assessed by real-time PCR and HPLC, respectively. Colonic damage due to TNBS administration was significantly ameliorated by PHGG treatment. Furthermore, PHGG significantly inhibited increases in MPO activity and TNF-α protein and mRNA expression in the colonic mucosa in TNBS-induced colitis. On analysis of intestinal microbiota, we found that the concentration of the Clostridium coccoides group (Clostridium cluster XIVa), the Clostridium leptum subgroup (Clostridium cluster IV) and the Bacteroides fragilis group had significantly increased in PHGG-fed mice. On analysis of SCFA, we found that the caecal content of acetic acid, propionic acid and butyric acid had significantly increased in PHGG-fed mice. Together, these results suggest that chronic ingestion of PHGG prevents the development of TNBS-induced colitis in mice by modulating the intestinal microbiota and SCFA, which may be significant in the development of therapeutics for inflammatory bowel disease.

Topics: Animals; Colitis; Colon; Disease Models, Animal; Fatty Acids, Volatile; Galactans; Gastrointestinal Microbiome; Hydrolysis; Inflammatory Bowel Diseases; Intestinal Mucosa; Intestines; Male; Mannans; Mice; Mice, Inbred C57BL; Peroxidase; Plant Gums; RNA, Messenger; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

Duchenne Muscular Dystrophy (DMD) is a fatal skeletal muscle wasting disease presenting with excessive myofibre necrosis and increased inflammation and oxidative stress. In the mdx mouse model of DMD, homeostasis of the amino acid taurine is altered, and taurine administration drastically decreases muscle necrosis, dystropathology, inflammation and protein thiol oxidation. Since the severe pathology of the Golden Retriever Muscular Dystrophy (GRMD) dog model more closely resembles the human DMD condition, we aimed to assess the generation of oxidants by inflammatory cells and taurine metabolism in this species. In muscles of 8 month GRMD dogs there was an increase in the content of neutrophils and macrophages, and an associated increase in elevated myeloperoxidase, a protein secreted by neutrophils that catalyses production of the highly reactive hypochlorous acid (HOCl). There was also increased chlorination of tyrosines, a marker of HOCl generation, increased thiol oxidation of many proteins and irreversible oxidative protein damage. Taurine, which functions as an antioxidant by trapping HOCl, was reduced in GRMD plasma; however taurine was increased in GRMD muscle tissue, potentially due to increased muscle taurine transport and synthesis. These data indicate a role for HOCl generated by neutrophils in the severe dystropathology of GRMD dogs, which may be exacerbated by decreased availability of taurine in the blood. These novel data support continued research into the precise roles of oxidative stress and taurine in DMD and emphasise the value of the GRMD dogs as a suitable pre-clinical model for testing taurine as a therapeutic intervention for DMD boys.

Topics: Animals; Biomarkers; Disease Models, Animal; Dogs; Inflammation; Macrophages; Male; Muscle Proteins; Muscle, Skeletal; Muscular Dystrophy, Duchenne; Neutrophils; Oxidation-Reduction; Oxidative Stress; Peroxidase; Tyrosine

Sodium hydrosulfide (NaHS) has presented antihypertensive and antioxidant effects and may reduce circulating soluble fms-like tyrosine kinase-1 (sFlt-1). We examined whether NaHS prevents maternal and fetal detrimental changes in a model of hypertension in pregnancy induced by N(G)-nitro-L-arginine methyl ester (L-NAME). Forty pregnant rats were divided into four groups (n = 10 per group): Norm-Preg, Preg + NaHS, HTN-Preg, or HTN-Preg + NaHS. Systolic blood pressure (SBP), number of viable fetuses, litter size, pups, and placentae weights were recorded. Circulating plasma sFlt-1, vascular endothelial growth factor (VEGF), myeloperoxidase (MPO), trolox equivalent antioxidant capacity (TEAC) levels, and biochemical determinants of nitric oxide (NO) formation were assessed. SBP values were elevated in the HTN-Preg group on gestational days 16, 18, and 20. However, HTN-Preg + NaHS group presented lower SBP values on days 18 and 20. Lower number of viable fetuses and litter size were found only in HTN-Preg group compared to other. Reductions in placental weight were found in HTN-Preg and HTN-Preg + NaHS groups. Increases in fetal weight were found only in Preg + NaHS group. Increases in circulating sFlt-1 and VEGF levels were observed only in HTN-Preg group compared to other. Higher MPO and lower TEAC plasma levels were found in HTN-Preg + NaHS and HTN-Preg groups. NO was diminished in HTN-Preg animals, and NaHS treatment increased NO levels only in hypertensive pregnant animals. Treatment with NaHS prevents hypertension in pregnancy and concomitantly reduces circulating plasma sFlt-1 and VEGF levels; this correlates with improved litter size with more viable fetuses and increase in NO levels. However, these beneficial effects presented no relation with oxidative stress.

Topics: Animals; Antihypertensive Agents; Biomarkers; Blood Pressure; Disease Models, Animal; Down-Regulation; Female; Fetal Viability; Fetal Weight; Gestational Age; Hypertension, Pregnancy-Induced; Litter Size; NG-Nitroarginine Methyl Ester; Nitric Oxide; Oxidative Stress; Peroxidase; Placentation; Pregnancy; Rats, Wistar; Sulfides; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1

Ischemia-induced chronic cerebral hypoperfusion (CCH) is associated with reduced cerebral blood flow and vascular dementia (VaD). Brain mitochondrial potassium (adenosine triphosphate-sensitive potassium [K. The method of 2-vessel occlusion (2VO) was used to induce CCH in mice. Cognitive impairment was assessed using Morris water maze. Serum nitrosative stress (nitrite/nitrate), brain cholinergic dysfunction (acetylcholinesterase [AChE] activity), brain oxidative stress (thiobarbituric acid reactive substances, glutathione [GSH], catalase [CAT], and superoxide dismutase [SOD]), inflammation (myeloperoxidase [MPO]), and infarct size (2,3,5-triphenyltetrazolium chloride staining) were assessed.. 2-vessels-occluded animals have shown significant cognitive impairment, serum nitrosative stress (reduced nitrite/nitrate), cholinergic dysfunction (increased brain AChE activity), and increased brain oxidative stress (reduction in GSH content and SOD and CAT activities with a significant increase in lipid peroxidation), along with a significant increase in MPO activity and infarct size. However, nicorandil treatment has significantly attenuated various CCH-induced behavioral and biochemical impairments.. It may be said that 2VO provoked CCH leading to VaD, which was attenuated by the treatment of nicorandil. So, modulation of K

Topics: Acetylcholinesterase; Animals; Behavior, Animal; Brain; Brain Ischemia; Catalase; Cerebrovascular Circulation; Cognition; Dementia, Vascular; Disease Models, Animal; Dose-Response Relationship, Drug; Glutathione; GPI-Linked Proteins; Inflammation Mediators; KATP Channels; Male; Maze Learning; Mice; Neuroprotective Agents; Nicorandil; Oxidative Stress; Peroxidase; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Time Factors

(-)-Linalool is a monoterpene constituent of many essential oils. This particular monoterpene has both anti-inflammatory and antimicrobial activity. Moreover, this compound has been shown to be antinociceptive. However, the poor chemical stability and short half-life prevents the clinical application of (-)-linalool and many other essential oils. Important to the topic of this study, β-cyclodextrin (β-CD) has been used to increase the solubility, stability, and pharmacological effects of numerous lipophilic compounds in vivo. In this study, the gastroprotective activities of (-)-linalool (LIN) and linalool incorporated into inclusion complex containing β-cyclodextrin (LIN-βCD) were evaluated using models of acute and chronic gastric ulcers in rodents. LIN and LIN-βCD showed strong gastroprotective activity (p < 0.001). The LIN-βCD complex revealed that the gastroprotective effect was significantly improved compared with LIN uncomplexed, suggesting that this improvement is related to increased solubility and stability. Taking together the potentiation of the antioxidant profile of this monoterpene, our results suggest that β-CD may represent an important tool for improved gastroprotective activity of (-)-linalool and other water-insoluble compounds.

Topics: Acetic Acid; Acyclic Monoterpenes; Animals; Anti-Ulcer Agents; Antioxidants; beta-Cyclodextrins; Cytoprotection; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Stability; Drug Therapy, Combination; Ethanol; Female; Gastric Mucosa; Lipid Peroxidation; Magnoliopsida; Male; Mice; Monoterpenes; Oils, Volatile; Peroxidase; Phytotherapy; Plant Oils; Plants, Medicinal; Rats, Wistar; Solubility; Stomach; Stomach Ulcer; Sulfhydryl Compounds

Mahaenggamseok-tang (MHGST), an herbal formula in traditional Asian medicine, has been used to treat patients with various pulmonary diseases including common cold and influenza. However, the potential therapeutic effect of MHGST on acute lung injury (ALI), a leading cause of death worldwide, and the anti-inflammatory mechanisms of MHGST remained less understood.. The methanol extract of MHGST was prepared and fingerprinted by HPLC. For the induction of ALI, C57BL/6 mice (n=5/group) received a single intraperitoneal (i.p.) injection of LPS. Referring to the dose for patients, two different amounts of MHGST were delivered in an aerosol to mouse lungs via trachea 2h after the i.p. LPS administration. Lung histology, bronchoalveolar lavage fluid, myeloperoxidase (MPO) activity, and the expression of inflammatory and Nrf2-dependent genes were analyzed to determine the effect of MHGST on lung inflammation. For mechanistic studies, western blotting and semi-quantitative RT-PCR were conducted using RAW 264.7 cells.. When administered 2h after the onset of ALI, MHGST relieved lung pathology characteristic to ALI, with decreases of neutrophil infiltration and MPO activity. While suppressing the expression of inflammatory genes, MHGST increased the expression of Nrf2-dependent genes in ALI mouse lungs. Concordantly, MHGST activated Nrf2 activity while suppressing NF-κB in RAW 264.7 cells.. MHGST suppressed neutrophilic lung inflammation, a hallmark of ALI, which was associated with the activation of anti-inflammatory Nrf2 and the suppression of pro-inflammatory NF-κB. Our results suggest that MHGST has a therapeutic potential against ALI.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Dose-Response Relationship, Drug; Down-Regulation; Drugs, Chinese Herbal; Inflammation Mediators; Lipopolysaccharides; Lung; Macrophages; Mice; Mice, Inbred C57BL; Neutrophil Infiltration; NF-E2-Related Factor 2; NF-kappa B; Peroxidase; Pneumonia; RAW 264.7 Cells; Signal Transduction

Hecogenin is a steroidal sapogenin plays important role in treatment of variety of inflammatory diseases. We have investigated the anti-inflammatory effects of Hecogenin (50 µg/animal) (HG), Fluticasone (50 µg/animal) (FC) and Hecogenin+Fluticasone (HG+FC) combination (25 µg/animal, each) on various inflammatory models. The anti-inflammatory effect of HG, FC and HG+FC combination was studied on % inhibition of dry weight of granuloma tissue, Δ ear weight, myeloperoxidase assay, serum pro-inflammatory cytokines, colon weight to length ratio, macroscopic lesions, adhesion score, diarrhoea score and histopathological analysis of ear and colon tissue on Cotton pellets induced granuloma in rats, Croton oil induced ear edema in mice and TNBS induced granuloma in rats. Topical administration of HG and its combination with FC showed significant decrease (p<0.001) in the % inhibition of dry weight of granuloma tissue, Δ ear weight, myeloperoxidase level, serum pro-inflammatory cytokines levels, colon weigh to length ratio as compared with Cotton pellets treated with acetone groups and Croton oil treated animals. Further histopathological analysis of ear tissue showed significant decrease in dermal thickness and epidermal hyperplasia and colon tissue showed reduction of edema, infiltration of inflammatory cells and normalization of crypt structure compared to DC animals. Thus, the findings of present study suggest the possible role of HG in the treatment of inflammation by reducing the dose of FC in combination with HG.

Topics: Animals; Anti-Inflammatory Agents; Body Weight; Colon; Cytokines; Disease Models, Animal; Fluticasone; Inflammation; Mice; Peroxidase; Rats; Rats, Wistar; Sapogenins

This study was undertaken to verify if two-weeks treatment of lipoic acid (LA) influence colon damage and pro-inflammatory cytokine synthesis during DSS-induced acute colitis. Moreover, as LA has anti-oxidative properties, we analyzed its influence on the level of antioxidative enzymes, HO-1 and eNOS, and their regulator- caveolin-1.. LA was administrated to male C57/BALBc mice at a dose of 25 or 50mg/kg/day (i.p.) for 21days. Acute colitis was induced by administration of 4% DSS (w/v) in drinking water for 5days, followed by 2days of normal drinking water. Mice in LA+DSS groups were treated with LA (25 or 50mg/kg/day; i.p.) starting 14days prior to 4% DSS. Control group received saline for 21days. In the colon tissue we measured myeloperoxidase activity (MPO), IL-1β, IL-6, IL-17A, IL-23 (ELISA method), and tissue level of cav-1, phospho-eNOS, total eNOS and HO-1 (Western blot).. Administration of DSS significantly increased total colon damage (p<0.001), myeloperoxidase (MPO) activity (p<0.05) and pro-inflammatory IL-6 (p<0.05). There was also a tendency towards higher IL-1β, IL-17A, and IL-23 in the colon. LA alone did not influence total colon damage, MPO activity, and pro-inflammatory cytokines concentration compared to control (p<0.05). Notably, mice treated with LA and DSS had significantly decreased total colon damage score (p<0.001), despite augmented colon MPO activity (p<0.01), but similar (IL-17A) or even significantly higher level (IL-1β, IL-23) as compared to the DSS group (p<0.05). IL-6 was insignificantly decreased after LA treatment at a dose of 50mg/kg. In acute colitis there was a tendency towards an increase in cav-1 and HO-1 and a decrease p-eNOS/total eNOS ratio. Moreover, the LA+DSS groups had higher expression of HO-1 and p-eNOS/total eNOS (p<0.05) compared to the DSS group, and a tendency towards higher cav-1 level. The changes did not depend on LA dose.. Our study indicated that LA, at lower doses, may influence cav-1-regulated antioxidative enzyme levels (HO-1 and p-eNOS/total eNOS) despite an increase in colon pro-inflammatory cytokine levels during acute colitis. Hence, LA treatment may be - to some extent - beneficial in attenuation of acute colitis.

Topics: Acute Disease; Animals; Antioxidants; Caveolin 1; Colitis, Ulcerative; Colon; Cytokines; Dextran Sulfate; Disease Models, Animal; Inflammation Mediators; Male; Mice, Inbred C57BL; Peroxidase; Thioctic Acid

Visceral hypersensitivity (VH) is a common condition in many gastrointestinal disorders such as inflammatory bowel diseases (IBDs) in human and animals. Most studies often induce Crohn's disease/colitis to investigate VH in small experimental animals. Although farm animals commonly suffer from IBDs, their VH has not been investigated so far. Because goats can suffer from Johne's disease, a naturally occurring Crohn's-like disease, they may be suitable to be used for studying the mechanism underlying VH in common intestinal disorders of large animals. In the present study, 60 healthy goats of either sex were equally divided into a 2, 4, 6-trinitrobenzenesulfonic acid (TNBS) group and saline group. A volume of 1.2 ml of TNBS-ethanol solution (30 mg TNBS in 40 % ethanol) or an equal volume of isotonic saline was injected into the wall of the terminal ileum through laparotomy. The severity of the developing ileitis was determined according to macro- and microscopic pathologic scores and the levels of myeloperoxidase, interleukin-1β, interleukin-6 and tumor necrosis factor-α, and VH was evaluated with visceromotor responses (VMR) to colorectal distension on days 3, 7, 14, 21 and 28. VMRs were assessed with a continuous ramp distention mode with 6 s for each pressure (20, 40, 60, 80 and 100 mmHg).. Compared to the saline group, the TNBS-treated goats showed apparent transmural pathological changes and a significant increase (P < 0.05) in macroscopic and microscopic change scores, and levels of myeloperoxidase, interleukin-1β, interleukin-6 and tumor necrosis factor-α in the ileum, and VMR to colorectal distension. The goats exhibited apparent ileitis at days 3 to 21, and VH at days 7 to 28 following TNBS treatment.. This experiment successfully established a reproducible ileitis and VH with administration of TNBS-ethanol solution in the ileal wall of goats. This model is useful for studying the pathogenesis of the IBD and the mechanism underlying VH, and for evaluating the efficacy of new therapeutic regimens.

Topics: Animals; Cytokines; Disease Models, Animal; Ethanol; Female; Goat Diseases; Goats; Hypersensitivity; Ileitis; Ileum; Inflammatory Bowel Diseases; Male; Peroxidase; Trinitrobenzenesulfonic Acid; Viscera

RBCs undergo numerous changes during storage and stored RBCs may induce adverse effects, ultimately resulting in organ injury in transfusion recipients. We tested the hypothesis that the addition of SP to stored RBCs would improve the quality of the stored RBCs and mitigate liver injury after transfusion in a murine model. RBCs were harvested from C57BL/6J mice and stored for 14 days in CPDA-1 containing either a solution of SP in saline or saline alone. Haemolysis, the 24-hour posttransfusion recovery, the oxygen-carrying capacity, and the SOD activity of stored RBCs were evaluated. The plasma biochemistry, hepatic MDA level, MPO activity, IL-6, TNF-

Topics: Animals; Blood Preservation; Blood Transfusion; Disease Models, Animal; Erythrocytes; Hemoglobins; Humans; Interleukin-6; Lactic Acid; Liver Diseases; Male; Malondialdehyde; Mice; Mice, Inbred C57BL; Oxygen; Peroxidase; Pyruvic Acid; Sodium; Superoxide Dismutase; Time Factors; Tumor Necrosis Factor-alpha

Hydrogen sulfide (H2S) has been proposed to exert pro- as well as anti-inflammatory effects in various models of critical illness. In this study, we compared bacterial lipopolysaccharide (LPS)‑induced changes in inflammatory mediator production, indices of multiple organ injury and survival in wild‑type (WT) mice and in mice with reduced expression of one of the three H2S‑producing enzymes, cystathionine-γ-lyase (CSE), cystathionine-β-synthase (CBS) or 3-mercaptopyruvate sulfurtransferase (3MST). Mice were injected intraperitoneally (i.p.) with LPS (10 mg/kg). After 6 h, the animals were sacrificed, blood and organs were collected and the following parameters were evaluated: blood urea nitrogen (BUN) levels in blood, myeloperoxidase (MPO) and malondialdehyde (MDA) in the lung, cytokine levels in plasma and the expression of the three H2S‑producing enzymes (CBS, CSE and 3MST) in the spleen, lung, liver and kidney. LPS induced a tissue‑dependent upregulation of some of the H2S‑producing enzymes in WT mice (upregulation of CBS in the spleen, upregulation of 3MST in the liver and upregulation of CBS, CSE and 3MST in the lung). Moreover, LPS impaired glomerular function, as evidenced by increased BUN levels. Renal impairment was comparable in the CSE‑/‑ and Δ3MST mice after LPS challenge; however, it was attenuated in the CBS+/‑ mice. MPO levels (an index of neutrophil infiltration) and MDA levels (an index of oxidative stress) in lung homogenates were significantly increased in response to LPS; these effects were similar in the WT, CBS+/‑, CSE‑/‑ and Δ3MST mice; however, the MDA levels tended to be lower in the CBS+/‑ and CSE‑/‑ mice. LPS induced significant increases in the plasma levels of multiple cytokines [tumor necrosis factor (TNF)α, interleukin (IL)‑1β, IL‑6, IL‑10, IL‑12 and interferon (IFN)γ] in plasma; TNFα, IL‑10 and IL‑12 levels tended to be lower in all three groups of animals expressing lower levels of H2S‑producing enzymes. The survival rates after the LPS challenge did not show any significant differences between the four animal groups tested. Thus, the findings of this study indicate that a deficiency in 3MST does not significantly affect endotoxemia, while a deficiency in CBS or CSE slightly ameliorates the outcome of LPS-induced endotoxemia in vivo.

Topics: Animals; Biomarkers; Blood Urea Nitrogen; Cystathionine beta-Synthase; Cystathionine gamma-Lyase; Cytokines; Disease Models, Animal; Endotoxemia; Gene Expression; Gene Expression Regulation, Enzymologic; Hydrogen Sulfide; Lipopolysaccharides; Male; Malondialdehyde; Mice; Mice, Knockout; Nitric Oxide; Oxidative Stress; Peroxidase; Sulfurtransferases

Tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a pro-inflammatory cytokine, which is closely associated with the pathogenesis of various types of cutaneous vasculitis (CV).. To investigate the therapeutic effects of an anti-TWEAK monoclonal antibody (mAb) in a mouse model of cutaneous reverse passive Arthus (RPA) reaction.. Cutaneous RPA reaction was induced in BALB/c mice by intradermal injection of anti-ovalbumin IgG into the left ear followed immediately by intravenous injection of chicken ovalbumin. After treatment, haemorrhagic lesions in the mouse skin were scored semiquantitatively. The amount of extravasated fluorescein isothiocyanate (FITC)-labelled bovine serum albumin (BSA) in the ears was detected spectrophotometrically. Expression of myeloperoxidase (MPO) was detected by immunohistochemical staining, while mRNA expression of TNF-α and interleukin (IL)-6 in lesional skin was detected by real-time quantitative (q)PCR.. Our results indicated that anti-TWEAK mAb significantly attenuated the clinical and histopathological changes in immune complex (IC)-induced mice, and also reduced the semiquantitative haemorrhage score, FITC-labelled BSA extravasation and MPO activity. Real-time qPCR showed that anti-TWEAK mAb significantly inhibited mRNA expression of TNF-α and IL-6 in lesional skin from IC-induced mice.. These data suggest that anti-TWEAK mAb can block vascular damage and leucocyte infiltration in IC-induced mice. TWEAK might be a candidate immunotherapeutic medicine for suppression of IC-induced CV.

Topics: Animals; Antibodies, Monoclonal; Arthus Reaction; Cytokine TWEAK; Cytokines; Disease Models, Animal; Male; Mice; Mice, Inbred BALB C; Peroxidase; Real-Time Polymerase Chain Reaction; Skin Diseases

The inflammatory response is an important source of secondary damage to neuronal tissue in the spinal cord following spinal cord injury (SCI). Hyperbaric oxygen (HBO) therapy reduces inflammation and promotes the restoration of locomotor function following SCI, however, the mechanisms underlying this effect remain to be determined. The aim of the current study was to investigate the mechanisms by which HBO therapy promotes recovery in a rat model of SCI by measuring expression levels of receptor for advanced glycation end products (RAGE) and monocyte chemoattractant protein‑1 (MCP‑1) in spinal cord tissue. Experimental animals (n=90) were divided into three groups: Sham‑operated (SH), SCI (T‑10 laminectomy) and SCI + HBO. Each group was further divided into five subgroups (n=6) that were examined at 12 h, and at 1, 3, 7 and 14 days post‑injury. Recovery of locomotor function was evaluated using the Basso, Beattie and Bresnahan (BBB) scoring system. Neutrophil infiltration was analyzed using myeloperoxidase (MPO) activity assays. The expression of RAGE and MCP‑1 was measured by immunohistochemistry, reverse transcription‑quantitative polymerase chain reaction and western blotting. RAGE and MCP‑1 expression and MPO activity were higher in the SCI groups than in the SH groups at each time point. HBO therapy reduced RAGE and MCP‑1 expression and MPO activity compared with untreated, injured animals at early post‑injury stages. In addition, HBO therapy improved BBB scores at post‑operative day 7 and 14. HBO therapy was, therefore, demonstrated to relieve secondary inflammatory responses, potentially by inhibiting the expression of RAGE and MCP‑1, resulting in significant recovery of locomotor function. The results of the present study may, therefore, be useful in improving the clinical application of HBO therapy for patients with SCI.

Topics: Animals; Chemokine CCL2; Disease Models, Animal; Gene Expression; Hyperbaric Oxygenation; Immunohistochemistry; Motor Activity; Neutrophil Infiltration; Peroxidase; Rats; Receptor for Advanced Glycation End Products; Recovery of Function; Spinal Cord Injuries

This study was designed to determine possible protective effect of betaine treatment against oxidative injury in pulmonary tissue induced with thermal trauma.. Under ether anesthesia, shaved dorsum of Wistar albino rats was exposed to a 90°C water bath for 10 seconds to induce burn injury. Betaine was administered orally (250 mg/kg) for a period of 21 days before burn injury, and single dose of betaine was administered after thermal injury. Control group rats were exposed to 25°C water bath for 10 seconds. Upon conclusion of experiment, rats were decapitated and blood was collected for analysis of pro-inflammatory cytokines and lactate dehydrogenase (LDH) activity. Lung tissue samples were taken to determine malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO), and Na+/K+-ATPase activity, in addition to histological analysis.. Burn injury caused significant increase in both cytokine levels and LDH activity. In lung samples, raised MDA levels, MPO activity, and reduced GSH levels and Na+/K+-ATPase activity were found due to burn injury.. Treatment of rats with betaine significantly restored GSH level and Na+/K+-ATPase activity, and decreased MDA level and MPO activity. According to the findings of the present study, betaine significantly diminishes burn-induced damage in tissue.

Topics: Administration, Oral; Animals; Antioxidants; Betaine; Burns; Cytokines; Disease Models, Animal; Female; Glutathione; L-Lactate Dehydrogenase; Lung Injury; Male; Malondialdehyde; Peroxidase; Rats; Rats, Wistar; Sodium-Potassium-Exchanging ATPase

IL-17 has been shown to be involved in liver inflammatory disorders in both mice and humans. Baicalin (BA), a major compound extracted from traditional herb medicine (Scutellariae radix), has potent hepatoprotective properties. Previous study showed that BA inhibits IL-17-mediated lymphocyte adhesion and downregulates joint inflammation. The aim of this study is to investigate the role of IL-17 in the hepatoprotective effects of BA in an acetaminophen (APAP)-induced liver injury mouse model.. Eight weeks male C57BL/6 (B6) mice were used for this study. Mice received intraperitoneal hepatotoxic injection of APAP (300 mg/kg) and after 30 min of injection, the mice were treated with BA at a concentration of 30 mg/kg. After 16 h of treatment, mice were killed. Blood samples and liver tissues were harvested for analysis of liver injury parameters.. APAP overdose significantly increased the serum alanine transferase (ALT) levels, hepatic activities of myeloperoxidase (MPO), expression of cytokines (TNF-α, IL-6, and IL-17), and malondialdehyde (MDA) activity when compared with the control animals. BA treatment after APAP administration significantly attenuated the elevation of these parameters in APAP-induced liver injury mice. Furthermore, BA treatment could also decrease hepatic IL-17-producing γδT cells recruitment, which was induced after APAP overdose.. Our data suggested that baicalin treatment could effectively decrease APAP-induced liver injury in part through attenuation of hepatic IL-17 expression. These results indicate that baicalin is a potential hepatoprotective agent.

Topics: Acetaminophen; Alanine Transaminase; Animals; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Flavonoids; Flow Cytometry; Immunohistochemistry; Interleukin-17; Interleukin-6; Liver; Liver Regeneration; Male; Malondialdehyde; Mice, Inbred C57BL; Peroxidase; Receptors, Antigen, T-Cell, gamma-delta; Superoxide Dismutase; T-Lymphocytes; Tumor Necrosis Factor-alpha

Current biomarkers of renal disease in systemic vasculitis lack predictive value and are insensitive to early damage. To identify novel biomarkers of renal vasculitis flare, we analysed the longitudinal urinary metabolomic profile of a rat model of anti-neutrophil cytoplasmic antibody (ANCA) vasculitis. Wistar-Kyoto (WKY) rats were immunised with human myeloperoxidase (MPO). Urine was obtained at regular intervals for 181 days, after which relapse was induced by re-challenge with MPO. Urinary metabolites were assessed in an unbiased fashion using nuclear magnetic resonance (NMR) spectroscopy, and analysed using partial least squares discriminant analysis (PLS-DA) and partial least squares regression (PLS-R). At 56 days post-immunisation, we found that rats with vasculitis had a significantly different urinary metabolite profile than control animals; the observed PLS-DA clusters dissipated between 56 and 181 days, and re-emerged with relapse. The metabolites most altered in rats with active or relapsing vasculitis were trimethylamine N-oxide (TMAO), citrate and 2-oxoglutarate. Myo-inositol was also moderately predictive. The key urine metabolites identified in rats were confirmed in a large cohort of patients using liquid chromatography-mass spectrometry (LC-MS). Hypocitraturia and elevated urinary myo-inositol remained associated with active disease, with the urine myo-inositol:citrate ratio being tightly correlated with active renal vasculitis.

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Citric Acid; Disease Models, Animal; Female; Humans; Immunization; Ketoglutaric Acids; Kidney Diseases; Least-Squares Analysis; Male; Metabolomics; Methylamines; Peroxidase; Rats; Rats, Inbred WKY; Recurrence

To investigate the anti-inflammatory effect and the possible mechanisms of an agonist of cannabinoid (CB) receptors, WIN55-212-2 (WIN55), in mice with experimental colitis, so as to supply experimental evidence for its clinical use in future.. We established the colitis model in C57BL/6 mice by replacing the animals' water supply with 4% dextran sulfate sodium (DSS) for 7 consecutive days. A colitis scoring system was used to evaluate the severity of colon local lesion. The plasma levels of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), and the myeloperoxidase (MPO) activity in colon tissue were measured. The expressions of cannabinoid receptors, claudin-1 protein, p38 mitogen-activated protein kinase (p38MAPK) and its phosphorylated form (p-p38) in colon tissue were determined by immunohistochemistry and Western blot. In addition, the effect of SB203580 (SB), an inhibitor of p38, was investigated in parallel experiments, and the data were compared with those from intervention groups of WIN55 and SB alone or used together.. The results demonstrated that WIN55 or SB treatment alone or together improved the pathological changes in mice with DSS colitis, decreased the plasma levels of TNF-α, and IL-6, and MPO activity in colon. The enhanced expression of claudin-1 and the inhibited expression of p-p38 in colon tissues were found in the WIN55-treated group. Besides, the expression of CB1 and CB2 receptors was enhanced in the colon after the induction of DSS colitis, but reduced when p38MAPK was inhibited.. These results confirmed the anti-inflammatory effect and protective role of WIN55 on the mice with experimental colitis, and revealed that this agent exercises its action at least partially by inhibiting p38MAPK. Furthermore, the results showed that SB203580, affected the expression of CB1 and CB2 receptors in the mouse colon, suggesting a close linkage and cross-talk between the p38MAPK signaling pathway and the endogenous CB system.

Topics: Animals; Anti-Inflammatory Agents; Benzoxazines; Cannabinoid Receptor Agonists; Colitis; Colon; Dextran Sulfate; Disease Models, Animal; Female; Imidazoles; Interleukin-6; Male; Mice, Inbred C57BL; Morpholines; Naphthalenes; p38 Mitogen-Activated Protein Kinases; Peroxidase; Protein Kinase Inhibitors; Pyridines; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Signal Transduction; Tumor Necrosis Factor-alpha

Acute pancreatitis (AP) is an inflammatory disorder that can affect adjacent and/or remote organs. Some evidence indicates that the production of reactive oxygen species is able to induce AP. Protein carbonyl (PC) derivatives, which can also be generated through oxidative cleavage mechanisms, have been implicated in several diseases, but there is little or no information on this biomarker in AP. We investigated the association between some inflammatory mediators and PC, with the severity of ischemia-reperfusion AP. Wistar rats (n = 56) were randomly assigned in the following groups : control; sham, 15- or 180-min clamping of splenic artery, with 24 or 72 h of follow-up. The relationships between serum level of PC and thiobarbituric acid reactive species (TBARS) to myeloperoxidase (MPO) activity in tissue homogenates and to cytokines in culture supernatants of pancreatic samples were analyzed. MPO activity was related to the histology scores and increased in all clamping groups. Tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1β), and interleukin-6 were higher in the 180-min groups. Significant correlations were found between MPO activity and the concentrations of TNF-α and IL-1β. PC levels increased in the 15-min to 24-h group. TBARS levels were not altered substantially. MPO activity and TNF-α and IL-1β concentrations in pancreatic tissue are correlated with AP severity. Serum levels of PC appear to begin to rise early in the course of the ischemia-reperfusion AP and are no longer detected at later stages in the absence of severe pancreatitis. These data suggest that PC can be an efficient tool for the diagnosis of early stages of AP.

Topics: Animals; Biomarkers; Cytokines; Disease Models, Animal; Female; Pancreatitis, Acute Necrotizing; Peroxidase; Protein Carbonylation; Rats, Wistar; Reperfusion Injury

Among the several disorders induced by sepsis, acute kidney injury (AKI) represents the most important economic burden problem that is associated with high mortality and morbidity rates. The aim of this study was to investigate the anti-inflammatory effects of ghrelin in sepsis-induced AKI and the possible role of vagus nerve.. Five groups were included: sham, cecal ligation and puncture (CLP), CLP-ghrelin, CLP-vagotomy and CLP-vagotomy-ghrelin group.. Ghrelin treatment immediately after induction of CLP, significantly improved renal Glomerular filtration rate (GFR), serum creatinine, BUN and renal necrosis score as compared to the unprotected CLP group. In addition, ghrelin significantly decreased renal TNF alpha (111.5 ± 10.35 vs. 291.8 ± 15.8 pg/mg ptn), VCAM1 (6.28 ± 1.7 vs. 12.9 ± 1.2 µ/g ptn) and MPO (0.95 ± 0.13 vs. 2.5 ± 0.4 µ/g ptn) without significant increase in renal IL-10. Those effects were abolished by vagotomy.. We concluded that ghrelin could represent new therapeutic window in early treatment of sepsis-induced AKI and this could be mainly due to its anti-inflammatory effects.

Topics: Acute Kidney Injury; Animals; Arterial Pressure; Blood Urea Nitrogen; Cecum; Creatine; Disease Models, Animal; Ghrelin; Glomerular Filtration Rate; Interleukin-10; Kidney; Male; Necrosis; Peroxidase; Rats; Sepsis; Tumor Necrosis Factor-alpha; Vagotomy; Vagus Nerve; Vascular Cell Adhesion Molecule-1

ANCA-activated phagocytes cause vasculitis and necrotizing crescentic GN (NCGN). ANCA-induced phagocyte NADPH oxidase (Phox) may contribute by generating tissue-damaging reactive oxygen species. We tested an alternative hypothesis, in which Phox restrains inflammation by downregulating caspase-1, thereby reducing IL-1β generation and limiting NCGN. In an antimyeloperoxidase (anti-MPO) antibody-mediated disease model, mice transplanted with either gp91(phox)-deficient or p47(phox)-deficient bone marrow showed accelerated disease with increased crescents, necrosis, glomerular monocytes, and renal IL-1β levels compared with mice transplanted with wild-type bone marrow. IL-1β receptor blockade abrogated aggravated NCGN in gp91(phox)-deficient mice. In vitro, challenge with anti-MPO antibody strongly enhanced caspase-1 activity and IL-1β generation in gp91(phox)-deficient and p47(phox)-deficient monocytes compared with wild-type monocytes. This enhanced IL-1β generation was abrogated when caspase-1 was blocked. ANCA-induced superoxide and IL-1β generation were inversely related in human monocytes. Furthermore, transplantation of gp91(phox)/caspase-1 double-deficient bone marrow rescued the accelerated NCGN phenotype in gp91(phox) bone marrow-deficient mice. These results suggest that Phox-generated reactive oxygen species downregulate caspase-1, thereby keeping the inflammasome in check and limiting ANCA-induced inflammation. IL-1 receptor blockade may provide a promising strategy in NCGN, whereas our data question the benefit of antioxidants.

Topics: Animals; Antibodies, Antineutrophil Cytoplasmic; Caspase 1; Cells, Cultured; Disease Models, Animal; Glomerulonephritis; Humans; In Vitro Techniques; Inflammasomes; Interleukin 1 Receptor Antagonist Protein; Interleukin-1beta; Kidney; Mice; Mice, Knockout; NADPH Oxidases; Peroxidase; Phagocytes; Reactive Oxygen Species; Receptors, Immunologic; Superoxides

Palmitoylethanolamide (PEA) acts via several targets, including cannabinoid CB1 and CB2 receptors, transient receptor potential vanilloid type-1 (TRPV1) ion channels, peroxisome proliferator-activated receptor alpha (PPAR α) and orphan G protein-coupled receptor 55 (GRR55), all involved in the control of intestinal inflammation. Here, we investigated the effect of PEA in a murine model of colitis.. Colitis was induced in mice by intracolonic administration of dinitrobenzenesulfonic acid (DNBS). Inflammation was assessed by evaluating inflammatory markers/parameters and by histology; intestinal permeability by a fluorescent method; colonic cell proliferation by immunohistochemistry; PEA and endocannabinoid levels by liquid chromatography mass spectrometry; receptor and enzyme mRNA expression by quantitative RT-PCR.. DNBS administration caused inflammatory damage, increased colonic levels of PEA and endocannabinoids, down-regulation of mRNA for TRPV1 and GPR55 but no changes in mRNA for CB1 , CB2 and PPARα. Exogenous PEA (i.p. and/or p.o., 1 mg·kg(-1) ) attenuated inflammation and intestinal permeability, stimulated colonic cell proliferation, and increased colonic TRPV1 and CB1 receptor expression. The anti-inflammatory effect of PEA was attenuated or abolished by CB2 receptor, GPR55 or PPARα antagonists and further increased by the TRPV1 antagonist capsazepine.. PEA improves murine experimental colitis, the effect being mediated by CB2 receptors, GPR55 and PPARα, and modulated by TRPV1 channels.

Topics: Administration, Oral; Amides; Animals; Anti-Inflammatory Agents; Benzenesulfonates; Capsaicin; Colitis; Colon; Disease Models, Animal; Endocannabinoids; Ethanolamines; Intestinal Absorption; Male; Mice, Inbred ICR; Oleic Acids; Palmitic Acids; Peroxidase; PPAR alpha; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Receptors, Cannabinoid; RNA, Messenger; TRPV Cation Channels

Although myeloperoxidase activity in vivo can be visualized by using noninvasive imaging, successful clinical translation requires further optimization of the imaging approach. We report a motion-sensitized driven-equilibrium MR imaging approach for the detection of a myeloperoxidase activity-specific gadolinium-containing imaging agent in experimental aneurysm models, which compensates for irregular blood flow, enabling vascular wall imaging in the aneurysm.. A phantom was built from rotational angiography of a rabbit elastase aneurysm model and was connected to a cardiac pulse duplicator mimicking rabbit-specific flow conditions. A T1-weighted turbo spin-echo-based motion-sensitized driven-equilibrium pulse sequence was optimized in vitro, including the addition of fat suppression and the selection of the velocity-encoding gradient parameter. The optimized sequence was applied in vivo to rabbit aneurysm models with and without inflammation in the aneurysmal wall. Under each condition, the aneurysms were imaged before and after intravenous administration of the imaging agent. The signal-to-noise ratio of each MR imaging section through the aneurysm was calculated.. The motion-sensitized driven-equilibrium sequence was optimized to reduce flow signal, enabling detection of the myeloperoxidase imaging agent in the phantom. The optimized imaging protocol in the rabbit model of saccular aneurysms revealed a significant increase in the change of SNR from pre- to post-contrast MR imaging in the inflamed aneurysms compared with naïve aneurysms and the adjacent carotid artery (P < .0001).. A diagnostic MR imaging protocol was optimized for molecular imaging of a myeloperoxidase-specific molecular imaging agent in an animal model of inflamed brain aneurysms.

Topics: Animals; Disease Models, Animal; Gadolinium DTPA; Image Enhancement; Intracranial Aneurysm; Magnetic Resonance Angiography; Male; Motion; Neuroimaging; Peroxidase; Phantoms, Imaging; Rabbits; Radiography; Signal-To-Noise Ratio

Current treatments for inflammation associated with bronchopulmonary dysplasia (BPD) fail to show clinical efficacy. Foxm1, a transcription factor of the Forkhead box family, is a critical mediator of lung development and carcinogenesis, but its role in BPD-associated pulmonary inflammation is unknown. Immunohistochemistry and RNA analysis were used to assess Foxm1 in lung tissue from hyperoxia-treated mice and patients with BPD. LysM-Cre/Foxm1(-/-) mice, in which Foxm1 was deleted from myeloid-derived inflammatory cells, including macrophages, monocytes, and neutrophils, were exposed to neonatal hyperoxia, causing lung injury and remodeling. Measurements of lung function and flow cytometry were used to evaluate the effects of Foxm1 deletion on pulmonary inflammation and repair. Increased Foxm1 expression was observed in pulmonary macrophages of hyperoxia-exposed mice and in lung tissue from patients with BPD. After hyperoxia, deletion of Foxm1 from the myeloid cell lineage decreased numbers of interstitial macrophages (CD45(+)CD11b(+)Ly6C(-)Ly6G(-)F4/80(+)CD68(-)) and impaired alveologenesis and lung function. The exaggerated BPD-like phenotype observed in hyperoxia-exposed LysM-Cre/Foxm1(-/-) mice was associated with increased expression of neutrophil-derived myeloperoxidase, proteinase 3, and cathepsin g, all of which are critical for lung remodeling and inflammation. Our data demonstrate that Foxm1 influences pulmonary inflammatory responses to hyperoxia, inhibiting neutrophil-derived enzymes and enhancing monocytic responses that limit alveolar injury and remodeling in neonatal lungs.

Topics: Airway Remodeling; Alveolar Epithelial Cells; Animals; Bronchopulmonary Dysplasia; Case-Control Studies; Cathepsin G; Disease Models, Animal; Forkhead Box Protein M1; Forkhead Transcription Factors; Humans; Hyperoxia; Infant, Newborn; Lung; Lung Injury; Macrophages; Mice, Knockout; Myeloblastin; Neutrophils; Peroxidase; Pneumonia

Vasoactive intestinal peptide (VIP) is an immunomodulatory neuropeptide with therapeutic properties in multiple murine models of inflammatory disease including the trinitrobenzene-sulfonic acid (TNBS)-colitis model of Crohn's disease. Understanding the spectrum of biological actions of endogenously produced VIP may help us dissect the complex and multifactorial pathogenesis of such inflammatory diseases. Our goal was to determine the contribution of endogenously produced VIP to TNBS-colitis by using VIP knockout (KO) mice.. TNBS was intracolonically administered to wild-type (WT) and VIP KO mice, and weight loss and colitis were assessed over time. Colon histopathological changes and myeloperoxidase activities were analyzed and the levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6 in colon and serum quantified. The proliferative response in vitro of splenocytes from TNBS WT and VIP KO administered mice to anti-CD3 and anti-CD28 was determined.. VIP KO mice did not exhibit the predicted exacerbated response to TNBS. Instead, they developed a milder clinical profile than WT mice, with lower TNF-α and IL-6 levels. Such potential defects seem selective, because other parameters such as the histopathological scores and the cytokine levels in the colon did not differ between the two strains of mice. Moreover, splenocytes from TNBS-treated VIP KO mice exhibited an enhanced proliferative response to anti-CD3/CD28 stimulation in vitro.. Chronic loss of VIP in mice leads to a disruption of certain but not all immunological compartments, corroborating recent findings that VIP KO mice exhibit reduced mortality in the lipopolysaccharide-induced endotoxemia model and attenuated clinical development of experimental autoimmune encephalomyelitis while developing robust T-cell responses.

Topics: Animals; Cell Proliferation; Colitis; Colon; Cytokines; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Mice; Mice, Inbred C57BL; Mice, Knockout; Peroxidase; RNA, Messenger; T-Lymphocytes; Time Factors; Trinitrobenzenesulfonic Acid; Vasoactive Intestinal Peptide

We have previously shown that the prophylactic treatment with cannabidiol (CBD) reduces inflammation in a model of acute lung injury (ALI). In this work we analyzed the effects of the therapeutic treatment with CBD in mice subjected to the model of lipopolysaccharide (LPS)-induced ALI on pulmonary mechanics and inflammation. CBD (20 and 80 mg/kg) was administered (i.p.) to mice 6 h after LPS-induced lung inflammation. One day (24 h) after the induction of inflammation the assessment of pulmonary mechanics and inflammation were analyzed. The results show that CBD decreased total lung resistance and elastance, leukocyte migration into the lungs, myeloperoxidase activity in the lung tissue, protein concentration and production of pro-inflammatory cytokines (TNF and IL-6) and chemokines (MCP-1 and MIP-2) in the bronchoalveolar lavage supernatant. Thus, we conclude that CBD administered therapeutically, i.e. during an ongoing inflammatory process, has a potent anti-inflammatory effect and also improves the lung function in mice submitted to LPS-induced ALI. Therefore the present and previous data suggest that in the future cannabidiol might become a useful therapeutic tool for the attenuation and treatment of inflammatory lung diseases.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; Cannabidiol; Chemotaxis, Leukocyte; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Injections, Intraperitoneal; Leukocytes; Lipopolysaccharides; Lung; Male; Mice, Inbred C57BL; Peroxidase; Pneumonia; Respiratory Function Tests

N-Palmitoylethanolamine or palmitoylethanolamide (PEA) is an anti-inflammatory compound that was recently shown to exert peroxisome proliferator-activated receptor-α-dependent beneficial effects on colon inflammation. The actions of PEA are terminated following hydrolysis by 2 enzymes: fatty acid amide hydrolase (FAAH), and the less-studied N-acylethanolamine-hydrolyzing acid amidase (NAAA). This study aims to investigate the effects of inhibiting the enzymes responsible for PEA hydrolysis in colon inflammation in order to propose a potential therapeutic target for inflammatory bowel diseases (IBDs). Two murine models of IBD were used to assess the effects of NAAA inhibition, FAAH inhibition, and PEA on macroscopic signs of colon inflammation, macrophage/neutrophil infiltration, and the expression of proinflammatory mediators in the colon, as well as on the colitis-related systemic inflammation. NAAA inhibition increases PEA levels in the colon and reduces colon inflammation and systemic inflammation, similarly to PEA. FAAH inhibition, however, does not increase PEA levels in the colon and does not affect the macroscopic signs of colon inflammation or immune cell infiltration. This is the first report of an anti-inflammatory effect of a systemically administered NAAA inhibitor. Because NAAA is the enzyme responsible for the control of PEA levels in the colon, we put forth this enzyme as a potential therapeutic target in chronic inflammation in general and IBD in particular.

Topics: Amides; Amidohydrolases; Animals; Anti-Inflammatory Agents; Arachidonic Acids; Chromatography, High Pressure Liquid; Colitis; Colon; Cytokines; Disease Models, Animal; Endocannabinoids; Enzyme-Linked Immunosorbent Assay; Ethanolamines; Gene Expression Regulation; Glycerides; Inflammation; Inflammatory Bowel Diseases; Male; Mice; Mice, Inbred C57BL; Neutrophils; Palmitic Acids; Peroxidase; Piperidines; Pyridines; Taurine

Spinal cord injury [SCI] leads to complex cellular and molecular interactions which affects various organ systems. The present study focused on determining the protection offered by Vitamin C against spinal injury-induced kidney damage in wistar rats. The experimental protocol was performed with three groups; Sham, SCI and Vitamin C [20 mg/kg/bw] followed by SCI. The kidney tissue was investigated for oxidative stress parameters [reactive oxygen species, protein carbonyl, sulphydryl content, thiobarbituric acid reactive species [TBARS], and myeloperoxidase activity] and antioxidant status [glutathione, superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase activity]. Further, inflammation studies were performed by analyzing expression of NF-κB, cycloxygenase-2, iNOS through western blot analysis and inflammatory cytokines by TNF-α and IL-1β levels. The present study shows clear evidence that Vitamin C treatment abrogated spinal injury-induced oxidative stress and inflammatory responses and enhanced the antioxidant status. Thus, the protection offered by Vitamin C against spinal cord injury-induced kidney damage is attributed to its anti-oxidant and anti-inflammatory effects.

Topics: Animals; Antioxidants; Ascorbic Acid; Cyclooxygenase 2; Cytokines; Disease Models, Animal; Down-Regulation; Glutathione; Laminectomy; Male; NF-kappa B; Nitric Oxide Synthase Type II; Peroxidase; Protein Carbonylation; Rats; Rats, Wistar; Reactive Oxygen Species; Retinal Diseases; Spinal Cord Injuries

It has been previously reported that Toll‑like receptor 4 (TLR4)/NF‑κB signaling mediates early inflammation during myocardial ischemia and reperfusion. It has additionally been suggested that resveratrol produces cardioprotective and anti‑inflammatory effects. The aim of the present study was to investigate whether resveratrol could modulate TLR4/NF‑κB signaling, reduce neutrophil accumulation and TNF‑α induction in an ischemia/reperfusion injured rat heart model. Rats were randomly exposed to a sham operation, myocardial ischemia and reperfusion (MI/R), MI/R + resveratrol or MI/R + resveratrol + L‑NAME. The data showed that following MI/R, the expression of myocardial TLR4 and NF‑κB increased significantly in the area of induced ischemia. As compared with MI/R, resveratrol significantly attenuated the expression of TLR4 and NF‑κB and reduced the levels of myeloperoxidase, serum and myocardial TNF‑α production, myocardial infarct size and myocardial apoptosis induced by MI/R. All the effects of resveratrol were abolished upon application of L‑NAME, a nitric oxide (NO) synthase inhibitor. These data provide evidence that resveratrol inhibits TLR4/NF‑κB signaling in the rat heart subjected to MI/R, and the anti‑inflammatory effect of resveratrol is associated with NO production.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Disease Models, Animal; Down-Regulation; Heart; Inflammation; Male; Myocardial Reperfusion Injury; Myocardium; Neutrophils; NF-kappa B; NG-Nitroarginine Methyl Ester; Nitric Oxide; Peroxidase; Rats; Rats, Sprague-Dawley; Resveratrol; Signal Transduction; Stilbenes; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

As a Traditional Chinese Medicine, Melilotus extracts have been reported to function as an anti‑inflammatory agent, antioxidant and inhibitor of capillary permeability. The present study aimed to identify the mechanisms by which Melilotus interferes with inflammation‑associated and oxidative stress pathways during sepsis. An animal model of cecal ligation‑perforation (CLP)‑induced sepsis was established. Two hours prior to surgery, animals in the treatment group were administered 25 mg/kg Melilotus extract tablets and subsequently every 8 h. At 24 h post‑administration, pathological modifications in lung tissue and expression levels of tumor necrosis factor‑α‑induced protein‑8‑like 2 (TIPE2) expression, nuclear factor (NF)‑κB, toll‑like receptor 4 (TLR4), heme oxygenase‑1 (HO‑1), inhibitor of κB kinase (IκB), pro‑inflammatory mediators (interleukin‑6 and tumor necrosis factor‑α), myeloperoxidase (MPO), malondialdehyde (MDA) and superoxide dismutase (SOD), were examined. The results showed that Melilotus extract had a marked effect on the pathological manifestation of lung tissue and lung inflammatory response, the upregulation of TIPE2, HO‑1 and IκB expression, and the inhibition of TLR4 and NF‑κB activities. In addition, following treatment with Melilotus extract, the model animals demonstrated decreased levels of MPO and MDA as well as increased levels of SOD. In conclusion, these results indicated that Melilotus extract may be a potential therapeutic agent for the treatment of CLP‑induced lung injury, the mechanism of which proceeded via inflammation‑ and oxidation‑associated pathways by increasing TIPE2 expression.

Topics: Animals; Cytokines; Disease Models, Animal; Gene Expression Regulation; Heme Oxygenase-1; Inflammation Mediators; Intracellular Signaling Peptides and Proteins; Lung Injury; Melilotus; Mice; Mice, Knockout; NF-kappa B; Peroxidase; Plant Extracts; Sepsis; Superoxide Dismutase; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Dextran sodium sulphate (DSS)-induced colitis is a widely used model for inflammatory bowel disease. However, various factors including nutrition may affect the development of this colitis. This study aimed to compare and characterize the impact of purified and non-purified basal diets on the development of DSS-induced colitis in the rat.. Wistar rats were fed a non-purified or a semi-synthetic purified diet for 21 days. Colitis was then induced in half of the rats by administration of DSS in drinking water (4% w/v) during the last 7 days of experimentation. At the end of the experimental period, colon sections were taken for histopathological examination, determination of various markers of inflammation (myeloperoxidase: MPO, cytokines) and oxidative stress (superoxide dismutase: SOD, catalase: CAT, glutathione peroxidase: GPx and glutathione reductase: GRed activities), and evaluation of the expression of various genes implicated in this disorder.. DSS ingestion induced a more marked colitis in animals receiving the purified diet, as reflected by higher histological score and increased MPO activity. A significant decrease in SOD and CAT activities was also observed in rats fed the purified diet. Also, in these animals, administration of DSS induced a significant increase in interleukin (IL)-1α, IL-1β and IL-6. In addition, various genes implicated in inflammation were over-expressed after ingestion of DSS by rats fed the purified diet.. These results show that a purified diet promotes the onset of a more severe induced colitis than a non-purified one, highlighting the influence of basal diet in colitis development.

Topics: Animals; Antioxidants; Body Weight; Catalase; Colitis; Colon; Cytokines; Dextran Sulfate; Diet; Disease Models, Animal; Energy Intake; Glutathione Peroxidase; Glutathione Reductase; Inflammation; Interleukin-1alpha; Interleukin-1beta; Interleukin-6; Male; Oxidative Stress; Peroxidase; Rats; Rats, Wistar; Superoxide Dismutase; Up-Regulation

miR-181 has deleterious effects on stroke outcome, and reducing miR-181a levels prior to middle cerebral artery occlusion (MCAO) was shown previously to be protective. Here we tested the effect of post-ischemic treatment with miR-181a antagomir by intracerebroventricular and intravenous routes of administration on infarct size, neurological outcome, inflammatory response and long term behavioral outcome. Post-treatment with miR-181a antagomir significantly reduced infarction size, improved neurological deficits and reduced NF-κB activation, numbers of infiltrating leukocytes and levels of Iba1. Targets affected by miR-181a antagomir administered after stroke onset include BCL2 and X-linked inhibitor of apoptosis protein (XIAP). Post-treatment with miR-181a antagomir significantly improved behavioral outcome assessed by rotarod at one month. These findings indicate that post-treatment with miR-181a antagomir has neuroprotective effects against ischemic neuronal damage and neurological impairment in mice, and the protection is long lasting including recovery of motor function and coordination over one month. The ability to protect the brain with post-treatment with miR-181a antagomir with long lasting effect makes this a promising therapeutic target and may be an innovative and effective new approach for stroke therapy.

Topics: Animals; Brain; Brain Infarction; Brain Ischemia; Calcium-Binding Proteins; Disease Models, Animal; Gene Expression Regulation; Injections, Intravenous; Injections, Intraventricular; Male; Mice; Mice, Inbred C57BL; Microfilament Proteins; MicroRNAs; Motor Activity; Nervous System Diseases; Oligonucleotides; Peroxidase; Psychomotor Performance; Recovery of Function; Time Factors

Neural cross-sensitization has been postulated as a mechanism underlying overlaps of chronic pelvic pain disorders such as bladder pain syndrome/interstitial cystitis (BPS/IC) and irritable bowel syndrome (IBS). Animals with experimental colitis have been used to study the underlying mechanisms for overlapped pelvic pain symptoms, and shown to exhibit bladder overactivity evidenced by frequent voiding; however, it has not directly been evaluated whether pain sensation derived from the lower urinary tract is enhanced in colitis models. Also, the cross-sensitization between the colon and urethra has not been studied previously. In the present study, we therefore investigated pain behaviors induced by nociceptive stimuli in the lower urinary tract and the involvement of C-fiber afferent pathways using rats with colitis induced by intracolonic application of 2,4,6-trinitrobenzenesulfonic acid (TNBS). In TNBS-induced colitis rats at 10 days, intravesical application of resiniferatoxin (RTx) induced a significantly greater number of episodes of both licking and freezing behaviors, which were reduced by capsaicin-sensitive C-fiber afferent desensitization. Histochemical studies using fluorescent dye tracers injected into the colon, bladder or urethra showed that dichotomized afferent neurons comprised 6.9-14.5% of L1, L6 and S1 dorsal root ganglion (DRG) neurons innervating the colon or the lower urinary tract. Transient receptor potential vanilloid 1 (TRPV1) mRNA expression was significantly increased in, the bladder, urethra and S1 DRG in colitis rats. An increase in myeloperoxidase (MPO) activity was found in the colon, but not in the bladder or urethra after intracolonic TNBS treatment. These results indicate that TNBS-induced colitis increased pain sensitivity in the bladder and urethra via activation of C-fiber afferent pathways due to colon-to-bladder and colon-to-urethral cross-sensitization, suggesting the contribution of pelvic organ cross-sensitization mechanisms to overlapped pain symptoms in BPS/IC and IBS.

Topics: Animals; Colitis; Colon; Disease Models, Animal; Diterpenes; Female; Freezing Reaction, Cataleptic; Ganglia, Spinal; Grooming; Neurons, Afferent; Pain; Peroxidase; Rats, Sprague-Dawley; RNA, Messenger; Trinitrobenzenesulfonic Acid; TRPV Cation Channels; Urethra; Urinary Bladder

Acute inflammation and angiogenesis are persistent features of several pathological conditions induced by biological agents leading to the resolution of local and systemic events. Glycoproteins derived from the protozoan Trypanosoma cruzi are suggested to mediate angiogenesis induced by inflammatory cells with still undescribed mechanisms. In this study, we investigated the effects of total antigen from trypomastigote forms of T. cruzi (Y strain), inoculated in sponges 24h after implantation in mice, on angiogenesis, inflammatory cell pattern and endogenous production of inflammatory and angiogenic mediators on days 1, 4, 7 and 14 post-implant. There was an increase in hemoglobin content and in the number of blood vessels associated with T. cruzi antigen stimuli on the 14th day, assessed by the hemoglobin of the implants and by morphometric analysis. However, these antigens were not able to increase type I collagen content on the 14th day. Parasite antigens also induced high production of vascular endothelial growth factor (VEGF) and inflammatory mediators TNF-alpha, CCL2 and CCL5 on the 7th day in sponges when compared to the unstimulated group. Neutrophils and macrophages were determined by measuring myeloperoxidase (MPO) and N-acetyl-β-d-glucosaminidase (NAG) enzyme activities, respectively. Only NAG was increased after stimulation with antigens, starting from day 4 and peaking at day 7. Together, these data showed that antigens from the Y strain of T. cruzi are able to promote inflammatory neovascularization probably induced by macrophage-induced angiogenic mediators in T. cruzi antigen-stimulated sponges in Swiss mice.

Topics: Acetylglucosaminidase; Angiogenic Proteins; Animals; Antigens, Protozoan; Biomarkers; Disease Models, Animal; Female; Inflammation; Inflammation Mediators; Macrophages; Mice; Neovascularization, Pathologic; Neutrophil Infiltration; Neutrophils; Peroxidase; Surgical Sponges; Time Factors; Trypanosoma cruzi

Sepsis is characterized as a systemic inflammatory response syndrome during infection, which can result in multiple organ dysfunction and death. Ursolic acid (UA), a pentacyclic triterpene acid, has been reported to have potent anti-inflammatory and antioxidant properties. The aim of this study was to detect the possible protective effects of UA on sepsis-evoked acute lung injury.. A rat model of sepsis induced by cecal ligation and puncture (CLP) was used. Rats were injected intraperitoneally with UA (10 mg/kg) after CLP, and then the survival was determined twice a day for 4 d. The protective effects of UA on CLP-induced acute lung injury were assayed at 24 h after CLP.. The results revealed that UA treatment markedly improved the survival of septic rats, and attenuated CLP-induced lung injury, including reduction of lung wet/dry weight ratio, infiltration of leukocytes and proteins, myeloperoxidase activity, and malondialdehyde content. In addition, UA significantly decreased the serum levels of tumor necrosis factor-α, interleukin-6, and interleukin-1β, inhibited the expression of inducible nitric oxide synthase and cyclooxygenase-2 in the lung, which are involved in the productions of nitric oxide and prostaglandin E2.. These findings indicate that UA exerts protective effects on CLP-induced septic rats. UA may be a potential therapeutic agent against sepsis.

Topics: Acute Lung Injury; Animals; Antineoplastic Agents, Phytogenic; Biomarkers; Cyclooxygenase 2; Cytokines; Dinoprostone; Disease Models, Animal; Drug Evaluation, Preclinical; Lung; Male; Malondialdehyde; Nitric Oxide; Nitric Oxide Synthase Type II; Peroxidase; Phytotherapy; Plant Extracts; Random Allocation; Rats, Sprague-Dawley; Sepsis; Triterpenes; Ursolic Acid

High prevalence of psychological comorbidities such as depression and anxiety in patients with inflammatory bowel disease (IBD) supports the premise that adding an anti-depressant drug with known anti-inflammatory effect to the medical treatment have beneficial effect in the course of the underlying disease. Colitis was induced by intracolonic instillation of 2 ml of 4% v/v acetic acid solution in rats. Anti-colitic effect of fluvoxamine was evaluated in two categories: A: normal rats, B: reserpinized (6 mg/kg, i.p.) depressed rats. In group A, fluvoxamine (2.5, 5, 10 mg/kg, i.p.) was administered 2 h after induction of colitis and in group B: reserpine (6 mg/kg, i.p.) was administered 1 h prior to colitis induction and then fluvoxamine (2.5, 5, 10 mg/kg, i.p.) was administered 2 h after colitis induction. Dexamethasone (1 mg/kg) was used as reference drug. All the treatments continued daily for five days. The effect was assessed on the basis of macroscopic score, biochemical (myeloperoxidase) changes and histopathological studies. Results showed that fluvoxamine (2.5 and 5 mg/kg) and dexamethasone treatment markedly reduced disease severity in both reserpinized and non-reserpinized rats as indicated by reduction in macroscopic and microscopic colonic damages while reserpine adversely exacerbated the colitis damage. Myeloperoxidase activity which was increased following colitis induction was also decreased. The findings of this study elucidate the anti-colitic and anti-inflammatory properties of fluvoxamine and so introduced it as a good candidate to treat depressive symptoms in people comorbid to IBD.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antidepressive Agents, Second-Generation; Antipsychotic Agents; Colitis, Ulcerative; Colon; Depression; Dexamethasone; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Resistance; Fluvoxamine; Gastrointestinal Agents; Intestinal Mucosa; Male; Neutrophil Infiltration; Peroxidase; Random Allocation; Rats, Wistar; Reserpine

Notoginsenoside R1 (R1) is the main bioactive component in Panax notoginseng, an old herb medicine widely used in Asian countries in the treatment of microcirculatory diseases. However, little is known about the effect of R1 on inflammatory bowel disease (IBD). The present study demonstrated that R1 alleviated the severity of dextran sulfate sodium-induced colitis in mice by decreasing the activity of myeloperoxidase, the production of cytokines, the expression of proinflammatory genes, and the phosphorylation of IκB kinase, IκBα, and p65 in the colon. Further studies indicated that R1 dose-dependently activated human/mouse pregnane X receptor (PXR), a known target for decreasing inflammation in IBD, and upregulated the expression of genes involved in xenobiotic metabolism in colorectal cells and the colon. Ligand pocket-filling mutant (S247W/C284W or S247W/C284W/S208W) of the human PXR abrogated the effect of R1 on PXR activation. Time-resolved fluorescence resonance energy transfer PXR competitive binding assay confirmed R1 (ligand) binding affinity. In addition, PXR overexpression inhibited nuclear factor-κB (NF-κB)-luciferase activity, which was potentiated by R1 treatment. PXR knockdown by small interfering RNA demonstrated the necessity of PXR in R1-induced upregulation of the expression of xenobiotic-metabolizing enzymes and downregulation of NF-κB activity. Finally, the anti-inflammatory effect of R1 was confirmed in trinitrobenzene sulfonic acid-induced colitis in mice. These findings suggest that R1 attenuates experimental IBD possibly via the activation of intestinal PXR signaling.

Topics: Animals; Anti-Inflammatory Agents; Colon; Disease Models, Animal; Female; Gene Expression; Ginsenosides; HT29 Cells; Humans; Inflammatory Bowel Diseases; Interleukin-6; Mice, Inbred C57BL; NF-kappa B; Peroxidase; Pregnane X Receptor; Receptors, Steroid; Signal Transduction; Tumor Necrosis Factor-alpha

Ischemia reperfusion injury (IRI) is a leading cause of acute kidney injury, which is associated with high morbidity. The aims of the present study were to examine whether mangiferin attenuates renal IRI in an animal model and to identify the underlying mechanism(s).. Male mice were subjected to right renal ischemia for 30min followed by reperfusion for 24h or to a sham operation during which the left kidney was removed. After the 24h reperfusion, all mice were humanely euthanized and kidney tissues collected. Renal damage and apoptosis were investigated by examining hematoxylin and eosin-stained tissues, and by TUNEL assay and immunohistochemistry. Renal function was examined by measuring the concentrations of creatinine, blood urea nitrogen, and potassium (K(+)) in the serum. MPO activity, the levels of NO, TNF-α, IL-1β, and adenosine, and CD73 expression in renal tissue were also examined.. Mangiferin reduced ischemia reperfusion-induced injury, improved kidney function, and inhibited both proinflammatory responses and tubular apoptosis. In addition, treatment with mangiferin increased adenosine production and CD73 expression in kidney's suffering IRI.. Mangiferin appears to attenuate renal IRI by inhibiting proinflammatory responses and tubular apoptosis and by increasing adenosine production. These effects are associated with the adenosine-CD73 signaling pathway.

Topics: 5'-Nucleotidase; Adenosine; Animals; Apoptosis; Blood Urea Nitrogen; Creatinine; Disease Models, Animal; Gene Expression Regulation; Humans; Interleukin-1beta; Kidney; Male; Mice; Mice, Inbred C57BL; Nitric Oxide; Peroxidase; Potassium; Reperfusion Injury; Signal Transduction; Tumor Necrosis Factor-alpha

What is the central question of this study? It is not known whether treatment with interleukin-10 (IL-10) attenuates hyperoxia-induced acute lung injury in mice. What is the main finding and its importance? Our results showed that exogenous IL-10 treatment alleviated hyperoxia-induced acute lung injury in mice, possibly by regulating neutrophil recruitment and the subsequent generation of cytokines, nitric oxide and matrix metalloproteinases. Lung injury caused by breathing air enriched with oxygen continues to be a major problem in clinical medicine. Here, we investigated the therapeutic role of interleukin-10 (IL-10) in hyperoxia-induced acute lung injury in mice. In the first experiment, mice were exposed to room air or 95% O2 and treated with IL-10 simultaneously. In the second experiment, wild-type mice and IL-10(-/-) mice were exposed to room air or 95% O2 . Exogenous IL-10 treatment attenuated hyperoxia-induced acute lung injury, evidenced by a reduced ratio of lung weight to body weight, ratio of lung wet weight to dry weight, cell numbers and protein content in bronchoalveolar lavage fluid and cell death. Interleukin-10 treatment markedly prolonged the survival of mice during oxygen exposure. Interleukin-10 treatment reduced the activity of myeloperoxidase and mRNA levels of interleukin-6, tumour necrosis factor-α and macrophage inflammatory protein 2, suppressed nuclear factor-κB activation and decreased inducible nitric oxide synthnase expression and nitric oxide formation in lungs of mice exposed to hyperoxia. Interleukin-10 treatment suppressed activities of matrix metalloproteinase 2 and matrix metalloproteinase 9 and reduced lung permeability in mice during oxygen exposure. Furthermore, absence of IL-10 aggravated hyperoxia-induced acute lung injury and reduced the duration of survival of mice during oxygen exposure, which was attenuated by treatment with IL-10. In conclusion, our results show that exogenous IL-10 treatment alleviates hyperoxia-induced acute lung injury in mice, possibly by regulating neutrophil recruitment and the subsequent generation of cytokines, nitric oxide and matrix metalloproteinases. This suggests that IL-10 treatment may be a promising therapeutic strategy to reduce lung injury in patients exposed to hyperoxia.

Topics: Acute Lung Injury; Animals; Body Weight; Bronchoalveolar Lavage Fluid; Cell Death; Chemokine CXCL2; Disease Models, Animal; Hyperoxia; Interleukin-10; Interleukin-6; Lung; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Neutrophil Infiltration; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Organ Size; Oxygen; Peroxidase; Tumor Necrosis Factor-alpha

Sepsis is characterized by a severe production of reactive oxygen species (ROS) and other radical species with consequent oxidative stress. S-allyl cysteine (SAC) is a water-soluble organosulfur component present in garlic which is a potent antioxidant and free radical scavenger. In the present study, the purpose was to explore the anti-inflammatory, antioxidant, and anti-apoptotic actions of SAC on lipopolysaccharide (LPS)-induced sepsis in rats. Thirty-two male Wistar rats were separated into 4 groups. These were control, SAC control, sepsis, and sepsis + SAC-induced groups. Sepsis was induced by administration of LPS (5 mg/kg) into 2 groups. SAC (50 mg/kg) was given orally to SAC control and SAC treatment groups per 12 h during 2 days after intraperitoneal LPS injection. Serum AST, ALT, ALP, and hsCRP levels and liver and lung MPO, NO, and DNA fragmentation levels were evaluated. In sepsis group, elevated levels of ALT, AST, ALP, and hsCRP were observed. The abnormal increases were decreased in sepsis + SAC group compared to sepsis group. In lung tissue, MPO and NO levels were increased in sepsis group compared to the control group. MPO activity and NO levels were decreased by SAC application in sepsis + SAC group compared with sepsis group. In liver tissue, DNA fragmentation was significantly higher in sepsis group than that in the control group. In contrast, a decreased level of DNA fragmentation was noted in sepsis + SAC group when compared with the sepsis group. In conclusion, SAC ameliorates LPS-induced indicators of liver damage and suppresses the discharge of NO and MPO in lung tissue via its antioxidant properties.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Antioxidants; Aspartate Aminotransferases; C-Reactive Protein; Cysteine; Disease Models, Animal; DNA Fragmentation; Lipopolysaccharides; Liver; Lung; Male; Nitric Oxide; Peroxidase; Rats, Wistar; Sepsis

The beneficial properties of the flavonoid fraction of bergamot juice (BJe) have been raising interest and have been the subject of recent studies, considering the potentiality of its health promoting substances. Flavonoids have demonstrated radical-scavenging and anti-inflammatory activities. The aim of the present study was to examine the effects of BJe in mice subjected to experimental colitis.. Colitis was induced in mice by intracolonic instillation of dinitrobenzene sulfonic acid (DNBS). BJe was administered daily orally (at 5, 10 and 20 mg/kg).. Four days after DNBS administration, colon nuclear factor NF-κB translocation and MAP kinase phospho-JNK activation were increased as well as cytokine production such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β. Neutrophil infiltration, by myeloperoxidase (MPO) activity, in the mucosa was associated with up-regulation of adhesion molecules (ICAM-1 and P-selectin). Immunohistochemistry for nitrotyrosine and poly ADP-ribose (PAR) also showed an intense staining in the inflamed colon. Treatment with BJe decreased the appearance of diarrhea and body weight loss. This was associated with a reduction in colonic MPO activity. BJe reduced nuclear NF-κB translocation, p-JNK activation, the pro-inflammatory cytokines release, the appearance of nitrotyrosine and PAR in the colon and reduced the up-regulation of ICAM-1 and P-selectin. In addition, colon inflammation was also associated with apoptotic damage. Treatment with BJe caused a decrease of pro-apoptotic Bax expression and an increase of anti-apoptotic Bcl-2 expression.. The results of this study suggested that administration of BJe induced, partly specified, anti-inflammatory mechanisms, which potentially may be beneficial for the treatment of IBD in humans.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; bcl-2-Associated X Protein; Benzenesulfonates; Beverages; Citrus; Colitis; Colon; Disease Models, Animal; Inflammatory Bowel Diseases; Intercellular Adhesion Molecule-1; Interleukin-1beta; Male; Mice; Neutrophil Infiltration; NF-kappa B; P-Selectin; Peroxidase; Plant Extracts; Poly Adenosine Diphosphate Ribose; Tumor Necrosis Factor-alpha; Tyrosine; Up-Regulation

The onset of acute pancreatitis (AP) is characterized by early protease activation followed by inflammation and organ damage, but the mechanisms are poorly understood.. We hypothesized that histone deacetylase (HDAC) inhibition might exert protective effects on AP and investigated the role of HDAC in trypsin activation, inflammation, and tissue damage in severe AP.. Male C57Bl/6 mice were treated i.p. with the HDAC inhibitor trichostatin A (2 mg/kg) prior to retrograde infusion of taurocholic acid (5 %) into the pancreatic duct. Serum levels of amylase and interleukin (IL)-6, pancreatic levels of macrophage inflammatory protein-2 (MIP-2) as well as tissue morphology and myeloperoxidase activity in the pancreas and lung were determined 24 h after taurocholate challenge. Trypsin activation was analyzed in isolated acinar cells. Quantitative RT-PCR was used to examine the expression of pro-inflammatory mediators in the pancreas.. Pretreatment with trichostatin A decreased amylase levels by 70 % and protected against tissue injury in the pancreas. Moreover, HDAC inhibition reduced systemic IL-6 by more than 95 % and pulmonary myeloperoxidase activity by 75 %. Notably, inhibition of HDAC abolished taurocholate-induced gene expression of cyclooxygenase-2, MIP-2, monocyte chemotactic protein-1, IL-6, and IL-1β in the pancreas. In addition, HDAC inhibition reduced cerulein-induced trypsinogen activation in isolated acinar cells.. Our findings show that HDAC regulates trypsin activation, inflammation, and tissue damage in AP. Thus, targeting HDAC could serve as novel therapeutic approach in the management of severe AP.

Topics: Acute Disease; Amylases; Animals; Anti-Inflammatory Agents; Ceruletide; Chemokine CXCL2; Cytoprotection; Disease Models, Animal; Enzyme Activation; Histone Deacetylase Inhibitors; Histone Deacetylases; Hydroxamic Acids; Inflammation Mediators; Injections, Intraperitoneal; Interleukin-6; Lung; Male; Mice, Inbred C57BL; Pancreas; Pancreatitis; Peroxidase; Signal Transduction; Taurocholic Acid; Trypsin

To test if MPO-Gd, a gadolinium-based magnetic resonance (MR) imaging probe that is sensitive and specific for the proinflammatory and oxidative enzyme myeloperoxidase (MPO), which is secreted by certain inflammatory cells, is more sensitive than diethylenetriaminepentaacetic acid (DTPA)-Gd in revealing early subclinical and chronic disease activity in the brain in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis.. The protocol for animal experiments was approved by the institutional animal care committee. A total of 61 female SJL mice were induced with EAE. Mice underwent MPO-Gd- or DTPA-Gd-enhanced MR imaging on days 6, 8, and 10 after induction, before clinical disease develops, and during chronic disease at remission and the first relapse. Brains were harvested at these time points for flow cytometric evaluation of immune cell subtypes and immunohistochemistry. Statistical analysis was performed, and P < .05 was considered to indicate a significant difference.. MPO-Gd helps detect earlier (5.2 vs 2.3 days before symptom onset, P = .004) and more (3.1 vs 0.3, P = .008) subclinical inflammatory lesions compared with DTPA-Gd, including in cases in which there was no evidence of overt blood-brain barrier (BBB) breakdown detected with DTPA-Gd enhancement. The number of MPO-Gd-enhancing lesions correlated with early infiltration of MPO-secreting monocytes and neutrophils into the brain (r = 0.91). MPO-Gd also helped detect more lesions during subclinical disease at remission (5.5 vs 1.3, P = .006) and at the first relapse (9.0 vs 2.7, P = .03) than DTPA-Gd, which also correlated well with the presence and accumulation of MPO-secreting inflammatory cells in the brain (r = 0.93).. MPO-Gd specifically reveals lesions with inflammatory monocytes and neutrophils, which actively secrete MPO. These results demonstrate the feasibility of detection of subclinical inflammatory disease activity in vivo, which is different from overt BBB breakdown.

Topics: Acute Disease; Animals; Chronic Disease; Contrast Media; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Gadolinium DTPA; Mice; Multiple Sclerosis; Peroxidase; Radionuclide Imaging

We aimed to investigate the preventive and therapeutic effect of apocynin (APO) on bleomycin (BLC)-induced lung injury in rats. Rats were assigned into groups as follows: control group; APO group, 20 mg/kg APO was given intraperitoneal for 29 days; BLC-1 and BLC-2 groups, a single intratracheal injection of BLC (2.5 mg/kg); APO+BLC-preventive group, 20 mg/kg APO was administered 12 h before the intratracheal BLC injection and continued for 14 days; BLC+APO-treatment group, 20 mg/kg APO was given on the 14th day after the intratracheal BLC injection and continued to sacrifice. The BLC-1 group was sacrificed on the 14th day of BLC administration to validate BLC-induced lung inflammation and fibrosis on the 14th of study initiation. All other groups were sacrificed on the 29th day after BLC administration. The semiquantitative histopathological assessment, tissue levels of malondialdehyde (MDA), superoxide dismutase, catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH), total antioxidant capacity, total oxidant status (TOS), and oxidative stress index (OSI) were measured. An addition to the serum myeloperoxidase (MPO), the cell count and cytokines (IL-1β, IL-6, and IL-8) of bronchoalveolar lavage (BAL) fluid were assayed. BLC-provoked histological changes were significantly detected compared to the control group. APO restored these histological damages in different quantity in the treatment and prevention groups. BLC caused a significant decrease in GSH, CAT, and GPX, which were accompanied with significantly the increased MDA, TOS levels, and OSI in the lung tissue concomitant with increased levels of the cellular account and proinflammatory cytokines in the BAL fluid. Otherwise, APO administration, both before and after BLC, reversed all biochemical markers and cytokine as well as histopathological changes induced by BLC. Interestingly, APO treatment reversed MPO activity in serum increased by BLC. In this study, both protective and therapeutic effects of APO against BLC-induced lung fibrosis were demonstrated for the first time.

Topics: Acetophenones; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Biomarkers; Bleomycin; Bronchoalveolar Lavage Fluid; Catalase; Disease Models, Animal; Female; Glutathione; Glutathione Peroxidase; Interleukin-1beta; Interleukin-6; Interleukin-8; Lung; Lung Injury; Malondialdehyde; Oxidative Stress; Peroxidase; Pulmonary Fibrosis; Rats; Rats, Wistar; Superoxide Dismutase

Few effective treatment options exist for stroke beyond the hyperacute period. Radical generation and myeloperoxidase (MPO) have been implicated in stroke. We investigated whether pharmacologic reduction or gene deletion of this highly oxidative enzyme reduces infarct propagation and improves outcome in the transient middle cerebral artery occlusion mouse model (MCAO). Mice were treated with 4-aminobenzoic acid hydrazide (ABAH), a specific irreversible MPO inhibitor. Three treatment regimens were used: (1) daily throughout the 21-day observational period, (2) during the acute stage (first 24 hours), or (3) during the subacute stage (daily starting on day 2). We found elevated MPO activity in ipsilateral brain 3 to 21 days after ischemia. 4-Aminobenzoic acid hydrazide reduced enzyme activity by 30% to 40% and final lesion volume by 60% (P<0.01). The MPO-knockout (KO) mice subjected to MCAO also showed a similar reduction in the final lesion volume (P<0.01). The ABAH treatment or MPO-KO mice also improved neurobehavioral outcome (P<0.001) and survival (P=0.01), but ABAH had no additional beneficial effects in MPO-KO mice, confirming specificity of ABAH. Interestingly, inhibiting MPO activity during the subacute stage recapitulated most of the therapeutic benefit of continuous MPO inhibition, suggesting that MPO-targeted therapies could be useful when given after 24 hours of stroke onset.

Topics: Animals; Brain; Disease Models, Animal; Enzyme Inhibitors; Magnetic Resonance Imaging; Mice; Mice, Inbred C57BL; Mice, Knockout; Peroxidase; Stroke

Patchouli alcohol (PA), a natural compound isolated from Pogostemon cablin, has been reported to possess anti-inflammatory activity. However, the effects of PA on lipopolysaccharide (LPS)-induced acute lung injury (ALI) have not yet been studied. In the present study, we investigated in vivo the effect of PA on ALI induced by LPS.. Mice were administrated intranasally with LPS to induce lung injury. PA was administrated intraperitoneally 1 h before or after the LPS challenge.. The results showed that PA significantly decreased the wet-to-dry weight ratio of lungs and the number of total cells, neutrophils, and macrophages in bronchoalveolar lavage fluid at 7 h after the LPS challenge. In addition, PA also suppressed the production of inflammatory cytokines, such as tumor necrosis factor-α, interleukin-1β, and interleukin-6 in bronchoalveolar lavage fluid. Furthermore, Western blot analysis showed that PA inhibited the phosphorylation of IκB-α and p65 nuclear factor κB (NF-κB) induced by LPS.. Our results suggest that the anti-inflammatory effects of PA against LPS-induced ALI may be due to its ability to inhibit NF-κB signaling pathways.

Topics: Acute Lung Injury; Animals; Bronchoalveolar Lavage Fluid; Cytokines; Disease Models, Animal; Drug Evaluation, Preclinical; Lamiaceae; Lipopolysaccharides; Lung; Male; Mice, Inbred BALB C; NF-kappa B; Peroxidase; Phytotherapy; Plant Extracts; Random Allocation; Sesquiterpenes

The K/BxN serum-transfer arthritis is a widely-used translational mouse model of rheumatoid arthritis, in which the immunological components have thoroughly been investigated. In contrast, little is known about the role of sensory neural factors and the complexity of neuro-immune interactions. Therefore, we analyzed the involvement of capsaicin-sensitive peptidergic sensory nerves in autoantibody-induced arthritis with integrative methodology.. Arthritogenic K/BxN or control serum was injected to non-pretreated mice or resiniferatoxin (RTX)-pretreated animals where capsaicin-sensitive nerves were inactivated. Edema, touch sensitivity, noxious heat threshold, joint function, body weight and clinical arthritis severity scores were determined repeatedly throughout two weeks. Micro-CT and in vivo optical imaging to determine matrix-metalloproteinase (MMP) and neutrophil-derived myeloperoxidase (MPO) activities, semiquantitative histopathological scoring and radioimmunoassay to measure somatostatin in the joint homogenates were also performed.. In RTX-pretreated mice, the autoantibody-induced joint swelling, arthritis severity score, MMP and MPO activities, as well as histopathological alterations were significantly greater compared to non-pretreated animals. Self-control quantification of the bone mass revealed decreased values in intact female mice, but significantly greater arthritis-induced pathological bone formation after RTX-pretreatment. In contrast, mechanical hyperalgesia from day 10 was smaller after inactivating capsaicin-sensitive afferents. Although thermal hyperalgesia did not develop, noxious heat threshold was significantly higher following RTX pretreatment. Somatostatin-like immunoreactivity elevated in the tibiotarsal joints in non-pretreated, which was significantly less in RTX-pretreated mice.. Although capsaicin-sensitive sensory nerves mediate mechanical hyperalgesia in the later phase of autoantibody-induced chronic arthritis, they play important anti-inflammatory roles at least partially through somatostatin release.

Topics: Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Capsaicin; Disease Models, Animal; Diterpenes; Edema; Hindlimb; Hyperalgesia; Matrix Metalloproteinases; Mice; Mice, Inbred C57BL; Nociceptors; Pain Threshold; Peroxidase; Reactive Oxygen Species; Sensory System Agents; Somatostatin; Tarsus, Animal; TRPV Cation Channels; X-Ray Microtomography

The presence of inflammatory cells and MPO (myeloperoxidase) in the arterial wall after vascular injury could increase neointima formation by modification of phospholipids. The present study investigates how these phospholipids, in particular oxidized and chlorinated species, are altered within injured vessels and how they affect VSMC (vascular smooth muscle cell) remodelling processes. Vascular injury was induced in C57BL/6 mice and high fat-fed ApoE-/- (apolipoprotein E) mice by wire denudation and ligation of the left carotid artery (LCA). Neointimal and medial composition was assessed using immunohistochemistry and ESI-MS. Primary rabbit aortic SMCs (smooth muscle cells) were utilized to examine the effects of modified lipids on VSMC proliferation, viability and migration at a cellular level. Neointimal area, measured as intima-to-media ratio, was significantly larger in wire-injured ApoE-/- mice (3.62±0.49 compared with 0.83±0.25 in C57BL/6 mice, n=3) and there was increased oxidized low-density lipoprotein (oxLDL) infiltration and elevated plasma MPO levels. Relative increases in lysophosphatidylcholines and unsaturated phosphatidylcholines (PCs) were also observed in wire-injured ApoE-/- carotid arteries. Chlorinated lipids had no effect on VSMC proliferation, viability or migration whereas chronic incubation with oxidized phospholipids stimulated proliferation in the presence of fetal calf serum [154.8±14.2% of viable cells at 1 μM PGPC (1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine) compared with control, n=6]. In conclusion, ApoE-/- mice with an inflammatory phenotype develop more neointima in wire-injured arteries and accumulation of oxidized lipids in the vessel wall may propagate this effect.

Topics: Animals; Apolipoproteins E; Carotid Arteries; Carotid Artery Injuries; Cell Movement; Cell Proliferation; Cell Survival; Cells, Cultured; Diet, High-Fat; Disease Models, Animal; Halogenation; Lipoproteins, LDL; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Neointima; Oxidation-Reduction; Peroxidase; Phenotype; Phospholipids; Vascular Remodeling

The present study has been designed to investigate the potential of rifampicin [Pregnane X receptors (PXR) agonist] in experimental dementia. Aluminum chloride (AlCl3) [100mg/kg, p.o. for 42days] was administered to Wistar rats (n=6) to induce dementia. Morris water maze (MWM) test was used to assess learning and memory and rota rod test was used to assess locomotor activity of the animals. A battery of biochemical tests and histopathological evaluation using hematoxylin and eosin (H&E) and Congo Red stains were performed at the end of the study. AlCl3-treated rats demonstrated impaired cognition and locomotor activity on MWM apparatus and rota rod test, respectively. These animals exhibited a significant rise in acetylcholinesterase (AChE) activity (138±3.6), thiobarbituric acid reactive species (TBARS) level (15±1.6), nitrite (56±2.4) level and myeloperoxidase (MPO) activity (4.1±0.9) along with decline in reduced glutathione (GSH) level (22±1.3) in comparison to the control group (p<0.05). Further the H&E and Congo Red-stained cerebral cortex sections of AlCl3-treated rats indicated severe neutrophilic infiltration and amyloid deposition. Rifampicin-treated AlCl3-rats exhibited significant attenuation in memory deficits, biochemical parameters like AChE activity (33±1.4), TBARS level (4.1±1.0), nitrite level (64±2.6), MPO activity (3.6±1.0) and GSH level (53±2.4) along with improved histopathological alterations and locomotor activity when compared with AlCl3-treated rats (p<0.05). Combined administration of ketoconazole (a PXR antagonist) and rifampicin to AlCl3-treated animals reversed the rifampicin-induced protective effects. Therefore the results obtained from the study indicate a defensive role of rifampicin in memory dysfunction which may probably be due to its anti-cholinesterase, anti-oxidative, anti-inflammatory and amyloid lowering effects. Moreover the study speculates the potential of PXR in the pathophysiology of dementia which is subject to further evaluation.

Topics: Acetylcholinesterase; Aluminum Chloride; Aluminum Compounds; Amyloid; Animals; Brain; Chlorides; Cognition; Dementia; Disease Models, Animal; Female; Glutathione; Ketoconazole; Male; Motor Activity; Neutrophils; Nitrites; Nootropic Agents; Peroxidase; Pregnane X Receptor; Rats, Wistar; Receptors, Steroid; Rifampin; Thiobarbituric Acid Reactive Substances

The purpose of this study is to examine the protective effect of δ-amyrone on ethanol-induced gastric ulcer in mice. The mice intragastric administration 75% (0.5 mL/100g) ethanol was pretreated with δ-amyrone (4 and 8 mg/kg) and cimetidine (100 mg/kg) or vehicles in different experimental groups for a continuous three-day, and animals were euthanized 3h after ethanol ingestion. The gastric lesions were significantly attenuated by δ-amyrone (4 and 8 mg/kg) as compared to the ulcer control group. Pre-treatment with δ-amyrone prevented the myeloperoxidase (MPO) activity, production of nitric oxide (NO) in serum, expression of inducible nitric oxide synthase (iNOS) and nuclear factor kappa B (NF-κB) p65 protein expression. Analysis of cytokines in gastric tissue and serum of ethanol-induced mice showed the levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) were decreased by δ-amyrone in response to NF-κB p65. These results suggested that δ-amyrone exerts its protective effect on experimental gastric ulcer by inhibiting NF-κB signaling pathways, which subsequently reduces overproduction of the inducible enzymes iNOS and suppresses the release of the inflammatory factors TNF-α, IL-6 and NO. Thus, δ-amyrone shows promise as a therapeutic agent in experimental gastric ulcer.

Topics: Animals; Cytokines; Disease Models, Animal; Ethanol; Gastric Acidity Determination; Gastric Mucosa; Immunohistochemistry; Male; Mice; Mucus; Nitric Oxide; Nitric Oxide Synthase Type II; Peroxidase; Protective Agents; Stomach Ulcer; Transcription Factor RelA; Triterpenes

To investigate the vasoactive intestinal peptides (VIP) expression in irritable bowel syndrome (IBS) and trinitrobenzene sulfonic acid (TNBS) induced colitis.. The VIP gene expression and protein plasma levels were measured in adult participants (45.8% male) who met Rome III criteria for IBS for longer than 6 mo and in a rat model of colitis as induced by TNBS. Plasma and colons were collected from naïve and inflamed rats. Markers assessing inflammation (i.e., weight changes and myeloperoxidase levels) were assessed on days 2, 7, 14 and 28 and compared to controls. Visceral hypersensitivity of the rats was assessed with colo-rectal distension and mechanical threshold testing on hind paws. IBS patients (n = 12) were age, gender, race, and BMI-matched with healthy controls (n = 12). Peripheral whole blood and plasma from fasting participants was collected and VIP plasma levels were assayed using a VIP peptide-enzyme immunoassay. Human gene expression of VIP was analyzed using a custom PCR array.. TNBS induced colitis in the rats was confirmed with weight loss (13.7 ± 3.2 g) and increased myeloperoxidase activity. Visceral hypersensitivity to colo-rectal distension was increased in TNBS treated rats up to 21 d and resolved by day 28. Somatic hypersensitivity was also increased up to 14 d post TNBS induction of colitis. The expression of an inflammatory marker myeloperoxidase was significantly elevated in the intracellular granules of neutrophils in rat models following TNBS treatment compared to naïve rats. This confirmed the induction of inflammation in rats following TNBS treatment. VIP plasma concentration was significantly increased in rats following TNBS treatment as compared to naïve animals (P < 0.05). Likewise, the VIP gene expression from peripheral whole blood was significantly upregulated by 2.91-fold in IBS patients when compared to controls (P < 0.00001; 95%CI). VIP plasma protein was not significantly different when compared with controls (P = 0.193).. Alterations in VIP expression may play a role in IBS. Therefore, a better understanding of the physiology of VIP could lead to new therapeutics.

Topics: Adult; Animals; Biomarkers; Case-Control Studies; Colitis; Colon; Disease Models, Animal; Female; Gene Expression Regulation; Humans; Hyperalgesia; Inflammation Mediators; Irritable Bowel Syndrome; Male; Middle Aged; Pain Threshold; Peroxidase; Pilot Projects; Rats, Sprague-Dawley; RNA, Messenger; Signal Transduction; Time Factors; Trinitrobenzenesulfonic Acid; Vasoactive Intestinal Peptide; Visceral Pain; Weight Loss; Young Adult

Sepsis is associated with acute lung injury (ALI) and high mortality. The aim of this study was to investigate the effects of different doses of penehyclidine hydrochloride (PHC) postconditioning on ALI induced by sepsis in a rat model.. A rat model of ALI was induced by intravenous injection of lipopolysaccharide (LPS). The different doses of PHC were administrated intravenously at 30 min after LPS administration (low dose, 0.3 mg/kg; medium dose, 1.0 mg/kg, and high dose, 3.0 mg/kg). After 6 h, arterial blood samples were obtained for blood gas analyses. Meanwhile, lung tissue was harvested and lung injury was assessed by the histopathologic changes (hematoxylin and eosin staining) and wet-to-dry lung weight ratio. The tumor necrosis factor-α and interleukin-6 levels in bronchoalveolar lavage fluid, as well as the nuclear factor-kappa B protein expressions, and the myeloperoxidase activities in lung tissues were measured by immunohistochemistry or enzyme-linked immunosorbent assay, respectively.. LPS-induced severe lung injury evidenced by increased pathologic scores and lung wet-to-dry weight ratio, which was accompanied by increases in the expression of pulmonary nuclear factor-kappa B protein and the activity of pulmonary myeloperoxidase and the levels of interleukin-6 and tumor necrosis factor-α in bronchoalveolar lavage fluid. The arterial oxygen tension (PaO2), pH, and the PaO2/fraction of inspired oxygen ratio (PaO2/FiO2) decreased significantly and the carbon dioxide tension (PaCO2) increased notedly after an LPS injection. All doses of PHC could significantly ameliorate lung injury and improve the previously mentioned variables (P < 0.05 or 0.01). Furthermore, the protection of medium dose (1.0 mg/kg) could be better than that of low or high dose.. These findings indicated that different doses of PHC, especially to medium dose, could prevent LPS-induced ALI in rats, at least in part, by inhibiting inflammatory response. Moreover, the protection of pharmacologic postconditioning with PHC is limited by a "ceiling effect."

Topics: Acute Lung Injury; Animals; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Drug Evaluation, Preclinical; Interleukin-6; Lipopolysaccharides; Lung; Male; NF-kappa B; Peroxidase; Pulmonary Gas Exchange; Quinuclidines; Rats, Sprague-Dawley; Sepsis; Tumor Necrosis Factor-alpha

The present work compared the behavioral outcomes of ACCS therapy delivered either intravenously (i.v.) or intracerebroventricularly (i.c.v.) after penetrating ballistic-like brain injury (PBBI). Histological markers for neuroinflammation and neurodegeneration were employed to investigate the potential therapeutic mechanism of ACCS.. Experiment-1, ACCS was administered either i.v. or i.c.v. for 1 week post-PBBI. Outcome metrics included behavioral (rotarod and Morris water maze) and gross morphological assessments. Experiment-2, rats received ACCS i.c.v for either 1 or 2 weeks post-PBBI. The inflammatory response was determined by immunohistochemistry for neutrophils and microglia reactivity. Neurodegeneration was visualized using silver staining.. Both i.v. and i.c.v. delivery of ACCS improved motor outcome but failed to improve cognitive outcome or tissue sparing. Importantly, only i.c.v. ACCS treatment produced persistent motor improvements at a later endpoint. The i.c.v. ACCS treatment significantly reduced PBBI-induced increase in myeloperoxidase (MPO) and ionized calcium binding adaptor molecule 1 (Iba1) expression. Concomitant reduction of both Iba1 and silver staining were detected in corpus callosum with i.c.v. ACCS treatment.. ACCS, as a treatment for TBI, showed promise with regard to functional (motor) recovery and demonstrated strong capability to modulate neuroinflammatory responses that may underline functional recovery. However, the majority of beneficial effects appear restricted to the i.c.v. route of ACCS delivery, which warrants future studies examining delivery routes (e.g. intranasal delivery) which are more clinically viable for the treatment of TBI.

Topics: Amnion; Animals; Brain; Calcium-Binding Proteins; Cytokines; Disease Models, Animal; Head Injuries, Penetrating; Immunohistochemistry; Male; Maze Learning; Microfilament Proteins; Motor Activity; Neuroimmunomodulation; Neuroprotective Agents; Peroxidase; Random Allocation; Rats, Sprague-Dawley; Rotarod Performance Test; Solutions

To study the effect of compound hypertonic saline solution ( HSD ) on sepsis.. 133 male Wistar rats were divided into four groups, sham operation group ( n = 15 ), cecal ligation and puncture ( CLP ) group ( n = 45 ), CLP plus normal saline ( NS ) group ( n = 45 ), and CLP plus HSD group ( n = 28 ). A rat model of sepsis was reproduced by CLP, and the rats in sham operation group received celiotomy without ligation and puncture. All rats in four groups received subcutaneous injection of 30 mL/kg 0.9% sodium chloride after laparotomy. The rats in CLP plus NS group and CLP plus HSD group received infusion of 5 mL/kg 0.9% sodium chloride or 7.5% sodium chloride/6% dextran post CLP via jugular vein for 3 hours, with the infusion rate of 0.4 mL×kg(-1)×min(-1). The survival rate of each group was observed 9 hours and 18 hours after laparotomy. Mean arterial pressure ( MAP ) at 0, 9, 18 hours were monitored. Blood specimens were collected from all rats 0, 9 and 18 hours after laparotomy, respectively, for measurement of the plasma levels of tumor necrosis factor-α ( TNF-α), interleukin-1β ( IL-1β ), and procalcitonin ( PCT ). The rats were all sacrificed, and their lung tissues were harvested for the neutrophil count in bronchoalveolar lavage fluid ( BALF ), myeloperoxidase ( MPO ) activity in lung tissue, wet/dry weight ratio ( W/D ) of lung, and pathological changes in lung tissue.. There was no death in the sham operation group. The survival rates at 9 hours and 18 hours were 62.2% and 31.1% in the CLP group, 57.8% and 35.6% in the CLP plus NS group, 85.7% and 64.3% in the CLP plus HSD group, and they were all significantly higher compared with those of the CLP group and the CLP plus NS group ( P<0.05 or P<0.01 ). MAP levels in the CLP group and the CLP plus NS group were significantly lower than those in sham operation group, and the plasma levels of TNF-α, IL-1β and PCT were significantly higher compared with those of sham operation group, while there was no difference between CLP group and the CLP plus NS group. MAP and the plasma levels of TNF-α, IL-1β and PCT in the CLP plus HSD group were significantly improved compared with those of the CLP plus NS group at 9 hours and 18 hours [ MAP ( mmHg, 1 mmHg = 0.133 kPa ) at 9 hours: 102±5 vs. 94±6, 18 hours: 90±2 vs. 72±3; TNF-α ( ng/L ) at 9 hours: 284.19±57.18 vs. 329.67±45.79, 18 hours: 263.46±42.58 vs. 349.68±52.40; IL-1β ( ng/L ) at 9 hours: 219.28±39.21 vs. 263.47±32.36, 18 hours: 195.98±39.06 vs. 250.10±41.57; PCT ( μg/L ) at 9 hours: 2.32±0.37 vs. 4.52±0.75, 18 hours: 2.89±0.62 vs. 5.02±0.84; P<0.05 or P<0.01 ]. The ratio of neutrophils in BALF, MPO activity and lung W/D at 18 hours in the CLP group and the CLP plus NS group were significantly higher than those of the sham operation group, while they were all significantly lower in the CLP plus HSD group than those of the CLP group and the CLP plus NS group [ ratio of neutrophils in BALF: 0.094±0.019 vs. 0.148±0.062, 0.151±0.055; MPO ( U/g ): 1.19±0.45 vs. 2.31±0.79, 2.64±0.69; lung W/D ratio: 4.02±0.63 vs. 5.14±0.59, 5.12±0.83, all P<0.05 ]. Under light microscope, no pathobiological changes were found in sham operation group. The lung tissues in the CLP group and the CLP plus NS group showed congestion, edema, infiltrating inflammatory changes, while the inflammatory changes in the lung tissue in the CLP plus HSD group were significantly alleviated.. HSD can obviously ameliorate the circulatory failure in septic rats, alleviate immune disturbance and acute lung injury, and improve the survival rate of rats with sepsis.

Topics: Acute Lung Injury; Animals; Bronchoalveolar Lavage Fluid; Calcitonin; Calcitonin Gene-Related Peptide; Disease Models, Animal; Interleukin-1beta; Lung; Male; Peroxidase; Protein Precursors; Rats; Rats, Wistar; Saline Solution, Hypertonic; Sepsis; Tumor Necrosis Factor-alpha

This study aimed to investigate the effects of astragaloside IV (AS-IV; 3-O-β-D-xylopyranosyl-6-O‑β-D-glucopyranosylcycloastragenol), which has been reported to have comprehensive pharmacological functions, on sodium taurocholate (NaTc)/L-arginine (L-Arg)-induced acute pancreatitis (AP) in rats in vivo and in rat pancreatic acinar cells in vitro. NaTc-induced experimental AP was induced in rats by injecting 4% NaTc (0.1 ml/100 g) in the retrograde direction of the biliopancreatic duct. L-Arg-induced experimental AP was induced in rats by 2 intraperitoneal injections of 20% L-arg (3 g/kg), with an interval of 1 h between the injections. The rats were pre-treated AS-IV (50 mg/kg) or the vehicle (DMSO) 2 h prior to the induction of AP. Enzyme-linked immunosorbent assay, H&E staining, myeloperoxidase (MPO) activity, reverse transcription-quantitative PCR, western blot analysis and immunohistochemistry were used to evaluate the effects of AS-IV on AP. The results revealed that treatment with AS-IV significantly reduced serum amylase and lipase levels, pancreatic pathological alterations, the secretion of pro-inflammatory cytokines, MPO activity, and the protein expression of nuclear factor-κB (NF-κB) in vivo. Moreover, pre-treatment with AS-IV significantly increased the expression levels of manganese superoxide dismutase and cuprum/zinc superoxide dismutase. In the in vitro experiment, treatment of the cells with AS-IV aslo reduced rat pancreatic acinar cell necrosis and nuclear NF-κB activity, and enhanced the protein expression of superoxide dismutase. In conclusion, this study indicates that the protective effects of AS-IV on experimental AP in rats may be closely related to the inhibition of NF-κB. In addition, our results indicate that AS-IV may exert potential antioxidant effects on AP. Therefore, AS-IV may be an effective therapeutic agent for AP.

Topics: Amylases; Animals; Antioxidants; Cytokines; Disease Models, Animal; Enzyme Activation; Inflammation Mediators; Lipase; Male; Necrosis; NF-kappa B; Pancreatitis; Peroxidase; Protein Transport; Rats; Saponins; Triterpenes

Rosiglitazone has been found to have anti-atherogenic effects and to increase serum high-density lipoprotein (HDL) cholesterol (HDL-C) levels. However, in vivo studies investigating the regulation of adenosine triphosphate-binding cassette transporter A1 (ABCA1) and scavenger receptor class B type I (SR-BI) by rosiglitazone are limited. Moreover, the effects of rosiglitazone on the function and levels of HDL are unclear. In the present study, we investigated the effects of rosiglitazone on HDL function and its mechanisms of action in atherosclerotic rabbits. Our results revealed that rosiglitazone induced a significant increase in serum HDL-C levels, paraoxonase 1 (PON1) activity, [(3)H]cholesterol efflux rates, and the expression of ABCA1 and SR-BI in hepatocytes and peritoneal macrophages. The expression of ABCA1 was also increased in aortic lesions. Rosiglitazone markedly reduced serum myeloperoxidase (MPO) activity, aortic intima-media thickness (IMT) and the percentage of plaque area in the aorta. It can thus be concluded that in atherosclerotic rabbits, rosigitazone increases the levels of HDL-C and hinders atherosclerosis. Thus, it improves HDL quality and function, as well as the HDL-induced cholesterol efflux, exerting anti-inflammatory and antioxidant effects.

Topics: Animals; Aryldialkylphosphatase; Atherosclerosis; ATP Binding Cassette Transporter 1; Cholesterol; Disease Models, Animal; Enzyme Activation; Gene Expression; Hepatocytes; Hypoglycemic Agents; Lipids; Lipoproteins, HDL; Macrophages, Peritoneal; Male; Peroxidase; Rabbits; Rosiglitazone; Scavenger Receptors, Class B; Thiazolidinediones

Liver ischemia-reperfusion injury (IRI) is a major cause of morbidity and mortality after resection surgery, liver transplantation, and hemorrhagic and septic shock. Mir-155 is upregulated by a broad range of inflammatory mediators, and it has been demonstrated to be involved in both innate and adaptive immune responses. However, the role of mir-155 in liver IRI has never been investigated. In this study, mir-155 deficiency protected mice from liver IRI, as shown by lower serum alanine aminotransferase (ALT) levels and Suzuki scores. Mir-155 deficiency results in the development of M2 macrophages, which respond to IR-induced innate immune stimulation by producing a regulatory inflammatory response with higher level of IL-10, but lower levels of TNF-α, IL-6, and IL-12p40. Mir-155 deficiency suppresses IL-17 expression, which contributes to the liver IRI development. In our further in vitro study, the results show that the Th17 differentiation is inhibited by SOCS1 overexpression and the promoted M2 macrophage development induced by mir-155 deficiency is abolished by SOCS1 knockdown. In conclusion, mir-155 deficiency attenuates liver IRI through upregulation of SOCS1, and this was associated with promoted M2 macrophage and inhibited Th17 differentiation.

Topics: Adaptive Immunity; Alanine Transaminase; Animals; CD4-Positive T-Lymphocytes; Cell Differentiation; Cell Separation; Disease Models, Animal; Flow Cytometry; Immunity, Innate; Inflammation; Interleukin-10; Interleukin-12 Subunit p40; Interleukin-6; Kupffer Cells; Liver; Liver Transplantation; Macrophages; Male; Mice; Mice, Inbred C57BL; MicroRNAs; Peroxidase; Reperfusion Injury; Suppressor of Cytokine Signaling 1 Protein; Suppressor of Cytokine Signaling Proteins; Th17 Cells; Tumor Necrosis Factor-alpha; Up-Regulation

Acute responses to intense stressors can give rise to post-traumatic stress disorder (PTSD). PTSD diagnostic criteria include trauma exposure history and self-reported symptoms. Individuals who meet PTSD diagnostic criteria often meet criteria for additional psychiatric diagnoses. Biomarkers promise to contribute to reliable phenotypes of PTSD and comorbidities by linking biological system alterations to behavioral symptoms. Here we have analyzed unbiased plasma metabolomics and other stress effects in a mouse model with behavioral features of PTSD. In this model, C57BL/6 mice are repeatedly exposed to a trained aggressor mouse (albino SJL) using a modified, resident-intruder, social defeat paradigm. Our recent studies using this model found that aggressor-exposed mice exhibited acute stress effects including changed behaviors, body weight gain, increased body temperature, as well as inflammatory and fibrotic histopathologies and transcriptomic changes of heart tissue. Some of these acute stress effects persisted, reminiscent of PTSD. Here we report elevated proteins in plasma that function in inflammation and responses to oxidative stress and damaged tissue at 24 hrs post-stressor. Additionally at this acute time point, transcriptomic analysis indicated liver inflammation. The unbiased metabolomics analysis showed altered metabolites in plasma at 24 hrs that only partially normalized toward control levels after stress-withdrawal for 1.5 or 4 wks. In particular, gut-derived metabolites were altered at 24 hrs post-stressor and remained altered up to 4 wks after stress-withdrawal. Also at the 4 wk time point, hyperlipidemia and suppressed metabolites of amino acids and carbohydrates in plasma coincided with transcriptomic indicators of altered liver metabolism (activated xenobiotic and lipid metabolism). Collectively, these system-wide sequelae to repeated intense stress suggest that the simultaneous perturbed functioning of multiple organ systems (e.g., brain, heart, intestine and liver) can interact to produce injuries that lead to chronic metabolic changes and disorders that have been associated with PTSD.

Topics: Animals; Behavior, Animal; Biomarkers; Brain; Disease Models, Animal; Gene Expression Regulation; Liver; Metabolomics; Mice; Oxidative Stress; Peroxidase; Stress Disorders, Post-Traumatic; Stress, Psychological

Aspergillus fumigatus (A. fumigatus) is a ubiquitous fungus that activates, suppresses or modulates the immune response by changing its cell wall structure and by secreting proteases. In this study, we show that chitin acts as an adjuvant in a murine model of A. fumigatus protease induced allergy. The mice were immunised intraperitoneally with A. fumigatus culture filtrate antigen either with or without chitin and were subsequently challenged with the culture filtrate antigen intranasally. Alum was used as an adjuvant control. Compared to alum, chitin induced a weaker inflammatory response in the lungs, measured as the total cell efflux in BAL, EPO and chitinase production. However, chitin enhanced the total IgE, specific IgE and specific IgG1 production as efficiently as alum. Pre-treatment with chitin but not with alum depressed the concentration of the Th2 cytokines IL-4 and IL-13 in BAL fluid. These results shows that chitin, in spite of a reduction of the Th2 cytokine levels in the lungs, enhanced the total and specific IgE production in A. fumigatus culture filtrate induced allergy.

Topics: Adjuvants, Immunologic; Allergens; Animals; Antigens, Fungal; Aspergillus fumigatus; Chitin; Chitinases; Cytokines; Disease Models, Animal; Eosinophils; Female; Hypersensitivity; Immunization; Immunoglobulin E; Immunoglobulin G; Lung; Mice; Peroxidase

This study aimed to investigate the effect and underlying mechanism of ghrelin on intestinal barrier dysfunction in dextran sulfate sodium (DSS)-induced colitis.. Acute colitis was induced in C57BL/6J mice by administering 2.5% DSS. Saline or 25, 125, 250 μg/kg ghrelin was administrated intraperitoneally (IP) to mice 1 day before colitis induction and on days 4, 5, and 6 after DSS administration. IP injection of a ghrelin receptor antagonist, [D-lys(3)]-GHRP-6, was performed immediately prior to ghrelin injection. Ghrelin (125 or 250 μg/kg) could reduce the disease activity index, histological score, and myeloperoxidase activities in experimental colitis, and also prevented shortening of the colon. Ghrelin could prevent the reduction of transepithelial electrical resistance and tight junction expression, and bolstered tight junction structural integrity and regulated cytokine secretion. Ultimately, ghrelin inhibited nuclear factor kappa B (NF-κB), inhibitory κB-α, myosin light chain kinase, and phosphorylated myosin light chain 2 activation.. Ghrelin prevented the breakdown of intestinal barrier function in DSS-induced colitis. The protective effects of ghrelin on intestinal barrier function were mediated by its receptor GHSR-1a. The inhibition of NF-κB activation might be part of the mechanism underlying the effects of ghrelin that protect against barrier dysfunction.

Topics: Animals; Colitis; Colon; Cytokines; Dextran Sulfate; Disease Models, Animal; Ghrelin; Intestinal Mucosa; Intestines; Male; Mice, Inbred C57BL; Myosin-Light-Chain Kinase; NF-kappa B; Oligopeptides; Peroxidase; Receptors, Ghrelin; Tight Junctions

To investigate the effects of amifostine, a cytoprotective agent, on pathophysiological changes in vasogenic brain edema induced by an experimental cold injury model and to compare these changes with dexamethasone.. A total of 138 rats divided into 6 groups. Brain water content (BWC), malondialdehyde (MDA) concentration and myeloperoxidase (MPO) activity in brain tissue were calculated to evaluate the pathophysiological changes following experimental cold injury. In addition, effects of cold injury on cell structure were assessed with direct light and transmission electron microscopy (TEM).. Extent of edema, MDA and MPO levels were significantly higher in cold injury groups than in controls. Although a decrease was noted in these parameters in both the amifostine and dexamethasone groups, the differences were significant only for MDA concentration in dexamethasone group, and for MPO activity in both groups. In addition, there was a significant difference between the group in which amifostine was administered prior to cold injury and dexamethasone group for MPO activity. Histopathologically, positive effects were observed in treatment groups.. Despite several positive effects of amifostine, its superiority to dexamethasone could not be clearly demonstrated. Further experimental and clinical studies are warranted to better delineate the neuroprotective effects of amifostine.

Topics: Amifostine; Animals; Brain Edema; Brain Injuries; Cold Temperature; Dexamethasone; Disease Models, Animal; Malondialdehyde; Neuroprotective Agents; Peroxidase; Rats

Acute lung injury (ALI) is still a leading cause of morbidity and mortality in critically ill patients. Inhaled nitric oxide (NO) has been reported to ameliorate ALI. However, reactive nitrogen species produced by NO can cause lung injury. Because hydrogen gas (H2) is reported to eliminate peroxynitrite, it is expected to reduce the adverse effects of NO. Moreover, we have found that H2 inhalation can attenuate lung injury. Therefore, we hypothesized that combination therapy with NO and H2 might afford more potent therapeutic strategies for ALI. In the present study, a mouse model of ALI was induced by intratracheal administration of lipopolysaccharide (LPS). The animals were treated with inhaled NO (20 ppm), H2 (2%), or NO + H2, starting 5 min after LPS administration for 3 h. We found that LPS-challenged mice exhibited significant lung injury characterized by the deterioration of histopathology and histologic scores, wet-to-dry weight ratio, and oxygenation index (ratio of oxygen tension to inspired oxygen fraction [Pao2/Fio2]), as well as total protein in the bronchoalveolar lavage fluid (BALF), which was attenuated by NO or H2 treatment alone. Combination therapy with NO and H2 had a more beneficial effect with significant interaction between the two. While the nitrotyrosine level in lung tissue was prominent after NO inhalation alone, it was significantly eliminated after breathing a mixture of NO with H2. Furthermore, NO or H2 treatment alone markedly attenuated LPS-induced lung neutrophil recruitment and inflammation, as evidenced by downregulation of lung myeloperoxidase activity, total cells, and polymorphonuclear neutrophils in BALF, as well as proinflammatory cytokines (tumor necrosis factor α, interleukins 1β and 6, and high-mobility group box 1) and chemokines (keratinocyte-derived chemokine, macrophage inflammatory proteins 1α and 2, and monocyte chemoattractant protein 1) in BALF. Combination therapy with NO and H2 had a more beneficial effect against lung inflammatory response. Moreover, combination therapy with NO and H2 could more effectively inhibit LPS-induced pulmonary early and late nuclear factor κB activation as well as pulmonary cell apoptosis. In addition, combination treatment with inhaled NO and H2 could also significantly attenuate lung injury in polymicrobial sepsis. Combination therapy with subthreshold concentrations of NO and H2 still had a significantly beneficial effect against lung injury induced by LPS and polymicrobia

Topics: Acute Lung Injury; Animals; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Gases; Hydrogen; Lipopolysaccharides; Lung; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Nitric Oxide; Oxygen; Peroxidase; Peroxynitrous Acid; Sepsis; Time Factors

The mitogen-activated protein kinases (MAPKs) signaling pathway is involved in inflammatory process. However, the mechanism is not clear. The present study was to investigate the role of p38 MAPK in acute pancreatitis in mice.. Mice were divided into 4 groups: saline control; acute pancreatitis induced with repeated injections of cerulein; control plus p38 MAPK inhibitor SB203580; and acute pancreatitis plus SB203580. The pancreatic histology, pancreatic enzymes, cytokines, myeloperoxidase activity, p38 MAPK and heat shock protein (HSP) 60 and 70 were evaluated.. Repeated injections of cerulein resulted in acute pancreatitis in mice, accompanying with the activation of p38 MAPK and overexpression of HSP60 and HSP70 in the pancreatic tissues. Treatment with SB203580 significantly inhibited the activation of p38 MAPK, and furthermore, inhibited the expression of HSP60 and HSP70 in the pancreas, the inflammatory cytokines in the serum, and myeloperoxidase activity in the lung.. The p38 MAPK signaling pathway is involved in the regulation of inflammatory response and the expression of HSP60 and HSP70 in acute pancreatitis.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents; Biomarkers; Ceruletide; Chaperonin 60; Disease Models, Animal; HSP70 Heat-Shock Proteins; Imidazoles; Inflammation Mediators; Lung; Mice, Inbred C57BL; Mitochondrial Proteins; p38 Mitogen-Activated Protein Kinases; Pancreas; Pancreatitis; Peroxidase; Phosphorylation; Protein Kinase Inhibitors; Pyridines; Signal Transduction

Myeloperoxidase is a key component of neutrophil granules involved in killing engulfed microorganisms. We obtained a zebrafish mutant (smu681) lacking Sudan black staining by large-scale screening, which was a neutrophil-replete but myeloperoxidase-deficient mutant. When infiltrated with Candida albicans, smu681 embryos and sibling embryos showed similar survival after infection. Proliferation of C. albicans was more rapid in smu681 embryos than in sibling embryos, although it was eventually suppressed. In addition, the number of neutrophils accumulating at the site of infection was significantly larger in mutant embryos than in sibling embryos, and mutant embryos showed increased expression of several inflammatory cytokines after C. albicans infection. These findings indicate that myeloperoxidase deficiency alters the inflammatory response to fungal infection.

Topics: Animals; Candida albicans; Disease Models, Animal; Fish Proteins; Immunity, Innate; Mutation; Peroxidase; Zebrafish

Enhanced activity of neutrophil elastase leads to a protease-antiprotease imbalance, and plays an essential pathogenic role in acute lung injury (ALI) and acute respiratory distress syndrome. We assayed the pharmacological effects and mechanisms of the action of sirtinol in human neutrophils, and in neutrophil elastase (HNE)-induced paw edema and lipopolysaccharide (LPS)-mediated ALI in mice. Sirtinol significantly inhibited the activity of HNE from human neutrophils in response to various stimulators. The inhibitory effects on HNE activity were not mediated through protein kinase A, calcium, extracellular-regulated kinase, c-Jun N-terminal kinase, p38 mitogen-activated protein kinase, Akt, or Src family kinases. Analysis of enzymatic activities showed that sirtinol inhibited HNE activity in a concentration-dependent manner. These results demonstrate that sirtinol does not affect neutrophil function and is an HNE inhibitor. In addition, administration of sirtinol significantly inhibited HNE-induced paw edema, and attenuated the myeloperoxidase activity and reduced pulmonary wet/dry weight ratio in the LPS-induced ALI mouse model. Our study indicates that sirtinol has anti-inflammatory effects through direct inhibition of HNE activity and attenuates HNE-induced and LPS-mediated tissue or organ injury in vivo. Sirtinol is a novel HNE inhibitor and may have the potential for clinical application in the treatment of inflammatory lung diseases.

Topics: Acute Lung Injury; Animals; Benzamides; Disease Models, Animal; Humans; Leukocyte Elastase; Lipopolysaccharides; Male; Mice; Naphthols; Neutrophils; Peroxidase; Protein Kinases

The objective of this study was to investigate whether berberine could ameliorate allodynia induced by chronic constriction injury (CCI) of the sciatic nerve in rats. After inducement of CCI, significant increases in the number of paw lifts from a cold plate test (cold allodynia) and decreased paw withdrawal threshold in the von Frey hair stimulation test (mechanical allodynia) were observed. However, these cold and mechanical allodynia were markedly alleviated by berberine administration in a dose-dependent manner. Sciatic nerve myeloperoxidase and malondialdehyde activities were also attenuated by berberine administration. Continuous injection for 7 days induced no development of tolerance. The antiallodynic effect of 20 mg/kg berberine was comparable to that of amitriptyline 10 mg/kg. This study demonstrated that berberine could mitigate allodynia induced by CCI, a neuropathic pain model, and it suggested that the anti-inflammatory and antioxidative properties of berberine contributed to the antiallodynic effect in the CCI model.

Topics: Amitriptyline; Analgesics; Animals; Berberine; Cold Temperature; Constriction; Disease Models, Animal; Dose-Response Relationship, Drug; Hyperalgesia; Male; Malondialdehyde; Neuralgia; Pain Perception; Pain Threshold; Peroxidase; Rats; Sciatic Nerve; Treatment Outcome

Inflammatory hyperalgesia is a complex process that depends on the sensitization of primary nociceptive neurons triggered by proinflammatory mediators, such as interleukin 1β (IL-1β). Recently, the peripheral activation of caspase-1 (previously known as IL-1β-converting enzyme) was implicated in the induction of acute inflammatory pain by promoting the processing of IL-1β from its precursor form, pro-IL-1β. Caspase-1 activation in several systems requires the assembly of an intracellular molecular platform called an inflammasome. Inflammasomes consist of 1 nucleotide-binding oligomerization domain-like receptor (NLR), the adapter molecule apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC), and caspase-1. NLRP3 and NLRC4 inflammasomes are well described. However, the identity of the inflammasome that is involved in the peripheral activation of caspase-1 that accounts for acute inflammatory hyperalgesia has not been described. The present findings demonstrated that mice deficient in NLRC4 or ASC, but not in NLRP3, present reduced mechanical and thermal acute inflammatory hyperalgesia induced by carrageenan. The reduced hyperalgesia was accompanied by significant impairments in the levels of mature forms of IL-1β (p17) and caspase-1 (p20) compared to wild-type mice at the inflammatory site. Therefore, these results identified the inflammasome components NLRC4 and ASC as the molecular platform involved in the peripheral activation of caspase-1 and IL-1β maturation, which are responsible for the induction of acute inflammatory pain. In conclusion, our study provides new therapeutic targets for the control of acute inflammatory pain.

Topics: Animals; Apoptosis Regulatory Proteins; Calcium-Binding Proteins; Caspase 1; Caspases; Caspases, Initiator; Cytokines; Dinoprostone; Disease Models, Animal; Gene Expression Regulation; Hyperalgesia; Inflammation; Interleukin-1beta; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Pain; Pain Measurement; Pain Threshold; Peroxidase; Receptors, Interleukin-1 Type I

Animal models are ideal to study the pathomechanism and therapy of acute pancreatitis (AP). The use of L-arginine-induced AP model is nowadays becoming increasingly popular in mice. However, carefully looking through the literature, marked differences in disease severity could be observed. In fact, while setting up the L-arginine (2×4 g/kg i.p.)-induced AP model in BALB/c mice, we found a relatively low rate (around 15%) of pancreatic necrosis, whereas others have detected much higher rates (up to 55%). We suspected that this may be due to differences between mouse strains. We administered various concentrations (5-30%, pH = 7.4) and doses (2×4, 3×3, or 4×2.5 g/kg) of L-arginine-HCl in BALB/c, FVB/n and C57BL/6 mice. The potential gender-specific effect of L-arginine was investigated in C57BL/6 mice. The fate of mice in response to the i.p. injections of L arginine followed one of three courses. Some mice (1) developed severe AP or (2) remained AP-free by 72 h, whereas others (3) had to be euthanized (to avoid their death, which was caused by the high dose of L-arginine and not AP) within 12 h., In FVB/n and C57BL/6 mice, the pancreatic necrosis rate (about 50%) was significantly higher than that observed in BALB/c mice using 2×4 g/kg 10% L-arginine, but euthanasia was necessary in a large proportion of animals, The i.p. injection of lower L-arginine concentrations (e.g. 5-8%) in case of the 2×4 g/kg dose, or other L-arginine doses (3×3 or 4×2.5 g/kg, 10%) were better for inducing AP. We could not detect any significant differences between the AP severity of male and female mice. Taken together, when setting up the L-arginine-induced AP model, there are several important factors that are worth consideration such as the dose and concentration of the administered L arginine-HCl solution and also the strain of mice.

Topics: Amylases; Animals; Arginine; Disease Models, Animal; Female; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Pancreas; Pancreatitis, Acute Necrotizing; Peroxidase

Oral mucositis (OM) is a common complication of treatments for head and neck cancer, particularly radiotherapy with or without chemotherapy. OM is characterised by oral erythema, ulceration, and pain. The aim of this study was to evaluate the effect of azilsartan (AZT), an angiotensin II receptor antagonist, on 5-fluorouracil (5-FU)-induced oral mucositis (OM) in Syrian hamsters. OM was induced by the intraperitoneal administration of 5-FU on experimental days 1 (60 mg/Kg) and 2 (40 mg/Kg). Animals were pretreated with oral AZT (1, 5, or 10 mg/kg) or vehicle 30 min before 5-FU injection and daily until day 10. Experimental treatment protocols were approved by the Animal Ethics Committee Use/CEUA (Number 28/2012) of the UFRN. Macroscopic analysis and cheek pouch samples were removed for histopathologic analysis. Myeloperoxidase (MPO), Malonyldialdehyde (MDA), interleukin-1 beta (IL-1β), interleukin-10 (IL-10), and tumour necrosis factor-alpha (TNF-α) were analysed by Enzyme Linked Immuno Sorbent Assay (ELISA). Vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), keratinocyte growth factor (KGF), and transforming growth factor (TGF)-α were measured by immunohistochemistry. Analysis of variance followed by Bonferroni's test was used to calculate the means of intergroup differences (p ≤ 0.05). Treatment with 1 mg/kg AZT reduced levels MPO (p<0.01), MDA (p<0.5) and histological inflammatory cell infiltration, and increased the presence of granulation tissue. AZT treatment at 1 mg/kg reduced the TNF-α (p<0.05) and IL-1β (p<0.05) levels, increased the cheek pouch levels of IL-10 (p<0.01), and upregulated VEGF, FGF, KGF, and TGF-α. Administration of AZT at higher doses (5 and 10 mg/kg) did not significantly reverse the OM. AZT at a dose of 1 mg/kg prevented the mucosal damage and inflammation associated with 5-FU-induced OM, increasing granulation and tissue repair.

Topics: Animals; Bacteremia; Benzimidazoles; Cricetinae; Cytokines; Disease Models, Animal; Fibroblast Growth Factor 7; Fibroblast Growth Factors; Intercellular Signaling Peptides and Proteins; Interleukin-10; Interleukin-1beta; Leukocytes; Male; Oxadiazoles; Peroxidase; Stomatitis; Transforming Growth Factor alpha; Tumor Necrosis Factor-alpha; Up-Regulation; Vascular Endothelial Growth Factor A

Casodex (bicalutamide), an androgen receptor antagonist, is used for the treatment of prostate cancer. Recent evidences show that Akt signaling pathway exerts organ-protective effects after injury. The aim of this study was to investigate whether Akt plays any role in the casodex-mediated attenuation of hepatic injury after trauma-hemorrhagic shock. Male Sprague-Dawley rats underwent trauma hemorrhage (mean blood pressure kept at approximately 35-40 mm Hg for 90 min), followed by fluid resuscitation. During resuscitation, a single dose of casodex (5 mg/kg, intravenous) with and without a phosphatidylinositol 3-kinase inhibitor wortmannin (1 mg/kg, intravenous), wortmannin or vehicle was administered. Plasma aspartate aminotransferase and alanine aminotransferase levels and various hepatic parameters were measured at 24 h after resuscitation. One-way analysis of variance and the Tukey test were used for statistical analysis. These results showed that trauma hemorrhage increased hepatic myeloperoxidase activity, interleukin 6 and intercellular adhesion molecule 1 levels, and plasma aspartate aminotransferase and alanine aminotransferase concentrations. In the trauma hemorrhage rats treated with casodex, these parameters were significantly improved. Casodex treatment also increased hepatic phospho-Akt expression compared with vehicle-treated trauma hemorrhaged rats. Coadministration of wortmannin with casodex abolished the casodex-induced advantageous effects on the aforementioned parameters and hepatic injury. Our results suggest that the protective effect of casodex administration on attenuation of hepatic injury after trauma hemorrhage, which is, at least in part, through Akt-dependent pathway.

Topics: Alanine Transaminase; Androstadienes; Anilides; Animals; Aspartate Aminotransferases; Disease Models, Animal; Dose-Response Relationship, Drug; Hemorrhage; Intercellular Adhesion Molecule-1; Interleukin-6; Male; Nitriles; Peroxidase; Phosphoinositide-3 Kinase Inhibitors; Rats; Rats, Sprague-Dawley; Resuscitation; Shock, Hemorrhagic; Time Factors; Tosyl Compounds; Wortmannin

Lysophosphatidic acid (LPA) is a bioactive lipid mediator of inflammation via the LPA receptors 1-6. We and others have previously described proinflammatory and profibrotic activities of LPA signaling in bleomycin- or lipopolysaccharide (LPS)-induced pulmonary fibrosis or lung injury models. In this study, we investigated if LPA signaling plays a role in the pathogenesis of systemic sepsis from an abdominal source. We report here that antagonism of the LPA receptor LPA1 with the small molecule ki16425 reduces the severity of abdominal inflammation and organ damage in the setting of peritoneal endotoxin exposure. Pretreatment of mice with intraperitoneal ki16425 eliminates LPS-induced peritoneal neutrophil chemokine and cytokine production, liver oxidative stress, liver injury, and cellular apoptosis in visceral organs. Mice pretreated with ki16425 are also protected from LPS-induced mortality. Tissue myeloperoxidase activity is not affected by LPA1 antagonism. We have shown that LPA1 is associated with LPS coreceptor CD14 and the association is suppressed by ki16425. LPS-induced phosphorylation of protein kinase C δ (PKCδ) and p38 mitogen-activated protein kinase (p38 MAPK) in liver cells and interleukin 6 production in Raw264 cells are likewise blunted by LPA1 antagonism. These studies indicate that the small molecule inhibitor of LPA1, ki16425, suppresses cytokine responses and inflammation in a peritoneal sepsis model by blunting downstream signaling through the LPA1-CD14-toll-like receptor 4 receptor complex. This anti-inflammatory effect may represent a therapeutic strategy for the treatment of systemic inflammatory responses to infection of the abdominal cavity.

Topics: Alanine Transaminase; Animals; Apoptosis; Cell Line; Cytokines; Disease Models, Animal; HEK293 Cells; Hep G2 Cells; Humans; Isoxazoles; Lipopolysaccharide Receptors; Lipopolysaccharides; Liver; Male; Mice; Mice, Inbred C57BL; Peritonitis; Peroxidase; Propionates; Receptors, Lysophosphatidic Acid; Sepsis; Signal Transduction; Translational Research, Biomedical

Hemorrhagic shock is a leading cause of morbidity and mortality in surgery and trauma patients. Despite a large number of preclinical trials conducted to develop therapeutic strategies against hemorrhagic shock, there is still an unmet need for effective therapy for hemorrhage patients. Wnt/β-catenin signaling controls developmental processes and cellular regeneration owing to its central role in cell survival and proliferation. We therefore hypothesized that the activation of Wnt signaling reduces systemic injury caused by hemorrhagic shock.. Adult male Sprague-Dawley rats underwent hemorrhagic shock by controlled bleeding of the femoral artery to maintain a mean arterial pressure of 30 mm Hg for 90 minutes, followed by resuscitation with crystalloid equal to two times the shed blood volume. After resuscitation, animals were infused with Wnt agonist (5 mg/kg) or vehicle (20% dimethyl sulfoxide in saline). Blood and tissue samples were collected 6 hours after resuscitation for analysis.. Hemorrhagic shock increased serum levels of aspartate aminotransferase, lactate, and lactate dehydrogenase. Treatment with Wnt agonist significantly reduced these levels by 40%, 36%, and 77%, respectively. Wnt agonist also decreased blood urea nitrogen and creatinine by 34% and 56%, respectively. The treatment reduced lung myeloperoxidase activity and interleukin 6 messenger RNA by 55% and 68%, respectively, and significantly improved lung histology. Wnt agonist treatment increased Bcl-2 protein to sham values and decreased cleaved caspase 3 by 46%, indicating attenuation of hemorrhage-induced apoptosis in the lungs. Hemorrhage resulted in significant reductions of β-catenin protein levels in the lungs as well as down-regulation of a Wnt target gene, cyclin D1, while Wnt agonist treatment preserved these levels.. The administration of Wnt agonist attenuated hemorrhage-induced organ injury, inflammation, and apoptosis. This was correlated with the preservation of the Wnt signaling pathway. Thus, Wnt/β-catenin activation could be protective in hemorrhagic shock.

Topics: Animals; Benzodioxoles; Biomarkers; Blotting, Western; Crystalloid Solutions; Disease Models, Animal; Interleukin-6; Isotonic Solutions; Male; Peroxidase; Pyrimidines; Rats; Rats, Sprague-Dawley; Resuscitation; Shock, Hemorrhagic; Wnt Signaling Pathway

Toll-like receptor-4 has been implicated in modulating ischemia-reperfusion injury in cardiac, hepatic, renal, and cerebral models. However, its role in lung ischemia-reperfusion injury is unknown. We hypothesize that toll-like receptor-4 has a key role in initiating the inflammatory cascade in lung ischemia-reperfusion injury.. We used toll-like receptor-4 specific short interference RNA to achieve toll-like receptor-4 knockdown in rats prior to undergoing ischemia and reperfusion. Lungs were explanted and studied for protein expression and markers of lung injury. Additional animals were evaluated for cellular uptake of toll-like receptor-4 short interference RNA. Toll-like receptor-4 short interference RNA localized to the alveolar macrophage.. In animals pretreated with toll-like receptor-4 short interference RNA, toll-like receptor-4 expression and mitogen-activated protein kinase phosphorylation were suppressed. Markers of lung injury including permeability index, myeloperoxidase content, and bronchoalveolar lavage inflammatory cell counts were all reduced with toll-like receptor-4 knockdown.. Toll-like receptor-4 is critical in the development of lung ischemia-reperfusion injury and its activation in the alveolar macrophage may be the initiating step.

Topics: Animals; Biomarkers; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Lung; Male; Peroxidase; Random Allocation; Rats; Reference Values; Reperfusion Injury; Risk Assessment; RNA, Small Interfering; Sensitivity and Specificity; Toll-Like Receptor 4

Lung transplantation is a well-established treatment of end-stage lung disease; however, it is limited by a shortage of donor lungs. To overcome this problem, donation after cardiac death (DCD) and ex vivo lung perfusion (EVLP) are being widely investigated. In this study, the effect of hydrogen gas, a known antioxidant, was investigated on a DCD lung model during EVLP.. Ten pigs were randomized into either a control (n = 5) or a hydrogen group (n = 5). After fibrillation by electric shock, no further treatment was administered in order to induce warm ischaemic injury for 1 h. The lungs were then procured, followed by 4 h of EVLP. During EVLP, the lungs were ventilated with room air in the control group, and with 2% hydrogen gas in the hydrogen group. Oxygen capacity (OC), pulmonary vascular resistance (PVR) and peak airway pressure (PAP) were measured every hour, and the expressions of interleukin-1 beta (IL-1β), IL-6 (IL-6), IL-8 (IL-8) and tumour necrosis factor-alpha (TNF-α) were evaluated in lung tissue after EVLP. Pathological evaluations were performed using lung injury severity (LIS) scores and the wet/dry ratio was also measured.. The OC in the hydrogen group was higher than in the control group, but the difference was not statistically significant (P = 0.0862). PVR (P = 0.0111) and PAP (P = 0.0189) were statistically significantly lower in the hydrogen group. Compared with the control group, the hydrogen group had a statistically significantly lower expression of IL-1β (P = 0.0317), IL-6 (P = 0.0159), IL-8 (P = 0.0195) and TNF-α (P = 0.0159). The LIS scores (P = 0.0358) and wet/dry ratios (P = 0.040) were also significantly lower in the hydrogen group.. Hydrogen gas inhalation during EVLP improved the function of DCD lungs, which may increase the utilization of DCD lungs.

Topics: Animals; Cytokines; Death; Disease Models, Animal; Extracorporeal Circulation; Female; Graft Survival; Hydrogen; Lung; Lung Diseases; Lung Transplantation; Organ Preservation; Oxygen Consumption; Peroxidase; Random Allocation; Reference Values; Swine; Tissue Donors; Vascular Resistance; Warm Ischemia

Ulcerative colitis is a chronic inflammatory bowel disease. Recent studies reported a pivotal role of elevated intracellular calcium in this disorder. Coenzyme Q10 (CoQ10) and amlodipine are known to maintain cellular energy, decrease intracellular calcium concentration in addition to their antioxidant and anti-inflammatory properties.. The aim of this study was to evaluate the possible protective effects of CoQ10, amlodipine and their combination on ulcerative colitis.. Colitis was induced in rats by intracolonic injection of 3% acetic acid. CoQ10 (10 mg/kg), amlodipine (3 mg/kg) and their combination were administered for 8 consecutive days before induction of colitis.. Our results showed that administration of CoQ10, amlodipine and their combination decreased colon tissue malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), prostaglandin E2 (PGE2), myeloperoxidase (MPO) and heat shock protein (HSP70) levels induced by intracolonic injection of acetic acid and restored many of the colon structure in histological examination. On the other hand, they increased superoxide dismutase (SOD) activity, adenosine-5'-triphosphate (ATP) and interleukin-10 (IL-10) colonic contents.. Administration of either CoQ10 or amlodipine was found to protect against acetic acid-induced colitis. Moreover, their combination was more effective than individual administration of either of them. The protective effect of CoQ10 and amlodipine may be in part via their antioxidant, anti-inflammatory and energy restoration properties.

Topics: Amlodipine; Animals; Anti-Inflammatory Agents; Antioxidants; Colitis, Ulcerative; Colon; Dinoprostone; Disease Models, Animal; Energy Metabolism; Interleukin-1beta; Male; Malondialdehyde; Peroxidase; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha; Ubiquinone

To design a novel model to study Cobalt-60 (Co-60)-induced radiation mucositis and to describe the pathways involved in its development.. Hamsters' cheeks were treated with Co-60 radiation (10, 20, 30 or 35 Gy). Three days later, oral mucosa scarification was performed with a needle. The animals were euthanized at day 13 (D + 13) after irradiation. Gross and microscopic alterations were evaluated by a new score system that we developed. Also, neutrophil infiltration, tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-10, inducible nitric oxide synthase (iNOS), nitric oxide (NO) and nitrite were assessed in oral mucosa. We also tried to establish the roles of TNF-α and IL-1β and iNOS in our model using pharmacological approaches with pentoxiphylline (PTX) and aminoguanidine (AMG), respectively.. We found that a single administration of 35 Gy of Co-60, followed by mechanical scratches 3 days later, induced oral mucositis in hamsters. Animals with mucositis lost weight and had a survival median of 13 days, the time at which peak inflammation occurs. We noticed increased levels of NO, iNOS, TNF-α and IL-1β and a reduced concentration of IL-10. PTX partially prevented the mucositis phenotype by reducing the levels of inflammatory mediators and iNOS expression. Additionally, AMG, a selective inhibitor of iNOS, reduced Co-60-induced oral mucositis through reducing NO production.. We described a novel model of megavoltage radiation-induced oral mucositis in hamsters. TNF-α, IL-1β and NO seem to play a role in the pathophysiology of this model.

Topics: Animals; Cobalt Radioisotopes; Cricetinae; Cytokines; Disease Models, Animal; Guanidines; Head and Neck Neoplasms; Humans; Inflammation Mediators; Interleukin-1beta; Male; Mesocricetus; Nitric Oxide; Nitric Oxide Synthase Type II; Pentoxifylline; Peroxidase; Radiation Injuries, Experimental; Radiotherapy, High-Energy; Stomatitis; Tumor Necrosis Factor-alpha

Acute hypercapnia maintains the microcirculatory oxygenation of the splanchnic region during sepsis. The first aim of this study was to characterize the role of K(+)ATP channels on the microcirculatory flow and oxygenation during acute moderate hypercapnia. The second aim was to investigate whether a short period of hypercapnia induces detrimental effects in an otherwise undamaged rodent lung.. Experiments were performed on 60 male Wistar rats. A moderate polymicrobial sepsis was induced by colon ascendens stent peritonitis (CASP) surgery. 24h after induction of sepsis volume-controlled and pressure-limited ventilation was established for 120 min, with either normocapnic (pCO2 35-45 mmHg) or moderate hypercapnic ventilation targets (pCO2 65-75 mmHg) and with or without non-selective K(+)ATP channel blockade with glibenclamide. Microcirculatory blood flow of the colonic wall as well as oxygen delivery and consumption were assessed with tissue laser Doppler and reflectance spectrophotometry. Hemodynamic variables were recorded and plasma cytokine levels and myeloperoxidase levels of the lungs were analyzed.. In septic animals microcirculatory oxygenation deteriorated progressively with normocapnia (-11.7 ± 11.8%) but was maintained (-2.9 ± 5.6%) with hypercapnia. This effect was associated with an increased microcirculatory oxygen consumption in septic animals with normocapnia (+25.7 ± 37.1%) that was decreased in the hypercapnia groups (-7.2 ± 28.1%). The effect of hypercapnia in septic animals was not altered by additional K(+)ATP channel blockade (-5.7 ± 32.7%). Hypercapnia neither induced an inflammatory response in lungs nor altered the systemic cytokine response.. The observed beneficial effect of hypercapnia on microvascular oxygenation of the colon in sepsis does not seem to be mediated via K(+)ATP channels.

Topics: Adenosine Triphosphate; Animals; Colon; Cytokines; Disease Models, Animal; Glyburide; Hemodynamics; Hypercapnia; Laser-Doppler Flowmetry; Lung; Male; Microcirculation; Oxygen; Oxygen Consumption; Peritonitis; Peroxidase; Potassium Channels; Rats; Rats, Wistar; Sepsis

To investigate the protective effect of bifidobacterium in endotoxin-induced intestinal injury in preweaning rats.. Preweaning rats were randomly divided into three groups (n = 40 for each): a control group (group C), a model group (group E) and a treatment group (group T). Both groups E and T were intraperitoneally injected with lipopolysaccharide (LPS) at a dose of 5 mg/kg (5 mg/L in normal saline), and group T was intragastrically administrated with bifidobacterium suspension (2.0 × 10(9) CFU/mL, 0.5 mL each time, twice a day, until the end of the experiment) 7 d before LPS administration. Group C was intraperitoneally injected with normal saline. After intraperitoneal injection and intragastric administration, the rats were placed back to the initial cage to receive breast feeding. The rats were killed at 2, 6, 12, 24 or 72 h, respectively, after endotoxin or physiological saline injection to collect serum and ileal tissue samples. Myeloperoxidase (MPO) contents in serum and ileum were detected at different times, and expression of ileal defensin-5 mRNA was evaluated by reverse transcription-polymerase chain reaction.. Serum and ileal MPO contents in group E were significantly higher than those in group C (serum contents: 107.50 ± 17.70 vs 157.14 ± 24.67, P < 0.05; ileal contents: 1.03 ± 0.21 vs 1.57 ± 0.33, P < 0.05), which peaked at 12 h and 6 h, respectively. MPO contents in group T were significantly lower than those in group E (serum contents: 114.38 ± 24.56 vs 145.25 ± 23.62, P < 0.05; ileal contents: 1.25 ± 0.24 vs 1.57 ± 0.33, P < 0.05). The expression of defensin-5 mRNA in group E was significantly higher than that in group C (0.953 ± 0.238 vs 0.631 ± 0.146, P < 0.05), which peaked at 2 h, and then decreased gradually. The expression of defensin-5 mRNA in group T was significantly lower than that in group E (0.487 ± 0.149 vs 0.758 ± 0.160, P < 0.05) apparently in 24 h. The expression of defensin-5 mRNA at 2 h in group T was significantly higher than that in group C (0.824 ± 0.158 vs 0.631 ± 0.146, P < 0.05).. MPO and defensin-5 mRNA increase in preweaning rats with LPS-induced intestinal injury. Bifidobacterium protects the gut by inhibiting MPO activity, not by increasing defensin-5 secretion.

Topics: Animals; Animals, Newborn; Bifidobacterium; Defensins; Disease Models, Animal; Female; Ileal Diseases; Ileum; Lactation; Lipopolysaccharides; Peroxidase; Probiotics; Rats, Wistar; RNA, Messenger; Time Factors

The role of the adenosine A3 receptor (A3AR) in experimental colitis is controversial. The A3AR agonist N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide (IB-MECA) has been shown to have a clinical benefit, although studies in A3AR-deficient mice suggest a pro-inflammatory role. However, there are no studies on the effect of 2-Cl-IB-MECA and the molecular mechanism of action of A3AR in murine colitis models in vivo. Is it the same as that observed in vitro? The interaction between 2-CL-IB-MECA and A3AR in a murine colitis model and the signaling pathways associated with this interaction remain unclear. Here we demonstrate a role for the NF-κB signaling pathway and its effect on modifying the activity of proinflammatory factors in A3AR-mediated biological processes. Our results demonstrated that A3AR activation possessed marked effects on experimental colitis through the NF-κB signaling pathway.

Topics: Adenosine; Adenosine A3 Receptor Agonists; Animals; Colitis; Cytokines; Disease Models, Animal; Gene Expression; Inflammation Mediators; Intestinal Mucosa; Mice; NF-kappa B; Peroxidase; Receptor, Adenosine A3; Signal Transduction

Recent studies suggest that endothelial progenitor cells (EPCs) and platelets have an important role in repair following vascular injury. Although evidence suggest that platelets are essential in EPC attracting, homing and differentiation to the injury site; however, the platelet effects on EPC function in atherosclerosis have received less attention. In this context, we followed the consequences of circulating EPCs and platelet microparticles (PMPs) administration on platelet-EPC interaction in atherosclerosis and the involved mechanisms. The experiments were performed on Golden Syrian hamsters divided in five equal groups: control (C), hypertensive-hypercholesterolemic (HH), HH treated with EPCs (HH-EPCs) or PMPs (HH-PMPs) and HH treated with EPCs and PMPs (HH-EPCs-PMPs).. Compared with C group, EPCs isolated from HH and HH-PMPs groups presented a reduction of endothelial nitric oxide synthase and vascular endothelial growth factor expressions and an increase in thrombospondin-1 expression and inflammatory molecule secretion: interleukin 8 (IL)-8, myeloperoxidase (MPO) and plasminogen activator inhibitor-1 (PAI-1). EPC administration had beneficial effects, the obtained results being similar with those from the C group, while the combination with PMPs did not improve the EPC influences. Static coincubation of EPCs from HH and HH-PMPs with analogous platelets resulted in an increased EPC adhesion/migration, and IL-8, monocyte chemotactic protein-1, regulated on activation, normal T expressed and secreted, MPO and PAI-1 release, explained by the platelet hyperaggregability induced by pronounced distribution of vasodilator-stimulated phosphoprotein and filamentous actin, and the secretion of proinflammatory factors: IL-1β, -6, -8, CD40 ligand. EPC therapy alone revealed an impaired platelet-EPC interaction directly correlated with the reduction of inflammatory markers and platelet aggregability. Moreover, in a dynamic flow system, EPCs and platelets from HH and HH-PMPs exhibited weakened interplay abilities, while EPC transplantation reinforces them.. The present study demonstrates that HH animals revealed functional impairment of EPCs and platelets, which correlate with their reduced contribution to re-endothelialisation at the injury site, although in vitro exposure to immobilised platelets promotes their adhesion and migration. EPC administration alone recovers EPC/platelet functions and consolidates their interaction under dynamic flow conditions. These findings disclose new advances in understanding the platelet-EPC interaction and its role in the vascular repair.

Topics: Animals; Atherosclerosis; Blood Platelets; CD40 Ligand; Cell Adhesion; Cell Adhesion Molecules; Cell Movement; Chemokine CCL2; Cricetinae; Disease Models, Animal; Endothelial Progenitor Cells; Inflammation; Interleukin-8; Microfilament Proteins; Nitric Oxide Synthase Type III; Peroxidase; Phosphoproteins; Plasminogen Activator Inhibitor 1; Thrombospondin 1; Vascular Endothelial Growth Factor A

Kaliotoxin 2 (KTX2), a neurotoxin isolated from Androctonus australis hector scorpion venom, presents a high affinity with the voltage-gated potassium channels. The targets of KTX2 in the brain and its toxic effects on the cerebral cortex have been extensively studied; however, its deleterious systemic effects on other organ systems have not yet been investigated. Inflammatory response induced by KTX2 is supported by cytokine release which could provoke multiple organ dysfunction and diverse biological disorders in mammals. The possibility that inflammatory response and brain injuries induced by KTX2 may lead to functional disturbances, e.g. in the pancreas and the liver, were investigated. The contribution of IL-6 and TNF-α to the modulation of pathophysiological effects induced by KTX2 was also tested.. NMRI mice were injected by the intracerebroventricular route with a sublethal dose of KTX2 or saline solution. Inflammatory response and oxidative stress were assessed in sera and tissue homogenates. Biomarkers of pancreatic and hepatic functions and the correlation with tissue damage in the brain, liver and pancreas were also analyzed.. The obtained results revealed that KTX2 injection induced an inflammatory process activation and imbalanced redox status. It also induced severe alterations in cerebral cortex, hepatic and pancreatic tissues associated with a significant increase in pancreatic and hepatic pathological biomarkers. Cytokine antagonists injected 30 min prior to KTX2 led to a significant reduction of all disturbances induced by KTX2.. In addition to its significant toxicity on the central nervous system, KTX2 can also affect pancreatic and hepatic functions, probably by an indirect mechanism involving activation of the inflammatory response with release of IL-6 and TNF-α.

Topics: Alanine Transaminase; Amylases; Animals; Aspartate Aminotransferases; Brain Injuries; Catalase; Cytokines; Disease Models, Animal; Encephalitis; Glutathione; Leukocyte Count; Lipid Metabolism; Malondialdehyde; Matrix Metalloproteinases; Mice; Neurotoxins; Neutrophil Infiltration; Peroxidase; Scorpion Venoms; Time Factors

Pathogenesis and treatment of inflammatory gut barrier failure is an important problem in critical care. In this study, we examined the role of pioglitazone, an agonist of peroxisome proliferator-activated receptor gamma, in gut barrier failure during experimental peritonitis in rats.. Male rats were randomly divided into three groups as follows: sham, sepsis, and sepsis + pioglitazone. Sepsis was achieved by means of the cecal ligation and puncture (CLP). Pioglitazone was administered intraperitoneally (10 mg/kg/d) for 7 d before the experiment. Animals were killed at 24 h or followed 72 h for survival. The tissue level of tumor necrosis factor-α, interleukin-6, superoxide dismutase, malondialdehyde, and myeloperoxidase was measured. Intestinal mucosa injury was assessed histologically. The plasma fluorescein isothiocyanate-dextran, D-lactic acid, and intestinal diamine oxidase were determined to evaluate the permeability and integrity of intestinal mucosal epithelium. Vena cava blood and tissue samples were used to monitor bacterial translocation.. Intestinal inflammation, oxidize stress, neutrophil infiltration, morphology injury, and impaired permeability of the small intestine in the CLP group were found more severe than those in the sham group. Application of pioglitazone not only minimized all the indicators of intestinal injury and barrier failure but also improved the survival of septic rats induced by CLP.. Our novel findings suggest that pioglitazone could protect against intestinal injury and maintain intestinal barrier integrity and might be a useful strategy to ameliorate intestinal failure in polymicrobial sepsis.

Topics: Amine Oxidase (Copper-Containing); Animals; Bacterial Translocation; Disease Models, Animal; Interleukin-6; Intestinal Mucosa; Intestines; Male; Oxidative Stress; Permeability; Peroxidase; Pioglitazone; PPAR gamma; Rats; Rats, Sprague-Dawley; Sepsis; Thiazolidinediones; Tumor Necrosis Factor-alpha

Myeloperoxidase (MPO) locally contributes to organ damage in various chronic inflammatory conditions by generating reactive intermediates. The contribution of MPO in the development of experimental lupus is unknown. The aim of this study was to define the role of MPO in murine lupus nephritis (LN).. LN was induced in C57BL/6 wild-type (WT) and MPO knockout (MPO(-/-) ) mice by intraperitoneal injection of pristane. Autoimmunity and glomerulonephritis were assessed 20 and 40 weeks after pristane administration. Cell apoptosis, leukocyte accumulation, and cytokine levels in the peritoneal cavity of WT and MPO(-/-) mice were assessed 3 or 6 days after pristane injection.. MPO(-/-) mice developed more severe nephritis than did WT mice 20 and 40 weeks after pristane injection, despite having reduced glomerular deposition of antibody and complement and diminished levels of markers of oxidative stress (oxidized DNA and glutathione sulfonamide). Enhancement of renal disease in MPO-deficient mice correlated with increased accumulation of CD4+ T cells and macrophages in glomeruli, which, in turn, was associated with augmented generation of CD4+ T cell responses and increased activation and migration of dendritic cells in secondary lymphoid organs. In addition, the enhanced renal injury in MPO(-/-) mice was associated with increased glomerular accumulation of neutrophils and deposition of neutrophil extracellular traps. MPO deficiency also increased early cell apoptosis, leukocyte accumulation, and proinflammatory cytokine expression in the peritoneum.. MPO attenuates pristane-induced LN by inhibiting early inflammatory responses in the peritoneum and limiting the generation of CD4+ T cell autoimmunity in secondary lymphoid organs.

Topics: Animals; Apoptosis; Autoimmunity; CD4-Positive T-Lymphocytes; Cytokines; Disease Models, Animal; Female; Injections, Intraperitoneal; Kidney Glomerulus; Lupus Nephritis; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Oxidative Stress; Peritoneum; Peroxidase; Terpenes

Down-regulation of some hepatic cytochrome P450s (CYP450s) was observed in patients and animals with ulcerative colitis (UC). This study examined changes of CYP450s activities in microsomes of liver (RLMs), intestine (RIMs) and kidney (RRMs) from rats with experimental acute colitis induced by 5% dextran sulfate sodium (DSS) for 7days and those receiving DSS treatment followed by 7-d cessation through measuring 6α-(CYP1A1), 7α-(CYP2A1), 16α-(CYP2C11) and 2β-/6β-(CYP3A2) hydroxytestosterone (OHT) formed from testosterone. Both pro-(IL-1β, IL-6, TNF-α) and anti-(IL-4, IL-10) inflammatory cytokines were elevated in acute colitis, while the production of the former was enhanced and that of the latter declined by DSS withdrawal. In RLMs, the CYP2A1 activity was significantly increased at DSS stimulation and partially returned to normal level when DSS treatment was terminated. Activity of other CYP450s were decreased by acute colitis and remained after DSS withdrawal. In RRMs, formations of 6α-, 16α- and 2β-OHT significantly declined in acute colitis and DSS termination further potentiated the down-regulation, while 7α-OHT formation was suppressed at DSS stimulation and remained after DSS withdrawal. The formation of 6β-OHT only showed significant decrease after DSS withdrawal. Two metabolites (6α- and 6β-OHT) formed in RIMs and 6β-OHT formation was significantly decreased by DSS stimulation and continued after DSS treatment halted. These findings indicate that the alterations of CYP450s activities vary with organ, CYP isoforms and colitis status, which arouse cautions on efficacy and toxicity of drug therapy during disease progression.

Topics: Animals; Aryl Hydrocarbon Hydroxylases; Colitis; Colitis, Ulcerative; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP3A; Cytochrome P450 Family 2; Cytokines; Disease Models, Animal; Intestinal Mucosa; Intestines; Kidney; Male; Microsomes; Microsomes, Liver; Peroxidase; Rats, Sprague-Dawley; Steroid 16-alpha-Hydroxylase; Steroid Hydroxylases; Testosterone

Myocardial infarction (MI) is associated with apoptosis in the amygdala and, ultimately, with clinical signs of depression. Different treatments have proven to be beneficial in preventing depression, including combination of the probiotics Lactobacillus helveticus and Bifidobacterium longum for prophylaxis. We have speculated previously that the benefit of these probiotics is due to their anti-inflammatory properties, and evidence suggests that an intact vagus nerve is important for this effect to occur. This study was designed to ascertain vagus nerve involvement in the beneficial influence of probiotics on caspase activities in our post-MI animal model of depression.. Probiotics and/or vehicle were administered daily to male adult rats, 14 days before MI and until euthanasia. Vagotomy was performed in subgroups of rats 40 min before MI. They were sacrificed after 3 days of reperfusion, and MI size was assessed along with caspase-3 and -8 activities in the amygdala.. Probiotics had no effect on infarct size but vagotomy increased it. Caspase-3 and caspase-8 activities in the amygdala were higher in MI than in sham-operated rats, and this outcome was reversed by probiotics. The beneficial influence of probiotics was abolished by vagotomy.. Our data indicate that the effect of probiotics on caspase activities in the amygdala after MI depends on an intact vagus nerve.

Topics: Amygdala; Animals; Apoptosis; Bifidobacterium; Caspase 3; Caspase 8; Depression; Disease Models, Animal; Heart; Intestine, Small; Lactobacillus helveticus; Male; Myocardial Infarction; Peroxidase; Probiotics; Rats; Vagotomy

Alcohol consumption has been commonly associated with gastric mucosal lesions including gastric ulcer. Diosmin (DIO) is a natural citrus flavone with remarkable antioxidant and anti-inflammatory features that underlay its protection against cardiac, hepatic and renal injuries. However, its impact on gastric ulcer has not yet been elucidated. Thus, the current study aimed to investigate the potential protective effects of DIO against ethanol-induced gastric injury in rats. Pretreatment with DIO (100 mg/kg p.o.) attenuated the severity of ethanol gastric mucosal damage as evidenced by lowering of ulcer index (UI) scores, area of gastric lesions, histopathologic aberrations and leukocyte invasion. These actions were analogous to those exerted by the reference antiulcer sucralfate. DIO suppressed gastric inflammation by curbing of myeloperoxidase (MPO) and tumor necrosis factor-α (TNF-α) levels along with nuclear factor kappa B (NF-κB) p65 expression. It also augmented the anti-inflammatory interleukin-10 (IL-10) levels. Meanwhile, DIO halted gastric oxidative stress via inhibition of lipid peroxides with concomitant enhancement of glutathione (GSH), glutathione peroxidase (GPx) and the total antioxidant capacity (TAC). With respect to gastric mucosal apoptosis, DIO suppressed caspase-3 activity and cytochrome C (Cyt C) with enhancement of the anti-apoptotic B cell lymphoma-2 (Bcl-2) in favor of cell survival. These favorable actions were associated with upregulation of the gastric cytoprotective prostaglandin E2 (PGE2) and nitric oxide (NO). Together, these findings accentuate the gastroprotective actions of DIO in ethanol gastric injury which were mediated via concerted multi-pronged actions, including suppression of gastric inflammation, oxidative stress and apoptosis besides boosting of the antioxidant and the cytoprotective defenses.

Topics: Animals; Anti-Ulcer Agents; Diosmin; Disease Models, Animal; Ethanol; Gene Expression Regulation; Male; Oxidative Stress; Peroxidase; Rats; Rats, Wistar; Stomach Ulcer; Sucralfate; Tumor Necrosis Factor-alpha

Ulcerative colitis (UC) involves chronic inflammation of the large intestine. Several agents are used to treat UC, but adverse side effects are remaining problems. We examined the effect of tropisetron as a new type of drug for UC using a dextran sulfate sodium (DSS)-induced model of colitis in mice. We developed a DSS-induced model of colitis and calculated the Disease Activity Index and colon length. We measured myeloperoxidase activity and determined the protein level and mRNA level of cytokines in the colon. DSS-induced colitis was ameliorated by administration of tropisetron and PNU282987. Pre-administration of methyllycaconitine diminished the suppressive effect of tropisetron upon DSS-induced colitis. These findings suggested that α7 nicotinic acetylcholine receptors (α7 nAChRs) were related to the suppressive effect of tropisetron on DSS-induced colitis. Additionally, stimulation of α7 nAChRs decreased the colon level of interleukin-6 and interferon-γ upon DSS administration. Furthermore, stimulation of α7 nAChRs decreased macrophage infiltration, with expression of α7 nAChR increased by DSS administration. These results suggest that the underlying mechanism of this suppressive effect on DSS-induced colitis is via stimulation of α7 nAChRs and involves suppression of expression of pro-inflammatory cytokines. Tropisetron could be a new type of therapeutic agent for UC.

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Animals; Colitis; Colitis, Ulcerative; Colon; Cytokines; Dextran Sulfate; Disease Models, Animal; Indoles; Inflammation Mediators; Male; Mice, Inbred ICR; Peroxidase; Tropisetron

Idiopathic pulmonary fibrosis (IPF) is characterized by alveolitis, progressing into fibrosis. Due to the involvement of both endothelin and platelet-derived growth factor signaling in IPF, combination effects of a bosentan and imatinib were studied in mouse model of bleomycin-induced pulmonary fibrosis.. Mice subjected to bleomycin instillation (0.05 U) and were administered with either bosentan (100 mg/kg) and/or imatinib (50 mg/kg). Inflammatory cell count, total protein estimation in bronchoalveolar lavage fluid, lung edema, superoxide dismutase, catalase, myeloperoxidase activities, and Hematoxylin & Eosin staining were performed on day 7. Hydroxyproline content, α-smooth muscle actin (SMA), collagens I and III gene expression analysis, immunohistochemistry, matrix metalloproteinases-9 and -2 activities, trichrome and sirius red staining were performed on day 21.. Combination treatment with bosentan and imatinib prevented bleomycin-induced mortality and loss of body weight more than the individual agents. On day 7, the combination therapy attenuated bleomycin-induced increase of total and differential inflammatory cell counts, total proteins, lung wet/dry weight ratio, myeloperoxidase activity, lung inflammatory cell infiltration more than individual agents alone. Bosentan but not imatinib ameliorated superoxide dismutase and catalase activities, which were lowered following bleomycin instillation. On day 21, combination therapy ameliorated bleomycin-induced increase of fibrosis score, collagen deposition, protein and gene expression of SMA, mRNA levels of collagens-I and -III, matrix metalloproteinase-9 and -2 activities more than monotherapy.. Combination of bosentan and imatinib exerted more enhanced protection against bleomycin-induced inflammation and fibrosis than either of the agents alone.

Topics: Actins; Animals; Anti-Inflammatory Agents; Bleomycin; Bosentan; Catalase; Collagen Type I; Collagen Type II; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Female; Hydroxyproline; Idiopathic Pulmonary Fibrosis; Imatinib Mesylate; Lung; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice, Inbred C57BL; Oxidative Stress; Peroxidase; Pneumonia; Pulmonary Edema; RNA, Messenger; Sulfonamides; Superoxide Dismutase; Time Factors

Thespesia populnea Sol. ex Correa (Malvaceae), an indigenous tree species in India, is of interest to researchers because traditionally its heartwood is used in the treatment of ulcer and colic pain.. To validate its folk use in the treatment of ulcerative colitis (UC).. Mice were administered intrarectal DNBS and then treated with different plant extracts (100 and 200 mg/kg), 30 min before and 24 and 48 h after DNBS infusion. Colonic mucosal injury was assessed by macroscopic and histological examination. Furthermore, malondialdehyde (MDA), myeloperoxidase (MPO), protease, and hemoglobin (Hb) contents were measured in tissue and blood samples.. Administration of various extracts ameliorated macroscopic and microscopic scores which were altered due to DNBS treatment in mice. Hb concentration in blood was restored significantly by the aqueous extract to 17.20 ± 0.5, which was reduced to 13.80 ± 0.5 after treatment with DNBS. MDA level was increased to 10.82 nm/mg and 10.25 nm/ml in tissue and blood, respectively, due to DNBS treatment which was reduced to 2.69 nm/mg and 3.59 nm/ml in tissue and blood, respectively, by aqueous extract treatment. Similarly, MPO level was increased to 412 U/mg and 404 U/ml in tissue and blood, respectively, which was significantly reduced to 205 U/mg and 219 U/ml in tissue and blood, respectively, by aqueous extract treatment. Aqueous extract significantly reduced protease activity which was markedly increased in DNBS-treated animals.. Aqueous extract of heartwood of T. populnea is effective in the treatment of UC.

Topics: Animals; Anti-Inflammatory Agents; Biomarkers; Colitis, Ulcerative; Colon; Dextran Sulfate; Disease Models, Animal; Gastrointestinal Agents; Hemoglobins; Intestinal Mucosa; Male; Malondialdehyde; Malvaceae; Mice; Peptide Hydrolases; Peroxidase; Phytotherapy; Plant Extracts; Plants, Medicinal

Celastrol had been proved effective in the treatment for IBD, probably with the modulation of oxidative stress, inflammatory cytokines and intestinal homeostasis. This study was aimed to investigate whether celastrol could ameliorate the inflammation of IL-10 deficient mice, a murine model of Crohn's disease (CD) with the induction of autophagy.. The mice included were divided into four groups, ##WT group, IL-10(-/-) group, Cel group and Control group (celastrol+3-Methyladenine). Celastrol (2 mg/kg) treatment by gavage was administered to mice daily over one week. 3-Methyladenine (autophagy inhibitors) was administered at a dose of 30 mg/kg by intraperitoneal injection. The histological evaluation of the colon, tissue myeloperoxidase (MPO), and colon inflammation of mice in the four groups was evaluated and compared. Furthermore, the PI3K/Akt/mTOR pathway and the status of autophagy in intestine affected by celastrol were also assessed.. The one-week administration of celastrol ameliorated established colitis in IL-10 deficient mice, associated with a reduction of marked histological inflammation, a decreased colon MPO concentration and suppression of colonic proinflammatory cytokine. Furthermore, the decreased neutrophil infiltration in proximal colon and improvement of inflammation in the Cel group was much more obvious than that in the Control group. The Western blotting analysis of the PI3K/Akt/mTOR pathway and autophagy showed that celastrol treatment up-regulated the autophagy of colon tissue by suppressing the PI3K/Akt/mTOR signaling pathway.. Celastrol ameliorates experimental colitis in IL-10 deficient mice via the up-regulation of autophagy by suppressing the PI3K/Akt/mTOR signaling pathway.

Topics: Animals; Anti-Inflammatory Agents; Autophagy; Blotting, Western; Colon; Crohn Disease; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Interleukin-10; Mice, Inbred C57BL; Mice, Knockout; Pentacyclic Triterpenes; Peroxidase; Real-Time Polymerase Chain Reaction; Signal Transduction; TOR Serine-Threonine Kinases; Triterpenes

Liver ischemia reperfusion (IR) injury triggers a systemic inflammatory response and is the main cause of organ dysfunction and adverse postoperative outcomes after liver surgery. Pentoxifylline (PTX) and hypertonic saline solution (HTS) have been identified to have beneficial effects against IR injury. This study aimed to investigate if the addition of PTX to HTS is superior to HTS alone for the prevention of liver IR injury.. Male Wistar rats were allocated into three groups. Control rats underwent 60 minutes of partial liver ischemia, HTS rats were treated with 0.4 mL/kg of intravenous 7.5% NaCl 15 minutes before reperfusion, and HPTX group were treated with 7.5% NaCl plus 25 mg/kg of PTX 15 minutes before reperfusion. Samples were collected after reperfusion for determination of ALT, AST, TNF-alpha, IL-6, IL-10, mitochondrial respiration, lipid peroxidation, pulmonary permeability and myeloperoxidase.. HPTX significantly decreased TNF-alpha 30 minutes after reperfusion. HPTX and HTS significantly decreased ALT, AST, IL-6, mitochondrial dysfunction and pulmonary myeloperoxidase 4 hours after reperfusion. Compared with HTS only, HPTX significantly decreased hepatic oxidative stress 4 hours after reperfusion and pulmonary permeability 4 and 12 hours after reperfusion.. This study showed that PTX added the beneficial effects of HTS on liver IR injury through decreases of hepatic oxidative stress and pulmonary permeability.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Capillary Permeability; Disease Models, Animal; Drug Synergism; Evans Blue; Free Radical Scavengers; Interleukin-1; Interleukin-10; Ischemia; Lipid Peroxidation; Liver Diseases; Lung; Male; Oxidative Stress; Pentoxifylline; Permeability; Peroxidase; Rats; Rats, Wistar; Reperfusion Injury; Saline Solution, Hypertonic; Tumor Necrosis Factor-alpha

Temporal expression of chemokines is a crucial factor in the regulation of renal ischemia/reperfusion (I/R) injury and repair. Beside their role in the migration and activation of inflammatory cells to sites of injury, chemokines are also involved in other processes such as angiogenesis, development and migration of stem cells. In the present study we investigated the role of the chemokine MCP-1 (monocyte chemoattractant protein-1 or CCL2), the main chemoattractant for monocytes, during renal I/R injury. MCP-1 expression peaks several days after inducing renal I/R injury coinciding with macrophage accumulation. However, MCP-1 deficient mice had a significant decreased survival and increased renal damage within the first two days, i.e. the acute inflammatory response, after renal I/R injury with no evidence of altered macrophage accumulation. Kidneys and primary tubular epithelial cells from MCP-1 deficient mice showed increased apoptosis after ischemia. Taken together, MCP-1 protects the kidney during the acute inflammatory response following renal I/R injury.

Topics: Animals; Apoptosis; Chemokine CCL2; Cytokines; Disease Models, Animal; Gene Expression; Genes, Lethal; Kidney Tubules; Leukocytes; Macrophages; Male; Mice; Mice, Knockout; Peroxidase; Reperfusion Injury; RNA, Messenger; Time Factors; Up-Regulation

Inflammatory bowel diseases (IBD) are complex multi-factorial diseases with increasing incidence worldwide but their treatment is far from satisfactory. Unconventional strategies have consequently been investigated, proposing the use of cells as an effective alternative approach to IBD. In the present study we examined the protective potential of exogenously administered human umbilical cord derived mesenchymal stem cells (UCMSCs) against Dextran Sulfate Sodium (DSS) induced acute colitis in immunodeficient NOD.CB17-Prkdc (scid)/J mice with particular attention to endoplasmic reticulum (ER) stress.. UCMSCs were injected in NOD.CB17-Prkdc (scid)/J via the tail vein at day 1 and 4 after DSS administration. To verify attenuation of DSS induced damage by UCMSCs, Disease Activity Index (DAI) and body weight changes was monitored daily. Moreover, colon length, histological changes, myeloperoxidase and catalase activities, metalloproteinase (MMP) 2 and 9 expression and endoplasmic reticulum (ER) stress related proteins were evaluated on day 7.. UCMSCs administration to immunodeficient NOD.CB17-Prkdc (scid)/J mice after DSS damage significantly reduced DAI (1.45 ± 0.16 vs 2.08 ± 0.18, p < 0.05), attenuating the presence of bloody stools, weight loss, colon shortening (8.95 ± 0.33 cm vs 6.8 ± 0.20 cm, p < 0.01) and histological score (1.97 ± 0.13 vs 3.27 ± 0.13, p < 0.001). Decrease in neutrophil infiltration was evident from lower MPO levels (78.2 ± 9.7 vs 168.9 ± 18.2 U/g, p < 0.01). DSS treatment enhanced MMP2 and MMP9 activities (>3-fold), which were significantly reduced in mice receiving UCMSCs. Moreover, positive modulation in ER stress related proteins was observed after UCMSCs administration.. Our results demonstrated that UCMSCs are able to prevent DSS-induced colitis in immunodeficient mice. Using these mice we demonstrated that our UCMSCs have a direct preventive effect other than the T-cell immunomodulatory properties which are already known. Moreover we demonstrated a key function of MMPs and ER stress in the establishment of colitis suggesting them to be potential therapeutic targets in IBD treatment.

Topics: Acute Disease; Animals; Body Weight; Catalase; Colitis; Colon; Dextran Sulfate; Disease Models, Animal; Humans; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Mice, Inbred NOD; Peroxidase; Severity of Illness Index; Transplantation, Heterologous; Umbilical Cord

Acute pancreatitis (AP) is an inflammatory disease characterized by acinar cell damage and inflammation of the pancreas with infiltration of leukocytes, predominantly neutrophils. We investigated whether neutrophil depletion protects against experimental AP induced by L-arginine.. AP was induced in C57BL/6 mice via two intraperitoneal L-arginine (4 g/kg) injections. Mice were pretreated with 250 and 100 µg anti-Gr-1 antibody via intraperitoneal injection at 24 and 4 h, respectively, before L-arginine challenge for neutrophil depletion. At 48 and 72 h after injection, the severity of AP was determined with the aid of biochemical and histological analyses. Amylase and MPO activity was detected using specific assay kits. The plasma cytokines levels were detected using ELISA.. Neutrophil depletion resulted in significantly reduced plasma amylase levels in pancreas, myeloperoxidase (MPO) activity in pancreas and lung, reactive oxygen species (ROS) generation and cell apoptosis, and decreased circulating neutrophil, tissue damage as well as expression levels of nuclear factor NF-κB.. Neutrophil depletion is capable of reducing tissue damage of pancreas and lung in mice with acute pancreatitis.

Topics: Acute Disease; Amylases; Animals; Apoptosis; Arginine; Cytokines; Disease Models, Animal; Lung; Male; Mice; Mice, Inbred C57BL; Neutrophils; NF-kappa B; Pancreas; Pancreatitis; Peroxidase; Reactive Oxygen Species

T helper (Th)1 and Th17 cells play a critical role in inflammatory bowel disease (IBD). 1,25-dihydroxyvitamin D3 (1,25(OH)2 D3 ) has emerged as a direct regulator of immune system function. Mice were grouped as follows: Control group (received PBS, n = 10), DSS group (received 2% DSS and PBS, n = 10), and DSS+VD group (received 2% DSS and 1,25(OH)2 D3 , n = 10). The disease activity index (DAI), colon length, and damage store of the mice were observed; the spleen length, weight, spleen index, and mononuclear cells of spleen were measured; mononuclear cells from mesenteric lymph nodes (MLN) were measured, and the levels of Th 1 and Th17 cytokines in the colon mucosa and spleen were measured. Mice in the DSS group developed severe diarrhea, rectal bleeding, and marked BW loss. Histological examination revealed extensive ulceration and inflammatory cell infiltration in the colon, and the structure of the spleen was disordered, infiltrated with inflammatory cytokines in red pulp. In the DSS group, mononuclear cell numbers from MLN and spleen were increased, and enhanced proteins and mRNA levels of Th 1 and Th17 cytokines were detected. In the DSS+VD group, 1,25(OH)2 D3 ameliorated the inflammation of the colon and spleen. In addition, 1,25(OH)2 D3 down-regulated the levels of Th 1 and Th17 cytokines. 1,25(OH)2 D3 represents a novel therapeutic drug for UC, which may correlate to inhibit the activation of Th1 and Th17 cells.

Topics: Animals; Calcitriol; Calcium; Chronic Disease; Colitis; Colon; Dextran Sulfate; Disease Models, Animal; Down-Regulation; Inflammation; Interferon-gamma; Interleukin-17; Interleukin-6; Intestinal Mucosa; Male; Mice; Mice, Inbred C57BL; Peroxidase; RNA, Messenger; Spleen; Th1 Cells; Th17 Cells; Tumor Necrosis Factor-alpha

Although gut microbiota perturbation is recognized as a main contributing factor to the pathogenesis of inflammatory bowel disease, synbiotic therapies, as prevention or treatment, have remained overlooked.. To verify whether Lactobacillus paracasei B21060-based synbiotic therapy could prevent or repair colon damage in a mouse model of colitis, we performed treatments before and after colitis induction.. The experimental study lasted 19 d. Experimental colitis was induced in BALB/c mice by giving them dextran sodium sulfate (DSS, 2.5%) in drinking water (days 7-12) followed by DSS-free water (days 13-19) (DSS group). L. paracasei B21060 (2.5 × 10(7) bacteria/10 g body weight) was orally administered 7 d before DSS [synbiotic as preventive treatment (P-SYN) group] or 2 d after DSS [synbiotic as therapeutic treatment (T-SYN) group] until day 19. Another group was not treated with DSS or synbiotic and was given tap water (control group), for a total of 4 groups.. Compared with the DSS group, both synbiotic-treated groups had significantly less pronounced weight loss and colon damage. Consistently, mRNA levels of chemokine (C-C motif) ligand 5 in the colon were reduced in both P-SYN and T-SYN mice compared with the DSS group (51%, P < 0.05 and 72%, P < 0.001, respectively). In the P-SYN and T-SYN groups, neutrophil elastase transcription was also reduced (51%, P < 0.01 and 59%, P < 0.001, respectively). Accordingly, oxidative/nitrosative stress was lower in P-SYN and T-SYN mice than in the DSS group. In P-SYN and T-SYN mice, colonic gene expression of tumor necrosis factor (47%, P < 0.01 and 61%, P < 0.001, respectively) and prostaglandin-endoperoxide synthase 2 (45%, P < 0.01 and 35%, P < 0.05, respectively) was lower, whereas interleukin 10 mRNA was doubled compared with the DSS group (both P < 0.5). Remarkably, epithelial barrier integrity (zonulin and occludin) and gut protection (β-defensin and mucin expression) were completely restored in P-SYN and T-SYN mice.. Our data highlight the beneficial effects of this synbiotic formulation in acutely colitic mice, suggesting that it may have therapeutic and possibly preventive efficacy in human colitis.

Topics: Animals; beta-Defensins; Colitis; Cyclooxygenase 2; Dextran Sulfate; Disease Models, Animal; Gastrointestinal Tract; Inflammation; Interleukin-10; Lactobacillus; Male; Malondialdehyde; Mice; Mice, Inbred BALB C; Mucin-1; Oxidative Stress; Peroxidase; PPAR gamma; RNA, Messenger; Synbiotics; Up-Regulation

Aim of the present study is to develop embelin lipid nanospheres (LNE) for better treatment of ulcerative colitis. Embelin LNs were developed using soya bean oil/virgin coconut oil as liquid lipid carrier and soya/egg lecithin as stabilizer by hot homogenization followed by ultrasonication technique. The particle size of LNEs ranged from 196.1±3.57 to 269.2±1.05nm with narrow polydispersity index values whereas zeta potential was from -36.6 to -62.0mV. Embelin was successfully incorporated into lipid nanospheres with entrapment efficiency about 99%. There was no interaction between embelin and selected liquid lipids which was confirmed by FTIR studies. In vitro drug release studies performed using Franz diffusion cell and results showed sustained release of embelin. Embelin LNs were stabilized with egg and soya lecithin, embelin release from these LNs followed Higuchi model and first order model, respectively, however mechanism of drug release in both LNs was non-Fickian. In vivo studies were carried out using acetic acid induced ulcerative colitis rat model and results revealed that treatment with embelin LNs significantly reduced clinical activity and macroscopic scores compared to embelin conventional suspension. Treatment with embelin LNs decreased MPO, LDH and LPO levels, increased reduced GSH levels which indicated better treatment of ulcerative colitis was achieved. This was also confirmed by improved histopathological conditions. Thus embelin LNs could be favourably used for treatment of ulcerative colitis.

Topics: Acetic Acid; Animals; Anti-Inflammatory Agents; Benzoquinones; Chemistry, Pharmaceutical; Coconut Oil; Colitis, Ulcerative; Colon; Delayed-Action Preparations; Diffusion; Disease Models, Animal; Excipients; Gastrointestinal Agents; Kinetics; L-Lactate Dehydrogenase; Lecithins; Lipid Peroxidation; Male; Models, Chemical; Nanospheres; Peroxidase; Plant Oils; Rats, Wistar; Solubility; Sonication; Soybean Oil; Spectroscopy, Fourier Transform Infrared; Technology, Pharmaceutical; Ultrasonics

Zuojin Pill (ZJP), a traditional Chinese medicinal decoction, contains two herbal drugs: Coptis chinensis Franch. and Tetradium ruticarpum (A. Juss.) Hartley in the ratio of 6:1 (w/w). In this study, ZJP was evaluated for its gastroprotective potential against mucosal lesions induced by ethanol in mice.. 50 mice were assigned to 5 groups: groups 1 and 2 were given distilled water orally. Group 3 was administered omeprazole 20mg/kg, groups 4 and 5 were given ZJP (1g/kg, 2g/kg, respectively). After an additional hour, the mice in groups 2-5 received ethanol (0.2ml/kg) orally while group 1 received distilled water instead. Mice were killed after 4h and their serum and stomachs subjected to further studies. The superoxidase dismutase (SOD) activities and malondialdehyde (MDA) level in serum were assayed by SOD and MDA kits, respectively. The myeloperoxidase (MPO) activities in stomachs were assayed by MPO kit. The levels of inflammatory mediators including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) in serum were assayed by enzyme-linked immunosorbent assay method (ELISA). Pathological changes were observed by hematoxylin-eosin (HE) staining. The levels of nuclear factor-кBp65 (NF-кBp65), P-NF-кBp65, P-IкBα, IкBα, P-IKKα, IKKα, P-IKKβ, IKKβ in stomachs were assayed by western blot.. The data showed that treatment with the ZJP markedly attenuated MPO, MDA, TNF-α, IL-6, IL-1βand increased SOD; and ZJP also decreased protein levels of P-NF-кBp65, P-IкBα, P-IKKαand P-IKKβin gastric stomachs.. It was concluded that ZJP may represents a potential therapeutic option to reduce the risk of gastric ulceration and the gastroprotective activity of ZJP might contribute in adjusting the inflammatory cytokine by regulating the NF-кB signaling pathway.

Topics: Animals; Anti-Ulcer Agents; Coptis; Cytokines; Disease Models, Animal; Drugs, Chinese Herbal; Ethanol; Evodia; Male; Malondialdehyde; Mice, Inbred ICR; Peroxidase; Phytotherapy; Stomach; Stomach Ulcer; Superoxide Dismutase

To develop thalidomide-loaded poly-lactide-co-glycolide implants and evaluate its in vivo release and biological activity against inflammation and angiogenesis after subcutaneous administration.. Implants were prepared by the hot molding technique and characterized using stereomicroscopy, thermal analysis and X-ray diffraction. Swiss mice, divided in groups 1-3, received a subcutaneous implant containing 25% (w/w), 50% (w/w) or 75% (w/w) of thalidomide, respectively (n=6). The drug levels were determined during a 28-day study period. The toxicity associated with the implants was evaluated by light microscopy. The potential of the developed implant in the inhibition of inflammation and angiogenesis was evaluated in vivo using the sponge model.. Thalidomide implant was developed and its characterization proved the stability of the drug and the polymer during preparation. Release profiles in vivo demonstrated an extended release of thalidomide from the implants during the 28 days. Histological evaluation did not show any sign of intense local inflammatory response to the presence of the implants in the subcutaneous pouch. The thalidomide implant reduced the number of vessels and N-acetyl-b-glucosaminidase (NAG) in vivo.. The biodegradable implants delivered safe doses of thalidomide that were also effective to induce angiogenesis and inflammation regression.

Topics: Acetylglucosaminidase; Animals; Biocompatible Materials; Calorimetry, Differential Scanning; Disease Models, Animal; Female; Hemoglobins; Inflammation; Injections, Subcutaneous; Lactic Acid; Mice; Neovascularization, Pathologic; Peroxidase; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Skin; Thalidomide; X-Ray Diffraction

Recent studies have linked histone deacetylases (HDAC) to remodeling of the heart and cardiac fibrosis in heart failure. However, the molecular mechanisms linking chromatin remodeling events with observed anti-fibrotic effects are unknown. Here, we investigated the molecular players involved in anti-fibrotic effects of HDAC inhibition in congestive heart failure (CHF) myocardium and cardiac fibroblasts in vivo.. MI was created by coronary artery occlusion. Class I HDACs were inhibited in three-week post MI rats by intraperitoneal injection of Mocetinostat (20 mg/kg/day) for duration of three weeks. Cardiac function and heart tissue were analyzed at six week post-MI. CD90+ cardiac fibroblasts were isolated from ventricles through enzymatic digestion of heart. In vivo treatment of CHF animals with Mocetinostat reduced CHF-dependent up-regulation of HDAC1 and HDAC2 in CHF myocardium, improved cardiac function and decreased scar size and total collagen amount. Moreover, expression of pro-fibrotic markers, collagen-1, fibronectin and Connective Tissue Growth Factor (CTGF) were reduced in the left ventricle (LV) of Mocetinostat-treated CHF hearts. Cardiac fibroblasts isolated from Mocetinostat-treated CHF ventricles showed a decrease in expression of collagen I and III, fibronectin and Timp1. In addition, Mocetinostat attenuated CHF-induced elevation of IL-6 levels in CHF myocardium and cardiac fibroblasts. In parallel, levels of pSTAT3 were reduced via Mocetinostat in CHF myocardium.. Anti-fibrotic effects of Mocetinostat in CHF are associated with the IL-6/STAT3 signaling pathway. In addition, our study demonstrates in vivo regulation of cardiac fibroblasts via HDAC inhibition.

Topics: Animals; Benzamides; Cicatrix; Collagen; Connective Tissue Growth Factor; Disease Models, Animal; Fibroblasts; Fibronectins; Fibrosis; Gene Expression; Heart Failure; Histone Deacetylase Inhibitors; Histone Deacetylases; Interleukin-6; Myocardial Ischemia; Pyrimidines; Rats; Signal Transduction; STAT3 Transcription Factor; Ventricular Function

Sepsis is characterized by systemic activation of coagulation and inflammation in response to microbial infection. Although cell-free DNA (cfDNA) released from activated neutrophils has antimicrobial properties, it may also exert harmful effects by activating coagulation and inflammation. The authors aimed to determine whether deoxyribonuclease (DNase) administration reduces cfDNA levels, attenuates coagulation and inflammation, suppresses organ damage, and improves outcome in a cecal ligation and puncture (CLP) model of polymicrobial sepsis. Healthy C57Bl/6 mice were subjected to CLP, a surgical procedure involving two punctures of the ligated cecum, or sham surgery (no ligation/puncture). Mice were given DNase or saline by intraperitoneal injection 2, 4, or 6 h after surgery. Two hours after treatment, organs were harvested and plasma levels of cfDNA, interleukin-6 (IL-6), IL-10, thrombin-antithrombin complexes, lung myeloperoxidase, creatinine, alanine transaminase, and bacterial load were quantified. Survival studies were also performed. The CLP-operated mice had rapid time-dependent elevations in cfDNA that correlated with elevations in IL-6, IL-10, and thrombin-antithrombin complexes and had organ damage in the lungs and kidneys. Administration of DNase at 2 h after CLP resulted in increased IL-6 and IL-10 levels and organ damage in the lungs and kidneys. In contrast, DNase administration at 4 or 6 h after CLP resulted in reduced cfDNA and IL-6 levels, increased IL-10, and suppressed organ damage and bacterial dissemination. Deoxyribonuclease administration every 6 h after CLP also rescued mice from death. Our studies are the first to demonstrate that delayed but not early administration of DNase may be protective in experimental sepsis.

Topics: Alanine Transaminase; Animals; Anti-Infective Agents; Antithrombins; Creatinine; Deoxyribonucleases; Disease Models, Animal; DNA; Drug Administration Schedule; Inflammation; Injections, Intraperitoneal; Interleukin-10; Interleukin-6; Lung; Male; Mice; Mice, Inbred C57BL; Multiple Organ Failure; Peroxidase; Sepsis; Thrombin; Time Factors

The present study investigated the flavonoids from Abrus cantoniensis against ethanol-induced gastric ulcers in mice. The flavonoids from A. cantoniensis were extracted with ethanol and purified by macroporous resin and polyamide. The 2,2-diphenyl-1-picrylhydrazyl assay was used to measure the antioxidative activities in vitro. The ethanol-induced ulcer mouse model was used to evaluate the gastroprotective activities of the flavonoids from A. cantoniensis. In addition, a method was established to ensure accuracy for animal ulcer evaluation. The flavonoids from A. cantoniensis showed a strong free radical scavenging capacity with an IC50 of 43.83 µg/mL in the 2,2-diphenyl-1-picrylhydrazyl assay. At doses between 28.16-112.67 mg/kg, the flavonoids conspicuously reduced the ulcer index in ethanol-induced mice (p<0.001). Significant differences were found in the levels of superoxide dismutase, catalase, glutathione, and myeloperoxidase in the stomach tissues between the flavonoids from the A. cantoniensis groups and the ethanol control group. The gastroprotective effect of the flavonoids from A. cantoniensis could be due to its antioxidative activity of the defensive mechanism. The data revealed that the flavonoids from A. cantoniensis could be a potential therapeutic agent for gastric ulcer prevention and treatment.

Topics: Abrus; Animals; Anti-Ulcer Agents; Antioxidants; Catalase; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Ethanol; Flavonoids; Glutathione; Male; Mice, Inbred ICR; Molecular Structure; Peroxidase; Stomach Ulcer; Superoxide Dismutase

Myocardial ischemia-reperfusion injury is known to trigger an inflammatory response involving edema, apoptosis, and neutrophil activation/accumulation. Recently, mechanical tissue resuscitation (MTR) was described as a potent cardioprotective strategy for reduction of myocardial ischemia-reperfusion injury. Here, we further describe the protective actions of MTR and begin to define its therapeutic window.. A left ventricular, free-wall ischemic area was created in anesthetized swine for 85 minutes and then reperfused for three hours. Animals were randomized to two groups: (1) untreated controls (Control) and (2) application of MTR that was delayed 90 minutes after the initiation of reperfusion (D90). Hemodynamics and regional myocardial blood flow were assessed at multiple time points. Infarct size and neutrophil accumulation were assessed following the reperfusion period. In separate cohorts, the effect of MTR on myocardial interstitial water (MRI imaging) and blood flow was examined.. Both groups had similar areas at risk (AAR), hemodynamics, and arterial blood gas values. MTR, even when delayed 90 minutes into reperfusion (D90, 29.2 ± 5.0% of AAR), reduced infarct size significantly compared to Controls (51.9 ± 2.7%, p = 0.006). This protection was associated with a 33% decrease in neutrophil accumulation (p = 0.047). Improvements in blood flow and interstitial water were also observed. Moreover, we demonstrated that the therapeutic window for MTR lasts for at least 90 minutes following reperfusion.. This study confirms our previous observations that MTR is an effective therapeutic approach to reducing reperfusion injury with a clinically useful treatment window.

Topics: Animals; Coronary Vessels; Diffusion Magnetic Resonance Imaging; Disease Models, Animal; Female; Myocardial Reperfusion Injury; Myocardium; Peroxidase; Regional Blood Flow; Resuscitation; Swine; Time Factors

Allicin, a molecule predominantly responsible for the pungent odor and the antibiotic function of garlic, exhibits various pharmacological activities and has been suggested to be beneficial in the treatment of various disorders. The present study aimed to elucidate the effect of allicin in cerebral ischemia/reperfusion (I/R) injury in rats. Rats were subjected to 1.5 h of transient middle cerebral artery occlusion (MCAO), followed by 24 h of reperfusion. Rats were randomly assigned to the sham surgery group, the MCAO group and the MCAO + allicin group. Neurological score, cerebral infarct size, brain water content, neuronal apoptosis, serum tumor necrosis factor (TNF)‑α and myeloperoxidase (MPO) activity were measured. The results suggested that allicin reduced cerebral infarction area, brain water content, neuronal apoptosis, TNF‑α levels and MPO activity in the serum. The results of the present study indicated that allicin protects the brain from cerebral I/R injury, which may be ascribed to its anti‑apoptotic and anti‑inflammatory effects.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Apoptosis; Brain; Brain Edema; Disease Models, Animal; Disulfides; Garlic; Infarction, Middle Cerebral Artery; Male; Neuroprotective Agents; Peroxidase; Rats, Sprague-Dawley; Reperfusion Injury; Sulfinic Acids; Tumor Necrosis Factor-alpha

Myeloperoxidase (MPO), a highly oxidative enzyme secreted by leukocytes has been implicated in human and experimental nonalcoholic steatohepatitis (NASH), but the underlying mechanisms remain unknown. In this study, we investigated how MPO contributes to progression from steatosis to NASH.. In C57Bl/6J mice fed a diet deficient in methionine and choline to induce NASH, neutrophils and to a lesser extent inflammatory monocytes are markedly increased compared with sham mice and secrete abundant amounts of MPO. Through generation of HOCl, MPO directly causes hepatocyte death in vivo. In vitro experiments demonstrate mitochondrial permeability transition pore induction via activation of SAPK/JNK and PARP. MPO also contributes to activation of hepatic stellate cells (HSCs), the most important source of collagen in the liver. In vitro MPO-activated HSCs have an activation signature (MAPK and PI3K-AKT phosphorylation) and upregulate COL1A1, α-SMA, and CXCL1. MPO-derived oxidative stress also activates transforming growth factor β (TGF-β) in vitro, and TGF-β signaling inhibition with SB-431542 decreased steatosis and fibrosis in vivo. Conversely, congenital absence of MPO results in reduced hepatocyte injury, decreased levels of TGF-β, fewer activated HSCs, and less severe fibrosis in vivo.. Cumulatively, these findings demonstrate important cross talk between inflammatory myeloid cells, hepatocytes, and HSCs via MPO and establish MPO as part of a proapoptotic and profibrotic pathway of progression in NASH, as well as a potential therapeutic target to ameliorate this disease.

Topics: Animals; Apoptosis; Cell Communication; Cell Membrane Permeability; Cytokines; Disease Models, Animal; Enzyme Activation; Gene Expression; Hepatic Stellate Cells; Hepatocytes; Intracellular Membranes; Liver Cirrhosis; Mice; Mice, Knockout; Mitochondria, Liver; Models, Biological; Myeloid Cells; Neutrophils; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Peroxidase; Signal Transduction; Transforming Growth Factor beta

The objective of this study is to evaluate the effect of allicin (10 mg/kg body weight, orally) in an experimental murine model of UC by administering 2.5% dextran sodium sulfate (DSS) in drinking water to BALB/c mice. DSS-induced mice presented reduced body weight, which was improved by allicin administration. We noted increases in CD68 expression, myeloperoxidase (MPO) activities, and Malonaldehyde (MDA) and mRNA levels of proinflammatory cytokines, such as tumor necrosis factor- (TNF-) α, interleukin- (IL-) 1β, IL-6, and IL-17, and decrease in the activities of enzymic antioxidants such as superoxide dismutase (SOD), Catalase (CAT), Glutathione reductase (GR), and Glutathione peroxidase (GPx) in DSS-induced mice. However, allicin treatment significantly decreased CD68, MPO, MDA, and proinflammatory cytokines and increased the enzymic antioxidants significantly (P < 0.05). In addition, allicin was capable of reducing the activation and nuclear accumulation of signal transducer and activator of transcription 3 (STAT3), thereby preventing degradation of the inhibitory protein IκB and inducing inhibition of the nuclear translocation of nuclear factor (NF)-κB-p65 in the colonic mucosa. These findings suggest that allicin exerts clinically useful anti-inflammatory effects mediated through the suppression of the NF-κB and IL-6/p-STAT3(Y705) pathways.

Topics: Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antioxidants; Colitis, Ulcerative; Colon; Cytokines; Dextran Sulfate; Disease Models, Animal; Disulfides; Malondialdehyde; Mice; Mice, Inbred BALB C; Microscopy, Confocal; NF-kappa B; Peroxidase; Real-Time Polymerase Chain Reaction; RNA, Messenger; STAT3 Transcription Factor; Sulfinic Acids

intra-articular co-injection of kaolin with carrageenan (CGN) in rodents is widely used as an experimental model of arthritis. However, the ability of kaolin to cause arthritis and related immune responses when administered alone is unclear. We evaluated the contribution of prostanoids and sensory C-fibres (and their neuropeptide substance P) to kaolin-induced inflammation in the rat knee.. Wistar rats, 8-10 weeks old, received an intra-articular injection of kaolin (1-10 μg/joint) or saline into the knee joint. Knee inflammation, proinflammatory cytokines, pain behaviour and secondary tactile allodynia were assessed over 5 h, when synovial leukocyte counts, histopathological changes and proinflammatory cytokine levels were evaluated.. The intra-articular injection of kaolin caused a dose- and time-dependent knee swelling and impairment of motion that were associated with secondary tactile allodynia, elevated concentrations of IL-1β, IL-6 and TNFα, leukocyte infiltration, and histopathological changes in the ipsilateral hindpaw. The neurokinin-1 (NK1) receptor antagonist SR140333 or neonatal treatment with capsaicin markedly reduced the inflammatory parameters, cytokines and allodynia but failed to significantly inhibit the impaired motion. The cyclo-oxygenase inhibitor indomethacin partially inhibited knee oedema and allodynia but did not affect the leukocyte influx, myeloperoxidase activity or impaired motion in the kaolin-injected rat.. We show the first evidence that intra-articular injection of kaolin without CGN produced severe acute monoarthritis. This was highly dependent on substance P (released from C-fibres) and NK1 receptor activation, which stimulated local production of proinflammatory cytokines. This model may be of critical importance for mechanistic studies and screening new anti-inflammatory/analgesic drugs.

Topics: Animals; Animals, Newborn; Antidiarrheals; Arthritis; Capsaicin; Cytokines; Disease Models, Animal; Edema; Enzyme Inhibitors; Hyperalgesia; Indomethacin; Kaolin; Knee Joint; Male; Pain Measurement; Peroxidase; Piperidines; Quinuclidines; Rats; Rats, Wistar; Receptors, Neurokinin-1; Synovial Fluid

Flavonoids have been subjected to considerable investigation because of its antioxidant and anti-inflammatory properties. However, there is no previously reported study about its effect on hepatic ischemia/reperfusion (I/R). We investigated the effects of micronized purified flavonoid fraction (MPFF) on hepatic I/R injury in rats.. Thirty rats were recruited in the study as follows: group A, sham operation (n = 10); group B, I/R (n = 10); and group C, I/R+MPFF (n = 10). In group C, rats received (80 mg/kg/day) MPFF by gavage for 3 days before surgery, 30 minutes before ischemia and just before the reperfusion. Blood samples were taken, and serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) levels were measured to assess liver functions. Liver tissues were taken for histological evaluation and to determine the total antioxidant capacity (TAC), catalase (CAT), total oxidant status (TOS), oxidative stress index (OSI), and myeloperoxidase (MPO).. The present data showed a decrease in AST, ALT, and LDH levels in the MPFF-treated rats when compared with I/R group rats (P < .001 for all). In the MPFF-treated rats, tissue levels of TOS, OSI, and MPO were significantly lower than those in the I/R group (P < .01, P < .001, and P < .05, respectively). Increases in TAC and CAT levels were statistically significant in the MPFF-treated rats compared with the I/R group (P = .01 for both). On the other hand, MPFF attenuated histological alterations that were induced by I/R.. The present study demonstrates that MPFF ameliorates I/R-induced liver damage, probably through antioxidant and anti-inflammatory properties.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Catalase; Disease Models, Animal; Flavonoids; L-Lactate Dehydrogenase; Liver Diseases; Liver Transplantation; Oxidative Stress; Peroxidase; Rats; Reperfusion Injury

It has been proved that TRAM-Derived Decoy peptides have anti-inflammatory properties. In this study, we synthesized a TRAM-Derived decoy peptide (TM6), belongs to TRAM TIR domain, of which sequence is "N"-RQIKIWFQNRRMKWK, KENFLRDTWCNFQFY-"C" and evaluated the effects of TM6 on lipopolysaccharide-induced mastitis in mice. In vivo, LPS-induced mice mastitis model was established by injection of LPS through the duct of mammary gland. TM6 was injected 1h before or after LPS treatment. In vitro, primary mouse mammary epithelial cells were used to investigate the effects of TM6 on LPS-induced inflammatory responses. The results showed that TM6 inhibited LPS-induced mammary gland histopathologic changes, MPO activity, and TNF-α, IL-1β and IL-6 production in mice. In vitro, TM6 significantly inhibited LPS-induced TNF-α and IL-6 production, as well as NF-κB and MAPKs activation. In conclusion, this study demonstrated that TM6 had protective effects on LPS-mastitis and may be a promising therapeutic reagent for mastitis treatment.

Topics: Adaptor Proteins, Signal Transducing; Animals; Anti-Inflammatory Agents; Cytokines; Disease Models, Animal; Epithelial Cells; Female; Inflammation Mediators; Lipopolysaccharides; Male; Mammary Glands, Animal; Mastitis; Mice, Inbred BALB C; Mitogen-Activated Protein Kinases; NF-kappa B; Peptide Fragments; Peroxidase; Time Factors; Tissue Culture Techniques

Ulcerative colitis is an inflammatory disorder characterized by neutrophils infiltration, oxidative stress, upregulation of pro-inflammatory mediators and cytokines. Cavidine possesses anti-inflammatory activity and has been used to treat various inflammatory diseases but its effect on ulcerative colitis has not been previously explored. The present study aims to evaluate the effect of cavidine on acetic acid-induced ulcerative colitis in mice. Colitis mice induced by intra-rectal acetic acid (5%, v/v) administration received cavidine (1, 5 and 10mg/kg, i.g) or sulfasalazine (500mg/kg, i.g) for seven consecutive days. After euthanized by cervical dislocation, colonic segments of mice were excised for clinical, macroscopic, biochemical and histopathological examinations. Results suggested treatment with cavidine significantly decreased mortality rate, body weight loss, disease activity index (DAI), wet colon weight, macroscopic and histological score when compared with that of acetic acid-induced controls. In addition, administration of cavidine effectively modulated expressions of MPO, GSH, SOD and MDA. Furthermore cavidine inhibited the level of TNF-α and IL-6 in the serum and colon tissue in response to the regulation of p65 NF-κB protein expression. All these results indicated cavidine exerts marked protective effect in experimental colitis, possibly by regulating the expression of oxygen metabolites, NF-κB and subsequent pro-inflammatory cytokines production.

Topics: Acetic Acid; Animals; Anti-Ulcer Agents; Antioxidants; Berberine Alkaloids; Colitis, Ulcerative; Colon; Cytokines; Disease Models, Animal; Glutathione; Interleukin-6; Male; Mice; NF-kappa B; Peroxidase; Signal Transduction; Tumor Necrosis Factor-alpha

The effects of dietary plant-origin glucosylceramide (GlcCer) on symptoms similar to those of inflammatory bowel diseasewere investigated in dextran sulfate sodium salt (DSS)-treated mice. Dietary GlcCer suppressed decreases in body weight due to DSS administration. To determine its effects on the colon, we examined its surface under a microscope following toluidine blue staining. Dietary GlcCer decreased DSS-induced chorionic crypt injury and elevated myeloperoxidase levels. Moreover, dietary GlcCer significantly suppressed the production of cytokines by the intestinal mucosa. These results provide evidence for the suppression of DSS-induced inflammation by dietary GlcCer.

Topics: Administration, Oral; Animals; Colon; Cytokines; Dextran Sulfate; Disease Models, Animal; Female; Glucosylceramides; Inflammatory Bowel Diseases; Intestinal Mucosa; Mice, Inbred BALB C; Peroxidase; Phytotherapy; Weight Loss

The aim of our study was to evaluate the anti-inflammatory, anti-nociceptive, and anti-oxidant action of Riparin B in vivo. We performed experiments in which we induced paw edema by carrageenan and other mediators, carrageenan-induced peritonitis and the level of myeloperoxidase (MPO) activity, pro-inflammatory cytokines (TNF-α and IL-1β), malondialdehyde (MDA) acid, and glutathione (GSH) from the peritoneal fluid. We also performed behavior tests such as acetic acid-induced writhing, formalin-induced linking, and the hot plate test. Among the doses tested of the Riparin B (1, 3, and 10 mg/kg), the dose of 10 mg/kg showed the strongest effect, and this dose was able to reduce the paw edema induced by carrageenan, dextran, histamine serotonin, bradykinin, 48/80, and PGE2. Similarly, the Riparin B in the same dose reduced cell migration and significantly decreased the nociception induced by formalin and acetic acid and reversed the parameters of the oxidative stress. Thus, we can infer that Riparin B exhibits anti-inflammatory, anti-nociceptive, and anti-oxidant actions in vivo.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Antioxidants; Benzamides; Carrageenan; Cytokines; Disease Models, Animal; Edema; Glutathione; Inflammation Mediators; Male; Malondialdehyde; Mice; Neutrophil Infiltration; Nociceptive Pain; Oxidative Stress; Peritonitis; Peroxidase; Phenethylamines; Time Factors

Simvastatin reduces ventilator-induced lung injury and is regularly used in clinical practice. This study aimed to test the hypotheses that long-term use of simvastatin could affect the incidence and severity of ventilator-induced lung injury after mechanical ventilation, and the process may involve heme oxygenase-1 (HO-1).. Forty healthy adult Sprague-Dawley rats were randomly divided into four groups, namely control, ventilation, simvastatin, and simvastatin + ventilation groups. Saline (control and ventilation groups) or 10 mg kg(-1) d(-1) simvastatin (simvastatin and simvastatin + ventilation groups) was administered by gavage to the animals for 4 wk. Mechanical ventilation (tidal volume 50 mL/kg) was then applied for 4 h to the ventilation and simvastatin + ventilation groups. Lung tissues were harvested for hematoxylin-eosin staining and pathologic examination, and HO-1 contents were measured by immunoblotting and polymerase chain reaction.. A severe pathologic damage was observed in rats that underwent mechanical ventilation. Interestingly, protein concentration, wet/dry weight ratio, myeloperoxidase activity, and malondialdehyde level were increased, and superoxide dismutase activity decreased, in lung tissues after mechanical ventilation. The pathologic damage was substantially alleviated in rats treated with simvastatin before mechanical ventilation: reduced protein concentration, wet/dry weight ratio, myeloperoxidase activity, and malondialdehyde level, and increased superoxide dismutase activity in lung tissues, compared with the ventilation group. Both mechanical ventilation and simvastatin administration induced HO-1 messenger RNA and protein expression in lung tissues.. Long-term administration of simvastatin significantly reduces the inflammatory response and pulmonary injury induced by mechanical ventilation, potentially by upregulating HO-1 in lung tissues.

Topics: Animals; Disease Models, Animal; Heme Oxygenase (Decyclizing); Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lung; Malondialdehyde; Peroxidase; Random Allocation; Rats, Sprague-Dawley; Respiration, Artificial; Simvastatin; Superoxide Dismutase; Up-Regulation; Ventilator-Induced Lung Injury

Oxidative renal injury is the mainstay in patients with spinal cord injury (SCI) and it may eventuate to chronic renal failure. In our study, we investigated the potential of α2-adrenoreceptor agonist Dexmedetomidine (Dex) in ameliorating SCI provoked oxidative renal assault.. Complete SCI was generated by surgical transaction of the cord at the T10-12 level. Dex administration (50 mcg/kg, b.wt, intraperitoneally) was initiated 12 h after the surgery for 10 days. Then, blood was collected and kidneys were removed to evaluate the efficacy of Dex on post-SCI renal complications.. Dex treatment significantly attenuated elevated serum creatinine and blood urea nitrogen in SCI rats to normalcy. Further in SCI rats elevated level of MDA, protein carbonyl and myeloperoxidase (MPO) were observed and Dex treatment significantly attenuated these toxic manifestations to normalcy. Besides in SCI rats, the antioxidants (SOD, CAT, Gpx and GST and GSH) levels were significantly diminished and Dex treated rats significantly restored the antioxidants level in renal tissue to normalcy. Notably, in our study the protein expression of inflammatory cytokines (TNF-α and IL-6) and cleaved caspase-3 were upregulated in renal tissue of SCI rats. Fascinatingly, Dex treatment downregulated the protein expression of TNF-α, IL-6 and cleaved caspase-3 by anti-inflammatory, antiapoptotic mechanism. Furthermore, SCI rats displayed upregulated protein expression of kidney of SCI rats. Dex treatment diminished the renal apoptosis by downregulating the cleaved caspase-3 expression.. Taken together, these results accentuate that Dex may be a beneficial clinical agent to combat post-SCI renal complications.

Topics: Adrenergic alpha-2 Receptor Agonists; Animals; Apoptosis; Caspase 3; Creatinine; Dexmedetomidine; Disease Models, Animal; Interleukin-6; Kidney; Oxidative Stress; Peroxidase; Postoperative Complications; Rats; Rats, Sprague-Dawley; Spinal Cord Injuries; Tumor Necrosis Factor-alpha

The present study was aimed to investigate the influence of Barnidipine treatment on early stage hypertension by determining the function and morphology of the mesenteric and renal arteries as well as the kidney in N(ω)-Nitro-L-Arginine Methyl Ester (L-NAME)-induced hypertensive rats. Barnidipine (3 mg/kg/day p.o) was applied to rats after 2 weeks of L-NAME (60 mg/kg/day) administration, and continued for the next 3 weeks concomitantly with L-NAME. The systolic blood pressure (SBP) of rats was determined to decrease significantly in Barnidipine treated hypertensive group when compared to that of rats received L-NAME alone. Myograph studies demonstrated that the contractile reactivity to noradrenaline were significantly reduced in both of the resistance arteries while endothelium-dependent relaxations to acethylcholine were significantly diminished particularly in the mesenteric arteries of L-NAME-induced hypertensive rats. The impaired contractile and endothelial responses were completely restored by concomitant treatment of Barnidipine with L-NAME. Histopathological examinations verified structural alterations in the arteries as well as the kidney. Moreover, a decrease in endothelial nitric oxide synthase (eNOS) expression was presented both in the arteries and kidney of hypertensive rats which were increased following Barnidipine treatment. Elevated plasma levels of malondialdehyde (MDA) and myeloperoxidase (MPO) were also reduced in Barnidipine treated hypertensive rats. In conclusion, besides to its efficacy in reducing the elevated SBP, amelioration of vascular function, modulation of arterial and renal eNOS expressions as well as reduction of the plasma levels of oxidative and inflammatory biomarkers are possible supportive mechanisms mediating the favorable implications of Barnidipine in L-NAME-induced hypertension model.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cytoprotection; Disease Models, Animal; Dose-Response Relationship, Drug; Hypertension; Inflammation Mediators; Kidney; Kidney Diseases; Male; Malondialdehyde; Mesenteric Arteries; NG-Nitroarginine Methyl Ester; Nifedipine; Nitric Oxide Synthase Type III; Oxidative Stress; Peroxidase; Rats, Wistar; Renal Artery; Time Factors; Vascular Remodeling; Vasoconstriction; Vasodilation

Interleukin-37 (IL-37) is a new discovered member of the interleukin family and plays anti-inflammatory effect in some inflammatory disease. A recent study found that IL-37 elevated significantly in peripheral blood of patients with acute myocardial infarction. We aimed to explore the effect IL-37 on cardiac function after mice myocardial infarction (MI) and its mechanism.. Acute MI mouse model was established and divided into three groups: sham group, MI group and IL-37 treatment group. MPO expression was detected by immunohistochemistry; NF-κB signaling pathway was tested by Western blot; and cardiac function was measured by echocardiography.. Compared with MI mice, IL-37 treatment showed an obvious decrease of MPO expression, suppression of p-p65 expression, and improved cardiac function by decreasing left ventricular shortening fraction (LVFS).. IL-37 may improve MI mice cardiac function via inhibition of inflammatory NF-κB signaling pathway.

Topics: Animals; Anti-Inflammatory Agents; Cardiotonic Agents; Disease Models, Animal; Inflammation Mediators; Interleukin-1; Male; Mice, Inbred C57BL; Myocardial Infarction; Myocardium; Peroxidase; Phosphorylation; Signal Transduction; Stroke Volume; Transcription Factor RelA; Ultrasonography; Ventricular Function, Left

Jungia rugosa Less (Asteraceae), popularly known in Ecuador as "Carne humana" or "Fompo", is a vine present into the Andean region. It is traditionally used as medicine for the treatment of bruises, cuts and other external inflammatory processes. This study was designed to investigate the anti-inflammatory activity of J. rugosa leaves extract (JRLE) in rodents.. The acute anti-inflammatory activity was evaluated by animal models, including croton oil-induced ear oedema in mice, carrageenan-induced paw oedema in rats and myeloperoxidase (MPO); the chronic anti-inflammatory activity was evaluated by cotton pellet-induced granuloma.. Intraperitoneal administration of JRLE (125, 250, 500mg/kg) significantly (p<0.01-0.001) inhibited the croton oil-induced ear oedema and MPO activity in mice; the carrageenan-induced paw oedema in rats was significantly (p<0.05) reduced by 500mg/kg. Repeated (6 days) administration of the extract to mice previously implanted with cotton pellets reduced the formed granuloma (125mg/kg: 11.7%; 250mg/kg: 17.9%; 500mg/kg: 32.4%) but only the inhibition by 500mg/kg reached statistical significance (p<0.01).. The results show that JRLE is effective as an anti-inflammatory agent in acute and chronic inflammation in mice, supporting its traditional use.

Topics: Animals; Anti-Inflammatory Agents; Asteraceae; Carrageenan; Cotton Fiber; Croton Oil; Disease Models, Animal; Edema; Granuloma, Foreign-Body; Male; Methanol; Mice; Neutrophils; Peroxidase; Plant Extracts; Plant Leaves; Rats, Wistar; Solvents

Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disease. Post-mortem hallmarks of MSA neuropathology include oligodendroglial α-synuclein (αSYN) inclusions, striatonigral degeneration, olivopontocerebellar atrophy, and increased microglial activation that accompanies the wide spread neurodegeneration. Recently, we demonstrated upregulation of myeloperoxidase (MPO) in activated microglia and provided evidence for the role of microglial MPO in the mediation of MSA-like neurodegeneration (Stefanova et al. Neurotox Res 21:393-404, 2015). The aim of the current study was to assess the therapeutic potency of MPO inhibition (MPOi) in a model of advanced MSA. We replicated the advanced pathology of MSA by intoxicating transgenic PLP-α-synuclein transgenic mice with 3-nitropropionic acid (3NP). After onset of the full-blown pathology, MSA mice received either MPOi or vehicle over 3 weeks. Motor phenotype and neuropathology were analyzed to assess the therapeutic efficacy of MPOi compared to vehicle treatment in MSA mice. MPOi therapy initiated after the onset of severe MSA-like neuropathology in mice failed to attenuate motor impairments and neuronal loss within the striatum, substantia nigra pars compacta, inferior olives, pontine nuclei, and cerebellar cortex. However, we observed a significant reduction of microglial activation in degenerating brain areas. Further, nitrated αSYN accumulation was reduced in the striatonigral region. In summary, delayed-start MPOi treatment reduced microglial activation and levels of nitrated αSYN in a mouse model of advanced MSA. These effects failed to impact on motor impairments and neuronal loss in contrast to previously reported disease modifying efficacy of early-start therapy with MPOi in MSA.

Topics: alpha-Synuclein; Animals; Brain; Disease Models, Animal; Enzyme Inhibitors; Humans; Male; Mice, Transgenic; Microglia; Motor Activity; Multiple System Atrophy; Myelin Proteolipid Protein; Neurons; Neuroprotective Agents; Nitro Compounds; Peroxidase; Propionates; Pyrimidinones; Pyrroles; Severity of Illness Index; Treatment Outcome

To characterize high-mobility group protein 1-toll-like receptor 4 (HMGB1-TLR4) and downstream signaling pathways in intestinal ischemia/reperfusion (I/R) injury.. Forty specific-pathogen-free male C57BL/6 mice were randomly divided into five groups (n = 8 per group): sham, control, anti-HMGB1, anti-myeloid differentiation gene 88 (MyD88), and anti-translocating-chain-associating membrane protein (TRIF) antibody groups. Vehicle with the control IgG antibody, anti-HMGB1, anti-MyD88, or anti-TRIF antibodies (all 1 mg/kg, 0.025%) were injected via the caudal vein 30 min prior to ischemia. After anesthetization, the abdominal wall was opened and the superior mesenteric artery was exposed, followed by 60 min mesenteric ischemia and then 60 min reperfusion. For the sham group, the abdominal wall was opened for 120 min without I/R. Levels of serum nuclear factor (NF)-κB p65, interleukin (IL)-6, and tumor necrosis factor (TNF)-α were measured, along with myeloperoxidase activity in the lung and liver. In addition,morphologic changes that occurred in the lung and intestinal tissues were evaluated. Levels of mRNA transcripts encoding HMGB1 and NF-κB were measured by real-time quantitative PCR, and levels of HMGB1 and NF-κB protein were measured by Western blot. Results were analyzed using one-way analysis of variance.. Blocking HMGB1, MyD88, and TRIF expression by injecting anti-HMGB1, anti-MyD88, or anti-TRIF antibodies prior to ischemia reduced the levels of inflammatory cytokines in serum; NF-κB p65: 104.64 ± 11.89, 228.53 ± 24.85, 145.00 ± 33.63, 191.12 ± 13.22, and 183.73 ± 10.81 (P < 0.05); IL-6: 50.02 ± 6.33, 104.91 ± 31.18, 62.28 ± 6.73, 85.90 ± 17.37, and 78.14 ± 7.38 (P < 0.05); TNF-α, 43.79 ± 4.18, 70.81 ± 6.97, 52.76 ± 5.71, 63.19 ± 5.47, and 59.70 ± 4.63 (P < 0.05) for the sham, control, anti-HMGB1, anti-MyD88, and anti-TRIF groups, respectively (all in pg/mL).Antibodies also alleviated tissue injury in the lung and small intestine compared with the control group in the mouse intestinal I/R model. The administration of anti-HMGB1, anti-MyD88, and anti-TRIF antibodies markedly reduced damage caused by I/R, for which anti-HMGB1 antibody had the most obvious effect.. HMGB1 and its downstream signaling pathway play important roles in the mouse intestinal I/R injury, and the effect of the TRIF-dependent pathway is slightly greater.

Topics: Adaptor Proteins, Vesicular Transport; Animals; Disease Models, Animal; Gene Expression Regulation; HMGB1 Protein; Inflammation; Inflammation Mediators; Interleukin-6; Intestine, Small; Liver; Lung; Male; Mesenteric Artery, Superior; Mesenteric Vascular Occlusion; Mice, Inbred C57BL; Myeloid Differentiation Factor 88; Peroxidase; Reperfusion Injury; RNA, Messenger; Signal Transduction; Toll-Like Receptor 4; Transcription Factor RelA; Tumor Necrosis Factor-alpha

There are contradictory results about the effects of exercise and sildenafil on cognitive functions.. To investigate the effects of sildenafil pretreatment and chronic exercise on anxiety and cognitive functions.. Wistar rats (n=42) were divided as sedentary and exercise groups. A moderate-intensity swimming exercise was performed for 6 weeks, 5 days/week, 1h/day. Some of the rats were administered orogastrically with sildenafil (25mg/kg/day) either acutely or chronically. Exposure to cat odor was used for induction of stress. The level of anxiety was evaluated by elevated plus maze test, while object recognition test was used to determine cognitive functions. Brain tissues were removed for the measurement of myeloperoxidase (MPO), malondialdehyde (MDA), nitric oxide levels, lucigenin-enhanced chemiluminescence, and for histological analysis.. Increased MPO and MDA levels in sedentary-stressed rats were decreased with sildenafil applications. Chronic exercise inhibited the increase in MPO levels. Increased nitric oxide and lucigenin chemiluminescence levels in sedentary-stressed rats, were diminished with chronic sildenafil pretreatment. The time spent in the open arms of the plus maze was declined in sedentary-stressed rats, while chronic sildenafil pretreatment increased the time back to that in non-stressed rats. Acute sildenafil application to exercised rats prolonged the time spent in open arms as compared to non-treated exercise group. The time spent with the novel object, which was decreased in sedentary-stressed rats, was increased with sildenafil pretreatment. Our results suggest that sildenafil pretreatment or exercise exerts a protective effect against acute stress and improves cognitive functions by decreasing oxidative damage.

Topics: Acute Disease; Animals; Anxiety Disorders; Cognition; Disease Models, Animal; Exercise Therapy; Exploratory Behavior; Hippocampus; Male; Malondialdehyde; Nitric Oxide; Peroxidase; Physical Conditioning, Animal; Psychotropic Drugs; Random Allocation; Rats, Wistar; Recognition, Psychology; Sildenafil Citrate; Stress, Psychological; Swimming; Treatment Outcome

Cardiac c-Kit+ cells have a modest cardiogenic potential that could limit their efficacy in heart disease treatment. The present study was designed to augment the cardiogenic potential of cardiac c-Kit+ cells through class I histone deacetylase (HDAC) inhibition and evaluate their therapeutic potency in the chronic heart failure (CHF) animal model. Myocardial infarction (MI) was created by coronary artery occlusion in rats. c-Kit+ cells were treated with mocetinostat (MOCE), a specific class I HDAC inhibitor. At 3 weeks after MI, CHF animals were retrogradely infused with untreated (control) or MOCE-treated c-Kit+ cells (MOCE/c-Kit+ cells) and evaluated at 3 weeks after cell infusion. We found that class I HDAC inhibition in c-Kit+ cells elevated the level of acetylated histone H3 (AcH3) and increased AcH3 levels in the promoter regions of pluripotent and cardiac-specific genes. Epigenetic changes were accompanied by increased expression of cardiac-specific markers. Transplantation of CHF rats with either control or MOCE/c-Kit+ cells resulted in an improvement in cardiac function, retardation of CHF remodeling made evident by increased vascularization and scar size, and cardiomyocyte hypertrophy reduction. Compared with CHF infused with control cells, infusion of MOCE/c-Kit+ cells resulted in a further reduction in left ventricle end-diastolic pressure and total collagen and an increase in interleukin-6 expression. The low engraftment of infused cells suggests that paracrine effects might account for the beneficial effects of c-Kit+ cells in CHF. In conclusion, selective inhibition of class I HDACs induced expression of cardiac markers in c-Kit+ cells and partially augmented the efficacy of these cells for CHF repair.. The study has shown that selective class 1 histone deacetylase inhibition is sufficient to redirect c-Kit+ cells toward a cardiac fate. Epigenetically modified c-Kit+ cells improved contractile function and retarded remodeling of the congestive heart failure heart. This study provides new insights into the efficacy of cardiac c-Kit+ cells in the ischemic heart failure model.

Topics: Acetylation; Animals; Benzamides; Biomarkers; Cell Differentiation; Cells, Cultured; Collagen; Disease Models, Animal; Epigenesis, Genetic; Heart Failure; Histone Deacetylase Inhibitors; Histones; Interleukin-6; Male; Myocardial Infarction; Myocytes, Cardiac; Pluripotent Stem Cells; Proto-Oncogene Proteins c-kit; Pyrimidines; Rats; Rats, Sprague-Dawley; Recovery of Function; Tissue Culture Techniques; Ventricular Function, Left; Ventricular Remodeling

The lung and kidney are two organs that are easily affected by hemorrhagic shock (HS). We investigated roles of biliary tract external drainage (BTED) in inflammation and edema of the lung and kidney in HS and its relationship with the heme oxygenase-1 (HO-1) pathway. Rat models of HS were induced by drawing blood from the femoral artery until a mean arterial pressure (MAP) of 40 ± 5 mmHg was achieved. A MAP of 40 ± 5 mmHg was maintained for 60 min. Thirty-six Sprague-Dawley rats were randomized to the following groups: sham group; HS group; HS + zinc protoporphyrin IX (ZnPP), a specific HO-1 inhibitor, group; HS + BTED group; HS + BTED + ZnPP group; and HS + BTED + bile infusion (BI) group. HO-1 levels, aquaporin-1 levels, and ratios of dry/wet in the lung and kidney increased markedly after BTED, but tumor necrosis factor-α and myeloperoxidase levels in the lung and kidney decreased significantly after BTED under HS conditions. Under the condition that HO-1 was inhibited by ZnPP, all these effects induced by BTED disappeared in the lung and kidney. These results demonstrated that inflammation and edema of the lung and kidney of HS rats are alleviated by BTED via the HO-1 pathway.

Topics: Animals; Aquaporin 1; Biliary Tract Surgical Procedures; Disease Models, Animal; Drainage; Enzyme Inhibitors; Heme Oxygenase (Decyclizing); Kidney; Lung; Male; Nephritis; Peroxidase; Pneumonia; Protoporphyrins; Pulmonary Edema; Rats, Sprague-Dawley; Shock, Hemorrhagic; Signal Transduction; Tumor Necrosis Factor-alpha; Up-Regulation

Cigarette smoke induces injury and neutrophilic inflammation in the airways of smokers. The stability and activity of inflammatory effectors, IL8 and neutrophil elastase (NE), can be prolonged by binding to airway heparan sulfate (HS)/syndecan-1, posing risk for developing chronic obstructive pulmonary disease(COPD). We hypothesize that antagonizing HS/syndecan-1 binding of the inflammatory effectors could reduce smoking-related neutrophil-mediated airway inflammation. Analysis of bronchoalveolar lavage fluid(BALF) of COPD patients found both total and unopposed NE levels to be significantly higher among smokers with COPD than non-COPD subjects. Similar NE burden was observed in smoke-exposed rats compared to sham air controls. We chose sulfated-maltoheptaose(SM), a heparin-mimetic, to antagonize HS/sydecan-1 binding of the inflammatory mediators in airway fluids and lung tissues of the smoke-exposed rat model. Airway treatment with SM resulted in displacement of CINC-1 and NE from complexation with bronchio-epithelial HS/syndecan-1, dissipating the chemokine gradient for neutrophil flux across to the bronchial lumen. Following SM displacement of NE from shed HS/syndecan-1 in bronchial fluids, NE became accessible to inhibition by α1-antitrypsin endogenous in test samples. The antagonistic actions of SM against syndecan-1 binding of NE and CINC-1 in smoke-exposed airways suggest new therapeutic opportunities for modulating airway inflammation in smokers with SM delivery.

Topics: Aged; alpha 1-Antitrypsin; Animals; Bronchi; Bronchoalveolar Lavage Fluid; Case-Control Studies; Chemokine CXCL1; Chitosan; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Glucans; Heparitin Sulfate; Humans; Inflammation; Inflammation Mediators; Leukocyte Elastase; Male; Middle Aged; Neutrophils; Peroxidase; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Sprague-Dawley; Smoking; Syndecan-1

In the present study, we investigated the protective role of ischemic postconditioning (IPOST) against intestine ischemia-reperfusion (I/R) injury in rats. Male Sprague-Dawley rats were divided into sham-operation group (S), I/R group (I/R), ischemic preconditioning group (IPC), ischemic postconditioning group (IPOST). After reperfusion, small intestines were resected for histopathologic evaluations. To evaluate DNA fragmentation, resolving agarose gel electrophoresis was performed. To measure cellular apoptotic rates in intestine tissues, we performed TUNEL staining. To examine lipid peroxidation, production of superoxide radicals and tissue neutrophil infiltration, we tested the content of malondialdehyde and activities of superoxidase dismutase and myeloperoxidase in intestine tissues, respectively. Under light microscope, intestinal mucosal impairment in IPOST and IPC groups was found milder than that in I/R group (P < 0.05). The number of apoptosis cells in I/R group was significantly higher than that in IPOST and IPC groups (P < 0.05). The content of malondialdehyde and activity of myeloperoxidase were significantly reduced in IPOST group and IPC group compared with I/R group, but the activity of superoxidase dismutase in IPOST group and IPC group was enhanced compared with I/R group (P < 0.05). These results suggest that IPOST results in protection against intestine I/R injury, which may be related to reduced production of reactive oxygen species, enhanced activities of antioxidant systems and inhibited apoptosis of intestinal mucosal cells.

Topics: Animals; Apoptosis; Biomarkers; Constriction; Disease Models, Animal; DNA Fragmentation; Intestine, Small; Ischemic Postconditioning; Lipid Peroxidation; Male; Malondialdehyde; Mesenteric Artery, Superior; Neutrophil Infiltration; Peroxidase; Rats, Sprague-Dawley; Reperfusion Injury; Splanchnic Circulation; Superoxide Dismutase; Time Factors

This study was aimed to evaluate the effect of Angelica Sinensis on experimental rat models in which spinal cord injury was induced by studying different factors. Different factors causing inflammation play a key role in pathophysiology of SCI. Here three groups of rats (n=15, each was used). These included a sham control group where only laminectomy was performed, SCI group where SCI was induced and AS/SCI group where although SCI was induced but Angelica Sinensis was also administered to study its effect and draw a comparison with control. The expression of I-kBα and NF-kB p65 was also studied using western blotting and after recording optical density (OD) values of western blots. MPO activity was used to measure the effect of 20 mg/kg Angelica Sinensis. The levels of proinflammatory cytokines TNF-α, IL-1β and IL-6 were also studied. As compared with SCI group and sham control it was observed that Angelica Sinensis significantly reduced the expression of I-kBα and NF-kB p65, (P<0.05), while MPO activity was also significantly reduced. Proinflammatory cytokine level was also reduced in treated group as compared to both other groups. On the basis of this study we concluded that the use of 20 mg/kg Angelica Sinensis in rat models can attenuate the secondary damage caused by SCI and thus help in controlling the pathology of SCI in rats.

Topics: Angelica sinensis; Animals; Anti-Inflammatory Agents; Cytokines; Disease Models, Animal; Drugs, Chinese Herbal; I-kappa B Proteins; Inflammation Mediators; Male; Myelitis; NF-KappaB Inhibitor alpha; Peroxidase; Phytotherapy; Plants, Medicinal; Rats, Sprague-Dawley; Spinal Cord; Spinal Cord Injuries; Transcription Factor RelA

To investigate the neuroprotective effects of glucagon-like peptide 2 (Glp-2), which increases cerebral blood flow, on the hippocampal complex after cerebral ischemia/reperfusion (I/R) injury in rats.. Animals were randomized into 4 groups: sham, I/R + 0.9% NaCl, I/R + pre-Glp-2, and I/R + post-Glp-2. Cerebral ischemia was performed via the occlusion of the bilateral internal carotid artery for 40 min and continued with a reperfusion process. At the end of 6 h of reperfusion, animals were decapitated in all groups and brain tissues were removed. Malondialdehyde (MDA) and natural intracellular antioxidant glutathione (GSH) levels and myeloperoxidase (MPO) activities were measured in the left hippocampal tissue. The right hippocampal tissues of all group members were taken for histopathologic study.. MDA levels and MPO activities increased from Group I to Group II and decreased from Group II to Groups III and IV. On the other hand, GSH levels were not significantly different among the groups. The number of apoptotic hippocampal tissue cells increased from Group I to Group II and decreased from Group II to Groups III and IV.. Our preliminary study revealed that Glp-2 treatment may decrease oxidative damage from I/R in cerebral tissue.

Topics: Animals; Apoptosis; Brain Ischemia; Cell Death; Disease Models, Animal; Glucagon-Like Peptide 2; Glutathione; Hippocampus; Male; Malondialdehyde; Neuroprotective Agents; Oxidative Stress; Peroxidase; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Superoxide Dismutase

We investigated the role of intracerebroventricular (ICV) injection of rimonabant (500ng), a CB1 antagonist, on lipopolysaccharide ((LPS) 5mg/kg)-induced pulmonary inflammation in rats in an isolated perfused lung model. There were decreases in pulmonary capillary pressure (Ppc) and increases in the ((Wet-Dry)/Dry lung weight)/(Ppc) ratio in the ICV-vehicle/LPS group at 4h. There were decreases in TLR4 pathway markers, such as interleukin receptor-associated kinase-1, IκBα, Raf1 and phospho-SFK (Tyr416) at 30min and at 4h increases in IL-6, vascular cell adhesion molecule-1 and myeloperoxidase in lung homogenate. Intracerebroventricular rimonabant attenuated these LPS-induced responses, indicating that ICV rimonabant modulates LPS-initiated pulmonary inflammation.

Topics: Animals; Anti-Inflammatory Agents; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Administration Schedule; Injections, Intraventricular; Lipopolysaccharides; Lung; Male; Peroxidase; Piperidines; Pneumonia; Pulmonary Edema; Pyrazoles; Rats; Rats, Sprague-Dawley; Rimonabant; Signal Transduction; Time Factors; Toll-Like Receptor 4

The paper is an attentative effort to evaluate the reaction and mechanism of estrogen on pregnant rabbits with acute lung injury caused by hemorrhagic shock.. Sixty pregnant New Zealand white rabbits were randomly divided into 6 groups, with 10 rabbits in each group, namely normal control group (NG group, with anesthesia only), estrogen group (E(2)G group, with additional estrogen injection at 60 min) and the other four hemorrhagic shock groups underwent hemorrhagic shock (i.e. E(2)SG, FSG, SBSG, E(2)SBSG group; mean blood pressure- 40 mmHg (1 mmHg = 0.133 kPa) by phlebotomy for 15 min. After maintenance of the pressure for 45 min, the rabbits were treated with E(2) (0.37 mg/kg), fructose injection (5%, 2 ml/kg), the p38 mitogen-activated protein kinases (p38MAPK) inhibitor SB-203580 (2 mg/kg) or E(2) plus SB-203580. Tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) were measured at different time points (0 min, 60 min, 80 min and 260 min), lung tissue methane dicarboxylic aldehyde (MDA) level, lung tissue myeloperoxidase (MOP), superoxide dismutase (SOD) activity, lung tissue dry weight/wet weight (DW/WW) value were measured after the experiment was finished, pulmonary pathology of the rabbits was observed.. (1) Serum TNF-α level of NG group and E(2)SG group were not significantly different compared with the other four groups at the 0 min and 60 min. At 80 min and 260 min of experiment, serum TNF-α level of all the four shock groups were increased, E(2)SG group [(172.4 ± 16.0) and (216.7 ± 18.6) ng/L], FSG group [(171.6 ± 9.1) and (263.9 ± 7.8) ng/L], SBSG group [(172.8 ± 7.2) and (300.6 ± 4.8) ng/L], E(2)SBSG group [(167.9 ± 4.8 ) and (261.8 ± 9.6) ng/L], and significantly higher than NG group and E(2)G group, separately (P < 0.05). (2) Serum IL-6 level of NG group and E(2)SG group were not significantly different compared with the other four groups at the 0 min, 60 min and 80 min. At 260 min, the serum IL-6 level [(98.3 ± 0.9) and (110.4 ± 1.8) ng/L; (120.9 ± 2.3) and (109.8 ± 2.6) ng/L] of the four shock groups (E(2)SG, FSG, SBSG, E(2)SBSG group) were significantly higher than NG group and E(2)G group (P < 0.05). (3) Lung tissue MDA level [(2.20 ± 0.12), (2.57 ± 0.11), (3.17 ± 0.08), (2.75 ± 1.09) nmol/mg] and MPO activity [(4.45 ± 0.25), (6.65 ± 0.56), (9.55 ± 0.30), (6.78 ± 0.11) U/mg] of the four shock groups (E(2)SG, FSG, SBSG, E(2)SBSG group) were higher than NG group and E(2)G group (P < 0.05). (4) Lung tissue SOD activity [(51.8 ± 1.8), (40.2 ± 1.5), (30.0 ± 1.7), (41.2 ± 2.0) U/mg] was significantly higher in the four shock groups (E(2)SG, FSG, SBSG, E(2)SBSG group) compared with NG group and E(2)G group (P < 0.05). (5) Lung tissue DW/WW value (0.143 ± 0.008, 0.127 ± 0.008, 0.109 ± 0.006, 0.125 ± 0.008) was significantly lower in the four shock groups (E(2)SG, FSG, SBSG, E(2)SBSG group) compared with NG group and E(2)G group (P < 0.05). (6) Lung tissue of the rabbits in NG group and E(2)G group is basically normal without obvious pathology changes. Lung tissue pathological damage of rabbits was observed in the four shock groups, and the pathological damage of rabbits in SBSG group was most serious.. Estrogen can reduce acute lung injury of pregnant rabbits with hemorrhagic shock, the p38MAPK pathway plays a critical role in mediating the salutary effects of E(2) on shock-induced acute lung injury.

Topics: Acute Lung Injury; Animals; Disease Models, Animal; Estrogens; Female; Imidazoles; Interleukin-6; Lung; p38 Mitogen-Activated Protein Kinases; Peroxidase; Pregnancy; Protective Agents; Pyridines; Rabbits; Shock, Hemorrhagic; Tumor Necrosis Factor-alpha

Ischemia/reperfusion (I/R) injury of skeletal muscles is common pathophysiology during surgeries and the superoxide dismutase (SOD) plays a critical role in this process. SOD-modeled coordination compound (MSODa) may simulate the protective effects as SOD.. Therefore, this study was designed to explore the protective effects and underlying mechanism of MSODa on malondialdehyde (MDA) and integrin-β2 (CD11b/CD18) in plasma, myeloperoxidase (MPO) and intercellular cell adhesion molecule-1 (ICAM-1) in tissue, and morphological changes before and after I/R injury. The rat model of I/R in hind limb was established and randomly divided into sham, ischemia, I/R, I/R-treated with saline, SOD, and MSODa, respectively.. These results showed that averaged values for MDA, MPO, CD11b/CD18, and ICAM-1 were significantly increased (P < 0.01 vs ischemia alone) in a time-dependent fashion along with marked tissue remodeling, such as abnormal arrangement of muscular fibers, interstitial edema, vasodilation with no-reflow, inflammatory cells adherent and infiltration, structural changes in mitochondrial, and decrease in glycogens as well. However, all parameter changes induced by I/R injury were reversed, at least partially, by MSODa and SOD treatments and intriguingly, the beneficial/protective effects of MSODa was superior to SOD with an early onset.. This novel finding demonstrates that MSODa improves I/R injury of skeletal muscles due at least partially to inhibition of adherent molecule expression and reduction of oxygen free radical formation during I/R pathophysiological processes and this protective action of MSODa was superior to SOD, highlighting the bright future for MSODa in clinical management of tissue I/R injury.

Topics: Animals; Biomimetic Materials; CD18 Antigens; Disease Models, Animal; Gene Expression Regulation; Intercellular Adhesion Molecule-1; Male; Malondialdehyde; Muscle, Skeletal; Peroxidase; Rats; Rats, Wistar; Reperfusion Injury; Superoxide Dismutase

The mechanisms of excessive migration of activated neutrophils into inflamed lungs, credited with tissue damage, are not fully understood. We explored the hitherto unknown expression of leukocyte-specific protein 1 (LSP1) in human and mouse lungs and neutrophils and examined its role in neutrophil migration in acute lung inflammation. Autopsied septic human lungs showed increased LSP1 labeling in epithelium, endothelium, and leukocytes, including in their nuclei compared with normal lungs. We induced acute lung inflammation through intranasal administration of E. coli lipopolysaccharide (LPS) (80 μg) in LSP1-deficient (Lsp1(-/-)) and wild-type (WT) 129/SvJ mice. Immunocytochemistry and Western blots showed increased expression of LSP1 and phosphorylated LSP1 in lungs of LPS-treated WT mice. Histology showed more congestion, inflammation, and Gr-1(+) neutrophils in lung of WT mice than Lsp1(-/-) mice. LPS-treated WT mice had significantly more neutrophils in bronchoalveolar lavage (BAL) and myeloperoxidase levels in lungs compared with Lsp1(-/-) mice. However, there were no differences in lung tissue and BAL concentrations of keratinocyte-derived chemokine, monocyte chemoattractant protein-1, macrophage inflammatory protein-1α and -1β, vascular permeability, and phosphorylated p38 MAPK between LPS-treated WT and Lsp1(-/-) mice, whereas TNF-α concentration was higher in BAL fluid from LPS-treated WT. Immunoelectron microscopy showed increased LSP1 in the nuclei of LPS-treated neutrophils. We also found increased levels of phosphorylated LSP1 associated with plasma membrane, nucleus, and cytosol at various times after LPS treatment of murine bone marrow-derived neutrophils, suggesting its role in modulation of neutrophil cytoskeleton and the membrane. These data collectively show increased expression of LSP1 in inflamed mouse and human lungs and its role in neutrophil recruitment and lung inflammation.

Topics: Acute Lung Injury; Animals; Bronchoalveolar Lavage; Calcium-Binding Proteins; Cell Membrane; Cell Nucleus; Cytoskeleton; Disease Models, Animal; Humans; Lipopolysaccharides; Mice; Mice, Knockout; Microfilament Proteins; Neutrophil Infiltration; Neutrophils; p38 Mitogen-Activated Protein Kinases; Peroxidase; Phosphorylation

Neuroendoscopy is an innovative technique for neurosurgery that can nonetheless result in traumatic brain injury. The accompanying neuroinflammation may lead to secondary tissue damage, which is the major cause of delayed neuronal death after surgery. The present study investigated the capacity of osthole to prevent secondary brain injury and the underlying mechanism of action in a mouse model of stab wound injury.. A mouse model of cortical stab wound injury was established by inserting a needle into the cerebral cortex for 20 min to mimic neuroendoscopy. Mice received an intraperitoneal injection of osthole 30 min after surgery and continued for 14 days. Neurological severity was evaluated 12 h and up to 21 days after the trauma. Brains were collected 3-21 days post-injury for histological analysis, immunocytochemistry, quantitative real-time PCR, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and enzyme-linked immunosorbent assays.. Neurological function improved in mice treated with osthole and was accompanied by reduced brain water content and accelerated wound closure relative to untreated mice. Osthole treatment reduced the number of macrophages/microglia and peripheral infiltrating of neutrophils and lowered the level of the proinflammatory cytokines interleukin-6 and tumor necrosis factor α in the lesioned cortex. Osthole-treated mice had fewer TUNEL+ apoptotic neurons surrounding the lesion than controls, indicating increased neuronal survival.. Osthole reduced secondary brain damage by suppressing inflammation and apoptosis in a mouse model of stab wound injury. These results suggest a new strategy for promoting neuronal survival and function after neurosurgery to improve long-term patient outcome.

Topics: Analysis of Variance; Animals; Brain Edema; Brain Injuries; Caspase 3; Cerebral Cortex; Coumarins; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Encephalitis; In Situ Nick-End Labeling; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Neurologic Examination; Neuroprotective Agents; Peroxidase; RNA, Messenger; Time Factors

Helminth immunomodulation in the host has been shown to have therapeutic implications in inflammatory bowel diseases. In this study we aimed to evaluate the therapeutic effect of Brugia malayi recombinant cystatin (rBmCys) in a dose-dependent manner on dextran sulfate sodium (DSS)-induced colitis in mice.. The anti-inflammatory activity of rBmCys on mice peritoneal exudate cells was initially analyzed in vitro. BALB/c mice were fed with 5% DSS for 7 days to induce colitis. The colitis mice were treated intraperitoneally with rBmCys (10, 25 or 50 µg for the three different groups of mice) on days 1, 3 and 5 of the DSS administration. Disease severity was assessed by the disease activity index (DAI) and macroscopic and histopathological scores of colon and myeloperoxidase activity in colonic mucosa. Cytokine profiles were measured in sera and cultured splenocytes of treated mice followed by stimulation with rBmCys.. rBmCys showed anti-inflammatory activity in vitro. Treatment of DSS-induced colitis with rBmCys in mice ameliorated the overall disease severity as reflected by a significant reduction in weight loss, the DAI, mucosal edema, colon damage and myeloperoxidase activity of the colonic mucosa. While the mRNA expressions of IFN-γ, TNF-α, interleukin (IL)-5, IL-6 and IL-17 were downregulated, IL-10 expression was upregulated in the splenocytes of colitis mice treated with rBmCys. The amelioration of DSS-induced colitis occurred in a dose-dependent manner.. The results of this study indicate an anti-inflammatory potential of rBmCys and provide evidence for using this protein as a promising therapeutic agent in ulcerative colitis.

Topics: Animals; Anti-Inflammatory Agents; Brugia malayi; Colitis; Colon; Cystatins; Dextran Sulfate; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Helminth Proteins; Interferon-gamma; Interleukin-10; Interleukin-17; Interleukin-5; Interleukin-6; Intestinal Mucosa; Mice; Mice, Inbred BALB C; Peroxidase; RNA, Messenger; Tumor Necrosis Factor-alpha; Weight Loss

Del-1 is an endothelial cell-secreted anti-inflammatory protein. In humans and mice, Del-1 expression is inversely related to that of IL-17, which inhibits Del-1 through hitherto unidentified mechanism(s). Here we show that IL-17 downregulates human endothelial cell expression of Del-1 by targeting a critical transcription factor, C/EBPβ. Specifically, IL-17 causes GSK-3β-dependent phosphorylation of C/EBPβ, which is associated with diminished C/EBPβ binding to the Del-1 promoter and suppressed Del-1 expression. This inhibitory action of IL-17 can be reversed at the GSK-3β level by PI3K/Akt signalling induced by D-resolvins. The biological relevance of this regulatory network is confirmed in a mouse model of inflammatory periodontitis. Intriguingly, resolvin-D1 (RvD1) confers protection against IL-17-driven periodontal bone loss in a Del-1-dependent manner, indicating an RvD1-Del-1 axis against IL-17-induced pathological inflammation. The dissection of signalling pathways regulating Del-1 expression provides potential targets to treat inflammatory diseases associated with diminished Del-1 expression, such as periodontitis and multiple sclerosis.

Topics: Alveolar Bone Loss; Animals; Calcium-Binding Proteins; Carrier Proteins; CCAAT-Enhancer-Binding Protein-beta; Cell Adhesion Molecules; Chromatin Immunoprecipitation; Disease Models, Animal; Docosahexaenoic Acids; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Gingiva; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Human Umbilical Vein Endothelial Cells; Humans; Immunoblotting; Immunoprecipitation; Intercellular Signaling Peptides and Proteins; Interleukin-17; Mice; Mice, Knockout; Periodontitis; Peroxidase; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Real-Time Polymerase Chain Reaction; Signal Transduction

We aimed to investigate the effects of Tempol on local organ damage in an experimental acute pancreatitis model.. This experimental study was conducted on 40 male Wistar- albino rats. The animals were randomly allocated into four groups: (i) Sham-operated group, laparotomies and cannulations of the pancreatic duct without acute necrotizing pancreatitis (ANP) (n=10); (ii) Sham + Tempol group, identical to group 1 except for intravenous tempol treatment for 4 hours (n = 10); (iii) ANP group, glycodeoxycholic acid was infused into the pancreatic duct and cerulein was infused intravenously for 6 hours for development of ANP (n=10); and (iv) ANP + Tempol treated group, in addition to the procedure in group 3, rats were administered tempol intravenously for 4 hours (n = 10). Injury of the pancreas was evaluated histopathologically. Malondialdehyde and myeloperoxidase levels of the pancreatic tissue, blood gas analysis, leukocyte and hematocrit levels were measured. Wet/dry weight of pancreatic tissue was also measured.. Serum amylase levels, pancreatic tissue malondialdehyde and myeloperoxidase levels, wet/dry weight ratio, pancreatic edema, acinar necrosis, fat necrosis and hemorrhage, inflammation and perivascular infiltration were significantly lower in the ANP + Tempol group compared with the ANP group.. Tempol infusion reduced local organ damage due to acute necrotizing pancreatitis in this experimental study. These findings demonstrate that tempol has protective effects on local organ damage due to acute necrotizing pancreatitis in rats.

Topics: Animals; Antioxidants; Cyclic N-Oxides; Disease Models, Animal; Drug Evaluation, Preclinical; Edema; Male; Malondialdehyde; Multiple Organ Failure; Pancreas; Pancreatitis, Acute Necrotizing; Peroxidase; Random Allocation; Rats, Wistar; Spin Labels

Gelsolin is the fourth most abundant protein in the body and its depletion in the blood has been found in multiple sclerosis (MS) patients. How gelsolin affects the MS brain has not been studied. We found that while the secreted form of gelsolin (pGSN) decreased in the blood of experimental autoimmune encephalomyelitis (EAE) mice, pGSN concentration increased in the EAE brain. Recombinant human pGSN (rhp-GSN) decreased extracellular actin and myeloperoxidase activity in the brain, resulting in reduced disease activity and less severe clinical disease, suggesting that gelsolin could be a potential therapeutic target for MS.

Topics: Actins; Animals; Brain; CD11b Antigen; Cell Line, Tumor; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Freund's Adjuvant; Gelsolin; Glioma; Humans; Mice; Multiple Sclerosis; Mycobacterium tuberculosis; Myelin Proteolipid Protein; Neutrophils; Peptide Fragments; Peroxidase; Time Factors

The aim of this study was to assess the ability of the combination treatment of methylprednisolone (MP) and placenta-derived mesenchymal stem cells (PDMSCs) in a rabbit model of spinal cord injury (SCI). Rabbits were randomly divided into four groups: group 1 (control), group 2 (MP), group 3 (PDMSCs) and group 4 (MP + PDMSCs). In all groups, the spinal cord injury model was created by the weight drop method. Levels of malondialdehyde (MDA), myeloperoxidase (MPO), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) were determined by kit. Histopathological examination was also performed. Neurological evaluation was carried out with the Tarlov scoring system. The results showed both MP and PDMSCs had neuroprotective effects, and combining the administration of MP with PDMSCs was shown a significant effect on the recovery of neurological function. Therefore, the combined use of MP and PDMSCs can be used as a potential therapeutic method for SCI.

Topics: Animals; Catalase; Combined Modality Therapy; Disease Models, Animal; Glutathione Peroxidase; Malondialdehyde; Mesenchymal Stem Cell Transplantation; Methylprednisolone; Neuroprotective Agents; Peroxidase; Rabbits; Recovery of Function; Spinal Cord; Spinal Cord Injuries; Superoxide Dismutase; Treatment Outcome

The NLR family, pyrin domain-containing 3 (NLRP3) inflammasome plays a key role in intracerebral hemorrhage (ICH)-induced inflammatory injury, and the purinergic 2X7 receptor (P2X7R) is upstream of NLRP3 activation. This study aimed to investigate how P2X7R functions in ICH-induced inflammatory injury and how the receptor interacts with the NLRP3 inflammasome.. Rats were treated with P2X7R small interfering RNA (siRNA) 24 h before undergoing collagenase-induced ICH. A selective P2X7R inhibitor (blue brilliant G, BBG) or a peroxynitrite (ONOO(-)) decomposition catalyst (5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron(III) [FeTPPS]) was injected 30 min after ICH. Brain water content, hemorrhagic lesion volume, and neurological deficits were evaluated, and western blot, immunofluorescence, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) were carried out.. Striatal P2X7R and NLRP3 inflammasomes were activated after ICH. Gene silencing of P2X7R suppressed NLRP3 inflammasome activation and interleukin (IL)-1β/IL-18 release and significantly ameliorated brain edema and neurological deficits. Additionally, enhanced NADPH oxidase 2 (NOX2, gp91(phox)) and inducible nitric oxide synthase (iNOS), as well as their cytotoxic product (ONOO(-)) were markedly attenuated by BBG treatment following ICH. This was accompanied by downregulations of the inflammasome components, IL-1β/IL-18 and myeloperoxidase (MPO, a neutrophil marker). Most importantly, inflammasome activation and IL-1β/IL-18 release were significantly inhibited by ONOO(-) decomposition with FeTPPS.. Our findings implicate that P2X7R exacerbated inflammatory progression and brain damage in ICH rats possibly via NLRP3 inflammasome-dependent IL-1β/IL-18 release and neutrophil infiltration. ONOO(-), a potential downstream signaling molecule of P2X7R, may play a critical role in triggering NLRP3 inflammasome activation.

Topics: Animals; Apoptosis Regulatory Proteins; Brain Edema; Brain Injuries; CARD Signaling Adaptor Proteins; Carrier Proteins; Caspase 1; Cerebral Hemorrhage; Cytokines; Disease Models, Animal; Male; Membrane Glycoproteins; NADPH Oxidase 2; NADPH Oxidases; Nitric Oxide Synthase Type II; NLR Family, Pyrin Domain-Containing 3 Protein; Peroxidase; Peroxynitrous Acid; Quaternary Ammonium Compounds; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P2X7; Time Factors; Up-Regulation

Ulcerative colitis, an inflammatory bowel disease, is associated with the massive infiltration of neutrophils. Although the initial infiltration of neutrophils is beneficial for killing bacteria, it is presumed that persistent infiltration causes tissue damage by releasing antibacterial products as well as inflammatory cytokines. A murine C-type lectin receptor, dendritic cell immunoreceptor 1 (Dcir1), is expressed on CD11b(+) myeloid cells, such as macrophages, dendritic cells and neutrophils. It was reported that Dcir1 is required to maintain homeostasis of the immune system to prevent autoimmunity, but it is also involved in the development of infectious disease resulting in the enhanced severity of cerebral malaria. However, the role of Dcir1 in intestinal immune responses during colitis remains unclear. In this study, we investigated the role of Dcir1 in intestinal inflammation using an experimental colitis model induced with dextran sodium sulfate (DSS).. In contrast to wild type (WT) mice, Dcir1 (-/-) mice exhibited mild body weight loss during the course of DSS colitis accompanied by reduced colonic inflammation. Dcir1 deficiency caused a reduced accumulation of neutrophils in the inflamed colon on day 5 of DSS colitis compared with WT mice. Consistently, the production of a neutrophil-attracting chemokine, MIP-2, was also decreased in the Dcir1 (-/-) colon compared with the WT colon on day 5. There were fewer myeloperoxidase-positive neutrophils in the inflamed colon of Dcir1 (-/-) mice than in that of WT mice. Moreover, bone marrow neutrophils from Dcir1 (-/-) mice produced less reactive oxygen species (ROS) by lipopolysaccharide stimulation than those from WT mice. This suggests that Dcir1 deficiency decreases the accumulation of tissue destructive neutrophils during DSS colitis.. Dcir1 enhances the pathogenesis of DSS colitis by altering neutrophil recruitment and their functions.

Topics: Animals; Chemokine CXCL2; Colitis; Cytokines; Dextran Sulfate; Disease Models, Animal; Lectins, C-Type; Leukocyte Count; Lipopolysaccharides; Mice; Mice, Knockout; Neutrophil Infiltration; Neutrophils; Peroxidase; Reactive Oxygen Species; Respiratory Burst

Chagas disease, which is caused by the parasite Trypanosoma cruzi, is an important cause of cardiomyopathy in Latin America. It is estimated that 10%-30% of all infected individuals will acquire chronic chagasic cardiomyopathy (CCC). The etiology of CCC is multifactorial and involves parasite genotype, host genetic polymorphisms, immune response, signaling pathways and autoimmune progression. Herein we verified the impact of the recombinant form of P21 (rP21), a secreted T. cruzi protein involved in host cell invasion, on progression of inflammatory process in a polyester sponge-induced inflammation model. Results indicated that rP21 can recruit immune cells induce myeloperoxidase and IL-4 production and decrease blood vessels formation compared to controls in vitro and in vivo. In conclusion, T. cruzi P21 may be a potential target for the development of P21 antagonist compounds to treat chagasic cardiomyopathy.

Topics: Animals; Cardiomyopathies; Cell Adhesion; Cell Line; Cell Survival; Chagas Disease; Chemotaxis; Cytokines; Disease Models, Animal; Inflammation; Interleukin-4; Leukocytes; Male; Mice; Mice, Inbred C57BL; Neovascularization, Physiologic; Peroxidase; Protozoan Proteins; Recombinant Proteins; Trypanosoma cruzi

Mucosal balance impairment, bacterial over-proliferation, cytokines, inflammatory mediators are known as responsible for inflammatory bowel disease. Besides known anorexigenic, neuroprotective, and anti-apoptotic effects, the major effect of nesfatin-1 on colitis is unknown. Our aim was to investigate the possible anti-inflammatory effects of nesfatin-1 in acetic acid induced colitis model and potential underlying mechanisms. Male Spraque-Dawley rats were anesthetized by intraperitoneal ketamine (100 mg/kg) and chlorpromazine (0.75 mg/kg). For nesfatin-1 and antagonist applications some of the rats were intracerebroventricularly (i.c.v.) cannulated. In colitis group, intrarectally (i.r.) 4% acetic acid solution (1 ml) and 10 minutes later i.c.v. nesfatin-1 (0.05 μg/5 μl) or vehicle (5 μl) were administered. Treatments continued for 3 days. In control group, physiological saline solution was used intrarectally. To identify the underlying effective mechanism of nesfatin-1, rats were divided into 3 subgroups, 5 minutes following colitis induction; i.c.v. atosiban (oxytocin receptor antagonist), SHU9119 (melanocortin receptor antagonist) or GHSR-1a antagonist (ghrelin receptor antagonist) were administered, 5 minutes later nesfatin-1 was administered for 3 days. On the fourth day, rats were decapitated, and colon tissues were sampled. Macroscopic and microscopic damage scores of distal colon, and colonic tissue malondialdehyde, glutathione, myeloperoxidase, superoxide dismutase, catalase, luminol and lucigenin chemiluminescence measurements were analysed. The increased myeloperoxidase activity, malondialdehyde levels, luminol and lucigenin chemiluminescence measurements, macroscopic and microscopic damage scores with colitis induction (P < 0.05 - 0.001) were decreased with nesfatin-1 treatment (P < 0.05 - 0.001). Nesfatin-1 may show this effect by inhibiting neutrophil infiltration through tissues and by decreasing formation of free oxygen radicals. Atosiban and GHSR-1a administration alleviated the protective effect of nesfatin-1 from microscopic and oxidant damage parameters and lipid peroxidation (P < 0.05 - 0.001). The results of the study suggest that nesfatin-1 had a protective effect from colitis induction, and the anti-inflammatory and antioxidant effects of nesfatin-1 on colitis might occur via oxytocin and ghrelin receptors.

Topics: Acetic Acid; Animals; Anti-Inflammatory Agents; Antioxidants; Calcium-Binding Proteins; Colitis; Disease Models, Animal; DNA-Binding Proteins; Glutathione; Lipid Peroxidation; Male; Malondialdehyde; Nerve Tissue Proteins; Nucleobindins; Peroxidase; Rats; Rats, Sprague-Dawley

Helicobacter pylori (H. pylori)-induced oxidative stress has been shown to play a very important role in the inflammation of the gastric mucosa and increases the risk of developing gastric cancer. Resveratrol has many biological functions and activities, including antioxidant and anti-inflammatory effect. The purpose of this study was to probe whether resveratrol inhibits H. pylori-induced gastric inflammation and to elucidate the underlying mechanisms of any effect in mice. A mouse model of H. pylori infection was established via oral inoculation with H. pylori. After one week, mice were administered resveratrol (100 mg/kg body weight/day) orally for six weeks. The mRNA and protein levels of iNOS and IL-8 were assessed using RT-PCR, Western blot and ELISA. The expression levels of IκBα and phosphorylated IκBα (which embodies the level and activation of NF-κB), Heme Oxygenase-1 (HO-1; a potent antioxidant enzyme) and nuclear factor-erythroid 2 related factor 2 (Nrf2) were determined using Western blot, and lipid peroxide (LPO) level and myeloperoxidase (MPO) activity were examined using an MPO colorimetric activity assay, thiobarbituric acid reaction, and histological-grade using HE staining of the gastric mucosa. The results showed that resveratrol improved the histological infiltration score and decreased LPO level and MPO activity in the gastric mucosa. Resveratrol down-regulated the H. pylori-induced mRNA transcription and protein expression levels of IL-8 and iNOS, suppressed H. pylori-induced phosphorylation of IκBα, and increased the levels of HO-1 and Nrf2. In conclusion, resveratrol treatment exerted significant effects against oxidative stress and inflammation in H. pylori-infected mucosa through the suppression of IL-8, iNOS, and NF-κB, and moreover through the activation of the Nrf2/HO-1 pathway.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Disease Models, Animal; Gastric Mucosa; Gastritis; Helicobacter Infections; Helicobacter pylori; Heme Oxygenase-1; Interleukin-8; Lipid Peroxides; Male; Mice; NF-kappa B; Nitric Oxide Synthase Type II; Oxidative Stress; Peroxidase; Phosphorylation; Resveratrol; Stilbenes

Severe thermal injury induces a pathophysiological response that affects most of the organs within the body; liver, heart, lung, skeletal muscle among others, with inflammation and hyper-metabolism as a hallmark of the post-burn damage. Oxidative stress has been implicated as a key component in development of inflammatory and metabolic responses induced by burn. The goal of the current study was to evaluate several critical mitochondrial functions in a mouse model of severe burn injury. Mitochondrial bioenergetics, measured by Extracellular Flux Analyzer, showed a time dependent, post-burn decrease in basal respiration and ATP-turnover but enhanced maximal respiratory capacity in mitochondria isolated from the liver and lung of animals subjected to burn injury. Moreover, we detected a tissue-specific degree of DNA damage, particularly of the mitochondrial DNA, with the most profound effect detected in lungs and hearts of mice subjected to burn injury. Increased mitochondrial biogenesis in lung tissue in response to burn injury was also observed. Burn injury also induced time dependent increases in oxidative stress (measured by amount of malondialdehyde) and neutrophil infiltration (measured by myeloperoxidase activity), particularly in lung and heart. Tissue mononuclear cell infiltration was also confirmed by immunohistochemistry. The amount of poly(ADP-ribose) polymers decreased in the liver, but increased in the heart in later time points after burn. All of these biochemical changes were also associated with histological alterations in all three organs studied. Finally, we detected a significant increase in mitochondrial DNA fragments circulating in the blood immediately post-burn. There was no evidence of systemic bacteremia, or the presence of bacterial DNA fragments at any time after burn injury. The majority of the measured parameters demonstrated a sustained elevation even at 20-40 days post injury suggesting a long-lasting effect of thermal injury on organ function. The current data show that there are marked time-dependent and tissue-specific alterations in mitochondrial function induced by thermal injury, and suggest that mitochondria-specific damage is one of the earliest responses to burn injury. Mitochondria may be potential therapeutic targets in the future experimental therapy of burns.

Topics: Animals; Burns; Disease Models, Animal; DNA Damage; DNA, Mitochondrial; Energy Metabolism; Lipid Peroxidation; Liver; Lung; Macrophages; Male; Mice; Mice, Inbred BALB C; Mitochondria; Mitochondria, Heart; Mitochondria, Liver; Myocardium; Neutrophil Infiltration; Oxidative Stress; Peroxidase

To investigate the preventive effect of kefir on colitis induced with dextran sulfate sodium (DSS) in rats.. Twenty-four male Wistar-albino rats were randomized into four groups: normal control, kefir-control, colitis, and kefir-colitis groups. Rats in the normal and kefir-control groups were administered tap water as drinking water for 14 d. Rats in the colitis and kefir-colitis groups were administered a 3% DSS solution as drinking water for 8-14 d to induce colitis. Rats in the kefir-control and kefir-colitis groups were administered 5 mL kefir once a day for 14 d while rats in the normal control and colitis group were administered an identical volume of the placebo (skim milk) using an orogastric feeding tube. Clinical colitis was evaluated with reference to the disease activity index (DAI), based on daily weight loss, stool consistency, and presence of bleeding in feces. Rats were sacrificed on the 15(th) day, blood specimens were collected, and colon tissues were rapidly removed. Levels of myeloperoxidase (MPO), tumor necrosis factor (TNF)-α, interleukin (IL)-10, malondialdehyde, and inducible nitric oxide synthase (iNOS) were measured in colon tissue.. The DAI was lower in the kefir-colitis group than in the colitis group (on the 3(rd) and 5(th) days of colitis induction; P < 0.01). The DAI was also significantly higher in the colitis group between days 2 and 6 of colitis induction when compared to the normal control and kefir-control groups. The DAI was statistically higher only on the 6(th) day in the kefir-colitis group when compared to that in the normal control groups. Increased colon weight and decreased colon length were observed in colitis-induced rats. Mean colon length in the colitis group was significantly shorter than that of the kefir-control group. Kefir treatment significantly decreased histologic colitis scores (P < 0.05). MPO activity in the colitis group was significantly higher than in the kefir-control group (P < 0.05). Kefir treatment significantly reduced the DSS colitis-induced TNF-α increase (P < 0.01). No statistically significant differences were observed among groups for IL-10 and MDA levels. Colon tissue iNOS levels in the colitis group were significantly higher than those in the control and kefir-colitis groups (P < 0.05).. Kefir reduces the clinical DAI and histologic colitis scores in a DSS-induced colitis model, possibly via reduction of MPO, TNF-α, and iNOS levels.

Topics: Animals; Colitis; Colon; Cultured Milk Products; Dextran Sulfate; Disease Models, Animal; Down-Regulation; Inflammation Mediators; Interleukin-10; Male; Malondialdehyde; Nitric Oxide Synthase Type II; Peroxidase; Rats, Wistar; Time Factors; Tumor Necrosis Factor-alpha

The objective of this study was to explore the gastroprotective properties of the aerial part of Lycium chinense Mill (LCA) against ethanol-induced gastric mucosa lesions in mice models. Administration of LCA at doses of 50, 100, 200 and 400 mg/kg body weight prior to ethanol consumption dose dependently inhibited gastric ulcers. The gastric mucosal injury was analyzed by gastric juice acidity, glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA), myeloperoxidase (MPO) activities. Furthermore, the levels of the inflammatory mediators, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) in serum were also analyzed using ELISA. Pathological changes were also observed with the aid of hematoxylin-eosin (HE) staining. Our results indicated that LCA significantly reduced the levels of MPO, MDA and increased SOD and GSH activities. Furthermore, LCA also significantly inhibited the levels of TNF-α, IL-6, and IL-1β in the serum of ulcerated mice in a dose dependent manner. Immunohistological analysis indicated that LCA also significantly attenuated the overexpression of nuclear factor-κB in pretreated mice models. This findings suggests Lycium chinense Mill possesses gastroprotective properties against ethanol-induced gastric injury and could be a possible therapeutic intervention in the treatment and management of gastric ulcers.

Topics: Animals; Anti-Ulcer Agents; Cytokines; Disease Models, Animal; Drug Evaluation, Preclinical; Ethanol; Gastric Juice; Glutathione; Hydrogen-Ion Concentration; Lycium; Male; Malondialdehyde; Mice, Inbred ICR; Oxidative Stress; Peroxidase; Plant Extracts; Stomach; Stomach Ulcer; Superoxide Dismutase; Transcription Factor RelA

The effect of recombinant human soluble thrombomodulin (TM-α) on acute liver failure (ALF) is unclear, and we elucidated the effect of TM-α in lipopolysaccharide (LPS)/d-galactosamine (GalN)-induced ALF in mice. Placebo (saline) or TM-α (100 mg/kg) was administered 1 h after LPS/GalN administration. Survival rates were evaluated for 24 h after LPS/GalN administration. Plasma and liver samples were evaluated 1, 3, and 7 h after LPS/GalN administration. Survival rates were significantly higher in the TM-α-treated group than in the placebo group. A significant augmentation of plasma high-mobility group box 1 protein (HMGB1) was observed 7 h after LPS/GalN administration. In the TM-α-treated mice, plasma HMGB1 was significantly lower than in the placebo group. A significant augmentation of hepatic nuclear factor (NF)-κB p65 was observed in the placebo-treated group, whereas a significant reduction, relative to placebo, was observed in the TM-α-treated group. Hepatic expression of tumor necrosis factor (TNF)-α and myeloperoxidase were significantly increased in the placebo group, and were similarly significantly attenuated in the TM-α-treated group. TM-α treatment also produced a significant attenuation of liver neutrophil accumulation after LPS/GalN administration. Thus, TM-α may become a useful treatment strategy for reducing the symptoms of ALF via the attenuation of LPS/GalN-induced HMGB1 levels.

Topics: Animals; Biomarkers; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Galactosamine; HMGB1 Protein; Lipopolysaccharides; Liver; Male; Mice, Inbred C57BL; Neutrophils; Peroxidase; Recombinant Proteins; Solubility; Survival Rate; Thrombomodulin; Transcription Factor RelA; Tumor Necrosis Factor-alpha

Acute lung injury (ALI) is one of the most serious complications in traumatic patients and is an important part of multiple organ dysfunction syndrome (MODS). Recombinant human brain natriuretic peptide (rhBNP) is a peptide with a wide range of biological activity. In this study, we investigated local changes in oxidative stress and the NF-κB-dependent matrix metalloproteinase-9 (MMP-9) pathway in rats with trauma/haemorrhagic shock (TH/S)-induced ALI and evaluated the effects of pretreatment with rhBNP. Forty-eight rats were randomly divided into four groups: sham operation group, model group, low-dosage rhBNP group and high-dosage rhBNP group (n = 12 for each group). Oxidative stress and MPO activity were measured by ELISA kits. MMP-9 activity was detected by zymography analysis. NF-κB activity was determined using Western blot assay. With rhBNP pretreatment, TH/S-induced protein leakage, increased MPO activity, lipid peroxidation and metalloproteinase (MMP)-9 activity were inhibited. Activation of antioxidative enzymes was reversed. The phosphorylation of NF-κB and the degradation of its inhibitor IκB were suppressed. The results suggested that the protection mechanism of rhBNP is possibly mediated through upregulation of anti-oxidative enzymes and inhibition of NF-κB activation. More studies are needed to further evaluate whether rhBNP is a suitable candidate as an effective inhaling drug to reduce the incidence of TH/S-induced ALI.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Antioxidants; Disease Models, Animal; Humans; I-kappa B Proteins; Inflammation Mediators; Lipid Peroxidation; Male; Matrix Metalloproteinase 9; Natriuretic Peptide, Brain; NF-kappa B; Oxidative Stress; Peroxidase; Phosphorylation; Proteolysis; Rats, Sprague-Dawley; Recombinant Proteins; Shock, Hemorrhagic; Signal Transduction

Oxidative damage is a central feature of ulcerative colitis. Here, we tested whether the antioxidant Mesna, when administered alone or in combination with n-3 polyunsaturated fatty acids (n-3 PUFAs), affects the outcome of dextran sodium sulphate (DSS)-induced ulcerative colitis in rats. After the induction of colitis, DSS-treated rats were further treated orally (p.o), intraperitoneally (i.p) or intrarectally (i.r) for either 7 or 14 days with Mesna, n-3 PUFAs or both. Rats were euthanized at the end of each treatment period. Clinical disease activity index was recorded throughout the experiment. At necropsy colorectal gross lesions were scored. Colitis was scored histologically, and the expression of myeloperoxidase (MPO), caspase-3, inducible nitric oxide synthase (iNOS) and nuclear factor κB (NF-κΒ) in colonic tissue was assessed by immunohistochemistry. Mesna alone was sufficient to significantly reduce colorectal tissue damage when administered orally or intraperitoneally. Orally coadministered n-3 PUFAs enhanced this effect, resulting in the significant suppression of DSS colitis after 7 days, and a remarkable recovery of colorectal mucosa was evident after 14 days of treatment. The amelioration of colon pathology co-existed with a significant decrease in MPO expression, overexpression of iNOS and reduction of nuclear NF-κB p65 in inflammatory cells, and the suppression of apoptosis in colonic epithelial cells. The simultaneous administration of Mesna and n-3 PUFAs is particularly effective in ameliorating DSS colitis in rats, by reducing oxidative stress, inflammation and apoptosis, probably through a mechanism that involves the inhibition of NF-κB and overexpression of iNOS.

Topics: Animals; Antioxidants; Apoptosis; Biomarkers; Caspase 3; Colitis, Ulcerative; Colon; Cytoprotection; Dextran Sulfate; Disease Models, Animal; Fatty Acids, Omega-3; Intestinal Mucosa; Male; Mesna; Nitric Oxide Synthase Type II; Oxidative Stress; Peroxidase; Rats, Wistar; Time Factors; Transcription Factor RelA

Recent study has shown that renin-angiotensin system plays an important role in the development of acute lung injury (ALI) with high level of angiotensin II (AngII) generated form AngI catalyzed by angiotensin-converting enzyme. AngII plays a major effect mainly through AT1 receptor. Therefore, we speculate inhibition of AT1 receptor may possibly attenuate the lung injury. Losartan, an antagonist of AT1 receptor for angiotensin II, attenuated lung injury by alleviation of the inflammation response in ALI, but the mechanism of losartan in ALI still remains unclear.. Thirty male Sprague-Dawley rats were randomly divided into Control group, ALI group (LPS), and Losartan group (LPS + Losartan). Bronchoalveolar lavage fluid (BALF) and lung tissue were obtained for analysis. The expressions of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), intercellular adhesion molecule-1 (ICAM-1) and caspase-3 were detected by reverse transcriptase polymerase chain reaction (RT-PCR) and western blotting.. In ALI group, TNF-α and protein level in BALF, MPO activity in lung tissue, pulmonary edema and lung injury were significantly increased. Losartan significantly reduced LPS-induced increase in TNF-α and protein level in BALF, MPO activity, pulmonary edema and lung injury in LPS-induced lung injury. The mRNA and protein expression levels of LOX-1 were significantly decreased with the administration of losartan in LPS-induced lung injury. Also, losartan blocked the protein levels of caspase-3 and ICAM-1 mediated by LOX-1 in LPS-induced lung injury.. Losartan attenuated lung injury by alleviation of the inflammation and cell apoptosis by inhibition of LOX-1 in LPS-induced lung injury.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Anti-Inflammatory Agents; Apoptosis; Bronchoalveolar Lavage Fluid; Caspase 3; Cytoprotection; Disease Models, Animal; Down-Regulation; Intercellular Adhesion Molecule-1; Lipopolysaccharides; Losartan; Lung; Lung Injury; Male; Neutrophil Infiltration; Peroxidase; Pulmonary Edema; Rats, Sprague-Dawley; Scavenger Receptors, Class E; Signal Transduction; Tumor Necrosis Factor-alpha

Inflammatory bowel disease is an urgent public health problem with a high incidence in developed countries. Alterations of lifestyle or dietary interventions may attenuate the disease progression and increase the efficacy of current therapies. Here we tested the effect of chronic supplementation with a mineral extract from red marine algae - rich in calcium (34%), magnesium, phosphorus, selenium and other trace minerals - in a clinically relevant model of spontaneous enterocolitis, interleukin (IL)-10(-/-) mice. The mineral extract was administered in the drinking water of Il10(-/-) mice on C57BL/6 J and BALB/c strain backgrounds for 25 weeks commencing from 3 to 4 weeks of age. The mineral extract ameliorated the spontaneous development of colitis and severity of disease in Il10(-/-) mice on a C57BL/6 J background. Mineral extract-treated Il10(-/-) C57BL/6 J strain mice had significantly reduced mortality, circulating levels of serum Amyloid A and reduced colonic tissue damage. In contrast, comparable treatment of Il10(-/-) mice on a BALB/c background with the mineral extract did not alter the course of colitis. These data demonstrate that chronic supplementation with a natural mineral extract selectively ameliorates spontaneous mild-moderate colitis in Il10(-/-) mice on a C57BL/6 J, but does not attenuate more moderate-severe colitis in BALB/c strain animals.

Topics: Animals; Calcium; Colon; Cytokines; Dietary Supplements; Disease Models, Animal; Enterocolitis; Female; Interleukin-10; Magnesium; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Minerals; Peroxidase; Phosphorus; Rhodophyta; Selenium; Serum Amyloid A Protein; Species Specificity

The most common cause of laryngitis is the laryngopharyngeal reflux disease. The symptoms of laryngitis can be hoarseness, globus, chronic cough, voice fatigue, throat pain, and dysphagia. Low-level laser therapy (LLLT) is beneficial to reduce the pain and inflammatory response without side effects. Therefore, LLLT may be a useful tool for the treatment of laryngitis. This study proposes to analyze the effect of laser therapy in a model of reflux-induced laryngitis. The animals were randomly put into three groups: control--non-intubated; nasogastric intubation--intubated; and nasogastric intubation with laser therapy-intubated treated with 105-J/cm(2) laser irradiation. For the induction of laryngitis, the animals were anesthetized and a nasogastric tube was inserted through the nasopharynx until it reached the stomach, for 1 week. Thereafter, measurement of myeloperoxidase activity and the histopathological procedures were performed. In conclusion, we observed in this study that 105-J/cm(2) infrared laser reduced the influx of neutrophils in rats, and it improved the reparative collagenization of the laryngeal tissues.

Topics: Animals; Disease Models, Animal; Fibrillar Collagens; Humans; Intubation, Gastrointestinal; Laryngitis; Laryngopharyngeal Reflux; Low-Level Light Therapy; Male; Neutrophils; Peroxidase; Rats; Rats, Wistar; Treatment Outcome

Advanced glycation end products (AGE) have been found in inflamed gingival tissue and have been shown to interfere with the integrity of extracellular matrix and cell-matrix interactions. This study aims to investigate the modulatory effect of aminoguanidine (AG), an AGE inhibitor, in various stages of experimental periodontitis.. Thirty-six Sprague-Dawley rats were used. AG or normal saline (NS) was systemically administered in the induction, progression, and recovery phases of ligature-induced periodontitis. Dynamic changes of the periodontium were evaluated by microcomputed tomography, histology, and immunohistochemistry of the receptor for AGE (RAGE). Molecular mechanisms were evaluated by myeloperoxidase activity, gene expression of RAGE, and markers associated with tissue repair and homeostasis, including vascular endothelial growth factor (VEGF), type I collagen, fibronectin, and periostin.. AG appeared to inhibit the degradation of the collagen matrix in the induction phase but promoted collagen reorganization in the progression and recovery phases of experimental periodontitis. In the induction sites, periodontal bone loss was significantly reduced (P <0.05), with significantly reduced RAGE (P <0.05) and significantly elevated fibronectin and periostin levels (P <0.01). No significant alterations in the levels of myeloperoxidase, VEGF, and collagen were noted. In the progression and recovery sites, similar trends were observed, with insignificant differences relative to NS-treated animals.. AG reduced periodontal bone loss during the induction of experimental periodontitis, and the effects appeared to be insignificant in the progression and recovery phases. This modulation was related to the inhibition of the AGE-RAGE axis to resume cell-matrix interactions and maintain tissue integrity.

Topics: Alveolar Bone Loss; Alveolar Process; Angiogenesis Inducing Agents; Animals; Biomarkers; Cell Adhesion Molecules; Collagen Type I; Disease Models, Animal; Disease Progression; Fibronectins; Gene Expression Regulation; Glycation End Products, Advanced; Guanidines; Image Processing, Computer-Assisted; Male; Nitric Oxide Synthase; Periodontitis; Periodontium; Peroxidase; Rats; Rats, Sprague-Dawley; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Vascular Endothelial Growth Factor A; Wound Healing; X-Ray Microtomography

The present study evaluated the topical anti-inflammatory potential of a standardized pomegranate rind extracts (SPRE) in parallel with its marker compound ellagic acid (EA, 13% w/w) against a mouse model of contact dermatitis. In the phenol-induced mouse ear edema, topical application of SPRE (5, 2.5, and 1 mg/ear) and EA (0.65, 0.325, and 0.13 mg/ear, equivalent to its content in SPRE) dose-dependently reduced the ear edema with the maximal inhibition of 79.12% and 73.63%, respectively. Triamcinolone (0.1 mg/ear) and diclofenac (1 mg/ear) as reference drugs inhibited the edema by 73.63% and 37.91%. Myeloperoxidase (MPO) activity in the mouse ear was also decreased by SPRE and EA up to 69.68% and 68.79%, respectively. Triamcinolone and diclofenac decreased the MPO activity by 76.66% and 80.14% similarly. The results indicated that topical application of SPRE and EA is promising for use in the treatment of inflammatory skin disorders.

Topics: Animals; Anti-Inflammatory Agents; Dermatitis, Contact; Disease Models, Animal; Edema; Ellagic Acid; Fruit; Lythraceae; Male; Mice; Mice, Inbred ICR; Peroxidase; Phenols; Plant Extracts

The aim of this study was to investigate the anti-inflammatory effect of the crude hydroalcoholic extract (CHE) from the aerial parts of Croton antisyphiliticus, its fractions and isolated compounds derived from it on the mouse model of pleurisy induced by carrageenan. The aerial parts of C. antisyphiliticus were dried, macerated and extracted with ethanol to obtain the CHE, which was fractionated by liquid-liquid extraction using solvents with increasing polarity to obtain hexane (Hex), ethyl acetate (EA) and aqueous (Aq) fractions. Vitexin and quinic acid were isolated from Aq fraction. Capillary electrophoresis analysis, physical characteristics and spectral data produced by infrared (IR), nuclear magnetic resonance ((1)H and (13)C NMR) and mass spectrometry analyses were used to identify and elucidate the structure of the isolated compounds. The experimental model of pleurisy was induced in mice by a single intrapleural injection of carrageenan (1 %). Leukocytes, exudate concentrations, myeloperoxidase (MPO) and adenosine-deaminase (ADA) activities and nitrate/nitrite (NOx), tumor necrosis factor-α (TNF-α) and interleukin-17 (IL-17) levels were determined in the pleural fluid leakage at 4 h after pleurisy induction. Animals pre-treated with CHE, Hex, EA, Aq, vitexin and quinic acid exhibited decreases in leukocytes, exudate concentrations, MPO and ADA activities and NOx levels (p < 0.05). Also CHE, Hex, EA and vitexin but not quinic acid inhibited TNF-α and IL-17 levels (p < 0.05). C. antisyphiliticus caused anti-inflammatory effect by inhibiting the activated leukocytes, exudate concentrations, NOx, TNF-α, and IL-17 levels. The compounds vitexin and quinic acid may be responsible for this anti-inflammatory action.

Topics: Adenosine Deaminase; Animals; Anti-Inflammatory Agents; Carrageenan; Croton; Disease Models, Animal; Female; Inflammation; Interleukin-17; Leukocytes; Mice; Nitrates; Nitrites; Peroxidase; Plant Extracts; Pleurisy; Tumor Necrosis Factor-alpha

In patients with acute kidney injury (AKI) mortality remains high, despite the fact that the patients are treated with continuous renal replacement therapy. The interaction between the kidney and the immune system might explain the high mortality observed in AKI. In order to elucidate the interaction between the kidney and immune system we developed a two-hit model of AKI and endotoxemia. Our hypothesis was that ischemia/reperfusion (I/R) of the kidney simultaneously with endotoxemia would generate a more extensive inflammatory response compared to I/R of the hind legs. Our expectation was that elevated levels of cytokines would be found in both blood and in organs distant to the kidneys. Forty mice were divided into five groups. The mice were subjected to the following operations: A: Sham only, no lipopolysaccharide (LPS); B: I/R of both kidneys + LPS; C: LPS only; D: Nephrectomy + LPS; E: I/R of both hind legs + LPS. In groups B and E, I/R times were identical. All mice were kept alive for 24 h and then sacrificed. Levels of interleukin (IL)-1β, IL-6, IL-10, and tumor necrosis factor-α were measured in the blood. The activity of myeloperoxidase (MPO) in lungs, kidneys, and liver was evaluated as an indirect measurement of accumulation of granulocytes. In this study, significantly higher amount of IL-6 and IL-10 in the plasma was observed following renal I/R compared to hind leg I/R. The elevated levels of cytokine in plasma were observed following nephrectomy and endotoxemia. The neutrophil infiltration of distant organs measured by the levels of MPO in the lung and liver also showed a significantly higher level in renal I/R compared to hind leg I/R. Renal I/R is associated with a more pronounced inflammatory response in blood and distant organs. The high cytokine levels measured following nephrectomy might be explained by compromised elimination of cytokines by the kidney in AKI.

Topics: Acute Kidney Injury; Animals; Disease Models, Animal; Endotoxemia; Inflammation; Interleukin-10; Interleukin-1beta; Interleukin-6; Ischemia; Kidney; Lipopolysaccharides; Liver; Lung; Male; Mice; Mice, Inbred C57BL; Nephrectomy; Neutrophil Infiltration; Peroxidase; Reperfusion Injury; Tumor Necrosis Factor-alpha

Surfactant therapy may be beneficial in acute lung injury (ALI). In spontaneously breathing newborn pigs with ALI supported with continuous positive airway pressure (CPAP), we evaluated the hypothesis that aerosolized KL4 surfactant (AERO KL4 S) would provide a similar therapeutic effect as intratracheal KL4 surfactant (ETT KL4 S) when compared to controls.. We randomized pigs with HCl-induced ALI to: (1) 175 mg/kg KL4 surfactant via endotracheal tube (ETT); (2) AERO KL4 S (22.5 mg/min phospholipid) for 60 min via continuous positive airway pressure (CPAP); or (3) sham procedure on CPAP. We obtained physiologic data and arterial blood gases throughout the 3-hr study. At study end, lungs were excised for analysis of interleukin-8 (IL-8), myeloperoxidase (MPO) levels and histomorphometric data.. Pigs treated with ETT KL4 S and AERO KL4 S had improved survival and sustained pO2 compared to controls. The AERO KL4 S group had higher pH compared to controls. Lung IL-8 levels were lower in the AERO KL4 S group compared to controls. Histomorphometric analysis showed less hemorrhage in the ETT and AERO KL4 S groups compared to controls. The AERO KL4 S group had more open lung units per fixed-field than the ETT KL4 S or controls.. AERO KL4 S produced similar improvements in survival, physiology, inflammatory markers, and morphology as ETT KL4 S in an ALI model.

Topics: Acute Lung Injury; Administration, Inhalation; Aerosols; Animals; Animals, Newborn; Continuous Positive Airway Pressure; Disease Models, Animal; Hydrochloric Acid; Intercellular Signaling Peptides and Proteins; Interleukin-8; Lung; Peptides; Peroxidase; Pulmonary Gas Exchange; Random Allocation; Survival Rate; Swine

Cepharanthine (CEP), a biscoclaurine alkaloid isolated from Stephania cepharantha Hayata, has been reported to have potent anti-inflammatory properties. However, the anti-inflammatory effects of CEP on a mouse model of lipopolysaccharide (LPS)-induced mastitis and its underlying molecular mechanisms remain to be elucidated. The purpose of the present study was to investigate the effects of CEP on LPS-induced mouse mastitis. The mouse model of mastitis was induced by inoculation of LPS through the canals of the mammary gland. CEP was administered intraperitoneally at 1 h before and 12 h after induction of LPS. The results show that CEP significantly attenuates the infiltration of neutrophils, suppresses myeloperoxidase activity, and reduces the levels of TNF-α, IL-1β, and IL-6 in LPS-induced mouse mastitis. Furthermore, CEP inhibited the phosphorylation of NF-κB p65 subunit and the degradation of its inhibitor IκBα. All the results suggest that CEP exerts potent anti-inflammatory effects on LPS-induced mouse mastitis. Accordingly, CEP might be a potential therapeutic agent for mastitis.

Topics: Animals; Anti-Inflammatory Agents; Benzylisoquinolines; Disease Models, Animal; Dose-Response Relationship, Drug; Down-Regulation; Female; Inflammation Mediators; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; Mammary Glands, Animal; Mastitis; Mice; Mice, Inbred BALB C; Neutrophil Infiltration; NF-kappa B; Peroxidase; Signal Transduction; Tumor Necrosis Factor-alpha

In the previous study, the anti-inflammatory effect of p-cymene had been found. In this study, we investigated anti-inflammatory effects of p-cymene on acute lung injury using lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model. The cell counting in the bronchoalveolar lavage fluid (BALF) was measured. The animal lung edema degree was evaluated by wet/dry weight (W/D) ratio. The superoxidase dismutase (SOD) activity and myeloperoxidase (MPO) activity was assayed by SOD and MPO kits, respectively. The levels of inflammatory mediators including tumor necrosis factor alpha (TNF-α), IL-1β, and IL-6 were assayed by enzyme-linked immunosorbent assay method. The pathological changes of the lung tissues were observed by hematoxylin and eosin staining. The inflammatory signal pathway-related protein levels of NF-κB were measured using Western blotting. The data showed that treatment with the p-cymene markedly attenuated inflammatory cell numbers in the BALF, decreased NF-κB protein level in the lungs, improved SOD activity, and inhibited MPO activity. Histological studies demonstrated that p-cymene substantially inhibited LPS-induced neutrophils in the lung tissue compared with the model group. The results indicated that p-cymene had a protective effect on LPS-induced ALI in mice.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; Cymenes; Cytoprotection; Disease Models, Animal; Female; Inflammation Mediators; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; Lung; Mice; Mice, Inbred BALB C; Monoterpenes; Neutrophil Infiltration; Peroxidase; Pulmonary Edema; Superoxide Dismutase; Transcription Factor RelA; Tumor Necrosis Factor-alpha

Studies have shown that diterpenes have anti-inflammatory and redox-protective pharmacological activities. The present study aimed to investigate the anti-inflammatory properties of phytol, a diterpene alcohol, in a mouse model of acute inflammation, and phytol effect on leukocyte recruitment, cytokines levels, and oxidative stress. The anti-inflammatory activities of phytol were assessed by measuring paw edema induced by different inflammatory agents (e.g., λ-carrageenan, compound 48/80, histamine, serotonin, bradykinin, and prostaglandin E2 [PGE2 ]), myeloperoxidase (MPO) activity, peritonitis model and cytokine levels. Further, oxidative stress was evaluated by determining glutathione (GSH) levels and malondialdehyde (MDA) concentration. The results showed that phytol (7.5, 25, 50, and 75 mg/kg) significantly reduced carrageenan-induced paw edema, in a dose-dependent manner. In addition, phytol (75 mg/kg) inhibited compound 48/80-, histamine-, serotonin-, bradykinin- and PGE2 -induced paw edema. It also inhibited the recruitment of total leukocytes and neutrophils; decreased MPO activity, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) levels, and MDA concentration; and increased GSH levels during carrageenan-induced acute inflammation. These results suggest that phytol attenuates the inflammatory response by inhibiting neutrophil migration that is partly caused by reduction in IL-1β and TNF-α levels and oxidative stress.

Topics: Animals; Anti-Inflammatory Agents; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Glutathione; Inflammation; Interleukin-1beta; Leukocytes; Male; Malondialdehyde; Mice; Neutrophils; Oxidative Stress; Peroxidase; Phytol; Tumor Necrosis Factor-alpha

Explosive traumatic injury to an extremity may lead to both local and distant organ injury. Regional traumatic tissue hypothermia has been reported to offer systemic protection; here we investigated the protective effects of regional limb hypothermia on local tissue trauma and the lungs. Furthermore, the optimal duration of regional traumatic limb hypothermic treatment was also evaluated.. Prospective, controlled, animal study.. University research laboratory.. Adult male Sprague-Dawley rats.. Anesthetized rats were randomized to sham, blast limb trauma, sham and regional hypothermia for 30 minutes, and blast limb trauma and regional hypothermia for 30 minutes, 60 minutes, and 6 hours. Blast limb trauma was created using chartaceous electricity detonators.. Distant lung and local tissue injury following blast limb trauma were attenuated by regional traumatic limb hypothermic treatment for 30 minutes, 60 minutes, and 6 hours reflected by reduced lung histopathological changes and water content. Regional traumatic limb hypothermic treatment for 60 minutes and 6 hours failed to further attenuate distant lung and local tissue injury compared with regional traumatic limb hypothermic treatment for 30 minutes. Inhibition of cystathionine gamma-lyase/hydrogen sulfide was reduced by regional traumatic limb hypothermic treatment for 30 minutes in blast limb trauma rats. A surrogate of neutrophil accumulation, myeloperoxidase activity, and release of tumor necrosis factor-α and interleukin-6 were also attenuated by regional traumatic limb hypothermic treatment for 30 minutes in blast limb trauma rats. Oxidative stress was alleviated by regional traumatic limb hypothermic treatment for 30 minutes evidenced by reduction of hydrogen peroxide and malondialdehyde and an increase of superoxide dismutase and glutathione in blast limb trauma rats.. Our data indicate that regional traumatic limb hypothermic treatment for 30 minutes offers both local protection for traumatic tissue and systemic protection for the lungs, which is likely associated with restoration of the cystathionine gamma-lyase/hydrogen sulfide pathway and inhibition of the inflammatory response and oxidative stress.

Topics: Animals; Blast Injuries; Blood Gas Analysis; Blood Pressure; Disease Models, Animal; Glutathione; Hydrogen Peroxide; Hypothermia, Induced; Interleukin-6; Leg Injuries; Lung; Lung Injury; Male; Malondialdehyde; Peroxidase; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Eucalyptol, also known as 1,8-cineol, is a monoterpene and has been shown to exert anti-inflammatory and antioxidant effect. It is traditionally used to treat respiratory disorders due to its secretolytic properties. In the present study, we evaluated the effect of 1,8-cineol on pulmonary inflammation in a mouse model of acute lung injury. We found that 1,8-cineol significantly decreased the level of TNF-α and IL-1β, and increased the level of IL-10 in lung tissues after acute lung injury induced by lipopolysaccharide (LPS). It also reduced the expression of nuclear factor kappa B (NF-κB) p65 and toll-like receptor 4 (TLR4), and myeloperoxidase activity in lung tissues. In addition, 1,8-cineol reduced the amounts of inflammatory cells in bronchoalveolar lavage fluid (BALF), including neutrophils and macrophages, and significantly decreased the protein content in BALF and the lung wet/dry weight (W/D) ratio. Its effect on LPS-induced pulmonary inflammation was associated with suppression of TLR4 and NF-κB expressions. Our results provide evidence that 1,8-cineol inhibits acute pulmonary inflammation, indicating its potential for the treatment of acute lung injury.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; Cyclohexanols; Disease Models, Animal; Dose-Response Relationship, Drug; Eucalyptol; Inflammation Mediators; Interleukin-10; Interleukin-1beta; Lipopolysaccharides; Lung; Male; Mice; Mice, Inbred ICR; Monoterpenes; Peroxidase; Pneumonia; Pulmonary Edema; Toll-Like Receptor 4; Transcription Factor RelA; Tumor Necrosis Factor-alpha

Dexmedetomidine reduced mortality and inhibited the inflammatory response during endotoxemia in rats. The aim of this study was to clarify the effect of dexmedetomidine-regulating inflammation on a noninfectious, ventilator-induced lung injury (VILI) in dogs.. Thirty healthy Beagles weighing between 8 and 12 kg were randomly divided into five groups: control group (group C, n = 6), mechanical ventilation (group MV, n = 6), and three different doses of dexmedetomidine group (group DEX1-3, n = 6). VILI was induced by high-tidal volume ventilation (tidal volume 20 mL/kg; respiratory rate 15 breaths/min; FiO2 0.5). Group DEX received intravenous Dex 20 min before endotracheal intubation (0.5, 1.0, and 2.0 μg/kg Dex was infused within 20 min and then a maintenance dose of 0.5, 1.0, and 2.0 μg/kg/h Dex was infused intravenously). Arterial blood samples were obtained from femoral artery at base state, MV1h, MV2h, and MV4h for blood gas analysis. After being mechanically ventilated for 4 h, dogs were killed and the levels of pulmonary inflammatory response and polymorphonuclear neutrophils (PMNs) count in bronchoalveolar lavage fluid were evaluated.. Histologic findings of the MV, DEX1, DEX2, and DEX3 groups revealed severe, moderate, mild, and normal to minimal inflammation, respectively. Myeloperoxidase level, PMNs/alveoli ratio, nuclear factor-κB messenger RNA (mRNA), tumor necrosis factor-alpha mRNA, and inducible nitric oxide synthase mRNA expression in lung tissues of the DEX2 and DEX3 were significantly lower than those of the MV group. Partial pressures of oxygen was decreased significantly at MV4h as compared with the baseline. There was no statistical significance in partial pressures of oxygen between MV and DEX2 group as well as between group MV and group DEX3.. Dexmedetomidine could mitigate pulmonary inflammatory response induced by VILI in dogs.

Topics: Adrenergic alpha-2 Receptor Agonists; Animals; Blood Gas Analysis; Dexmedetomidine; Disease Models, Animal; Dogs; Lung; Neutrophils; NF-kappa B; Nitric Oxide Synthase Type II; Organ Size; Peroxidase; Random Allocation; Respiration, Artificial; Tumor Necrosis Factor-alpha; Ventilator-Induced Lung Injury

The endogenous immune response is influenced by the stimulation of the vagal nerve. Stimulation or ablation has a direct impact on the release of pro- and anti-inflammatory mediators. In the progression of acute pancreatitis from local to systemic disease, these mediators play a pivotal role. This study evaluates the effect of pharmacologic stimulation of the cholinergic system on pancreatic damage in experimental necrotizing pancreatitis.. Experimental severe necrotizing pancreatitis was induced in male Wistar rats using the glycodeoxycholic acid model. Animals with acute pancreatitis (n = 6) were compared with animals with acute pancreatitis and prophylactic or therapeutic pharmacologic activation of the cholinergic system using nicotine, physostigmine, or neostigmine (n = 36). Twelve hours after the induction of acute pancreatitis, morphological damage as well as the myeloperoxidase levels of the pancreas and the serum levels of high-mobility group box 1 protein were evaluated.. Prophylactic and delayed therapeutic application of nicotine, physostigmine, or neostigmine significantly attenuated the severity of acute pancreatitis 12 hours after the induction of severe necrotizing pancreatitis compared with untreated controls as evaluated with histological scores, myeloperoxidase, and high-mobility group box 1 levels (P < 0.05).. Stimulation of the cholinergic system is useful to attenuate damage in experimental acute pancreatitis. Not only prophylactic but also delayed application was effective in the present study.

Topics: Animals; Cholinergic Agents; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Glycodeoxycholic Acid; HMGB1 Protein; Humans; Male; Neostigmine; Nicotine; Pancreas; Pancreatitis, Acute Necrotizing; Peroxidase; Physostigmine; Rats; Rats, Wistar

Acute lung injury is marked by profound influx of activated neutrophils, which have delayed apoptosis, along with fluid accumulation that impairs lung function and causes high mortality. Inflammatory and antimicrobial molecules, such as reactive oxygen species from activated neutrophils with prolonged lifespan, cause tissue damage and contribute to lung dysfunction. Angiostatin, an endogenous antiangiogenic molecule, is expressed in the lavage fluid of patients with acute respiratory distress syndrome and modifies neutrophil infiltration in a mouse model of peritonitis. Our aim was to investigate the therapeutic role of angiostatin in acute lung injury. We analyzed bronchoalveolar lavage and lung tissues from C57BL/6 mouse model of Escherichia coli LPS-induced acute lung injury to assess the effects of angiostatin treatment. Subcutaneous angiostatin administered at 5 h after LPS treatment reduces histological signs of inflammation, protein accumulation, lung Gr1+ neutrophils, myeloperoxidase activity, and expression of phosphorylated p38 MAPK in lung tissues and peripheral blood neutrophils, while increasing the number of apoptotic cells in the lungs without affecting the levels of macrophage inflammatory protein-1 α, IL-1β, keratinocyte chemoattractant, and monocyte chemoattractant protein-1 in lavage and lung homogenates at 9 and 24 h after LPS treatment. In contrast, angiostatin administered intravenously 5 h after LPS treatment did not reduce histological sign of inflammation, BAL cell recruitment, and protein concentration at 9 h of LPS treatment. We conclude that angiostatin administered subcutaneously after LPS challenge inhibits acute lung inflammation up to 24 h after LPS treatment.

Topics: Acute Lung Injury; Angiostatins; Animals; Anti-Inflammatory Agents; Apoptosis; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Injections, Subcutaneous; Lipopolysaccharides; Lung; Male; Mice; Mice, Inbred C57BL; Neutrophil Infiltration; Neutrophils; p38 Mitogen-Activated Protein Kinases; Peroxidase

Milk κ-casein-derived bovine glycomacropeptide (GMP) exerts immunomodulatory effects. It exhibits intestinal anti-inflammatory activity in chemically induced models of colitis. However, to validate its clinical usefulness as a nutraceutical, it is important to assess its effects in a model with a closer pathophysiological connection with human inflammatory bowel disease. Therefore, in the present study, we used the lymphocyte-transfer model of colitis in mice and compared the effects of GMP in this model with those obtained in the dextran sulphate sodium (DSS) model. GMP (15 mg/d) resulted in higher body-weight gain and a reduction of the colonic damage score and myeloperoxidase (MPO) activity in Rag1(-/-) mice with colitis induced by the transfer of naïve T cells. The colonic and ileal weight:length ratio was decreased by approximately 25%, albeit non-significantly. GMP treatment reduced the percentage of CD4⁺ interferon (IFN)-γ⁺ cells in mesenteric lymph nodes (MLN). The basal production of IL-6 by MLN obtained from the GMP-treated mice ex vivo was augmented. However, concanavalin A-evoked production was similar. The colonic expression of regenerating islet-derived protein 3γ, S100A8, chemokine (C-X-C motif) ligand 1 and IL-1β was unaffected by GMP, while that of TNF-α and especially IFN-γ was paradoxically increased. In the DSS model, GMP also reduced the activity of colonic MPO, but it failed to alter weight gain or intestinal weight:length ratio. GMP augmented the production of IL-10 by MLN cells and was neutral towards other cytokines, except exhibiting a trend towards increasing the production of IL-6. The lower effect was attributed to the lack of the effect of GMP on epithelial cells. In conclusion, GMP exerts intestinal anti-inflammatory effects in lymphocyte-driven colitis.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biomarkers; Caseins; Cattle; Colon; Dietary Supplements; Disease Models, Animal; Female; Gastrointestinal Agents; Homeodomain Proteins; Ileum; Inflammatory Bowel Diseases; Intestinal Mucosa; Mesenteric Lymphadenitis; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophil Infiltration; Peptide Fragments; Peroxidase; Random Allocation; Weight Gain

The present study aimed to investigate the potential anti-inflammatory and anti-nociceptive effects of carvacryl acetate, a derivative of carvacrol, in mice.. The anti-inflammatory activity was evaluated using various phlogistic agents that induce paw edema, peritonitis model, myeloperoxidase (MPO) activity, pro and anti-inflammatory cytokine levels. Evaluation of antinociceptive activity was conducted through acetic acid-induced writhing, hot plate test, formalin test, capsaicin and glutamate tests, as well as evaluation of motor performance on rotarod test.. Pretreatment of mice with carvacryl acetate (75 mg/kg) significantly reduced carrageenan-induced paw edema (P<0.05) when compared to vehicle-treated group. Likewise, carvacryl acetate (75 mg/kg) strongly inhibited edema induced by histamine, serotonin, prostaglandin E2 and compound 48/80. In the peritonitis model, carvacryl acetate significantly decreased total and differential leukocyte counts, and reduced levels of myeloperoxidase and interleukin-1 beta (IL-1β) in the peritoneal exudate. The levels of IL-10, an anti-inflammatory cytokine, were enhanced by carvacryl acetate. Pretreatment with carvacryl acetate also decreased the number of acetic acid-induced writhing, increased the latency time of the animals on the hot plate and decreased paw licking time in the formalin, capsaicin and glutamate tests. The pretreatment with naloxone did not reverse the carvacryl acetate-mediated nociceptive effect.. In conclusion, the current study demonstrated that carvacryl acetate exhibited anti-inflammatory activity in mice by reducing inflammatory mediators, neutrophil migration and cytokine concentration, and anti-nociceptive activity due to the involvement of capsaicin and glutamate pathways.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Cytokines; Disease Models, Animal; Edema; Immune System Diseases; Inflammation; Inflammation Mediators; Leukocyte Disorders; Male; Mice; Monoterpenes; Pain; Peritonitis; Peroxidase

In the present work biocompatible quercetin and curcumin nanovesicles were developed as a novel approach to prevent and restore skin tissue defects on chronic cutaneous pathologies. Stable and suitable quercetin- and curcumin-loaded phospholipid vesicles, namely liposomes and penetration enhancer-containing vesicles (PEVs), were prepared. Vesicles were made from a highly biocompatible mixture of phospholipids and alternatively a natural polyphenol, quercetin or curcumin. Liposomes were obtained by adding water, while PEVs by adding polyethylene glycol 400 and Oramix®CG110 to the water phase. Transmission electron microscopy, cryogenic-transmission electron microscopy and small- and wide-angle X-ray scattering showed that vesicles were spherical, oligo- or multilamellar and small in size (112-220 nm). In vitro and in vivo tests underlined a good effectiveness of quercetin and curcumin nanovesicles in counteracting phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) induced lesions and inflammation. Myeloperoxydase activity, used to gauge inflammation, was markedly inhibited by quercetin liposomes (59%) and curcumin liposomes and polyethylene glycol (PEG)-PEVs (∼ 68%). Histology showed that PEG-PEVs provided an extensive re-epithelization of the TPA-damaged skin, with multiple layers of thick epidermis. In conclusion, nanoentrapped polyphenols prevented the formation of skin lesions abrogating the various biochemical processes that cause epithelial loss and skin damage.

Topics: Animals; Curcumin; Disease Models, Animal; Edema; Female; Liposomes; Mice; Mice, Inbred ICR; Nanoparticles; Particle Size; Peroxidase; Quercetin; Regeneration; Scattering, Small Angle; Skin; Static Electricity; Sus scrofa; X-Ray Diffraction

Occlusal alignment is known clinically to have a widespread influence on the stomatognathic system, including the temporomandibular joint and masticatory muscles. However, while occlusion is still an important determinant of most dental treatments, the exact effect of occlusal alignment is unclear because of a lack of conclusive scientific evidence. In this study, a malocclusion model system is used to examine the cellular and histologic alterations in the contralateral condyle of mice after a malocclusion was induced by a build-up of resin on the left maxillary molars. A significant decrease in the thickness of the condylar cartilage was found in the 1-week experimental group, together with increased apoptosis and decreased proliferation in the condylar head, which included cartilage and subchondral bone. Additionally, the number of TRAP-positive osteoclasts and MPO- and F4/80-positive inflammatory cells in the subchondral bone were significantly higher in the 1-week experimental group. Unbalanced malocclusion caused increased bone remodeling, as evidenced by increased osteoclastic activity and inflammatory responses (macrophages and neutrophils, respectively). However, these alterations in the 1-week experimental group were subsequently attenuated and restored almost to the baseline at 3 weeks after the induction of the malocclusion.

Topics: Acid Phosphatase; Animals; Disease Models, Animal; Imaging, Three-Dimensional; In Situ Nick-End Labeling; Isoenzymes; Ki-67 Antigen; Male; Malocclusion; Mandibular Condyle; Mice; Mice, Inbred C57BL; Peroxidase; Tartrate-Resistant Acid Phosphatase

Camel milk has traditionally been used to treat cancer, but this practice awaits scientific scrutiny, in particular its role in tumor angiogenesis, the key step involved in tumor growth and metastasis. We aimed to investigate the effects of camel milk on key components of inflammatory angiogenesis in sponge implant angiogenesis model. Polyester-polyurethane sponges, used as a framework for fibrovascular tissue growth, were implanted in Swiss albino mice and camel milk (25, 50 and 100 mg/kg/day) was administered for 14 days through installed cannula. The implants collected at day 14 post-implantation were processed for the assessment of hemoglobin (Hb), myeloperoxidase (MPO), N-acetylglucosaminidase (NAG), and collagen, which were used as indices for angiogenesis, neutrophil, and macrophage accumulation and extracellular matrix deposition, respectively. Relevant inflammatory, angiogenic, and fibrogenic cytokines were also determined. Camel milk treatment attenuated the main components of the fibrovascular tissue, wet weight, vascularization (Hb content), macrophage recruitment (NAG activity), collagen deposition and the levels of vascular endothelial growth factor (VEGF), interleukin (IL)-1β, IL-6, IL-17, tumor necrosis factor-α, and transforming growth factor-β. A regulatory function of camel milk on multiple parameters of the main components of inflammatory angiogenesis has been revealed, giving insight into the potential therapeutic benefit underlying the anti-cancer actions of camel milk.

Topics: Acetylglucosaminidase; Angiogenesis Inhibitors; Animals; Camelus; Chemoprevention; Collagen; Cytokines; Disease Models, Animal; Hemoglobins; Inflammation; Interleukin-17; Interleukin-1beta; Interleukin-6; Lactation; Macrophages; Male; Mice; Milk; Neoplasms; Neovascularization, Pathologic; Neutrophils; Peroxidase; Polyesters; Polyurethanes; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

Mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB) signaling pathways are pleiotropic regulator of many genes involved in lipopolysaccharide (LPS)-induced acute lung injury (ALI). The present study aimed to reveal the protective effect of isotetrandrine (ITD), a small molecule inhibitor, on various aspects of LPS-induced inflammation in vitro and in vivo.. In vitro, RAW 264.7 cells were pretreated with different dose of ITD 1 h before treatment with 1 mg/L of LPS. In vivo, to induce ALI, male BALB/c mice were injected intranasally with LPS and treated with ITD (20 and 40 mg/kg) 1 h before LPS.. In vitro, the cytokine levels of tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 in supernatant were reduced by ITD. Meanwhile, in vivo, pulmonary inflammatory cell infiltration, myeloperoxidase activity, total cells, neutrophils, macrophages, along with the levels of tumor necrosis factor-α, IL-1β, and IL-6 in bronchoalveolar lavage fluid were dose-dependently attenuated by ITD. Furthermore, our data showed that ITD significantly inhibited the activation of MAPK and NF-κB, which are induced by LPS in ALI model.. These results suggested that ITD dose-dependently suppressed the severity of LPS-induced ALI by inactivation of MAPK and NF-κB, which may involve the inhibition of tissue oxidative injury and pulmonary inflammatory process.

Topics: Acute Lung Injury; Animals; Benzylisoquinolines; Bronchoalveolar Lavage Fluid; Cell Line; Disease Models, Animal; Dose-Response Relationship, Drug; Immunosuppressive Agents; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; Mitogen-Activated Protein Kinases; NF-kappa B; Peroxidase; Pulmonary Edema

This study aimed to evaluate the effects of pulmonary artery perfusion with a urinary trypsin inhibitor (UTI) as a lung protective strategy in order to provide an experimental basis for immature lung clinical protective strategies on deep hypothermia with low-flow (DHLF) cardiopulmonary bypass (CPB)-induced pulmonary injury in an infant piglet model.. The piglets (n=15), aged 18.7±0.3 days, weight 4.48±0.21kg, were randomly divided into 3 groups, with 5 piglets in each group: the control group, the pulmonary artery perfusion without UTI group (Group P) and the pulmonary artery perfusion with UTI group (Group U). The levels of the cytokines tumour necrosis factor-α, myeloperoxidase, malondialdehyde and interleukin-10 (TNF-α, MPO, MDA and IL-10) in pulmonary venous serum and lung tissue and the activity of NF-kappa B in lung tissue were measured by enzyme-linked immunosorbent assay (ELISA) and electrophoresis mobility shift assay (EMSA), respectively.. After DHLF-CPB, all of the piglets demonstrated a state of lung injury as a deterioration of lung function indices, lung injury scores, pulmonary ultrastructure changes, expression of TNF-α, MPO, MDA and IL-10 and the activities of nuclear factor-kappa B (NF-κB), while pulmonary artery perfusion with UTI significantly ameliorated lung function and histopathological changes, with greatly decreased serum levels of TNF-α and MPO compared to the other two groups. Also, we found an increase in the level of IL-10 in Group U lungs compared with that in Group P lungs, which correlated with a strong inhibition in the activity of NF-κB.. Pulmonary artery perfusion with UTI ameliorated the DHLF-induced immature pulmonary injury in the lungs via a reduction of pro-inflammatory cytokine expression and up-regulated levels of IL-10 by inhibiting the activity of NF-κB.

Topics: Animals; Cardiopulmonary Bypass; Disease Models, Animal; Glycoproteins; Hypothermia, Induced; Interleukin-10; Lung Injury; Malondialdehyde; Peroxidase; Pulmonary Artery; Swine; Trypsin Inhibitors; Tumor Necrosis Factor-alpha

Butorphanol tartrate is a synthetic opioid partial agonist analgesic. Butorphanol targets the heart, mainly via κ-opioid receptor (κ-OR) activation. The purpose of this study was to determine the effect and mechanism underlying butorphanol postconditioning (B-Post) on myocardial ischaemia reperfusion injury in rats.. Seventy-five male Sprague-Dawley rats were randomly divided into five groups of 15 each: Group sham; Group I/R (ischaemia/reperfusion); Group B (butorphanol postconditioning); Group B/N (butorphanol postconditioning + antagonist of κ-OR nor-binaltorphimine [Nor-BNI]); Group B/G (butorphanol postconditioning + nonselective ATP-sensitive potassium (KATP) channel blocker glibenclamide [GLI]). The left coronary anterior descending artery (LAD) was occluded for 30 min, followed by a 120-min reperfusion. Blood samples were obtained at the end of reperfusion for determination of serum tumour necrosis factor (TNF)-α and interleukin (IL)-6 concentrations. The hearts were then excised for determination of myocardial infarct size by triphenyltetrazolium chloride staining. The myocardial tissues were used for determination of the expression of myocardial superoxide dismutase (SOD), malondialdehyde (MDA) and myeloperoxidase (MPO).. Myocardial infarct size was significantly reduced in B (26.4 ± 1.83%), B/N (34.5 ± 1.56%) and B/G (31.5 ± 1.27%) Groups compared with Group I/R (46.8 ± 1.41%) (all P < 0. 001). The serum TNF-α and IL-6 concentrations and the MDA and MPO activities in the ischaemic area in B, B/N and B/G Groups were significantly lower than those in the I/R Group (all P < 0.001). In addition, myocardial infarct size, TNF-α and IL-6 concentrations and the MDA and MPO activities in B/N and B/G Groups were higher than those in the B Group (all P < 0.001). In contrast, SOD activity was significantly increased in B, B/N and B/G Groups, and SOD activity in B/N and B/G Groups was less than in the B Group (all P < 0.001).. These results suggest that postconditioning of butorphanol tartrate can provide a potent cardioprotective effect against myocardial ischaemic and reperfusion injury. Both the κ-OR and the KATP channels were involved in this effect.

Topics: Analgesics, Opioid; Animals; Butorphanol; Cytoprotection; Disease Models, Animal; Drug Partial Agonism; Interleukin-6; KATP Channels; Male; Malondialdehyde; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Peroxidase; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Superoxide Dismutase; Time Factors; Tumor Necrosis Factor-alpha

After activation, platelets express mediators that modulate inflammation. We hypothesized that drug-induced platelet inactivation may interfere in the inflammatory process in experimental periodontal disease by suppressing the release of biological mediators to the injury site.. To evaluate the effects of antiplatelet drugs on experimental periodontal disease, 60 rats were randomly assigned to six groups (n = 10) and ligatures were placed around lower first molars in three groups. The other three groups were not subjected to the induction of periodontal disease and were used as negative controls. During the experimental period, animals were given aspirin (30 mg/kg) or clopidogrel (75 mg/kg) intragastrically once daily for 3 d. On day 3, they were killed and gingival tissue were used to evaluate myeloperoxidase activity and the expression of the chemokine CXCL4. Hemi-mandibles were used for microscopic evaluation.. Clopidogrel significantly reduced the inflammatory infiltrate and increased the amount of collagen fibers. Histometric analysis showed that clopidogrel impaired alveolar bone loss. Expression of CXCL4 was significantly increased (p < 0.001) in rats subjected to periodontal disease. Systemic administration of aspirin and clopidogrel induced a significant decrease ( p < 0.05) in the expression of CXCL4. Treatment with antiplatelet drugs resulted in a significant reduction of myeloperoxidase activity when compared to saline-treated animals with periodontal disease.. Clopidogrel but not aspirin showed the ability of preventing bone loss in experimental periodontitis.

Topics: Alveolar Bone Loss; Animals; Anti-Inflammatory Agents; Aspirin; Clopidogrel; Collagen; Connective Tissue; Disease Models, Animal; Gingiva; Inflammation Mediators; Male; Mandibular Diseases; Periodontitis; Peroxidase; Platelet Aggregation Inhibitors; Platelet Factor 4; Random Allocation; Rats; Rats, Sprague-Dawley; Ticlopidine

Sulfur mustard (SM) is a vesicant warfare agent which causes severe skin injuries. Currently, we lack effective antidotes against SM-induced skin injuries, in part due to lack of appropriate animal model(s) that can be used for efficacy studies in laboratory settings to identify effective therapies. Therefore, to develop a relevant mouse skin injury model, we examined the effects of nitrogen mustard (NM), a primary vesicant and a bifunctional alkylating agent that induces toxic effects comparable to SM. Specifically, we conducted histopathological and immunohistochemical evaluation of several applicable cutaneous pathological lesions following skin NM (3.2mg) exposure for 12-120h in SKH-1 and C57BL/6 mice. NM caused a significant increase in epidermal thickness, incidence of microvesication, cell proliferation, apoptotic cell death, inflammatory cells (neutrophils, macrophages and mast cells) and myleoperoxidase activity in the skin of both mouse strains. However, there was a more prominent NM-induced increase in epidermal thickness, and macrophages and mast cell infiltration, in SKH-1 mice relative to what was seen in C57BL/6 mice. NM also caused collagen degradation and edema at early time points (12-24h); however, at later time points (72 and 120h), dense collagen staining was observed, indicating either water loss or start of integument repair in both the mouse strains. This study provides quantitative measurement of NM-induced histopathological and immunohistochemical cutaneous lesions in both hairless and haired mouse strains that could serve as useful tools for screening and identification of effective therapies for treatment of skin injuries due to NM and SM.

Topics: Animals; Apoptosis; Blister; Cell Proliferation; Chemical Warfare Agents; Dermatitis, Contact; Disease Models, Animal; Edema; Immunohistochemistry; Male; Mechlorethamine; Mice; Mice, Hairless; Mice, Inbred C57BL; Peroxidase; Skin; Skinfold Thickness; Species Specificity

Necrotizing enterocolitis (NEC) is a serious condition, predominantly observed in premature infants. We used an experimental NEC model to investigate the effects of vascular endothelial growth factor (VEGF) cloned into a plasmid.. Twenty-four newborn Wistar albino rats were randomized equally into three groups as follows: control, NEC and NEC+VEGF. NEC was induced by hyperosmolar enteral formula feeding, exposure to hypoxia/reoxygenation and cold stress. In the NEC+VEGF group, VEGF (1 μg) incorporated into plasmid (2 μg) was administered subcutaneously once daily for a total of 3 days starting on the first day of the NEC procedure. All rats were sacrificed on the 4th day of life, and the specimens were harvested for histopathological and biochemical examinations [including tissue oxidative stress (malondialdehyde and nitric oxide), inflammation (myeloperoxidase, interleukin-6 and tumor necrosis factor alpha) and apoptosis (caspase-3 activity) parameters].. In the NEC+VEGF group, tissue malondialdehyde, nitric oxide, interleukin-6, tumor necrosis factor alpha levels and caspase-3 activity were significantly decreased. In addition, the myeloperoxidase level was increased compared to that of the NEC group (p < 0.05). Histopathologically, VEGF overexpression enhanced angiogenesis, alleviated villous atrophy and tissue edema (p < 0.05).. VEGF overexpression with plasmids seems to be a promising approach in the management of NEC.

Topics: Animals; Apoptosis; Caspase 3; Disease Models, Animal; Enterocolitis, Necrotizing; Enzyme-Linked Immunosorbent Assay; Interleukin-6; Malondialdehyde; Nitric Oxide; Oxidative Stress; Peroxidase; Polymerase Chain Reaction; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

It has been well proved that acute inflammatory response and hepatocellular apoptosis contributed to the pathogenesis of liver ischemia reperfusion (IR) injury. A vast amount of research has demonstrated that magnesium lithospermate B (MLB) has potent anti-apoptosis and potential anti-inflammatory pharmacological properties. However, it has not previously been examined whether MLB can attenuate hepatic IR injury. Firstly, the optimal dose of MLB to protect against hepatic IR injury was determined using hepatic IR model in mice. Then, the effect of MLB on IR-induced inflammatory response was detected in detail. We found that MLB exhibited protective effect from the beginning of 50 mg/kg and culminated at the doses of 100 and 200 mg/kg. The alanine aminotransferase and aspartate aminotransferase levels in MLB group were markedly decreased. Severe hepatocellular swelling/necrosis, sinusoidal/vascular congestion and inflammatory cell infiltration were seen and a large number of apoptotic cells were found in the liver samples from Saline group, while minimal damage and very few apoptotic cells were noted in the samples from MLB group. Kuppfer cells infiltration, myeloperoxidase activity and mRNA level of CD11b in MLB group was significantly decreased. Serum TNF-a and IL-6, and mRNA expression of CXCL-10 and ICAM-1 was markedly decreased in the samples from MLB group. Inflammatory signaling pathway activation was largely prevented in MLB group. MLB can significantly attenuate IR-induced hepatocellular damage and hepatocellular apoptosis by preventing inflammatory signaling pathways activation, inflammatory mediators expression and macrophage and neutrophil infiltration.

Topics: Alanine Transaminase; Animals; Apoptosis; Aspartate Aminotransferases; CD11b Antigen; Chemokine CXCL10; Disease Models, Animal; Drugs, Chinese Herbal; Inflammation Mediators; Intercellular Adhesion Molecule-1; Interleukin-6; Liver; Macrophages; Male; Mice; Mice, Inbred C57BL; Neutrophils; Peroxidase; Reperfusion Injury; Signal Transduction; Tumor Necrosis Factor-alpha

Dodonaea polyandra is a medicinal plant used traditionally by the Kuuku I'yu (Northern Kaanju) indigenous people of Cape York Peninsula, Australia. The most potent of the diterpenoids previously identified from this plant, polyandric acid A (1), has been examined for inhibition of pro-inflammatory cytokine production and other inflammatory mediators using well-established acute and chronic mouse ear edema models and in vitro cellular models. Topical application of 1 significantly inhibited interleukin-1β production in mouse ear tissue in an acute model. In a chronic skin inflammation model, a marked reduction in ear thickness, associated with significant reduction in myeloperoxidase accumulation, was observed. Treatment of primary neonatal human keratinocytes with 1 followed by activation with phorbol ester/ionomycin showed a significant reduction in IL-6 secretion. The present study provides evidence that the anti-inflammatory properties of 1 are due to inhibition of pro-inflammatory cytokines associated with skin inflammation and may be useful in applications for skin inflammatory conditions including psoriasis and dermatitis.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Australia; Cytokines; Disease Models, Animal; Diterpenes, Clerodane; Ear; Edema; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; Macrophages; Mice; Mice, Inbred BALB C; Molecular Structure; Nitric Oxide; Peroxidase; Plants, Medicinal; Psoriasis; Sapindaceae; Skin; Tetradecanoylphorbol Acetate; Tumor Necrosis Factor-alpha

Preclinical and clinical studies have shown beneficial effects of infusions of apolipoprotein A-I (ApoA-I) on atherosclerosis. ApoA-I is also a target for myeloperoxidase-mediated oxidation, leading in vitro to a loss of its ability to promote ATP-binding cassette transporter A1-dependent macrophage cholesterol efflux. Therefore, we hypothesized that myeloperoxidase-mediated ApoA-I oxidation would impair its promotion of reverse cholesterol transport in vivo and the beneficial effects on atherosclerotic plaques.. ApoA-I(-/-) or apolipoprotein E-deficient mice were subcutaneously injected with native human ApoA-I, oxidized human ApoA-I (myeloperoxidase/hydrogen peroxide/chloride treated), or carrier. Although early postinjection (8 hours) levels of total ApoA-I in plasma were similar for native versus oxidized human ApoA-I, native ApoA-I primarily resided within the high-density lipoprotein fraction, whereas the majority of oxidized human ApoA-I was highly cross-linked and not high-density lipoprotein particle associated, consistent with impaired ATP-binding cassette transporter A1 interaction. In ApoA-I(-/-) mice, ApoA-I oxidation significantly impaired reverse cholesterol transport in vivo. In advanced aortic root atherosclerotic plaques of apolipoprotein E-deficient mice, native ApoA-I injections led to significant decreases in lipid content, macrophage number, and an increase in collagen content; in contrast, oxidized human ApoA-I failed to mediate these changes. The decrease in plaque macrophages with native ApoA-I was accompanied by significant induction of their chemokine receptor CCR7. Furthermore, only native ApoA-I injections led to a significant reduction of inflammatory M1 and increase in anti-inflammatory M2 macrophage markers in the plaques.. Myeloperoxidase-mediated oxidation renders ApoA-I dysfunctional and unable to (1) promote reverse cholesterol transport, (2) mediate beneficial changes in the composition of atherosclerotic plaques, and (3) pacify the inflammatory status of plaque macrophages.

Topics: Animals; Aorta; Apolipoprotein A-I; Apolipoproteins E; Atherosclerosis; ATP Binding Cassette Transporter 1; Biological Transport; Cell Line; Cholesterol; Cholesterol, HDL; Collagen; Disease Models, Animal; Humans; Inflammation; Injections, Subcutaneous; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Oxidation-Reduction; Peroxidase; Plaque, Atherosclerotic; Receptors, CCR7

Parstatin is a 41-amino acid peptide, formed by proteolytic cleavage on activation of the protease activated receptor-1, with antiangiogenic properties. The purpose of this study is to evaluate the influence of synthetic parstatin on experimental periodontal disease and repair in rats.. Ligature-induced periodontitis was established in rats and the influence of parstatin administration was assessed after 8 and 15 days for periodontal disease and 24 hours and 8 days after repair after ligature removal.. Parstatin administration significantly inhibited gingival myeloperoxidase activity, interleukin (IL)-1β, tumor necrosis factor-α, and IL-6 levels and led to suppression of macrophages and collagen degradation. At periodontal tissues under repair, parstatin increased the gingival levels of endostatin and decreased vascular endothelial growth factor expression and blood vessel number but did not influence histologic healing. In addition, the tomographic linear bone loss was significantly reduced at 15 days of periodontitis when the rats were treated with parstatin compared to their respective phosphate-buffered saline-treated controls.. Parstatin suppresses the periodontal tissue breakdown followed by experimental periodontitis in rats and did not impair periodontal tissue repair, despite its antiangiogenic effect. Parstatin may represent a novel approach to modulate host response in chronic periodontal disease.

Topics: Alveolar Bone Loss; Alveolar Process; Angiogenesis Inhibitors; Animals; Blood Vessels; Collagen; Disease Models, Animal; Endostatins; Gingiva; Interleukin-1beta; Interleukin-6; Macrophages; Male; Peptide Fragments; Periodontitis; Peroxidase; Rats; Rats, Sprague-Dawley; Receptor, PAR-1; Time Factors; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A; Wound Healing; X-Ray Microtomography

The abundance of Faecalibacterium prausnitzii, an abundant and representative bacterium of Firmicutes phylum, has consistently been observed to be lower in patients with Crohn's disease than in healthy individuals. We have shown that both F. prausnitzii and its culture supernatant (SN) have anti-inflammatory and protective effects in a TNBS-induced acute colitis mouse model. Here, we tested the effects of both F. prausnitzii and its SN in moderate and severe DNBS-induced chronic colitis mouse models.. Colitis was induced by intrarectal administration of DNBS. After either 4 or 10 days of recovery (severe and moderate protocols, respectively), groups of mice were intragastrically administered either with F. prausnitzii A2-165 or with its culture SN for 7 or 10 days. Three days before being sacrificed, colitis was reactivated by administration of a lower dose of DNBS. The severity of colitis at the time of being sacrificed was assessed by weight loss and macroscopic and microscopic scores. Myeloperoxidase (MPO) activity, cytokine levels, lymphocyte populations, and changes in microbiota were studied.. Intragastric administration of either F. prausnitzii or its SN led to a significant decrease in colitis severity in both severe and moderate chronic colitis models. The lower severity of colitis was associated with down-regulation of MPO, pro-inflammatory cytokines, and T-cell levels.. We show, for the first time, protective effects of both F. prausnitzii and its SN during both the period of recovery from chronic colitis and colitis reactivation. These results provide further evidence that F. prausnitzii is an anti-inflammatory bacterium with therapeutic potential for patients with inflammatory bowel disease.

Topics: Animals; Chronic Disease; Colitis; Dinitrofluorobenzene; Disease Models, Animal; Lactococcus lactis; Male; Mice; Mice, Inbred C57BL; Peroxidase; Probiotics; Prognosis; Ruminococcus

To determine whether low molecular weight heparin (LMWH) is able to reduce pulmonary inflammation and improve the survival in rats with endotoxin-induced acute lung injury (ALI). Rat ALI model was reproduced by injection of lipopolysaccharide (LPS) into tail vein. Rats were divided randomly into three groups: control group, ALI group, LMWH-treated group. Blood was collected and lung tissue was harvested at the designated time points for analysis. The lung specimens were harvested for morphological studies, streptavidin-peroxidase immunohistochemistry examination. Lung tissue edema was evaluated by tissue water content. The levels of lung tissue myeloperoxidase (MPO) were determined. Meanwhile, the nuclear factor-kappa B (NF-κB) activation, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) levels and high mobility group box 1 (HMGB1) and intercellular adhesion molecule-1 (ICAM-1) protein levels in the lung were studied. In survival studies, a separate group of rats were treated with LMWH or sterile saline after LPS administration. Then, the mortality was recorded. Treatment with LMWH after ALI was associated with a reduction in the severity of LPS-induced lung injury. Treatment with LMWH significantly decreased the expression of TNF-α, IL-1β, HMGB1 and ICAM-1 in the lung of ALI rats. Similarly, treatment with LMWH dramatically diminished LPS-induced neutrophil sequestration and markedly reduced the enhanced lung permeability. In the present study, LMWH administration inhibited the nuclear translocation of NF-κB in the lung. Survival was significantly higher among the LMWH-treated group compared with the ALI group. These data suggest that LMWH attenuates inflammation and prevents lethality in endotoxemic rats.

Topics: Active Transport, Cell Nucleus; Acute Lung Injury; Animals; Cytokines; Disease Models, Animal; Edema; Endotoxemia; Endotoxins; Heparin, Low-Molecular-Weight; HMGB1 Protein; Intercellular Adhesion Molecule-1; Interleukin-1beta; Lung; Male; Neutrophils; NF-kappa B p50 Subunit; Peroxidase; Random Allocation; Rats; Rats, Wistar; Transcription Factor RelA; Tumor Necrosis Factor-alpha

Ischaemia-reperfusion (I/R) injury is encountered in conditions that diminish intestinal blood flow. There is no clinically feasible technique available for mucosal preservation.. One hundred Wistar rats were subjected to intestinal ischaemia for 15 and 60 min (I15', I60'), followed by 1 and 7 days of reperfusion (R1d, R7d). Rats were subjected to ischaemia by clamping the superior mesenteric artery. Prostaglandin E1 (PGE1) (2.500 ng/kg intra-arterial bolus or 20 ng/kg intravenous infusion) was administered immediately prior to the commencement of the experimental period. Animals were divided into 20 groups: sham (laparotomy alone), sacrificed at 1 or 7 days; saline administration, 15 or 60 min of ischaemia, 1 or 7 days of reperfusion; prostaglandin E1 administration, 15 or 60 min of ischaemia, 1 or 7 days of reperfusion, each one for intra-arterial or intravenous administration. Ileal segments were excised and assessed for histopathological score, polymorphonuclear (PMN) leucocytes encountered and myeloperoxidase (MPO) activity measurement.. I/R caused deterioration of histological characteristics. Prophylactic administration of PGE1 resulted in a significant decrease in the histological score compared with the respective saline group (analysis of variance, P < 0.005). In groups treated with PGE1, PMN leucocyte infiltration was lower for the 60 min of ischaemia group (I60'/R1d *P = 0.026; I60'/R7d P = 0.015). I15'/R7d did not lead to a significant reduction in PMN infiltration (P = 0.061). Pretreatment with PGE1 attenuates MPO levels after intestinal I/R injury (P < 0.05). No differences were encountered between types of administration.. Results of this study showed that administration of prostaglandin E1 prevents I/R injury by diminishing histological damage parameters, inhibiting PMN leucocyte infiltration and attenuating MPO activity.

Topics: Alprostadil; Animals; Cytoprotection; Disease Models, Animal; Ileal Diseases; Ileum; Infusions, Intravenous; Injections, Intra-Arterial; Mesenteric Vascular Occlusion; Neutrophil Infiltration; Neutrophils; Peroxidase; Protective Agents; Rats; Rats, Wistar; Reperfusion Injury; Time Factors

To evaluate neutrophil activation after exposure to standard HBC-201 (suspended in lactate Ringer's solution) versus HBOC-201 suspended in hypertonic 7.5% saline solution.. We use plasma and tissue obtained from pigs subjected to controlled hemorrhagic shock and an ex vivo model of stimulated human whole blood. The pigs were resuscitated with the following (n = 8 per group) standard HBOC-201, or hypertonic HBOC-201. We used HTS 7.5%, Ringer's lactate as control resuscitation. Human blood was stimulated with same fluids. We measured the following neutrophil markers; IL-8, H2O2 in pig plasma, MPO in pig tissue, and H2O2, IL-8, and CD11b/CD18 in human whole blood.. H2O2 and IL-8 as well as tissue MPO were significantly decreased in pigs resuscitated with HT-HBOC-201 and HT 7.5%. Ex vivo experiments blood diluted with HTS and HT-HBOC-201 revealed lower expression of CD11b/CD18, H2O2, and IL-8. Blood diluted with HBOC-201 had a higher CD11b/CD18 expression than blood diluted with LR solution.. Our in vivo and ex vivo experiments indicate that HBOC-201 suspended in hypertonic 7.5% saline solution is associated with significantly less neutrophil activation when compared to standard HBOC-201 suspended in lactate Ringer's solution.

Topics: Animals; Blood Substitutes; CD11b Antigen; CD18 Antigens; Disease Models, Animal; Hemoglobins; Humans; Hydrogen Peroxide; Interleukin-8; Neutrophil Activation; Neutrophils; Peroxidase; Saline Solution, Hypertonic; Shock, Hemorrhagic; Swine

As a water-soluble extracellular β-glucan produced by Agrobacterium sp. ZX09, Salecan has an excellent toxicological profile and exerts multiple physiological effects. The aims of the present study were to investigate the protective effects of a Salecan diet in the well-defined dextran sulphate sodium (DSS) model of experimental murine colitis and to elucidate the mechanism involved in its effects with special attention being paid to its effect on the production of TNF-α, a primary mediator involved in the inflammatory response. Male C57BL/6J mice were fed a diet supplemented with either 4 or 8 % Salecan for 26 d and DSS was administered to induce acute colitis during the last 5 d of the experimental period. Several clinical and inflammatory parameters as well as mRNA expression of TNF-α and Dectin-1 were evaluated. The results indicated that the dietary incorporation of Salecan attenuated the severity of DSS colitis as evidenced by the decreased disease activity index, reduced severity of anaemia, attenuated changes in colon architecture and reduced colonic myeloperoxidase activity. This protection was associated with the down-regulation of TNF-α mRNA levels, which might derive from its ability to increase Dectin-1 mRNA levels. In conclusion, the present study suggests that Salecan contributes to the reduction of colonic damage and inflammation in mice with DSS-induced colitis and holds promise as a new, effective nutritional supplement in the management of inflammatory bowel disease.

Topics: Analysis of Variance; Animals; beta-Glucans; Colitis; Colon; Dextran Sulfate; Dietary Supplements; Disease Models, Animal; Down-Regulation; Inflammation; Intestinal Mucosa; Lectins, C-Type; Male; Mice; Mice, Inbred C57BL; Peroxidase; Real-Time Polymerase Chain Reaction; RNA, Messenger; Tumor Necrosis Factor-alpha

Superoxide dismutase (SOD) can prevent and cure inflammatory bowel diseases by decreasing the amount of reactive oxygen species. Unfortunately, short half-life of SOD in the gastrointestinal tract limited its application in the intestinal tract. This study aimed to investigate the treatment effects of recombinant SOD Lactobacillus fermentum in a colitis mouse model.. In this study, we expressed the sodA gene in Lact. fermentum I5007 to obtain the SOD recombinant strain. Then, we determined the therapeutic effects of this SOD recombinant strain in a trinitrobenzene sulphonic acid (TNBS)-induced colitis mouse model. We found that SOD activity in the recombinant Lact. fermentum was increased by almost eightfold compared with that in the wild type. Additionally, both the wild type and the recombinant Lact. fermentum increased the numbers of lactobacilli in the colon of mice (P < 0·05). Colitis mice treated with recombinant Lact. fermentum showed a higher survival rate and lower disease activity index (P < 0·05). Recombinant Lact. fermentum significantly decreased colonic mucosa histological scoring for infiltration of inflammatory cells, lipid peroxidation, the expression of pro-inflammatory cytokines and myeloperoxidase (P < 0·05) and inhibited NF-κB activity in colitis mice (P < 0·05).. SOD recombinant Lact. fermentum significantly reduced oxidative stress and inflammation through inhibiting NF-κB activation in the TNBS-induced colitis model.. This study provides insights into the anti-inflammatory effects of SOD recombinant Lact. fermentum, indicating the potential therapeutic effects in preventing and curing intestinal bowel diseases.

Topics: Animals; Colitis; Cytokines; Disease Models, Animal; Female; Inflammation; Intestinal Mucosa; Limosilactobacillus fermentum; Lipid Peroxidation; Mice; Mice, Inbred BALB C; NF-kappa B; Organisms, Genetically Modified; Oxidative Stress; Peroxidase; Superoxide Dismutase

The aim of this study was to evaluate the healing effect of topically applied platelet-rich fibrin (PRF) on experimental oral mucositis induced by chemotherapy in hamsters.. Oral mucositis was induced in 93 Syrian golden hamsters by an intraperitoneal injection of 5-fluorouracil, which was followed by light scratching of the cheek pouch. The hamsters were randomly divided into a PRF group, a fibrin group, and an untreated control group. The recovery stage of oral mucositis was evaluated through daily weighing, measurements of the ulcer area, histopathologic analysis, and a myeloperoxidase activity assay.. The PRF group exhibited significant improvements in the size and histologic features of the ulcer and in the myeloperoxidase activity compared with the control group (P < .05).. The current findings suggest the consideration for future clinical trials in humans.

Topics: Administration, Topical; Animals; Blood Platelets; Cricetinae; Disease Models, Animal; Fibrin; Fluorouracil; Male; Mesocricetus; Peroxidase; Random Allocation; Stomatitis; Wound Healing

Pneumococcal meningitis (PM) results in high mortality rates and long-lasting neurological deficits. Hippocampal apoptosis and cortical necrosis are histopathological correlates of neurofunctional sequelae in rodent models and are frequently observed in autopsy studies of patients who die of PM. In experimental PM, inhibition of matrix metalloproteinases (MMPs) and/or tumor necrosis factor (TNF)-converting enzyme (TACE) has been shown to reduce brain injury and the associated impairment of neurocognitive function. However, none of the compounds evaluated in these studies entered clinical development. Here, we evaluated two second-generation MMP and TACE inhibitors with higher selectivity and improved oral availability. Ro 32-3555 (Trocade, cipemastat) preferentially inhibits collagenases (MMP-1, -8, and -13) and gelatinase B (MMP-9), while Ro 32-7315 is an efficient inhibitor of TACE. PM was induced in infant rats by the intracisternal injection of live Streptococcus pneumoniae. Ro 32-3555 and Ro 32-7315 were injected intraperitoneally, starting at 3 h postinfection. Antibiotic (ceftriaxone) therapy was initiated at 18 h postinfection, and clinical parameters (weight, clinical score, mortality rate) were recorded. Myeloperoxidase activities, concentrations of cytokines and chemokines, concentrations of MMP-2 and MMP-9, and collagen concentrations were measured in the cerebrospinal fluid. Animals were sacrificed at 42 h postinfection, and their brains were assessed by histomorphometry for hippocampal apoptosis and cortical necrosis. Both compounds, while exhibiting disparate MMP and TACE inhibitory profiles, decreased hippocampal apoptosis and cortical injury. Ro 32-3555 reduced mortality rates and cerebrospinal fluid TNF, interleukin-1β (IL-1β) and collagen levels, while Ro 32-7315 reduced weight loss and cerebrospinal fluid TNF and IL-6 levels.

Topics: ADAM Proteins; ADAM17 Protein; Animals; Apoptosis; Brain Injuries; Collagen; Cytokines; Disease Models, Animal; Hydroxamic Acids; Imidazoles; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Meningitis, Pneumococcal; Peroxidase; Rats; Sulfonamides; Weight Loss

Severe respiratory disease arising from influenza virus infection has a high fatality rate. Neutrophil myeloperoxidase (MPO) has been implicated in the pathogenesis of severe influenza-induced pneumonia because extracellularly released MPO mediates the production of hypochlorous acid, a potent tissue injury factor. To search for candidate anti-influenza compounds, we screened leucomycin A3 (LM-A3), spiramycin (SPM), an erythromycin derivative (EM900, in which anti-bacterial activity has been eliminated), and clarithromycin (CAM), by analyzing their ability to inhibit MPO release in neutrophils from mice and humans. When each candidate was injected into mice infected with a lethal dose of A/H1N1 influenza virus (PR-8), LM-A3 produced the highest survival rate (80.9%). We found that LM-A3 induced beneficial effects on lung pathology and viral proliferation involved in the regulatory activity of MPO release, pro-inflammatory cytokines and interferon-α production in the lung. SPM and EM900 also induced positive survival effects in the infected mice, whereas CAM did not. We further found that these compounds inhibit virus proliferation in human pneumonia epithelial A549 cells in vitro. LM-A3 showed effective action against influenza A virus infection with high anti-viral activity in human host cells, indicating the possibility that LM-A3 is a prospective lead compound for the development of a drug for human influenza. The positive survival effect induced by EM900 suggests that pharmacological architectures between anti-bacterial and anti-influenza virus activities can be dissociated in macrolide derivatives. These observations provide valuable evidence for the potential development of novel macrolide derivatives that have strong anti-viral but no anti-bacterial activity.

Topics: Animals; Antiviral Agents; Cell Line, Tumor; Clarithromycin; Cytokines; Disease Models, Animal; Disease Progression; Drug Design; Epithelial Cells; Erythromycin; Female; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Josamycin; Lung; Mice; Mice, Inbred BALB C; Neutrophils; Peroxidase; Spiramycin; Survival Rate

The hallmarks of acute lung injury (ALI) are the compromised alveolar-capillary barrier and the extravasation of leukocytes into the alveolar space. Given the fact that the peroxisome proliferator-activated receptor-γ agonist rosiglitazone holds significant anti-inflammatory properties, we aimed to evaluate whether rosiglitazone could dampen these hallmarks of local pulmonary inflammation in a porcine model of lung injury. For this purpose, we used a model of lipopolysaccharide (LPS, 50 μg/kg)-induced ALI. One hundred twenty minutes following the infusion of LPS, we started the exposure to rosiglitazone through inhalation or infusion. We found that intravenous rosiglitazone significantly controlled local pulmonary inflammation as determined through the expression of cytokines within the alveolar compartment. Furthermore, we found a significant reduction of the protein concentration and neutrophil activity within the alveolar space. In summary, we therefore conclude that the treatment with rosiglitazone might dampen local pulmonary inflammation during the initial stages of ALI.

Topics: Acute Lung Injury; Administration, Inhalation; Animals; Bronchoalveolar Lavage Fluid; Bronchoscopy; Catheterization; Disease Models, Animal; Endotoxins; Hemodynamics; Hypoglycemic Agents; Inflammation; Infusions, Intravenous; Lipopolysaccharides; Lung; Peroxidase; Pulmonary Alveoli; Rosiglitazone; Swine; Thiazolidinediones

Intestinal mucositis is an important toxic side effect of 5-fluorouracil (5-FU) treatment. Saccharomyces boulardii is known to protect from intestinal injury via an effect on the gastrointestinal microbiota. The objective of the present study was to evaluate the effect of S. boulardii on intestinal mucositis induced by 5-FU in a murine model. Mice were divided into saline, saline (control)+5-FU or 5-FU+S. boulardii (16 × 10⁹ colony-forming units/kg) treatment groups, and the jejunum and ileum were removed after killing of mice for the evaluation of histopathology, myeloperoxidase (MPO) activity, and non-protein sulfhydryl group (mainly reduced glutathione; GSH), nitrite and cytokine concentrations. To determine gastric emptying, phenol red was administered orally, mice were killed 20 min after administration, and the absorbance of samples collected from the mice was measured by spectrophotometry. Intestinal permeability was measured by the urinary excretion rate of lactulose and mannitol following oral administration. S. boulardii significantly reversed the histopathological changes in intestinal mucositis induced by 5-FU and reduced the inflammatory parameters: neutrophil infiltration (control 1·73 (SEM 0·37) ultrastructural MPO (UMPO)/mg, 5-FU 7·37 (SEM 1·77) UMPO/mg and 5-FU+S. boulardii 4·15 (SEM 0·73) UMPO/mg); nitrite concentration (control 37·00 (SEM 2·39) μm, 5-FU 59·04 (SEM 11·41) μm and 5-FU+S. boulardii 37·90 (SEM 5·78) μm); GSH concentration (control 477·60 (SEM 25·25) μg/mg, 5-FU 270·90 (SEM 38·50) μg/mg and 5-FU+S. boulardii 514·00 (SEM 38·64) μg/mg). Treatment with S. Boulardii significantly reduced the concentrations of TNF-α and IL-1β by 48·92 and 32·21 % in the jejunum and 38·92 and 61·79 % in the ileum. In addition, S. boulardii decreased the concentrations of chemokine (C-X-C motif) ligand 1 by 5-fold in the jejunum and 3-fold in the ileum. Interestingly, S. boulardii reduced the delay in gastric emptying (control 25·21 (SEM 2·55) %, 5-FU 54·91 (SEM 3·43) % and 5-FU+S. boulardii 31·38 (SEM 2·80) %) and induced the recovery of intestinal permeability (lactulose:mannitol ratio: control 0·52 (SEM 0·03), 5-FU 1·38 (SEM 0·24) and 5-FU+S. boulardii 0·62 (SEM 0·03)). In conclusion, S. boulardii reduces the inflammation and dysfunction of the gastrointestinal tract in intestinal mucositis induced by 5-FU.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cytokines; Disease Models, Animal; Down-Regulation; Feces; Gastric Emptying; Gastrointestinal Agents; Glutathione; Ileum; Intestinal Absorption; Intestinal Mucosa; Jejunum; Male; Mice; Mucositis; Neutrophil Infiltration; Nitric Oxide; Peroxidase; Prebiotics; Random Allocation; Saccharomyces

Phytogenic compounds with anti-oxidant and anti-inflammatory properties, such as ginsenoside metabolite compound K (CK) or berberine (BBR), are currently discussed as promising complementary agents in the prevention and treatment of cancer and inflammation. The latest study showed that ginsenoside Rb1 and its metabolites could inhibit TNBS-induced colitis injury. However, the functional mechanisms of anti-inflammation effects of ginsenoside, particularly its metabolite CK are still not clear. Here, using dextran sulfate sodium (DSS)-induced colitis in mice, clinical parameters, intestinal integrity, pro-inflammatory cytokines production, and signaling pathways in colonic tissues were determined. In mild and sever colitis mice, CK and BBR (as a positive agent) alleviated colitis histopathology injury, ameliorated myeloperoxidase (MPO) activity, reduced pro-inflammatory cytokines production, such as, IL-6, IL-1β, TNF-α, and increased anti-inflammatory cytokine IL-10 production in both mice colon tissues and blood. Nevertheless, the results revealed that CK and BBR inhibited NF-κB p65 nuclear translocation, downregulated p-IκBα and upregulated IκBα, indicating that CK, as well as BBR, suppressed the activation of the NF-κB pathway in the progression of colitis with immunofluorescence, immunohistochemical and western blotting analysis. Furthermore, CK inhibited pro-inflammatory cytokines production in LPS-activated macrophages via down-regulation of NF-κB signaling pathway. Taken together, our results not only reveal that CK promotes the recovery of the progression of colitis and inhibits the inflammatory responses by suppressing NF-κB activation, but also suggest that CK downregulates intestinal inflammation through regulating the activation of macrophages and pro-inflammatory cytokines production.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Berberine; Cell Line; Colitis; Colon; Cytokines; Dextran Sulfate; Disease Models, Animal; Inflammation Mediators; Macrophages; Mice; NF-kappa B; Peroxidase; Signal Transduction

Evidence indicates that angiotensin II type 2 receptors (AT2R) exert cerebroprotective actions during stroke. A selective non-peptide AT2R agonist, Compound 21 (C21), has been shown to exert beneficial effects in models of cardiac and renal disease, as well as hemorrhagic stroke. Here, we hypothesize that C21 may exert beneficial effects against cerebral damage and neurological deficits produced by ischemic stroke. We determined the effects of central and peripheral administration of C21 on the cerebral damage and neurological deficits in rats elicited by endothelin-1 induced middle cerebral artery occlusion (MCAO), a model of cerebral ischemia. Rats infused centrally (intracerebroventricular) with C21 before endothelin-1 induced MCAO exhibited significant reductions in cerebral infarct size and the neurological deficits produced by cerebral ischemia. Similar cerebroprotection was obtained in rats injected systemically (intraperitoneal) with C21 either before or after endothelin-1 induced MCAO. The protective effects of C21 were reversed by central administration of an AT2R inhibitor, PD123319. While C21 did not alter cerebral blood flow at the doses used here, peripheral post-stroke administration of this agent significantly attenuated the MCAO-induced increases in inducible nitric oxide synthase, chemokine (C-C) motif ligand 2 and C-C chemokine receptor type 2 mRNAs in the cerebral cortex, indicating that the cerebroprotective action is associated with an anti-inflammatory effect. These results strengthen the view that AT2R agonists may have potential therapeutic value in ischemic stroke, and provide the first evidence of cerebroprotection induced by systemic post stroke administration of a selective AT2R agonist.

Topics: Angiotensin II Type 2 Receptor Blockers; Animals; Brain Infarction; Brain Ischemia; CD11b Antigen; Cerebrovascular Circulation; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin-1; Glial Fibrillary Acidic Protein; Imidazoles; Male; Nitric Oxide Synthase Type II; Peroxidase; Pyridines; Rats; Rats, Sprague-Dawley; Stroke; Sulfonamides; Thiophenes; Time Factors

The major compounds of Cochinchina momordica seed extract (SK-MS10) include momordica saponins. We report that the gastroprotective effect of SK-MS10 in an ethanol-induced gastric damage rat model is mediated by suppressing proinflammatory cytokines and downregulating cytosolic phospholipase A2 (cPLA2), 5-lipoxygenase (5-LOX), and the activation of calcitonin gene-related peptide. In this study, we evaluated the gastroprotective effects of SK-MS10 in the nonsteroidal anti-inflammatory drug (NSAID)-induced gastric damage rat model.. The pretreatment effect of SK-MS10 was evaluated in the NSAID-induced gastric damage rat model using aspirin, indomethacin, and diclofenac in 7-week-old rats. Gastric damage was evaluated based on the gross ulcer index by gastroenterologists, and the damage area (%) was measured using the MetaMorph 7.0 video image analysis system. Myeloperoxidase (MPO) was measured by enzyme-linked immunosorbent assay, and Western blotting was used to analyze the levels of cyclooxygenase (COX)-1, COX-2, cPLA2, and 5-LOX.. All NSAIDs induced gastric damage based on the gross ulcer index and damage area (p<0.05). Gastric damage was significantly attenuated by SK-MS10 pretreatment compared with NSAID treatment alone (p<0.05). The SK-MS10 pretreatment group exhibited lower MPO levels than the diclofenac group. The expression of cPLA2 and 5-LOX was decreased by SK-MS10 pretreatment in each of the three NSAID treatment groups.. SK-MS10 exhibited a gastroprotective effect against NSAID-induced acute gastric damage in rats. However, its protective mechanism may be different across the three types of NSAID-induced gastric damage models in rats.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonate 5-Lipoxygenase; Calcitonin Gene-Related Peptide; Cyclooxygenase 1; Cyclooxygenase 2; Disease Models, Animal; Gastric Mucosa; Group IV Phospholipases A2; Male; Momordica; Peroxidase; Plant Extracts; Rats; Rats, Sprague-Dawley; Seeds; Stomach Ulcer; Treatment Outcome

In this study, we evaluated the effect of different doses of polysaccharides extracted from Caripia montagnei mushroom at different intervals of treatment on colonic injury in the model of colitis induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS). The FT-IR analysis and NMR showed that the polysaccharides from this species of mushroom are composed of α- and β-glucans. The colonic damage was evaluated by macroscopic, histological, biochemical and immunologic analyses. The results showed the reduction of colonic lesions in all groups treated with the glucans. Such glucans significantly reduced the levels of IL-6 (50 and 75 mg/kg, p < 0.05), a major inflammatory cytokine. Biochemical analyses showed that the glucans from C. montagnei acted on reducing levels of alkaline phosphatase (75 mg/kg, p < 0.01) and myeloperoxidase (p < 0.001), a result confirmed by the reduction of cellular infiltration observed microscopically. The increase of catalase activity possibly indicates a protective effect of these glucans on colonic tissue, confirming their anti-inflammatory potential.

Topics: Agaricales; Alkaline Phosphatase; Animals; Catalase; Colitis; Cytokines; Disease Models, Animal; Enzyme Activation; Glucans; Intestinal Mucosa; Male; Nitric Oxide; Nuclear Magnetic Resonance, Biomolecular; Peroxidase; Rats; Spectroscopy, Fourier Transform Infrared; Trinitrobenzenesulfonic Acid

To histologically and immunologically assess experimental peri-implant mucositis at surface enhanced modified (mod) hydrophilic titanium implants.. In a split-mouth design (n = 6 foxhounds), four different implants were inserted on each side of the maxilla: three titanium-zirconium alloy implants (TiZr) with either modSLA (sand-blasted, acid etched and chemically mod), modMA (machined, acid etched and chemically mod), or M (machined) surfaces in the transmucosal portion, and one titanium implant with a machined transmucosal portion (TiM). Experimental mucositis was induced at one randomly assigned side (NPC), whereas the contra-lateral maxillary side received mechanical plaque removal three times per week (PC). At 16 weeks, tissue biopsies were processed for histological (primary outcome: apical extension of the inflammatory cell infiltrate measured from the mucosal margin - PM-aICT) and immunohistochemical (CD68 antigen reactivity) analyses. Peri-implant sulcus fluid was analysed for interleukin (IL)-1β, IL-8, matrix metalloproteinase (MMP)-8 and myeloperoxidase (MPO).. Mean PM-aICT values varied between 1.86 (TiZrmodSLA) and 3.40 mm (TiM) in the UPC group, and between 0.88 (TiZrmodSLA) and 2.08 mm (TiZrM) in the PC group. Mean CD68, IL-1β, IL-8, MMP-8 and MPO values were equally distributed between mod- and control implants in both NPC and PC groups.. The progression of experimental mucositis was comparable at all implant surfaces investigated.

Topics: Acid Etching, Dental; Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Dental Alloys; Dental Etching; Dental Implants; Dental Plaque; Dental Prosthesis Design; Disease Models, Animal; Dogs; Female; Hydrophobic and Hydrophilic Interactions; Interleukin-1beta; Interleukin-8; Macrophages; Male; Matrix Metalloproteinase 8; Peroxidase; Random Allocation; Stomatitis; Surface Properties; Titanium; Zirconium

In this study, we examined the in-vivo characteristics of a novel microencapsulated thalidomide formulation in a murine model of experimental Crohn's disease. Crohn's disease was induced with a single intra-colonic injection of 120 mg/kg of bodyweight of 2,5,6-trinitrobenzene sulfonic acid (TNBS) dissolved in 30% ethanol in Balb/c mice. Level of tumor necrosis factor alpha (TNF-α), interleukin one beta (IL-1β), interleukin 6 (IL-6) and nitric oxide (NO) were measured in tissue homogenate. Moreover, myeloperoxidase (MPO) activity was determined to assess the extent of neutrophil infiltration. Dose response study showed that treating the mice with microencapsulated thalidomide (100 mg/kg of bodyweight) for two weeks significantly decreased the degree of intestinal inflammation related to Crohn's disease. Higher and lower doses (0, 25, 50 and 200 mg/kg of bodyweight) did not exhibit comparable effects. The present study validates the success of alginate-poly-L-lysine-alginate (APA) microcapsules containing thalidomide in reducing colonic inflammation, and proposes a potential remedy for Crohn's disease.

Topics: Alginates; Animals; Anti-Inflammatory Agents; Biomarkers; Capsules; Chemistry, Pharmaceutical; Colitis; Colon; Disease Models, Animal; Gastrointestinal Agents; Inflammation Mediators; Interleukin-1beta; Interleukin-6; Male; Mice; Mice, Inbred BALB C; Neutrophil Infiltration; Particle Size; Peroxidase; Polylysine; Solubility; Technology, Pharmaceutical; Thalidomide; Time Factors; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

The aim of this study was to investigate whether BML-111 can exert protective effects on cerulein-induced acute pancreatitis-associated lung injury (APALI) via activation of nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant responsive element (ARE) signaling pathway. Severe acute pancreatitis (SAP) was established by intraperitoneal injection of cerulein (50 μg/kg) seven times at hourly intervals and Escherichia coli lipopolysaccharide (10 mg/kg) once after the last dose of cerulein immediately. BML-111 (1 mg/kg) was administered 1 h before the first injection of cerulein. Samples were taken at 3, 6, 12, and 24 h after the last injection. Pathologic lesions of the pancreas and lung tissues as well as the levels of serum amylase were analyzed; Myeloperoxidase (MPO), malondialdehyde (MDA), superoxide dismutase (SOD), Nrf2, heme oxygenase-1 (HO-1), and. quinone oxidoreductase-1 (NQO1) of lung tissue were determined. The findings revealed that the injuries of pancreas and lung were typically induced by cerulein. The administration of BML-111 reduced the levels of serum amylase, lung MPO, lung MDA, the wet-to-dry weight ratio, and the pathology injury scores of the lung and pancreas, which increased in the SAP group. The expressions of Nrf2, HO-1, NQO1, and activity of SOD in lung tissue increased in the BML-111 group compared with those in the SAP group. This study indicates that BML-111 may play a critical protective role in APALI induced by cerulein. The underlying mechanisms of protective role may be attributable to its antioxidant effects through the activation of Nrf2/ARE pathway.

Topics: Acute Disease; Acute Lung Injury; Animals; Ceruletide; Disease Models, Animal; Heme Oxygenase-1; Heptanoic Acids; Lipopolysaccharides; Lung; Male; Malondialdehyde; Membrane Proteins; Mice; Mice, Inbred BALB C; NAD(P)H Dehydrogenase (Quinone); NF-E2-Related Factor 2; Pancreatitis; Peroxidase; Response Elements; Signal Transduction; Superoxide Dismutase

Salvia miltiorrhiza (SM) is mainly used for the treatment of coronary heart disease in China, but previous studies demonstrated that it also shows anti‑inflammatory effects and the underlying mechanisms of these effects are not well understood. The present study aimed to investigate the effect of an injection of SM powder on the expression of transcription factor Foxp3 (Foxp3) in experimental colitis in mice. Mice were grouped and treated with SM powder for injection at the time of colonic instillation of trinitrobenzene sulfonic acid. Expression studies were performed by quantitative polymerase chain reaction and western blot analysis and histological studies were performed by hematoxylin and eosin staining. Myeloperoxidase activity was also tested for the evaluation of colitis. In the treated groups, the expression of Foxp3 mRNA and protein in the spleen were increased, the inflamed colonic lesions were relieved and the myeloperoxidase activity in the colon decreased significantly. Thus, it was demonstrated that SM exhibited its anti‑inflammatory by promoting Foxp3 expression. SM may be effective for the treatment of inflammatory disease, particularly for inflammatory bowel disease.

Topics: Animals; Anti-Inflammatory Agents; Colitis; Disease Models, Animal; Female; Forkhead Transcription Factors; Gene Expression Regulation; Medicine, Chinese Traditional; Mice; Peroxidase; RNA, Messenger; Salvia miltiorrhiza; Spleen

Severe acute pancreatitis (SAP) is the sudden onset of pancreatic inflammation, which is characterized by edema, acinar cell necrosis, hemorrhage and severe inflammation of the pancreas and is associated with a high mortality rate. Daphnetin has been shown to alleviate organ injury in a variety of preclinical animal models of coagulation disorders. The aim of the present study was to investigate the protective effects of daphnetin on severe acute pancreatitis in a rat model. Severe acute pancreatitis in the rat model was induced by retrograde infusion of 5% sodium taurocholate (1 ml/kg) into the bile-pancreatic duct. Daphnetin (4 mg/kg) was administered intraperitoneally at 30 min prior to the infusion of sodium taurocholate. The severity of pancreatitis was evaluated by various analyses of serum amylase and lipase, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) levels, myeloperoxidase (MPO) activity and malondialdehyde (MDA) content, as well as by histological grading. The levels of TNF-α and IL-1β in the serum were measured by ELISA. The results revealed that the daphnetin-treated SAP rat group (SAP-D) exhibited a lower pathological score of the pancreas compared with the SAP group (SAP). Further analyses demonstrated that the SAP-D group had lower levels of serum amylase, lipase and pro-inflammatory cytokines, including TNF-α and IL-1β, and a decreased MPO activity and MDA content 3, 6 and 12 h subsequent to the infusion of sodium taurocholate compared with the SAP group (SAP). These findings indicated that daphnetin exerted a protective function in the SAP rat model. Therefore, daphnetin may be considered as a potential compound for the therapy and prevention of acute pancreatitis.

Topics: Amylases; Animals; Cytokines; Disease Models, Animal; Inflammation Mediators; Lipase; Male; Malondialdehyde; Pancreatitis; Peroxidase; Protective Agents; Rats; Taurocholic Acid; Umbelliferones

Linezolid is considered as a therapeutic alternative to the use of glycopeptides for the treatment of pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA). Clinical studies reported a potent survival advantage conferred by the oxazolidinone and called into question the use of glycopeptides as first-line therapy.. In a mouse model of MRSA-induced pneumonia, quantitative bacteriology, proinflammatory cytokine concentrations in lung, myeloperoxidase activity, Ly6G immunohistochemistry, and endothelial permeability were assessed to compare therapeutic efficacy and immunomodulative properties of linezolid and vancomycin administered subcutaneously every 12 hours.. Significant antibacterial activity was achieved after 48 hours of treatment for linezolid and vancomycin. Levels of interleukin 1β, a major proinflammatory cytokine, and macrophage inflammatory protein 2, a chemokine involved in the recruitment of neutrophils, were decreased by both antimicrobials. Only linezolid was able to dramatically reduce the production of tumor necrosis factor α. Analysis of myeloperoxidase activity and Ly6G immunostaining showed a dramatic decrease of neutrophil infiltration in infected lung tissues for linezolid-treated animals. A time-dependent increase of endothelial permeability was observed for the control and vancomycin regimens. Of interest, in the linezolid group, decreased endothelial permeability was detected 48 hours after infection.. Our results indicate that linezolid could be superior to vancomycin for the management of MRSA pneumonia by attenuating an excessive inflammatory reaction and protecting the lung from pathogen-associated damages.

Topics: Acetamides; Animals; Anti-Bacterial Agents; Antigens, Ly; Bacterial Load; Cytokines; Disease Models, Animal; Endothelial Cells; Immunologic Factors; Injections, Subcutaneous; Linezolid; Lung; Methicillin-Resistant Staphylococcus aureus; Mice; Neutrophils; Oxazolidinones; Peroxidase; Pneumonia, Staphylococcal; Vancomycin

To investigate the effects of sodium alginate (AL-Na) on indomethacin-induced small intestinal lesions in rats.. Gastric injury was assessed by measuring ulcerated legions 4 h after indomethacin (25 mg/kg) administration. Small intestinal injury was assessed by measuring ulcerated legions 24 h after indomethacin (10 mg/kg) administration. AL-Na and rebamipide were orally administered. Myeloperoxidase activity in the stomach and intestine were measured. Microvascular permeability, superoxide dismutase content, glutathione peroxidase activity, catalase activity, red blood cell count, white blood cell count, mucin content and enterobacterial count in the small intestine were measured.. AL-Na significantly reduced indomethacin-induced ulcer size and myeloperoxidase activity in the stomach and small intestine. AL-Na prevented increases in microvascular permeability, superoxide dismutase content, glutathione peroxidase activity and catalase activity in small intestinal injury induced by indomethacin. AL-Na also prevented decreases in red blood cells and white blood cells in small intestinal injury induced by indomethacin. Moreover, AL-Na suppressed mucin depletion by indomethacin and inhibited infiltration of enterobacteria into the small intestine.. These results indicate that AL-Na ameliorates non-steroidal anti-inflammatory drug-induced small intestinal enteritis via bacterial translocation.

Topics: Alginates; Anemia; Animals; Anti-Ulcer Agents; Atrophy; Bacterial Translocation; Biomarkers; Capillary Permeability; Catalase; Cytoprotection; Disease Models, Animal; Enteritis; Gastric Mucosa; Glucuronic Acid; Glutathione Peroxidase; Hexuronic Acids; Indomethacin; Intestinal Mucosa; Intestine, Small; Male; Peroxidase; Rats, Sprague-Dawley; Stomach Ulcer; Superoxide Dismutase

Melipona marginata is an endangered species of stingless bee from Brazil that produces honey with particular physicochemical features and a remarkable exotic flavor. To the best of our knowledge, this is the first report devoted to exploring the medicinal potential of this honey. Thus, the aim of this paper was to investigate the potential anti-inflammatory activity of honey extract from M. marginata on skin inflammation. The honey sample was classified as a monofloral honey of Mimosa scabrella. The presence of 11 phenolic compounds as kaempferol and caffeic acid was detected using the high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-UV-ESI-MS) method. The anti-inflammatory activity was measured using a 12-O-tetradecanoylphorbol-13-acetate-induced ear edema model of inflammation in mice. The topical application of the M. marginata honey extract (1.0 mg/ear) was able to reduce ear edema with an inhibitory effect of 54 ± 5%. This extract decreased the myeloperoxidase activity in 75 ± 3%, which suggests a lower leucocyte infiltration that was confirmed by histological analysis. This extract also provided a reduction of 55 ± 14% in the production of reactive oxygen species. This anti-inflammatory activity could be due to a synergic effect of the phenolic compounds identified in the honey sample. Taken together, these results open up new possibilities for the use of M. marginata honey extract in skin disorders.

Topics: Administration, Cutaneous; Animals; Anti-Inflammatory Agents; Bees; Brazil; Chromatography, High Pressure Liquid; Dermatologic Agents; Disease Models, Animal; Edema; Honey; Male; Mice; Mimosa; Oxidative Stress; Peroxidase; Phenols; Reactive Oxygen Species; Skin Diseases; Tandem Mass Spectrometry; Tetradecanoylphorbol Acetate

The spontaneous crescentic glomerulonephritis-forming/Kinjoh (SCG/Kj) mouse, a model of human crescentic glomerulonephritis (CrGN) and systemic vasculitis, is characterized by the production of myeloperoxidase-specific anti-neutrophil cytoplasmic autoantibody (MPO-ANCA) and marked leucocytosis. This study was performed to identify the specific populations of leucocytes associated with CrGN and susceptibility loci for pathogenic leucocytosis. Four hundred and twenty female (C57BL/6 × SCG/Kj) F2 intercross mice were subjected to serial flow cytometry examination of the peripheral blood (PB). Kidney granulocytes and monocytes were examined histopathologically. Linkage analyses were performed with 109 polymorphic microsatellite markers. Correlation studies revealed that increase of the granulocytes, F4/80(+) cells, CD3(+) CD4(-) CD8(-) T cells and dendritic cells (DCs) in peripheral blood (PB) were associated significantly with glomerulonephritis, crescent formation and vasculitis. In kidney sections, F4/80(low) cells were observed in crescent, while F4/80(high) cells were around the Bowman's capsules and in the interstitium. Numbers of F4/80(+) cells in crescents correlated significantly with F4/80(+) cell numbers in PB, but not with numbers of F4/80(+) cells in the interstitium. Genome-wide quantitative trait locus (QTL) mapping revealed three SCG/Kj-derived non-Fas QTLs for leucocytosis, two on chromosome 1 and one on chromosome 17. QTLs on chromosome 1 affected DCs, granulocytes and F4/80(+) cells, but QTL on chromosome 17 affected DCs and granulocytes. We found CrGN-associated leucocytes and susceptibility QTLs with their positional candidate genes. F4/80(+) cells in crescents are considered as recruited inflammatory macrophages. The results provide information for leucocytes to be targeted and genetic elements in CrGN and vasculitis.

Topics: Animals; Antibodies, Antineutrophil Cytoplasmic; Antigens, Differentiation; Autoantigens; Cell Movement; Disease Models, Animal; Female; Genetic Linkage; Genetic Predisposition to Disease; Glomerulonephritis; Granulocytes; Humans; Kidney; Leukocytosis; Mice; Mice, Inbred C57BL; Microsatellite Repeats; Monocytes; Peroxidase; Quantitative Trait Loci; Systemic Vasculitis

Ulcerative colitis (UC) is a chronic inflammatory disease of the colon. α-Mangostin (α-MG), the most abundant xanthone in mangosteen fruit, exerts anti-inflammatory and antibacterial activities in vitro. We evaluated the impact of dietary α-MG on murine experimental colitis and on the gut microbiota of healthy mice.. Colitis was induced in C57BL/6J mice by administration of dextran sulfate sodium (DSS). Mice were fed control diet or diet with α-MG (0.1%). α-MG exacerbated the pathology of DSS-induced colitis. Mice fed diet with α-MG had greater colonic inflammation and injury, as well as greater infiltration of CD3(+) and F4/80(+) cells, and colonic myeloperoxidase, than controls. Serum levels of granulocyte colony-stimulating factor, IL-6, and serum amyloid A were also greater in α-MG-fed animals than in controls. The colonic and cecal microbiota of healthy mice fed α-MG but no DSS shifted to an increased abundance of Proteobacteria and decreased abundance of Firmicutes and Bacteroidetes, a profile similar to that found in human UC.. α-MG exacerbated colonic pathology during DSS-induced colitis. These effects may be associated with an induction of intestinal dysbiosis by α-MG. Our results suggest that the use of α-MG-containing supplements by patients with UC may have unintentional risk.

Topics: Amyloid; Animals; Colitis, Ulcerative; Colon; Dextran Sulfate; Diet; Dietary Supplements; Disease Models, Animal; Dysbiosis; Female; Fruit; Garcinia mangostana; Interleukin-6; Mice; Mice, Inbred C57BL; Peroxidase; Proteobacteria; Xanthones

TBI (traumatic brain injury) triggers an inflammatory cascade, gliosis and cell proliferation following cell death in the pericontusional area and surrounding the site of injury. In order to better understand the proliferative response following CCI (controlled cortical impact) injury, we systematically analyzed the phenotype of dividing cells at several time points post-lesion. C57BL/6 mice were subjected to mild to moderate CCI over the left sensory motor cortex. At different time points following injury, mice were injected with BrdU (bromodeoxyuridine) four times at 3-h intervals and then killed. The greatest number of proliferating cells in the pericontusional region was detected at 3 dpi (days post-injury). At 1 dpi, NG2+ cells were the most proliferative population, and at 3 and 7 dpi the Iba-1+ microglial cells were proliferating more. A smaller, but significant number of GFAP+ (glial fibrillary acidic protein) astrocytes proliferated at all three time points. Interestingly, at 3 dpi we found a small number of proliferating neuroblasts [DCX+ (doublecortin)] in the injured cortex. To determine the cell fate of proliferative cells, mice were injected four times with BrdU at 3 dpi and killed at 28 dpi. Approximately 70% of proliferative cells observed at 28 dpi were GFAP+ astrocytes. In conclusion, our data suggest that the specific glial cell types respond differentially to injury, suggesting that each cell type responds to a specific pattern of growth factor stimulation at each time point after injury.

Topics: Animals; Antigens; Brain Injuries; Bromodeoxyuridine; Calcium-Binding Proteins; CD11b Antigen; Cell Proliferation; Cerebral Cortex; Disease Models, Animal; Doublecortin Domain Proteins; Doublecortin Protein; Glial Fibrillary Acidic Protein; Male; Mice; Mice, Inbred C57BL; Microfilament Proteins; Microtubule-Associated Proteins; Neuroglia; Neuropeptides; Peroxidase; Proteoglycans; S100 Calcium Binding Protein beta Subunit; Time Factors

Neutrophil elastase (NE) is a proteinase in granulocytes and plays an important role in the pathogenesis of inflammatory disorders. It has been reported that NE activity is elevated in both colonic mucosa and blood in inflammatory bowel disease (IBD) patients, and that it can act as an aggravating factor in IBD. To develop novel therapies for IBD, we examined the effects of an NE inhibitor, Elaspor®, on murine experimental colitis.. Acute colitis was induced in BALB/c mice by administration of dextran sulfate sodium (DSS) in drinking water for 7 days. NE inhibitor was administered subcutaneously to mice prior to and during the induction of colitis. Disease activity index (DAI), colonic myeloperoxidase (MPO) activity, luminal NE activity, and mRNA expression in the colon were then investigated.. Subcutaneous administration of NE inhibitor ameliorated the severity of DSS-induced colitis. NE activity was elevated in inflamed colon, and was reduced by NE inhibitor administration. mRNA expression levels of IL-17, a Th17-based inflammatory factor, was also decreased in the colon of NE inhibitor-administered mice.. These results suggest that NE inhibitor ameliorated colonic inflammation by decreasing both the activity of NE and the effects of cytokine balance. Clinically, NE inhibitor improves injuries associated with systemic inflammatory response syndrome. Similarly, clinical use of this inhibitor would further clarify its usefulness in clinical colonic inflammation.

Topics: Animals; Chemokines; Colitis; Colon; Cytokines; Dextran Sulfate; Disease Models, Animal; Female; Glycine; Interleukin-17; Leukocyte Elastase; Mice; Mice, Inbred BALB C; Peroxidase; Proteinase Inhibitory Proteins, Secretory; RNA, Messenger; Sulfonamides

Sulphated polysaccharides from marine algae are widely used in biotechnological and pharmaceutical areas. In this study, we evaluated the effects of sulphated polysaccharides from the green marine alga Caulerpa mexicana (Cm-SPs) in nociceptive and inflammatory models in rodents. Cm-SPs (10 or 20 mg/kg), administered i.v. in Swiss mice, significantly reduced nociceptive responses, as measured by the number of writhes in response to acetic acid. Cm-SPs (10 or 20 mg/kg) also reduced second-phase responses in the formalin test, but did not exhibit a significant antinociceptive effect in the hot plate test, suggesting that its antinociceptive action occurs through a peripheral mechanism. Cm-SPs (5, 10 or 20 mg/kg), administered s.c. in wistar rats 1 hr before carrageenan, dextran, histamine or serotonin, were tested in paw oedema models. Cm-SPs (10 or 20 mg/kg) reduced carrageenan-induced paw oedema and myeloperoxidase activity in the paw. In addition, Cm-SPs (20 mg/kg) inhibited dextran- or histamine-induced paw oedema, but not serotonin-induced oedema, suggesting that histamine is the major target of Cm-SPs anti-oedematogenic activity. Finally, Cm-SPs (20 mg/kg) administered in mice did not show significant signs of toxicity. In conclusion, Cm-SPs appear to be promising natural modulatory agents for pain and inflammatory conditions.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Carrageenan; Caulerpa; Dextrans; Disease Models, Animal; Edema; Female; Histamine; Inflammation; Male; Mice; Pain; Pain Measurement; Peroxidase; Polysaccharides; Rats; Rats, Wistar; Serotonin

The aim of the present study was to explore the regulatory mechanism of heme oxygenase-1 (HO-1) expression induced by sevoflurane (Sevo) in lipopolysaccharide (LPS)‑induced acute lung injury (ALI). Sprague-Dawley rats were divided randomly into six groups: (A) Control, (B) 2.4% Sevo only, (C) LY294002 (PI3K inhibitor) only, (D) LPS + 2.4% Sevo, (E) LY294002 + LPS + 2.4% Sevo and (F) LPS only. The pathological changes in wet/dry weight ratio (W/D), the activities of superoxide dismutase, myeloperoxidase (MPO), malondialdehyde, and HO-1, as well as the expression of intercellular adhesion molecule (ICAM-1), HO-1, phospho-phosphatidylinositol 3-kinase (pPI3K) and phospho-Akt (pAkt) were recorded. Sevo post-conditioning was able to effectively protect from ALI with decreasing pathomorphological scores, MPO activity, W/D and the mRNA and protein expression levels of ICAM-1. Sevo promotes HO-1 expression via the PI3K/protein kinase B (PI3K/Akt) pathway with activation of pPI3K and pAkt. Inhibition of the PI3K/Akt pathway by LY294002 partly eliminates the protective effects of Sevo. It is concluded that Sevo post-conditioning has a vital role in inducing the upregulation of HO-1 expression via the PI3K/Akt pathway to alleviate ALI.

Topics: Acute Lung Injury; Animals; Disease Models, Animal; Gene Expression Regulation; Heme Oxygenase-1; Lipopolysaccharides; Male; Malondialdehyde; Methyl Ethers; Peroxidase; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; RNA, Messenger; Sevoflurane; Signal Transduction; Superoxide Dismutase

Glycyrrhizin, a triterpene glycoside isolated from licorice root, is known to have anti-inflammatory activities. However, the effect of glycyrrhizin on mastitis has not been reported. The purpose of this study was to investigate the anti-inflammatory effect and mechanism of action of glycyrrhizin on lipopolysaccharide (LPS)-induced mastitis in mouse. An LPS-induced mouse mastitis model was used to confirm the anti-inflammatory activity of glycyrrhizin in vivo. Primary mouse mammary epithelial cells were used to investigate the molecular mechanism and targets of glycyrrhizin. In vivo, glycyrrhizin significantly attenuated the mammary gland histopathological changes, myeloperoxidase activity and infiltration of neutrophilic granulocytes and downregulated the expression of tumor necrosis factor-α, interleukin (IL)-1β and IL-6 caused by LPS. In vitro, glycyrrhizin dose-dependently inhibited the LPS-induced expression of tumor necrosis factor-α, IL-6, and RANTES. Western blot analysis showed that glycyrrhizin suppressed LPS-induced nuclear factor-κB and interferon regulatory factor 3 activation. However, glycyrrhizin did not inhibit nuclear factor-κB and interferon regulatory factor 3 activation induced by MyD88-dependent (MyD88, IKKβ) or TRIF-dependent (TRIF, TBK1) downstream signaling components. Moreover, glycyrrhizin did not act though affecting the function of CD14 or expression of Toll-like receptor 4. Finally, we showed that glycyrrhizin decreased the levels of cholesterol of lipid rafts and inhibited the translocation of Toll-like receptor 4 to lipid rafts. Moreover, glycyrrhizin activated ATP-binding cassette transporter A1, which could induce cholesterol efflux from lipid rafts. In conclusion, we find that the anti-inflammatory effects of glycyrrhizin may be attributable to its ability to activate ATP-binding cassette transporter A1. Glycyrrhizin might be a useful therapeutic reagent for the treatment of mastitis and other inflammatory diseases.

Topics: Animals; Cell Survival; Disease Models, Animal; Epithelial Cells; Glycyrrhizic Acid; Interleukin-1beta; Interleukin-6; Mammary Glands, Animal; Mastitis; Mice; NF-kappa B; Peroxidase; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Myeloperoxidase (MPO) activity is suggested to reduce the function of vascular nitric oxide, thereby contributing to endothelial dysfunction, although data in rodents are inconclusive. We examined vascular contractile and relaxant responses in MPO-deficient (MPO(-/-)) and wild-type mice to investigate the role for myeloperoxidase in the development of endothelial dysfunction. Carotid and saphenous arteries were taken from 8-month-old mice and studied in a myograph. Responses of carotid arteries to phenylephrine, high potassium, or acetylcholine (Ach) were statistically not different from controls. Treatment with lipopolysaccharide (LPS; to enhance endothelial dysfunction) reduced responses to Ach in MPO(-/-) but did not affect responses in wild-type. In response to high concentrations of Ach, carotid arteries responded with transient contractions, which were not different between the groups and not affected by LPS treatment. Saphenous arteries from MPO(-/-) had smaller normalized diameters and developed less contractile force. Vessels from MPO(-/-) were less sensitive to Ach than controls. These data suggest that mature MPO-deficient mice do not show enhanced endothelial function compared to wild-type mice, even when provoked with LPS treatment. The EDHF response appears to be reduced in MPO deficiency.

Topics: Acetylcholine; Animals; Carotid Arteries; Disease Models, Animal; Endothelium, Vascular; Female; Lipopolysaccharides; Metabolism, Inborn Errors; Mice; Mice, Inbred C57BL; Peroxidase; Vasoconstriction

Interleukin-17 (IL-17) is involved in a wide range of inflammatory disorders and in recruitment of inflammatory cells to injury sites. A recent study of IL-17 knock-out mice revealed that IL-17 contributes to neuroinflammation and neuropathic pain after peripheral nerve injury. Surprisingly, little is known of micro-environment modulation by IL-17 in injured sites and in pathologically related neuroinflammation and chronic neuropathic pain. Therefore, we investigated nociceptive sensitization, immune cell infiltration, myeloperoxidase (MPO) activity, and expression of multiple cytokines and opioid peptides in damaged nerves of wild-type (IL-17(+/+)) and IL-17 knock-out (IL-17(-/-)) mice after partial sciatic nerve ligation. Our results demonstrated that the IL-17(-/-) mice had less behavioral hypersensitivity after partial sciatic nerve ligation, and inflammatory cell infiltration and pro-inflammatory cytokine (tumor necrosis factor-α, IL-6, and interferon-γ) levels in damaged nerves were significantly decreased, with the levels of anti-inflammatory cytokines IL-10 and IL-13, and expressions of enkephalin, β-endorphin, and dynorphin were also decreased compared to those in wild-type control mice. In conclusion, we provided evidence that IL-17 modulates the micro-environment at the level of the peripheral injured nerve site and regulates progression of behavioral hypersensitivity in a murine chronic neuropathic pain model. The attenuated behavioral hypersensitivity in IL-17(-/-) mice could be a result of decreased inflammatory cell infiltration to the injured site, resulting in modulation of the pro- and anti-inflammatory cytokine milieu within the injured nerve. Therefore, IL-17 may be a critical component for neuropathic pain pathogenesis and a novel target for therapeutic intervention for this and other chronic pain states.

Topics: Animals; Behavior, Animal; beta-Endorphin; Central Nervous System Sensitization; Cytokines; Disease Models, Animal; Dynorphins; Enkephalins; Hyperalgesia; Inflammation; Interleukin-10; Interleukin-13; Interleukin-17; Interleukin-1beta; Interleukin-2; Interleukin-6; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuralgia; Neutrophils; Nociception; Peripheral Nerve Injuries; Peroxidase; Sciatic Nerve; T-Lymphocytes; Tumor Necrosis Factor-alpha

Intestinal ischemia-reperfusion (II/R) is associated with high morbidity and mortality. The aim of this study was to investigate the effects of osthole on lung injury and mortality induced by II/R.. A rat model of II/R was induced by clamping the superior mesenteric artery for 90 min followed by reperfusion for 240 min. Osthole was administrated intraperitoneally at 30 min before intestinal ischemia (10 or 50 mg/kg). The survival rate and mean arterial pressure were observed. Blood samples were obtained for blood gas analyses. Lung injury was assessed by the histopathologic changes (hematoxylin and eosin staining), lung wet-to-dry weight ratio, and pulmonary permeability index. The levels of reactive oxygen species, malondialdehyde, interleukin 6, and tumor necrosis factor α, as well as the activities of superoxide dismutase and myeloperoxidase in lung were measured.. The survival rate, ratio of arterial oxygen tension to fraction of inspired oxygen, and mean arterial pressure decreased significantly after II/R. Results also indicated that II/R-induced severe lung injury evidenced by increase in pathologic scores, lung wet-to-dry weight ratio, and pulmonary permeability index, which was accompanied by increases in the levels of pulmonary reactive oxygen species, malondialdehyde, interleukin 6, tumor necrosis factor α, and the pulmonary myeloperoxidase activity and a decrease in superoxide dismutase activity. Osthole could significantly ameliorate lung injury and improve the previously mentioned variables.. These findings indicated that osthole could attenuate the lung injury induced by II/R in rats, at least in part, by inhibiting inflammatory response and oxidative stress.

Topics: Acute Lung Injury; Animals; Blood Pressure; Calcium Channel Blockers; Coumarins; Disease Models, Animal; Interleukin-6; Lung; Male; Malondialdehyde; Organ Size; Oxidative Stress; Peroxidase; Pulmonary Gas Exchange; Rats; Rats, Wistar; Reactive Oxygen Species; Reperfusion Injury; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Pseudomonas aeruginosa infection is a clinically relevant infection involved in pneumonia in ICUs. Understanding the type of immune response initiated by the host during pneumonia would help defining new strategies to interfere with the bacteria pathogenicity. In this setting, the role of natural killer cells remains controversial. We assessed the role of systemic natural killer cells in a Pseudomonas aeruginosa mouse pneumonia model.. Experimental study.. Research laboratory from a university hospital.. RjOrl:SWISS and BALB/cJ mice (weight, 20-24 g).. Lung injuries were assessed by bacterial load, myeloperoxidase activity, endothelial permeability (pulmonary edema), immune cell infiltrate (histological analysis), proinflammatory cytokine release, and Ly6-G immunohistochemistry. Bacterial loads were assessed in the lungs and spleen. Natural killer cell number and status were assessed in spleen (flow cytometry and quantitative polymerase chain reaction). Depletion of natural killer cells was achieved through an IV anti-asialo-GM1 antibody injection.. Pseudomonas aeruginosa tracheal instillation led to an acute pneumonia with a rapid decrease of bacterial load in lungs and with an increase of endothelial permeability, proinflammatory cytokines (tumor necrosis factor-α and interleukin-1β), and myeloperoxidase activity followed by Ly6-G positive cell infiltrate in lungs. Pseudomonas aeruginosa was detected in the spleen. Membrane markers of activation and maturation (CD69 and KLRG1 molecules) were increased in splenic natural killer cells during Pseudomonas aeruginosa infection. Splenic natural killer cells activated upon Pseudomonas aeruginosa infection produced interferon-γ but not interleukin-10. Ultimately, mice depleted of natural killer cells displayed an increased neutrophil numbers in the lungs and an increased mortality rate without bacterial load modifications in the lungs, indicating that mice depleted of natural killer cells were much more susceptible to infection compared with control animals.. We report for the first time that natural killer cells play a major role in the mice susceptibility toward a Pseudomonas aeruginosa-induced acute pneumonia model.

Topics: Animals; Cell Separation; Disease Models, Animal; Disease Susceptibility; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Interferon-gamma; Interleukin-10; Killer Cells, Natural; Lung; Mice; Mice, Inbred Strains; Neutrophils; Peroxidase; Pseudomonas aeruginosa; Pseudomonas Infections; Spleen; Tumor Necrosis Factor-alpha

T cells have been proven to be therapeutically effective in patients with relapsed leukemias, although target antigens on leukemic cells as well as T-cell receptors (TCRs), potentially recognizing those antigens, are mostly unknown. We have applied an immunopeptidomic approach and isolated human leukocyte antigen (HLA) ligands from primary leukemia cells. We identified a number of ligands derived from different genes that are restrictedly expressed in the hematopoietic system. We exemplarily selected myeloperoxidase (MPO) as a potential target and isolated a high-avidity TCR with specificity for a HLA-B*07:02-(HLA-B7)-restricted epitope of MPO in the single HLA-mismatched setting. T cells transgenic for this TCR demonstrated high peptide and antigen specificity as well as leukemia reactivity in vitro and in vivo. In contrast, no significant on- and off-target toxicity could be observed. In conclusion, we here demonstrate, exemplarily for MPO, that leukemia-derived HLA ligands can be selected for specific effector tool development to redirect T cells to be used for graft manipulation or adoptive T-cell therapies in diverse transplant settings. This approach can be extended to other HLA ligands and HLA molecules in order to provide better treatment options for this life-threatening disease.

Topics: Animals; Antigen Presentation; CD8-Positive T-Lymphocytes; Cell Line; Cell Survival; Disease Models, Animal; Epitope Mapping; Epitopes, T-Lymphocyte; Heterografts; Histocompatibility Antigens Class I; HLA Antigens; HLA-B7 Antigen; Humans; Leukemia, Myeloid; Ligands; Mice; Peptides; Peroxidase; Receptors, Antigen, T-Cell; T-Cell Antigen Receptor Specificity; T-Lymphocytes; Transduction, Genetic

In the present study, we investigated the protective effects of Shen-Fu injection (SFI) on a caerulein-induced rat pancreatitis (AP) model.. SFI was given to rats in the SFI treated group through intraperitoneal injection. Blood and pancreas samples were collected for serological and histopathological studies.. Our results showed that AP caused significant decrease in tissue glutathione (GSH) and serum IL-4 and IL-10, while pancreatic malondialdehyde (MDA) and myeloperoxidase (MPO) were increased. Furthermore, TNF-α, IL-1β, amylase, and lipase levels were also significantly increased. On the other hand, SFI treatment reserved all these biochemical indices as well as histopathologic alterations that were induced by caerulein.. Our findings suggest that the SFI protects against caerulein-induced AP in rats via modulation of cytokines, oxidative stress, and Nuclear Factor-kappa B (NF-κB) activity.

Topics: Acute Disease; Amylases; Animals; Cytokines; Disease Models, Animal; Drugs, Chinese Herbal; Glutathione; Injections; Lipase; Male; Malondialdehyde; Pancreas; Pancreatitis; Peroxidase; Protective Agents; Rats; Rats, Sprague-Dawley; Transcription Factor RelA

To investigate the neuroprotective effects of Sulindac on the hippocampal complex after global cerebral ischemia/reperfusion (I/R) injury in rats.. Thirty one Sprague-Dawley rats were used, distributed into group I (sham) n:7 were used as control. For group II (n:8), III (n:8) and IV (n:8) rats, cerebral ischemia was performed via the occlusion of bilateral internal carotid artery for 45 minutes and continued with reperfusion process. 0.3 mL/kg/h 0.9 % sodium chloride was infused intraperitoneally to the Group II rats before ischemia, 5μg/kg/h/0.3 ml sulindac was infused intraperitoneally to the Group III rats before ischemia and 5μg/kg/h/0.3 ml sulindac was infused intraperitoneally to the Group IV rats after ischemia and before reperfusion process. The levels of MDA, GSH and MPO activity were measured in the left hippocampus tissue. The hippocampal tissue of all group members were taken for histopathological study.. The MDA and MPO levels increased from group I (control) to group II (I/R) (P<0.05) and decreased from group II (I/R) to group III (presulindac + I/R) and IV (postsulindac + I/R) (P<0.05). Beside these, the GSH levels decreased from group I (control) to group II (I/R) (P<0.05) and increased from group II (I/R) to group III (presulindac + I/R) and IV (postsulindac + I/R) (P<0.05).The number of apoptotic neurons increased from group I (control) to group II (I/R) (P<0.05) and decreased from group II (I/R) to group III (presulindac + I/R) and IV (postsulindac + I/R) (P<0.05).. The Sulindac may have neuroprotective effects on ischemic neural tissue to prevent the reperfusion injury after ischemia.

Topics: Animals; Apoptosis; Brain Ischemia; Cyclooxygenase Inhibitors; Disease Models, Animal; Glutathione; Hippocampus; Infusions, Parenteral; Malondialdehyde; Neuroprotective Agents; Oxidative Stress; Peroxidase; Rats, Sprague-Dawley; Reperfusion Injury; Reproducibility of Results; Sulindac

Pancreatic acinar cell necrosis is indicative of severe pancreatitis and the degree of necrosis is an index of its outcome. We studied whether the dose and duration of injury correlates with severity, particularly in terms of necrosis, in caerulein-induced acute pancreatitis (AP) in Swiss albino mice. In addition to control group 1 (G1), groups 2 and 3 received four injections of caerulein every hour but were sacrificed at five hours (G2) and nine hours (G3) respectively, and group 4 received eight injections and was sacrificed at nine hours (G4). The severity of pancreatitis was assessed histopathologically and biochemically. The histopathological scores of pancreatitis in groups 3 and 4 were significantly higher than in groups 1 and 2 (4 vs. 1, 4 vs. 2, 3 vs. 1, 3 vs. 2; P < 0.05). TUNEL-positive apoptotic cells were significantly higher in groups 2 and 3 compared with groups 1 and 4 (P < 0.05). Necrosis was significantly more in group 4 than other groups (37.49% (4.68) vs. 19.97% (1.60) in G2; 20.36% (1.56) in G3; P = 0.006 for G 2 vs. 4 and P = 0.019 for G 3 vs. 4). Electron microscopy revealed numerous autophagosomes in groups 2 and 3 and mitochondrial damage and necrosis in group 4. The pancreatic and pulmonary myeloperoxidase activity in group 4 was significantly higher than that in the other groups (P < 0.01). Hence, severity of pancreatitis is a function of the dose of injurious agent, while inflammation is both dose and duration dependent, which may also explain the wide spectrum of severity of AP seen in clinical practice.

Topics: Acute Disease; Animals; Apoptosis; Behavior, Animal; Ceruletide; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Kidney; Lung; Male; Mice; Necrosis; Pancreas; Pancreatitis; Peroxidase; Severity of Illness Index; Time Factors

To investigate whether mesenteric lymph from rats with severe intraperitoneal infection (SII) induces lung injury in healthy rats.. Twenty adult male specific pathogen-free Wistar rats were divided into two groups. Animals in the SII group received intraperitoneal injection of Escherichia coli (E. coli) at a dose of 0.3 mL/100 g. Control rats underwent the same procedure, but were injected with normal saline rather than E. coli. We ligated and drained the mesenteric lymphatic vessels and collected the mesenteric lymph. Mesenteric lymph collected from SII or control rats was infused intravenously into male healthy rats at a rate of 1 mL/h for 4 h. At the end of the infusion, all rats were sacrificed. Lungs were removed and examined histologically, and wet-to-dry weight (W/D) ratio and myeloperoxidase (MPO) activity were determined. Enzyme-linked immunosorbent assay (ELISA) was performed to determine the levels of the proinflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6. We performed Western blot to investigate the activation of Toll-like receptor (TLR)-4, and nuclear factor (NF)-κB p65.. Compared with the control infusion group, there were obvious pathological changes in the SII group. The W/D ratio was significantly increased in the SII compared to control infusion group (5.86 ± 0.06 vs 5.37 ± 0.06, P < 0.01). MPO activity significantly increased in the SII infusion rats with a mean level of 0.86 ± 0.02 U/g compared to 0.18 ± 0.05 U/g in the control group (P < 0.01). The concentrations of TNF-α and IL-6 were significantly increased in the SII infusion group. The concentration of TNF-α was significantly increased in the SII infusion rats compared to control infusion rats (2104.46 ± 245.91 vs 1475.13 ± 137.82 pg/mL, P < 0.01). The concentration of IL-6 was significantly increased in the SII infusion rats with a mean level of 50.56 ± 2.85 pg/mL compared to 43.29 ± 2.02 pg/mL (P < 0.01). The expression levels of TLR-4 (7496.68 ± 376.43 vs 4589.02 ± 233.16, P < 0.01) and NF-κB (8722.19 ± 323.96 vs 6498.91 ± 338.76, P < 0.01) were significantly increased in the SII infusion group compared to the control infusion group. The infusion of SII lymph, but not control lymph, caused lung injury.. The results indicate that SII lymph is sufficient to induce acute lung injury.

Topics: Acute Lung Injury; Animals; Disease Models, Animal; Escherichia coli Infections; Inflammation Mediators; Infusions, Intravenous; Interleukin-6; Lung; Lymph; Male; Peritonitis; Peroxidase; Pulmonary Edema; Rats, Wistar; Sepsis; Severity of Illness Index; Time Factors; Toll-Like Receptor 4; Transcription Factor RelA; Tumor Necrosis Factor-alpha

To ascertain whether glutamine (Gln) pretreatment protects rats with obstructive jaundice from hepatic ischemia/reperfusion (I/R) injury and to determine the underlying molecular mechanisms.. An obstructive jaundice rat model was developed by bile duct ligation. On the first day after the operation, all rats were randomized into two groups and received oral Gln or normal saline (NS) daily for 7 days. Then both groups underwent a 15-min liver ischemia via the Pringle maneuver. Blood samples as well as liver and intestinal tissues were harvested and measured after 1, 6 and 24 h of reperfusion.. The results showed that the histological morphology of the liver and intestinal tissues significantly improved in the Gln group after I/R injury compared with the NS group. Serum proteins and enzymes associated with hepatic function also significantly improved in the Gln group. The level of glutathione increased and the levels of malondialdehyde and myeloperoxidase decreased in the Gln group. The levels of interleukin-1β and tumor necrosis factor-α decreased in the Gln group. Moreover, bcl-2 protein expression was upregulated and intercellular adhesion molecule 1 and bax protein expression downregulated in the Gln group; the caspase 3 mRNA level significantly increased in the Gln group.. The study demonstrates that preconditioning with Gln significantly improves hepatic structure and function after I/R injury in rats with obstructive jaundice. The protective effect of Gln was mediated by the inhibition of reactive oxygen species and inflammation as well as a reduction in hepatocyte apoptosis.

Topics: Animals; Apoptosis; Disease Models, Animal; Down-Regulation; Glutamine; Glutathione; Hepatocytes; Interleukin-1beta; Jaundice, Obstructive; Liver; Male; Malondialdehyde; Peroxidase; Rats; Rats, Wistar; Reactive Oxygen Species; Reperfusion Injury; Time Factors; Tumor Necrosis Factor-alpha; Up-Regulation

Inflammatory activation plays a vital role in the pathophysiological mechanisms of stroke and diabetes mellitus (DM), exerts the deleterious effects on the progression of the brain and leads to vascular damage in diabetic stroke. The objectives of this study were to investigate the effects of 8-O-acetyl shanzhiside methylester (ND01) on tumour necrosis factor-α (TNF-α)-stimulated SH-SY5Y cell line in vitro and the experimental ischaemic diabetic stroke model in vivo. TNF-α-stimulated SH-SY5Y cells were pre-incubated with ND01, then analysed protein expression. For in vivo experiment, the diabetic rats were subjected to middle cerebral artery occlusion (MCAO) for 30 min. followed by reperfusion for 23 hr. Treatment of SH-SY5Y cells with ND01 blocked TNF-α-induced nuclear transcription factor κB (NF-κB) activation and decreased high-mobility group box-1 (HMGB-1) expression. ND01 40 mg/kg demonstrated significant neuroprotective effect even after delayed administration at 4 hr after I/R. ND01 40 mg/kg attenuated the histopathological damage, decreased brain swelling, inhibited NF-κB activation and reduced HMGB-1 expression in ischaemic brain tissue. These data show that ND01 protects diabetic brain against I/R injury with a favourable therapeutic time-window by alleviating diabetic cerebral I/R injury and attenuating blood-brain barrier (BBB) breakdown, and its protective effects may involve HMGB-1 and NF-κB signalling pathway.

Topics: Animals; Anti-Inflammatory Agents; Blood-Brain Barrier; Brain Ischemia; Diabetes Mellitus, Experimental; Disease Models, Animal; Glucosides; HMGB1 Protein; Male; NF-kappa B; Peroxidase; Pyrans; Rats, Sprague-Dawley; Reperfusion Injury; Tumor Necrosis Factor-alpha

Although emphysema destroys alveolar structures progressively and causes death eventually, no drug has been discovered to prevent, intervene, and/or resolve this life-threatening disease. We recently reported that sulfated caffeic acid dehydropolymer CDSO3 is a novel potent triple-action inhibitor of elastolysis, oxidation, and inflammation in vitro, and therefore, a potential anti-emphysema agent. However, the in vivo therapeutic potency, duration and mode of actions, and effective route remain to be demonstrated.. Emphysema was induced in rats with human sputum elastase (HSE) combined with cigarette smoke extract (CSE). CDSO3 at 5, 30, or 100 μg/kg was dosed to the lung or injected subcutaneously at 2, 6, or 24 h before or 1 or 24 h or 1 week after the HSE/CSE instillation. At 1 h or 48 h or on day 21-22 or day 28, lungs were examined for airway-to-blood injurious barrier damage; their elastolytic, oxidative, and inflammatory activities; lung luminal leukocytes infiltration; functional treadmill exercise endurance; and/or morphological airspace enlargement.. CDSO3, when dosed to the lung at 30 or 100 μg/kg, but not via systemic subcutaneous injection, significantly (43-93 %) attenuated HSE/CSE-induced (1) barrier damage measured by luminal hemorrhage and protein leak; (2) elastolytic, oxidative, and inflammatory activities measured with elastase, reduced glutathione, and TNFα levels, respectively; (3) luminal neutrophil infiltration and tissue myeloperoxidase activity; (4) functional impairment of exercise endurance; and (5) airspace enlargement, in both preventive and interventional dosing protocols. Notably, the effects were shown to last for 24 h at the greater 100-μg/kg dose, and the 1-week-delayed administration was also capable of attenuating the development of emphysema.. CDSO3 is a novel, potent, long-acting, nonpeptidic macromolecule that inhibits HSE/CSE-induced elastolysis, oxidation, and inflammation in the lung and thereby attenuates the development of emphysema in rats, in both preventive and interventional manners, when administered locally to the lung.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Biomarkers; Bronchoalveolar Lavage Fluid; Caffeic Acids; Disease Models, Animal; Drug Administration Schedule; Glutathione; Humans; Inflammation Mediators; Injections, Subcutaneous; Lung; Male; Oxidative Stress; Pancreatic Elastase; Peroxidase; Pulmonary Emphysema; Rats, Sprague-Dawley; Serine Proteinase Inhibitors; Smoke; Smoking; Sputum; Sulfuric Acid Esters; Time Factors; Tumor Necrosis Factor-alpha

The phytochemical study of Pittocaulon filare afforded three oplopanes (1-3), a eudesmane (6), and three oplopane glucosides (7-9), one of them reported as its acetyl derivative (7a), together with several known compounds. The structures of the compounds were elucidated by spectroscopic analysis and chemical reactions. The anti-inflammatory activity of compounds 1-5 was determined using the 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ear edema model, and the effect of compounds 1-4 on the recruitment of neutrophils was evaluated using the myeloperoxidase test. Compounds 1 and 2 were the more active anti-inflammatory agents, with lower ID50 values (0.17 and 0.18 μmol/ear, respectively) than indomethacin (0.24 μmol/ear), but they had a lesser effect on the inhibition of neutrophil infiltration than both indomethacin and compound 3, indicating that the tested compounds do not have the same ability to inhibit edema and to prevent cell infiltration.

Topics: Animals; Anti-Inflammatory Agents; Asteraceae; Disease Models, Animal; Edema; Glucosides; Indomethacin; Mexico; Neutrophil Infiltration; Neutrophils; Nuclear Magnetic Resonance, Biomolecular; Peroxidase; Sesquiterpenes; Stereoisomerism; Tetradecanoylphorbol Acetate

To evaluate the role of exogenous normal lymph (ENL) on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in rats.. ALI was induced by the jugular vein injection of LPS (iv, 15 mg/kg) in rats of the LPS and LPS+ENL groups within 15 min, then, ENL without cell components (5 ml/kg) was infused at the speed of 0.5 ml per minute in the LPS+ENL group, the same amount of saline was administered in the LPS group. The rats in the sham group received the same surgical procedure and saline. The histomorphology and the levels of P-selectin, intercellular adhesion molecule-1 (ICAM-1), myeloperoxidase (MPO) in pulmonary tissue were assessed.. LPS induced pulmonary injury as well as increased the wet/dry weight ratio (W/D) and the levels of P-selectin, ICAM-1, and MPO in pulmonary tissues. These deleterious effects of LPS were significantly ameliorated by ENL treatment.. Exogenous normal lymph could markedly alleviate the acute lung injury induced by lipopolysaccharide, and its effects might be related to lessening the adhesion molecules.

Topics: Acute Lung Injury; Animals; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Intercellular Adhesion Molecule-1; Lipopolysaccharides; Lung; Lymph; Male; P-Selectin; Peroxidase; Random Allocation; Rats, Wistar; Time Factors

A huge body evidences suggest that obesity is the single great risk factor for the development of dementia. Recently, silymarin, a flavonoid, clinically in use as a hepatoprotectant, has been reported to prevent amyloid beta-induced memory impairment by reducing oxidative stress and inflammation in mice brain. However, its potential in high-fat-diet (HFD)-induced dementia has not yet been investigated. Therefore, the present study is designed to explore the role of silymarin in HFD-induced experimental dementia in mice. Morris water maze test was employed to assess learning and memory. Various biochemical estimations including brain acetylcholinerstarse activity (AchE), thiobarbituric acid-reactive species (TBARS) level, reduced glutathione level (GSH), nirate/nitrite, and myeloperoxidase (MPO) activity were measured. Serum cholesterol level was also determined. HFD significantly impaired the cognitive abilities, along with increasing brain AchE, TBARS, MPO, nitrate/nitrite, and serum cholesterol levels. Marked reduction of brain GSH levels was observed. On the contrary, silymarin significantly reversed HFD-induced cognitive deficits and the biochemical changes. The present study indicates strong potential of silymarin in HFD-induced experimental dementia.

Topics: Acetylcholinesterase; Animals; Body Weight; Brain; Cholesterol; Dementia; Diet, High-Fat; Disease Models, Animal; Female; Glutathione; Male; Maze Learning; Memory Disorders; Mice; Neuroprotective Agents; Nitrates; Nitrites; Peroxidase; Silymarin; Thiobarbituric Acid Reactive Substances

To study the therapeutic effect of focused ultrasound on abscesses induced by methicillin-resistant Staphylococcus aureus (MRSA). MRSA is a major nosocomial pathogen where immunocompromised patients are prone to develop infections that are less and less responsive to regular treatments. Because of its capability to induce a rise of temperature at a very precise location, the use of focused ultrasound represents a considerable opportunity for therapy of localized MRSA-related infections.. 50 μl of MRSA strain USA400 bacteria suspension at a concentration of 1.32 ± 0.5 × 10(5) colony forming units (cfu)/μl was injected subcutaneously in the left flank of BALB/c mice. An abscess of 6 ± 2 mm in diameter formed after 48 h. A transducer operating at 3 MHz with a focal length of 50 mm and diameter of 32 mm was used to treat the abscess. The focal point was positioned 2 mm under the skin at the abscess center. Forty-eight hours after injection four ultrasound exposures of 9 s each were applied to each abscess under magnetic resonance imaging guidance. Each exposure was followed by a 1 min pause. These parameters were based on preliminary experiments to ensure repetitive accurate heating of the abscess. Real-time estimation of change of temperature was done using water-proton resonance frequency and a communication toolbox (matMRI) developed inhouse. Three experimental groups of animals each were tested: control, moderate temperature (MT), and high temperature (HT). MT and HT groups reached, respectively, 52.3 ± 5.1 and 63.8 ± 7.5 °C at the end of exposure. Effectiveness of the treatment was assessed by evaluating the bacteria amount of the treated abscess 1 and 4 days after treatment. Myeloperoxidase (MPO) assay evaluating the neutrophil amount was performed to assess the local neutrophil recruitment and the white blood cell count was used to evaluate the systemic inflammatory response after focused ultrasound treatment.. Macroscopic evaluation of treated abscess indicated a diminution of external size of abscess 1 day after treatment. Treatment did not cause open wounds. The median (lower to upper quartile) bacterial count 1 day after treatment was 6.18 × 10(3) (0.76 × 10(3)-11.18 × 10(3)), 2.86 × 10(3) (1.22 × 10(3)-7.07 × 10(3)), and 3.52 × 10(3) (1.18 × 10(3)-6.72 × 10(3)) cfu/100 μl for control, MT and HT groups, respectively; for the 4-day end point, the count was 1.37 × 10(3) (0.67 × 10(3)-2.89 × 10(3)), 1.35 × 10(3) (0.09 × 10(3)-2.96 × 10(3)), and 0.07 × 10(3) (0.03 × 10(3)-0.36 × 10(3)) cfu/100 μl for control, MT and HT, showing a significant reduction (p = 0.002) on the bacterial load four days after focused ultrasound treatment when treating at high temperature (HT). The MPO amount remained unchanged between groups and days, indicating no change on local neutrophil recruitment in the abscess caused by the treatment. The white blood cell count remained unchanged between groups and days indicating that no systemic inflammatory response was caused by the treatment.. Focused ultrasound induces a therapeutic effect in abscesses induced by MRSA. This effect is observed as a reduction of the number bacteria without significantly altering the amount of MPO at the site of a MRSA-induced abscess. These initial results suggest that focused ultrasound is a viable option for the treatment of localized MRSA-related infections.

Topics: Abscess; Animals; Bacterial Load; Disease Models, Animal; Feasibility Studies; Female; Hot Temperature; Hyperthermia, Induced; Leukocyte Count; Magnetic Resonance Imaging; Methicillin-Resistant Staphylococcus aureus; Mice, Inbred BALB C; Neutrophil Activation; Peroxidase; Staphylococcal Infections; Time Factors; Ultrasonic Therapy

Granulocyte colony-stimulating factor (G-CSF) is a pharmacologic agent inducing neutrophil mobilization and a new candidate for neuroprotection and neuroregeneration in stroke. Its effects when used in combination with tissue plasminogen activator (tPA) were explored during the acute phase of ischemic stroke.. We used a middle cerebral artery occlusion (MCAO) model of cerebral ischemia, associated with treatment with tPA, in male spontaneously hypertensive rats (SHR). Granulocyte colony-stimulating factor (G-CSF; 60 μg/kg) was injected just before tPA. Neutrophil response in peripheral blood and in the infarct area was quantified in parallel to the infarct volume. Protease matrix metallopeptidase 9 (MMP-9) release from circulating neutrophils was analyzed by immunochemistry and zymography. Vascular reactivity and hemorrhagic volume in the infarct area was also assessed.. Twenty four hours after ischemia and tPA, G-CSF administration induced a significant increase of neutrophils in peripheral blood (P <0.05). At 72 hours post-ischemia, G-CSF was significantly associated with an increased risk of hemorrhage in the infarct area (2.5 times more likely; P <0.05) and significant cerebral endothelium-dependent dysfunction. Ex vivo, an increased MMP-9 release from neutrophils after tPA administration correlated to the increased hemorrhagic risk (P <0.05). In parallel, G-CSF administration was associated with a decreased neutrophil infiltration in the infarct area (-50%; P <0.05), with a concomitant significant neuroprotective effect (infarct volume: -40%; P <0.05).. We demonstrate that G-CSF potentiates the risk of hemorrhage in experimental stroke when used in combination with tPA by inducing neutrophilia. This effect is concomitant to an increased MMP-9 release from peripheral neutrophils induced by the tPA treatment. These results highlight the potential hemorrhagic risk of associating G-CSF to thrombolysis during the acute phase of stroke.

Topics: Animals; Brain Infarction; Disease Models, Animal; Drug Administration Schedule; Endothelium; Fibrinolytic Agents; Granulocyte Colony-Stimulating Factor; Hemorrhage; Infarction, Middle Cerebral Artery; Male; Matrix Metalloproteinase 9; Neutrophil Infiltration; Neutrophils; Peroxidase; Rats; Rats, Inbred SHR; Reperfusion Injury; Statistics, Nonparametric; Time Factors; Tissue Plasminogen Activator

The nucleoside adenosine is a known regulator of immunity and inflammation that mediates, at least in part, the anti-inflammatory effect of methotrexate, an immunosuppressive agent widely used to treat autoimmune inflammatory diseases. Adenosine A2A receptors play a key role in the inhibition of the inflammatory process besides promoting wound healing. Therefore, we aimed to determine the topical effect of a selective agonist, CGS-21680, on a murine model of skin hyperplasia with a marked inflammatory component. Pretreatment with either CGS-21680 (5 μg per site) or the reference agent dexamethasone (200 μg/site) prevented the epidermal hyperplasia and inflammatory response induced by topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA, 2 nmol/site) for three consecutive days. The histological analysis showed that both CGS-21680 and dexamethasone produced a marked reduction of inflammatory cell infiltrate, which correlated with diminished myeloperoxidase (MPO) activity in skin homogenates. Both treatments reduced the levels of the chemotactic mediators LTB4 and CXCL-1, and the inflammatory cytokine TNF-α, through the suppression of NFκB phosphorylation. The immunohistochemical analysis of the hyperproliferative markers cytokeratin 6 (CK6) and Ki67 revealed that while both agents inhibit the number of proliferating cells in the epidermis, CGS-21680 treatment promoted dermal fibroblasts proliferation. Consistently, increased collagen deposition in dermis was observed in tissue sections from agonist-treated mice. Our results showed that CGS 21680 efficiently prevents phorbol-induced epidermal hyperplasia and inflammation in mice without the deleterious atrophic effect of topical corticosteroids.

Topics: Adenosine; Adenosine A2 Receptor Agonists; Administration, Topical; Animals; Anti-Inflammatory Agents; Cell Proliferation; Collagen; Cytokines; Dexamethasone; Disease Models, Animal; Epidermis; Female; Hyperplasia; Inflammation; Mice; Peroxidase; Phenethylamines; Skin Diseases; Tetradecanoylphorbol Acetate

The aim of this study was to investigate the alleviating effect of Lactobacillus paracasei subsp. paracasei LC-01 (LC-01) on the murine model of colitis induced by dextran sulphate sodium (DSS). 50 pathogen-free, 6-week-old male BALB/c mice were divided randomly into 5 groups, including a control group and four DSS-LC-01-treated groups (DSS, DSS-106, DSS-108, and DSS-1010 with 0, 1×106, 1×108 and 1×1010 cfu/ml LC-01, respectively). To test the effectiveness of LC-01 as a prophylactic it was administered for 7 days before the onset of the disease in DSS-LC-01-treated mice. After 7 days, colitis was induced by administration of 2.5% (w/v) DSS in drinking water for a further 7 days. The disease activity index (DAI), histological score, myeloperoxidase (MPO) activity and the level of the pro-inflammatory cytokines interleukin-1β (IL-1β) and tumour necrosis factor α (TNF-α) were measured. DAI, histological scores and MPO activity of mice treated with a medium or high dose of LC-01 were significantly lower compared to a low-dose of LC-01 and DSS treatment alone (P<0.05). Colon length shortening could be prevented with increasing dose of LC-01. In addition, the levels of IL-1β and TNF-α were suppressed significantly by treatment with a medium and high dose of LC-01. However, no significant difference in the indices mentioned above were observed between a low dose of LC-01 and treatment with DSS alone (P≯0.05). An appropriate dose of LC-01 can prevent intestinal damage in mice with DSS-induced colitis. The expression of inflammatory cytokines related to pathogenesis of DSS-induced colitis decreased following treatment with LC-01.

Topics: Administration, Oral; Animals; Colitis; Colon; Dextran Sulfate; Disease Models, Animal; Feces; Inflammation; Interleukin-1beta; Intestinal Mucosa; Lactobacillus; Male; Mice; Mice, Inbred BALB C; Peroxidase; Probiotics; Tumor Necrosis Factor-alpha

Cysteinyl leukotrienes (CysLTs) propagate inflammatory reactions that result from allergen exposure in asthma. Montelukast, a CysLT type-1 receptor antagonist, disrupts mediator-receptor interactions and minimizes inflammatory response. In this study, we have evaluated anti-asthmatic efficacy of inhalable montelukast-loaded large porous particulate formulations in ovalbumin-induced rat airway inflammation model that mimics asthma.. The anti-inflammatory effects of a montelukast-loaded formulation were investigated in rats by measuring the total protein content, levels of injury markers and number of inflammatory cells in the bronchoalveolar lavage fluid (BALF). The histopathological studies assessed the morphological and structural changes that occur in asthmatic lungs. Animals were also challenged with methacholine to examine the airway hyper-reactivity.. Compared with healthy animals, asthmatic animals showed a 3.8- and 4.77-fold increase in the protein content and number of inflammatory cells in BALF, respectively. Intratracheal montelukast particles reduced the protein content by 3.3-fold and the number of inflammatory cells by 2.62-fold. Also, montelukast particles reduced the lactate dehydrogenase (LDH) and myeloperoxidase (MPO) levels by a 4.87- and 6.8-fold in BALF, respectively. Montelukast particles reduced the airway wall thickness by 2.5-fold compared with untreated asthmatic lungs. Further, particulate formulation protected the lungs against methacholine-induced bronchial provocation (p < 0.05).. Respirable large porous particles containing montelukast alleviated allergen-induced inflammatory response in an animal model and prevented histological changes associated with asthma. Thus montelukast-loaded large porous polylactic acid (PLA) particles could be an aerosolized delivery approach for administration of currently available oral montelukast.

Topics: Acetates; Aerosols; Animals; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Bronchoalveolar Lavage Fluid; Cyclopropanes; Cysteine; Disease Models, Animal; Inflammation; L-Lactate Dehydrogenase; Lactic Acid; Leukotrienes; Lung; Ovalbumin; Peroxidase; Polyesters; Polymers; Quinolines; Rats; Rats, Sprague-Dawley; Sulfides

The prevalence of peptic ulcer disease has not decreased mainly due to an increase in the use of NSAIDs. This study was conducted in order to determine whether a chronic NSAID-induced gastric inflammation model could be established by repeated administration of NSAID.. Indomethacin (10 mg/kg) was administered once per week for six weeks in 8- and 26-week rats and animals were sacrificed every week after administration. Gross ulcer index, histologic damage index, myeloperoxidase (MPO) activity, and mucus (glucosamine) levels were measured. Small bowel damage was also evaluated.. Gross gastric damage index showed a peak level at three weeks and then decreased slowly in the 26-week indomethacin group. Gastric mucosal glucosamine level increased in both the 8-week (p=0.038) and 26-week groups (p=0.007). In addition, gastric mucosal MPO level decreased in the 8-week group (p=0.018) but did not show a decrease in the 26-week group. Small bowel damage began to occur at three weeks during the schedule and eight of 36 rats (22.2%) died due to perforation or peritonitis of the small bowel in the 8- and 26-week indomethacin groups, respectively.. Due to gastric adaptation and small bowel damage, repeated administration of NSAID to experimental animals may not be an adequate method for establishment of the chronic gastric inflammation model.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Disease Models, Animal; Gastric Mucosa; Glucosamine; Indomethacin; Intestine, Small; Male; Peroxidase; Rats; Rats, Sprague-Dawley; Time Factors

Pulmonary tuberculosis (TB), caused by the intracellular bacterial pathogen Mycobacterium tuberculosis (Mtb), is a major world health problem. The production of reactive nitrogen species (RNS) is a potent cytostatic and cytotoxic defense mechanism against intracellular pathogens. Nevertheless, the protective role of RNS during Mtb infection remains controversial. Here we use an anti-nitrotyrosine antibody as a readout to study nitration output by the zebrafish host during early mycobacterial pathogenesis. We found that recognition of Mycobacterium marinum, a close relative of Mtb, was sufficient to induce a nitrosative defense mechanism in a manner dependent on MyD88, the central adaptor protein in Toll like receptor (TLR) mediated pathogen recognition. However, this host response was attenuated by mycobacteria via a virulence mechanism independent of the well-characterized RD1 virulence locus. Our results indicate a mechanism of pathogenic mycobacteria to circumvent host defense in vivo. Shifting the balance of host-pathogen interactions in favor of the host by targeting this virulence mechanism may help to alleviate the problem of infection with Mtb strains that are resistant to multiple drug treatments.

Topics: Animals; Animals, Genetically Modified; Disease Models, Animal; Interleukin-8; Mycobacterium; Mycobacterium Infections; Myeloid Differentiation Factor 88; Neutrophils; Peroxidase; Reactive Nitrogen Species; Receptors, Interleukin-1; Receptors, Interleukin-8B; Signal Transduction; Toll-Like Receptors; Tyrosine; Zebrafish

The antioxidant N-acetyl-l-cysteine (NAC) had been shown to inhibit replication of seasonal human influenza A viruses. Here, the effects of NAC on H9N2 swine influenza virus-induced acute lung injury (ALI) were investigated in mice. BALB/c mice were inoculated intranasally with 10(7) 50% tissue culture infective doses (TCID(50)) of A/swine/HeBei/012/2008/(H9N2) viruses with or without NAC treatments to induce ALI model. The result showed that pulmonary inflammation, pulmonary edema, MPO activity, total cells, neutrophils, macrophages, TNF-α, IL-6, IL-1β and CXCL-10 in BALF were attenuated by NAC. Moreover, our data showed that NAC significantly inhibited the levels of TLR4 protein and TLR4 mRNA in the lungs. Pharmacological inhibitors of TLR4 (E5564) exerted similar effects like those determined for NAC in H9N2 swine influenza virus-infected mice. These results suggest that antioxidants like NAC represent a potential additional treatment option that could be considered in the case of an influenza A virus pandemic.

Topics: Acetylcysteine; Acute Lung Injury; Animals; Antioxidants; Cytokines; Disease Models, Animal; Humans; Inflammation Mediators; Influenza A Virus, H9N2 Subtype; Influenza, Human; Lipid A; Lung; Male; Mice; Mice, Inbred BALB C; Orthomyxoviridae Infections; Peroxidase; Swine; Toll-Like Receptor 4; Virus Replication

We have earlier shown that PACAP-38 decreases neurogenic inflammation. However, there were no data on its receptorial mechanism and the involvement of its PAC1 and VPAC1/2 receptors (PAC1R, VPAC1/2R) in this inhibitory effect. Neurogenic inflammation in the mouse ear was induced by topical application of the Transient Receptor Potential Ankyrin 1 (TRPA1) receptor activator mustard oil (MO). Consequent neurogenic edema, vasodilation and plasma leakage were assessed by measuring ear thickness with engineer's micrometer, detecting tissue perfusion by laser Doppler scanning and Evans blue or indocyanine green extravasation by intravital videomicroscopy or fluorescence imaging, respectively. Myeloperoxidase activity, an indicator of neutrophil infiltration, was measured from the ear homogenates with spectrophotometry. The selective PAC1R agonist maxadilan, the VPAC1/2R agonist vasoactive intestinal polypeptide (VIP) or the vehicle were administered i.p. 15 min before MO. Substance P (SP) concentration of the ear was assessed by radioimmunoassay. Maxadilan significantly diminished MO-induced neurogenic edema, increase of vascular permeability and vasodilation. These inhibitory effects of maxadilan may be partially due to the decreased substance P (SP) levels. In contrast, inhibitory effect of VIP on ear swelling was moderate, without any effect on MO-induced plasma leakage or SP release, however, activation of VPAC1/2R inhibited the increased microcirculation caused by the early arteriolar vasodilation. Neither the PAC1R, nor the VPAC1/2R agonist influenced the MO-evoked increase in tissue myeloperoxidase activity. These results clearly show that PAC1R activation inhibits acute neurogenic arterial vasodilation and plasma protein leakage from the venules, while VPAC1/2R stimulation is only involved in the attenuation of vasodilation.

Topics: Animals; Capillary Permeability; Disease Models, Animal; Ear; Edema; Female; Insect Proteins; Male; Mice; Microcirculation; Mustard Plant; Peroxidase; Plant Oils; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; Receptors, Vasoactive Intestinal Peptide, Type II; Receptors, Vasoactive Intestinal Polypeptide, Type I; Skin Physiological Phenomena; Substance P; Vasoactive Intestinal Peptide; Vasoconstrictor Agents; Vasodilation

The role of myeloperoxidase (MPO) is essential in the killing of phagocytosed bacteria. Certain steroid hormones increase MPO plasma concentration. Our aim was to test the effect of MPO, its inhibitor indomethacin, and certain steroid hormones on bactericidal activity.. Human polymorphonuclear leukocytes (PMN) were incubated with opsonised Escherichia coli and either MPO, indomethacin, estradiol, or hydrocortisone. Intracellular killing capacity was evaluated with UV microscopy after treatment with fluorescent dye. Next, an in vivo experiment was performed with nine groups of rats: in the first phase of the study indomethacin treatment and Pasteurella multocida infection (Ii), indomethacin treatment without infection (I0), untreated control with infection (Mi) and untreated control without infection (M0); in the second phase of the study rats with infection and testosterone treatment (NT), castration, infection and testosterone treatment (CT), castration, infection and estradiol treatment (CE), non-castrated infected control (N0), and castrated infected control (C0). After treatment bacteria were reisolated from the liver and heart blood on agar plates, and laboratory parameters were analyzed. For the comparison of laboratory results ANOVA or Kruskal-Wallis test and LSD post hoc test was used.. Indomethacin did not have a remarkable effect on the bacterial killing of PMNs, while the other compounds increased bacterial killing to various degrees. In the animal model indomethacin and infection caused a poor clinical state, a great number of reisolated bacteria, elevated white blood cell (WBC) count, decreased C-reactive protein (CRP) and serum albumin levels. Testosterone treatment resulted in less bacterial colony numbers in group NT, but not in group CT compared to respective controls (N0, C0). Estradiol treatment (CE) decreased colony numbers compared to control (C0). Hormone administration resulted in lower WBC counts, and in group CE, a decreased CRP.. MPO, estradiol, and hydrocortisone improve bacterial killing activity of PMNs. Indomethacin treatment and castration weaken immune responses and clinical state of infected rats, while testosterone and estradiol have a beneficial effect.

Topics: Adult; Animal Structures; Animals; Anti-Infective Agents; Blood Bactericidal Activity; Cells, Cultured; Disease Models, Animal; Escherichia coli; Female; Humans; Indomethacin; Male; Microbial Viability; Neutrophils; Pasteurella Infections; Pasteurella multocida; Peroxidase; Rats, Wistar; Steroids; Young Adult

Inflammatory bowel disease (IBD) is characterized by excessive innate immune cell activation, which is responsible for tissue damage and induction of adaptive immune responses. All-trans retinoic acid (ATRA), the ligand of retinoic acid receptors (RAR), has been previously shown to regulate adaptive immune responses and restore Th17/Treg balance, while its role in regulation of innate immune cell function such as macrophages remains to be elucidated. The study was performed to explore the effect of ATRA on regulation of innate immune responses during dextran sulfate sodium (DSS) induced murine colitis. The mice with DSS colitis were administered with vehicle, ATRA, or LE135. Colitis was evaluated by clinical symptoms, tissue myeloperoxidase (MPO) activity, and the expressions of CD68 and nuclear factor (NF) κB p65, and tumor necrosis factor (TNF) level in inflamed colon. RAW 264.7 cells were pretreated with vehicle, ATRA, or LE135, followed by LPS challenge in vitro. ATRA administration ameliorates DSS-induced colitis evidenced with decreased TNF level and CD68 expression, while LE135 leads to exacerbation of colitis. ATRA treatment in vitro dampens LPS induced NF-κB activation and TNF production of RAW 264.7 cells. Together, our data show a crucial role of ATRA in the progress of acute colitis through inhibiting NF-κB activation, and suggest that ATRA represents a novel therapeutic approach for the management of IBD.

Topics: Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Cell Line; Colitis; Dextran Sulfate; Disease Models, Animal; Female; Lipopolysaccharides; Macrophages; Mice; Neutrophil Infiltration; NF-kappa B; Peroxidase; Signal Transduction; Tretinoin; Tumor Necrosis Factors

To explore protective mechanism of Panax notoginseng saponins (PNS) on rat hemorrhagic shock model in recovery stage. 72 Wistar rats were selected and divided into control group, model group and PNS group with 24 rats in each group. 200 mg/kg PNS was injected intravenously at 60 min of hemorrhagic shock stage in PNS groups. Changes of endotoxin, MPO, IL-6, SOD, MDA and TNF α were observed at 30 and 120 min of recovery stage by ELISA; water content of lung and intestine was detected; HE staining was applied to observe morphological change of intestinal mucosa, kidney, liver and lung; western blot was used to detect intercellular adhesion molecule-1 (ICAM-1) level in lung tissue and intestine tissue. At 30 min and 120 min of recovery stage, MDA, MPO, endotoxin, TNF α and IL-6 levels significantly increased in model group compared with control group, however SOD level significantly decreased, the difference was statistically significant (P < 0.05); PNS dose-dependently decreased MDA, MPO, endotoxin, TNF α and IL-6 levels, and increased SOD level, which was statistically significant (P < 0.05); In results of water content detection, water content in lung tissue and intestine tissue was significantly higher than in control group, however, after being treated with PNS, the water content was significantly decreased; HE staining showed the morphologic change of lung tissue cells; Western blot showed that in lung tissue and intestine tissue, ICAM-1 level in model group was significantly higher than in control group, and it was lower in PNS group than in model group. PNS can increase SOD activity, decrease levels of MDA, endotoxin and MPO, decrease expression of TNF α and IL-6, and decrease water content in lung tissue and intestine tissue. Thus, PNS is protective to rat hemorrhagic shock model by anti oxidative stress and anti-inflammatory pathways, and ICAM-1 may play an important role in the mechanism.

Topics: Animals; Disease Models, Animal; Endotoxins; Enzyme-Linked Immunosorbent Assay; Intercellular Adhesion Molecule-1; Interleukin-6; Lung; Male; Malondialdehyde; Panax notoginseng; Peroxidase; Protective Agents; Rats; Rats, Wistar; Saponins; Shock, Hemorrhagic; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Intestinal ischemia-reperfusion injury is one of the main factors leading to multiple organ failure after resuscitation of prolonged hemorrhagic shock; however, the current conventional fluid resuscitation still cannot effectively reduce intestinal injury caused by prolonged hemorrhagic shock. To investigate the effect of ECMO resuscitation on alleviating intestinal ischemia-reperfusion injury in a prolonged hemorrhagic shock rabbit model. Thirty New Zealand white rabbits were randomly divided into three groups: control group, conventional fluid resuscitation group, and ECMO resuscitation group. The prolonged hemorrhagic shock model was established by keeping the arterial blood pressure from 31 to 40 mmHg for 3 h through the femoral artery bleeding, and performing the resuscitation for 2 h by conventional fluid resuscitation and ECMO resuscitation, respectively. Chiu's score of intestinal injury, serum lactate and TNF-α levels, intestinal mucosamyeloperoxidase (MPO) activity, intercellular adhesion molecule (ICAM-1), and Claudin-1expression were detected. The mean arterial blood pressure in Group 2 was significantly higher after resuscitation than in Group 1, but serum lactate and inflammatory cytokines TNF-α level were significantly lower. And Chiu's score of intestinal injury and myeloperoxidase (MPO) activity level and ICAM-1 expression were significantly lower in the ECMO resuscitation group, in which the Claudin-1 levels were significantly increased. ECMO resuscitation for the prolonged hemorrhagic shock improves tissue perfusion and reduces the systemic inflammation, and thus alleviates intestinal damage caused by prolonged hemorrhagic shock.

Topics: Animals; Blood Pressure; Claudin-1; Disease Models, Animal; Extracorporeal Membrane Oxygenation; Intercellular Adhesion Molecule-1; Intestinal Mucosa; Intestines; Lactic Acid; Male; Peroxidase; Rabbits; Reperfusion Injury; Severity of Illness Index; Shock, Hemorrhagic; Tumor Necrosis Factor-alpha

Curcumin, a polyphenol derived from the herb Curcuma longa, has number of antioxidant, anti-inflammatory, antimicrobial, and anti-carcinogenic activities. Its anti-inflammatory property was here studied alone and in combination with clarithromycin in a mouse model of acute inflammation.. A total of 80 mice divided into four groups were used. Mice receiving curcumin and/or clarithromycin were fed orally with curcumin (150 mg/kg/day) for 15 days prior to infection, whereas clarithromycin was administered orally (30 mg/kg/day) 12 hours post infection. Simultaneously, the control group receiving only infection but no treatment was also set up. Bacterial load estimation, histopathological examination and analysis of inflammatory parameters was performed on various days for all groups.. Intranasal inoculation of bacteria resulted in significant increase in neutrophil infiltration along with increased production of various inflammatory mediators (malondialdehyde, myeloperoxidase, nitric oxide, TNFα) in lung tissue. Clarithromycin treatment significantly decreased the bacterial load and other inflammatory components in infected mice, but animals receiving curcumin alone or in combination with clarithromycin showed a much more significant (p < 0.05) reduction in neutrophil influx along with reduced levels of various inflammatory parameters. Though treatment with curcumin did not reduce the bacterial load, in combination with clarithromycin, both bacterial proliferation and lung tissue damage were checked.. Though clarithromycin, because of its associated side effects, may not be the preferred treatment, it can be used in conjunction with curcumin. The latter as an adjunct therapy will help to down regulate the exaggerated state of immune response during acute lung infection.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Clarithromycin; Curcumin; Disease Models, Animal; Drug Therapy, Combination; Female; Klebsiella Infections; Klebsiella pneumoniae; Male; Malondialdehyde; Mice, Inbred BALB C; Nitric Oxide; Peroxidase; Pneumonia; Tumor Necrosis Factor-alpha

To investigate the inhibitory effect of kukoamine B (KB) on lung inflammatory responses in mice with sepsis and its possible molecular mechanism.. Twenty-eight male mice were randomly divided into control group (n=8), lipopolysaccharide (LPS) group (n=10), and LPS + KB group (n=10). Sepsis model was reproduced by intra-peritoneal injection of 20 mg/kg LPS, while equivalent normal saline was given in control group, and 20 μg/kg KB was injected through caudal vein 4 hours after LPS challenge in LPS + KB group. After 8 hours of LPS challenge, the concentration of LPS in plasma and the activity of myeloperoxidase (MPO) in the lung tissue were determined. The contents of tumor necrosis factor-α (TNF-α) and interleukin-1β(IL-1β) in plasma, alveolar lavage fluid and lung tissue homogenates were assessed by enzyme linked immunosorbent assay (ELISA). The activation of nuclear factor-ΚB (NF-ΚB) and the expression of inducible nitric oxide synthase (iNOS) in lung tissue were determined by Western Blot. The pathological changes in lung tissues were observed with hematoxylin-eosin (HE) staining. The expression of intercellular adhesion molecule-1 (ICAM-1) in lung tissue was determined by immunohistochemistry.. Compared with control group, the concentration of LPS in plasma (1 155.650±147.149 kEU/L vs. 31.390±18.859 kEU/L), MPO activity (1.177±0.093 U/g vs. 0.775±0.166 U/g), NF-ΚB activity (gray value: 1.557±0.105 vs. 0.824±0.032) and the expression of iNOS (gray value: 0.650±0.129 vs. 0.392±0.097) were significantly increased in LPS group (all P<0.05). After KB intervention, the concentration of LPS (624.461±149.012 kEU/L), MPO activity (0.919±0.023 U/g), NF-ΚB activity (1.127±0.074) and the expression of iNOS (0.425±0.066) were significantly lowered (all P<0.05). Compared with control group, the contents of TNF-α (47.325±13.864 ng/L vs. 6.534±0.544 ng/L, 13.382±2.231 ng/L vs. 3.748±0.692 ng/L, 31.127±7.399 ng/L vs. 14.948±4.673 ng/L) and IL-1β (74.329±11.890 ng/L vs. 29.921±6.487 ng/L, 9.422±2.674 ng/L vs. 1.105±0.364 ng/L, 528.509±32.073 ng/L vs. 109.945±13.561 ng/L) in plasma, alveolar lavage fluid and lung tissue homogenates were obviously enhanced in LPS group (all P<0.05). With KB intervention, the contents of TNF-α (20.331±7.789 ng/L, 7.145±1.202 ng/L, 15.966±2.946 ng/L) and IL-1β (57.707±8.098 ng/L, 2.212±0.878 ng/L, 426.154±11.270 ng/L) were markedly reduced (plasma TNF-α: F=16.052, P=0.002; IL-1β: F=20.649, P=0.000; lung tissue homogenates TNF-α: F=31.134, P=0.001; IL-1β: F=22.792, P=0.002; alveolar lavage fluid TNF-α: F=10.013, P=0.009; IL-1β: F=319.857, P=0.000). In addition, leukocyte infiltration to the lung tissue was attenuated, and the expression of ICAM-1 was reduced by KB in histological examination.. KB, as a neutralizer of LPS, can inhibit the release of inflammatory mediators, reduce the pulmonary inflammatory response and protect the function of lung in septic mice.

Topics: Animals; Caffeic Acids; Disease Models, Animal; Interleukin-1beta; Lung; Male; Mice; Mice, Inbred ICR; NF-kappa B; Nitric Oxide Synthase Type II; Peroxidase; Sepsis; Spermine; Tumor Necrosis Factor-alpha

Crohn's disease (CD) and ulcerative colitis are two main clinically defined forms of chronic inflammatory bowel disease (IBD). Our understanding of IBD depends largely on rodent models. DSS-induced intestinal inflammation in mice and T cell transfer colitis in SCID mice are most widely used and accepted models that can recapitulate the human diseases. Here, we provide detailed protocols of these two mouse models of experimentally induced intestinal inflammation. We also discuss the protocols for the isolation and analysis of inflammatory T cell from the colon.

Topics: Acute Disease; Animals; CD4-Positive T-Lymphocytes; Chronic Disease; Colitis, Ulcerative; Colon; Disease Models, Animal; Enzyme Assays; Homeodomain Proteins; Humans; Leukocyte Common Antigens; Lymph Nodes; Male; Mice; Peroxidase; Staining and Labeling; Tissue and Organ Harvesting; Tissue Culture Techniques

The purpose of this study was to investigate the effect of etoricoxib on oxidative injury induced with ischemia-reperfusion (I/R) in rat kidney tissue in terms of biochemistry and immunohistochemistry. Male Albino Wistar rats were divided into renal I/R (RIR), 50 mg/kg etoricoxib+RIR (ETO-50), 100 mg/kg etoricoxib+RIR (ETO-100) and sham operation (SG) groups. Animals in the ETO-50 and ETO-100 groups were given etoricoxib by the oral route at dosages of 50 and 100 mg/kg, respectively. The RIR and SG groups were given distilled water as solvent. One hour after drug administration, 1h of ischemia and 3h of reperfusion were applied to the left kidneys of all rats (apart from SG) under 25 mg/kg thiopental sodium anesthesia. At the end of that time, kidneys were extracted and biochemical and immunohistochemical analyses were performed. Etoricoxib reduced, in a dose-dependent manner, levels of MDA, MPO and COX-2 that normally rise with I/R in rat kidney tissues. Etorixicob did not alter COX-1 activity at 50 and 100 mg/kg doses, but significantly prevented loss of tGSH in tissues with I/R. In addition, Bcl-2' gene expression inhibited with I/R was prevented in renal tubular and glomerular cells. Furthermore, etoricoxib significantly decreased the caspase-3 gene expression which increased with I/R. Etoricoxib significantly prevented I/R injury in a dose-dependent manner. The results of this study show that etoricoxib treatment could decrease kidney injury during IR.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Caspase 3; Cells, Cultured; Cyclooxygenase 2; Disease Models, Animal; Etoricoxib; Gene Expression Regulation; Humans; Kidney; Male; Malondialdehyde; Oxidative Stress; Peroxidase; Proto-Oncogene Proteins c-bcl-2; Pyridines; Rats; Rats, Wistar; Reperfusion Injury; Sulfones

In this study, we aimed to investigate our hypothesis starting that Schisantherin A (SchA), which exerts significant anti-inflammatory effects in vitro, could reduce the pulmonary inflammatory response in an acute lung injury (ALI) model. ALI was induced in mice by exposure to lipopolysaccharide (LPS, 20 mg/kg), and the inflammatory mediator production, neutrophil infiltration, and histopathological changes were evaluated. SchA at a dose of 100 mg/kg significantly improved survival rate of mice injected with LPS. The levels of TNF-α and IL-6 in bronchoalveolar lavage fluid (BALF) and the histopathological changes due to the injury were significantly inhibited when SchA was administered before or after LPS insult, and the infiltration of neutrophils and macrophages in lung tissues induced by LPS were suppressed by SchA. Additionally, pretreatment with SchA notably blocked the activation of nuclear factor-kappaB (NF-κB) and mitogen-activated protein kinases (MAPKs). Taken together, SchA showed obvious anti-inflammatory effects in an LPS-induced ALI model via blockage of the NF-κB and MAPK pathways. Thus, SchA may be an innovative therapy for inflammatory diseases.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; Cell Movement; Cyclooctanes; Dioxoles; Disease Models, Animal; Dose-Response Relationship, Drug; Lignans; Lipopolysaccharides; Male; Malondialdehyde; Mice; Mice, Inbred BALB C; Neutrophil Infiltration; Neutrophils; Peroxidase; Pulmonary Edema; Signal Transduction; Superoxide Dismutase; Survival Analysis

The immunomodulatory effects of PD-1 and CD4(+)CD25(+) Tregs in the resolution of ALI are still poorly understood. Accordingly, 1 million Tregs were isolated from spleens of WT C57BL/6 or PD-1(-/-) mice (magnetical bead purification and subsequent labeling with/without Vybrant dye) and then AT into mice subjected to Hem shock during their resuscitation period, which were subsequently subjected to CLP/septic challenge (24 h post-Hem) to induce iALI. Initially, we demonstrated that Vybrant-labeled AT Tregs appear in the lungs of iALI mice. Subsequently, we found that AT of WT Tregs induced a significant repression of the indices of lung injury: a reduction of neutrophil influx to the lung tissue and a decrease of lung apoptosis compared with vehicle-treated iALI mice. In addition, these mice had substantially higher concentrations of BALF and lung-tissue IL-10 but significantly decreased levels of lung KC. However, these beneficial effects of the AT of Tregs were lost with the administration of PD-1(-/-) mouse Tregs to the recipient WT mice. ALI was exacerbated in these recipient mice receiving AT PD-1(-/-) Tregs to the same extent as iALI mice that did not receive Tregs. These data imply that Tregs can act directly to modify the innate immune response induced by experimental iALI, and this is mediated, in part, by PD-1. Hence, the manipulation of Tregs may represent a plausible target for treating iALI.

Topics: Acute Lung Injury; Adoptive Transfer; Animals; Bronchoalveolar Lavage Fluid; Caspase 3; CTLA-4 Antigen; Cytokines; Disease Models, Animal; Gene Knockdown Techniques; Immunomodulation; Immunophenotyping; Inflammation Mediators; Male; Mice; Mice, Knockout; Neutrophils; Peroxidase; Phenotype; Programmed Cell Death 1 Receptor; Shock, Septic; Spleen; T-Lymphocytes, Regulatory

Nonalcoholic steatohepatitis (NASH) has been associated with irinotecan (IRI)-based cancer chemotherapy regimens. The purpose of this study was to propose and test a consistent model of IRI-induced NASH, filling a gap in the medical literature.. Swiss male mice were distributed in groups (n = 8) and injected with saline (5 mL/kg, i.p.; control) or IRI (25, 50, 75 or 100 mg/kg, i.p.) thrice a week for 7 weeks. Blood samples were collected to measure the serum concentrations of proteins, alanine and aspartate aminotransferases (ALT and AST). Each week animals were euthanized, and the livers were submitted to myeloperoxidase (MPO) assay, lipid dosage, immunohistochemistry for inducible nitric oxide synthase (iNOS), TNF-α and interleukin-1β (IL-1β), and histopathological analysis. Survival rates were also determined.. Mice treated with IRI had a significantly (p < 0.05) lower survival rate than controls and time- and dose-dependent body weight loss. ALT and AST plasma levels increased in relation to controls only in mice receiving IRI 50 mg/kg (p < 0.05). The histopathological features characteristic of NASH was observed, including steatosis, lobular neutrophil infiltration and ballooning hepatocytic degeneration. Additional findings included increased MPO, lipid accumulation, portal neutrophil infiltration, IL-1β and iNOS expression and fibrosis in liver tissues and low serum protein levels compared to controls.. This is the first report of a consistent model of IRI-induced NASH capable of mimicking clinical findings.

Topics: Alanine Transaminase; Animals; Antineoplastic Agents, Phytogenic; Aspartate Aminotransferases; Camptothecin; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Fatty Liver; Humans; Interleukin-1beta; Irinotecan; Liver; Male; Mice; Peroxidase; Time Factors; Tumor Necrosis Factor-alpha; Weight Loss

To test the role of mast cells in gut inflammation and colitis using interleukin (IL)-10-deficient mice as an experimental model.. Mast cell-deficient (Kit (W-sh/W-sh) ) mice were crossbred with IL-10-deficient mice to obtain double knockout (DKO) mice. The growth, mucosal damage and colitis status of DKO mice were compared with their IL-10-deficient littermates.. DKO mice exhibited exacerbated colitis compared with their IL-10-deficient littermates, as shown by increased pathological score, higher myeloperoxidase content, enhanced Th1 type pro-inflammatory cytokines and inflammatory signaling, elevated oxidative stress, as well as pronounced goblet cell loss. In addition, deficiency in mast cells resulted in enhanced mucosal damage, increased gut permeability, and impaired epithelial tight junctions. Mast cell deficiency was also linked to systemic inflammation, as demonstrated by higher serum levels of tumor necrosis factor α and interferon γ in DKO mice than that in IL-10-deficient mice.. Mast cell deficiency in IL-10-deficient mice resulted in systematic and gut inflammation, impaired gut barrier function, and severer Th1-mediated colitis when compared to mice with only IL-10-deficiency. Inflammation and impaired gut epithelial barrier function likely form a vicious cycle to worsen colitis in the DKO mice.

Topics: Animals; Colitis; Colon; Disease Models, Animal; Feces; Genotype; Inflammation Mediators; Inflammatory Bowel Diseases; Interferon-gamma; Interleukin-10; Intestinal Mucosa; Male; Mast Cells; Mice, Inbred C57BL; Mice, Knockout; Oxidative Stress; Peroxidase; Phenotype; Proto-Oncogene Proteins c-kit; Signal Transduction; Th1 Cells; Time Factors; Tumor Necrosis Factor-alpha

To analyze the in vivo effect of Escherichia coli Nissle 1917 (EcN) with different courses and different doses to Sprague-Dawley rats with trinitrobenzene sulfonic acid (TNBS)-induced colitis.. The probiotic was orally administered with different courses of treatment (with or without pre-administration) and different doses (10(7)-10(9) CFU/day) to Sprague-Dawley rats with TNBS-induced colitis. Therapeutic effects, levels of cytokine in serum, mRNA and protein expression were analyzed.. Oral EcN administration after TNBS-induced improved colitis dose dependently. In parallel, a reduction of disease activity index and colonic MPO activity together with a decreased level of TNF-α and a trend of increased IL-10 expression was detected. Pre-administration of 10(7)CFU/day EcN to TNBS-treated rats resulted in a significant protection against inflammatory response and colons isolated from these rats exhibited a more pronounced expression of ZO-1 than the other groups. In the group of pre-administration of 10(9)CFU/day, the condition was not improved but deteriorated.. This study convincingly demonstrates that pre-administration of probiotic EcN with low dose is able to protect colitis of rats and mediate up-regulation of ZO-1 expression, but long-term of high-dose EcN may do harm to colitis.

Topics: Animals; Anti-Inflammatory Agents; Colitis; Colon; Disease Models, Animal; Escherichia coli; Female; Ileum; Interleukin-10; Intestinal Mucosa; Peroxidase; Probiotics; Rats, Sprague-Dawley; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha; Zonula Occludens-1 Protein

Myocardial infarction (MI) remains a major cause of death and disability worldwide, despite available reperfusion therapies. Inflammatory signaling is considered nodal in defining final infarct size. Activation of the innate immune receptor toll-like receptors (TLR) 9 prior to ischemia and reperfusion (I/R) reduces infarct size, but the consequence of TLR9 activation timed to the onset of ischemia is not known.. The TLR9-agonist; CpG B was injected i.p. in C57BL/6 mice immediately after induction of ischemia (30 minutes). Final infarct size, as well as area-at-risk, was measured after 24 hours of reperfusion. CpG B injection resulted in a significant increase in circulating granulocytes and monocytes both in sham and I/R mice. Paradoxically, clear evidence of reduced cardiac infiltration of both monocytes and granulocytes could be demonstrated in I/R mice treated with CpG B (immunocytochemistry, myeloperoxidase activity and mRNA expression patterns). In addition, systemic TLR9 activation elicited significant alterations of cardiac inflammatory genes. Despite these biochemical and cellular changes, there was no difference in infarct size between vehicle and CpG B treated I/R mice.. Systemic TLR9-stimulation upon onset of ischemia and subsequent reperfusion does not alter final infarct size despite causing clear alterations of both systemic and cardiac inflammatory parameters. Our results question the clinical usefulness of TLR9 activation during cardiac I/R.

Topics: Animals; Disease Models, Animal; Female; Inflammation; Male; Mice; Monocytes; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Oligonucleotides; Peroxidase; Toll-Like Receptor 9

A suitable small animal model may help in the screening and evaluation of new drugs, especially those from natural products, which can be administered at lower dosages, fulfilling an urgent worldwide need. In this study, we explore whether zebrafish could be a model organism for carrageenan-induced abdominal edema. The research results showed that intraperitoneal (i.p.) administration of 1.5% λ-carrageenan in a volume of 20 µL significantly increased abdominal edema in adult zebrafish. Levels of the proinflammatory proteins tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS) were increased in carrageenan-injected adult zebrafish during the development of abdominal edema. An associated enhancement was also observed in the leukocyte marker, myeloperoxidase (MPO). To support these results, we further observed that i.p. methylprednisolone (MP; 1 µg), a positive control, significantly inhibited carrageenan-induced inflammation 24 h after carrageenan administration. Furthermore, i.p. pretreatment with either an anti-TNF-α antibody (1∶5 dilution in a volume of 20 µL) or the iNOS-selective inhibitor aminoguanidine (AG; 1 µg) inhibited carrageenan-induced abdominal edema in adult zebrafish. This new animal model is uncomplicated, easy to develop, and involves a straightforward inducement of inflammatory edema for the evaluation of small volumes of drugs or test compounds.

Topics: Animals; Anti-Inflammatory Agents; Carrageenan; Disease Models, Animal; Edema; Inflammation; Male; Methylprednisolone; Nitric Oxide Synthase Type II; Peroxidase; Tumor Necrosis Factor-alpha; Zebrafish

The purpose of this study was to investigate the protective effects and molecular mechanisms of scoparone on lipopolysaccharide (LPS)-induced acute lung injury in mice. Mice model of acute lung injury (ALI), induced by intranasal instillation of LPS, was used to investigate the protective effects of scoparone in vivo. The alveolar macrophages were used to investigate the molecular mechanisms of scoparone in vitro. The results showed that scoparone treatment remarkably attenuated LPS-induced pulmonary edema, histological severities, myeloperoxidase activity, and TNF-α, IL-6 and IL-1β production in vivo. We also found that scoparone inhibited LPS-induced TLR4 expression, NF-κB activation, TNF-α, IL-6 and IL-1β production in alveolar macrophages in vitro. In conclusion, our results suggest that scoparone has a protective effect on LPS-induced ALI via suppression of TLR4-mediated NF-κB signaling pathways.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents, Non-Steroidal; Artemisia; Cells, Cultured; Coumarins; Cytokines; Disease Models, Animal; Gene Expression Regulation; Humans; Lipopolysaccharides; Macrophages, Alveolar; Male; Mice; Mice, Inbred BALB C; NF-kappa B; Peroxidase; Pulmonary Edema; Signal Transduction; Toll-Like Receptor 4

To verify the effects of N-acetylcysteine (NAC) administered before and after ischaemia in an animal model of lung ischaemia-reperfusion (IR) injury.. Twenty-four Wistar rats were subjected to an experimental model of selective left pulmonary hilar clamping for 45 min followed by 2 h of reperfusion. The animals were divided into four groups: control group (SHAM), ischaemia-reperfusion, N-acetylcysteine-preischaemia (NAC-Pre) and NAC-postischaemia (NAC-Post). We recorded the haemodynamic parameters, blood gas analysis and histology. We measured the thiobarbituric acid reactive substances concentration; the expression of superoxide dismutase (SOD), inducible nitric oxide synthase (iNOS), nitrotyrosine, cleaved caspase 3, nuclear factor κB (NF-κB), NF-kappa-B inhibitor alpha (IκB-α), tumour necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β); myeloperoxidase activity (MPO).. No significant differences were observed in the haemodynamic parameters, blood gas analysis and SOD activity among the groups. Lipid peroxidation was significantly higher in the IR and NAC-Pre groups (P < 0.01). The expression of nitrotyrosine, cleaved caspase 3, NF-κB, IκB-α, TNF-α and IL-1β were significantly higher in the IR group when compared with the SHAM and NAC groups (P < 0.01). The NAC-Pre group showed a significantly higher expression of these proteins when compared with the SHAM and NAC-Post groups (P < 0.05). After reperfusion, the expression of iNOS increased almost uniformly in all groups when compared with the SHAM group (P < 0.01). The histological analysis showed fewer inflammatory cells in the NAC groups.. The intravenous administration of NAC demonstrated protective properties against lung IR injury. The use of NAC immediately after reperfusion potentiates its protective effects.

Topics: Acetylcysteine; Administration, Intravenous; Animals; Anti-Inflammatory Agents; Antioxidants; Caspase 3; Cytoprotection; Disease Models, Animal; Hemodynamics; I-kappa B Kinase; Inflammation Mediators; Interleukin-1beta; Lipid Peroxidation; Lung; Lung Injury; NF-kappa B; Nitric Oxide Synthase Type II; Oxidative Stress; Peroxidase; Rats, Wistar; Reperfusion Injury; Superoxide Dismutase; Time Factors; Tumor Necrosis Factor-alpha; Tyrosine

The fatty acid amide palmitoylethanolamide (PEA) has been studied extensively for its anti-inflammatory and neuroprotective actions. The lipidic nature and large particle size of PEA in the native state may limit its solubility and bioavailability when given orally, however. Micronized formulations of a drug enhance its rate of dissolution and reduce variability of absorption when orally administered. The present study was thus designed to evaluate the oral anti-inflammatory efficacy of micronized/ultramicronized versus nonmicronized PEA formulations.. Micronized/ultramicronized PEA was produced by the air-jet milling technique, and the various PEA preparations were subjected to physicochemical characterization to determine particle size distribution and purity. Each PEA formulation was then assessed for its anti-inflammatory effects when given orally in the carrageenan-induced rat paw model of inflammation, a well-established paradigm of edema formation and thermal hyperalgesia.. Intraplantar injection of carrageenan into the right hind paw led to a marked accumulation of infiltrating inflammatory cells and increased myeloperoxidase activity. Both parameters were significantly decreased by orally given micronized PEA (PEA-m; 10 mg/kg) or ultramicronized PEA (PEA-um; 10 mg/kg), but not nonmicronized PeaPure (10 mg/kg). Further, carrageenan-induced paw edema and thermal hyperalgesia were markedly and significantly reduced by oral treatment with micronized PEA-m and ultramicronized PEA-um at each time point compared to nonmicronized PeaPure. However, when given by the intraperitoneal route, all PEA formulations proved effective.. These findings illustrate the superior anti-inflammatory action exerted by orally administered, micronized PEA-m and ultramicronized PEA-um, versus that of nonmicronized PeaPure, in the rat paw carrageenan model of inflammatory pain.

Topics: Administration, Oral; Amides; Analgesics; Animals; Carrageenan; Chemistry, Pharmaceutical; Chromatography, High Pressure Liquid; Disease Models, Animal; Edema; Ethanolamines; Hyperalgesia; Inflammation; Male; Microscopy, Electron, Scanning; Pain; Palmitic Acids; Peroxidase; Rats; Rats, Sprague-Dawley

Pulmonary fibrosis, a progressive and lethal lung disease characterized by inflammation and accumulation of extracellular matrix components, is a major therapeutic challenge for which new therapeutic strategies are warranted. Cyclooxygenase (COX) inhibitors have been previously utilized to reduce inflammation. Histamine H4 receptor (H4R), largely expressed in hematopoietic cells, has been identified as a novel target for inflammatory and immune disorders. The aim of this study was to evaluate the effect of JNJ7777120 (1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine), a selective H4R antagonist, and naproxen, a well known nonsteroidal anti-inflammatory drug, and their combination in a murine model of bleomycin-induced fibrosis. Bleomycin (0.05 IU) was instilled intratracheally to C57BL/6 mice, which were then treated by micro-osmotic pump with vehicle, JNJ7777120 (40 mg/kg b.wt.), naproxen (21 mg/kg b.wt.), or a combination of both. Airway resistance to inflation, an index of lung stiffness, was assessed, and lung specimens were processed for inflammation, oxidative stress, and fibrosis markers. Both drugs alone were able to reduce the airway resistance to inflation induced by bleomycin and the inflammatory response by decreasing COX-2 and myeloperoxidase expression and activity and thiobarbituric acid-reactive substance and 8-hydroxy-2'-deoxyguanosine production. Lung fibrosis was inhibited, as demonstrated by the reduction of tissue levels of transforming growth factor-β, collagen deposition, relative goblet cell number, and smooth muscle layer thickness. Our results demonstrate that both JNJ7777120 and naproxen exert an anti-inflammatory and antifibrotic effect that is increased by their combination, which could be an effective therapeutic strategy in the treatment of pulmonary fibrosis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Anti-Inflammatory Agents; Bleomycin; Collagen; Cyclooxygenase 2; Deoxyguanosine; Disease Models, Animal; Goblet Cells; Indoles; Lung; Mice; Muscle, Smooth; Naproxen; Oxidative Stress; Peroxidase; Piperazines; Pneumonia; Pulmonary Fibrosis; Thiobarbituric Acid Reactive Substances; Transforming Growth Factor beta

In this study, we investigated the protective effect and mechanism of curcumin on a rat model of intestinal ischemia/reperfusion (I/R), which induces an acute liver lesion.. Curcumin was injected into rats in the curcumin groups through left femoral vein. The same volume of vehicle (0.9% normal saline) was injected into sham and I/R groups. Blood and liver tissue were gathered for serological and histopathological determination.. Intestinal I/R led to severe liver injury manifested as a significant increase in serum AST and ALT levels; all of those were reduced by treatment with curcumin. Simultaneously, the activity of SOD in liver decreased after intestinal I/R, which was increased by curcumin treatment. On the other hand, curcumin reduced MPO activity of liver tissue, as well as serum IL-6 and TNF-α levels observably. This is in parallel with the decreased level of liver intercellular cell adhesion molecule-1 (ICAM-1) and nuclear factor-κB (NF-κB) expression.. Our findings suggest that curcumin treatment attenuates liver lesion induced by intestinal I/R, attributable to the antioxidative and anti-inflammatory effect via inhibition of the NF-κB pathway.

Topics: Acute Disease; Alanine Transaminase; Animals; Aspartate Aminotransferases; Curcumin; Disease Models, Animal; Intercellular Adhesion Molecule-1; Interleukin-6; Liver; Liver Diseases; Male; NF-kappa B; Peroxidase; Protective Agents; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Signal Transduction; Superoxide Dismutase

To investigate the effects of ischemia/reperfusion on rat submandibular glands without denervation and the possible protective effects of ischemia preconditioning on the glands that experienced ischemia/reperfusion, in-situ ischemia/reperfusion and ischemia preconditioning experimental models of submandibular glands of healthy male Wistar rats were conducted. For ischemia/reperfusion groups, the glands were subjected to 90 min of ischemia without denervation, followed by 1, 12, 24, or 72 h of reperfusion. Ischemia preconditioning was achieved by 3 min of ischemia following 3 min of reperfusion, performed three times before ischemia/reperfusion. Salivary secretion, histological changes, alterations of tight junctions, myeloperoxidase activity, cellular apoptosis, and reactive oxygen species levels were detected. In ischemia/reperfusion glands, rising acute-inflammation responses, reduced tight-junction width, and increased myeloperoxidase activity, reactive oxygen species levels, and apoptotic cell numbers were observed, along with secretory dysfunction, especially at 1 and 12 h post-reperfusion, which seemed to gradually return to normal by 72 h post-reperfusion. In contrast, ischemia preconditioning showed the potential to ameliorate the injury-stress responses caused by ischemia/reperfusion. Our study revealed that ischemia/reperfusion could cause a series of injury-stress responses and ultimately lead to hyposecretion, independently of the parasympathetic nerve supply, which might play an important role in the early-phase dysfunction of the transplanted glands. Ischemia preconditioning could protect the involved glands and improve ischemia/reperfusion-induced hyposecretion.

Topics: Animals; Apoptosis; Disease Models, Animal; In Situ Nick-End Labeling; Ischemic Preconditioning; Male; Microscopy, Electron, Transmission; Monocytes; Neutrophils; Peroxidase; Random Allocation; Rats; Rats, Wistar; Reactive Oxygen Species; Reperfusion Injury; Saliva; Salivary Ducts; Secretory Rate; Submandibular Gland; Tight Junctions; Time Factors

Traditionally, Biophytum sensitivum (L.) DC (Oxalidaceae) is used in Indian medicine to treat diseases include stomachache, convulsions, cramps, inflammation, and ulcer.. The present study examines the effect of aerial parts of B. sensitivum (methanol extract) on a murine model of ulcerative colitis (UC).. UC was induced by intracolonic injection of 3% acetic acid in Wistar rats. B. sensitivum (50 or 100 mg/kg b wt) or reference drug sulfasalazine (100 mg/kg b wt) was administrated intra-peritoneally for 5 consecutive days before induction of colitis.. In the present study, we demonstrated for the first time that the administration of B. sensitivum (50 mg/kg b wt) was found to inhibit colitis by lowering macroscopic score (up to 3.66 ± 0.77) and also showed significant reduction (p < 0.01) in lactate dehydrogenase (LDH) and myeloperoxidase (MPO) activities. Furthermore, a significant reduction (p < 0.01) in mucosal content of lipid peroxidation (LPO), glutathione (GSH), superoxide dismutase (SOD), and nitric oxide (NO) confirms that B. sensitivum could significantly inhibit colitis. The study showed significant reduction (p < 0.01) in colonic tumor necrosis factor-α (TNF-α), interleukin-1-β (IL-1β), and IL-6 levels as well as the expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) after treatment compared with the colitis control group. The histopathological study also confirms the foregoing findings. Treatment with B. sensitivum was also able to inhibit the activation and translocation of transcription factors, nuclear factor (NF)-κB subunits (p65/p50).. These results suggest that B. sensitivum exhibits protective effect against acetic acid-induced UC.

Topics: Acetic Acid; Animals; Colitis, Ulcerative; Disease Models, Animal; Dose-Response Relationship, Drug; L-Lactate Dehydrogenase; Male; Oxalidaceae; Peroxidase; Plant Components, Aerial; Plant Extracts; Rats; Rats, Wistar; Sulfasalazine

To evaluate surfactant protein A levels in an hepatopulmonary syndrome rat model. To date, there have been no studies aimed at evaluating surfactant levels in the setting of cirrhosis or hepatopulmonary syndrome.. A total of 35 rats were divided into control, sham, and experimental HPS groups. We evaluated surfactant protein A levels in rats and the experimental model designed to induce hepatopulmonary syndrome was common bile duct ligation. Statistical analysis was performed using GraphPad Prism Software(r). Differences were considered statistically significant when p<0.05.. Lung homogenate of surfactant protein A levels were lower in the experimental hepatopulmonary syndrome and sham groups in comparison to the control group (p<0.05). Serum SP-A levels were the same in experimental hepatopulmonary syndrome and control groups but decreased in the sham group compared with the experimental groups (p<0.05). Myeloperoxidase activity was higher in the experimental hepatopulmonary syndrome group than the other two groups (p<0.05).. Surfactant protein A is present in experimental hepatopulmonary syndrome and leads to an imbalance between serum and pulmonary levels due to systemic inflammatory response.

Topics: Animals; Blood Gas Analysis; Common Bile Duct; Disease Models, Animal; Hepatopulmonary Syndrome; Ligation; Lung; Male; Peroxidase; Pulmonary Surfactant-Associated Protein A; Rats, Wistar; Reference Values

Preeclampsia is associated with oxidative stress, which is suspected to play a role in hypertension, placental ischemia, and fetal demise associated with the disease. Various cellular sources of oxidative stress, such as neutrophils, monocytes, and CD4(+) T cells have been suggested as culprits in the pathophysiology of preeclampsia. The objective of this study was to examine a role of circulating and placental CD4(+) T cells in oxidative stress in response to placental ischemia during pregnancy. CD4(+) T cells and oxidative stress were measured in preeclamptic and normal pregnant women, placental ischemic and normal pregnant rats, and normal pregnant recipient rats of placental ischemic CD4(+) T cells. Women with preeclampsia had significantly increased circulating (P=0.02) and placental CD4(+) T cells (P=0.0001); lymphocyte secretion of myeloperoxidase (P=0.004); and placental reactive oxygen species (P=0.0004) when compared with normal pregnant women. CD4(+) T cells from placental ischemic rats cause many facets of preeclampsia when injected into normal pregnant recipient rats on gestational day 13. On gestational day 19, blood pressure increased in normal pregnant recipients of placental ischemic CD4(+) T cells (P=0.002) compared with that in normal pregnant rats. Similar to preeclamptic patients, CD4(+) T cells from placental ischemic rats secreted significantly more myeloperoxidase (P=0.003) and induced oxidative stress in cultured vascular cells (P=0.003) than normal pregnant rat CD4(+)Tcells. Apocynin, a nicotinamide adenine dinucleotide phosphate inhibitor, attenuated hypertension and all oxidative stress markers in placental ischemic and normal pregnant recipient rats of placental ischemic CD4(+)Tcells (P=0.05). These data demonstrate an important role for CD4(+) T cells in mediating another factor, oxidative stress, to cause hypertension during preeclampsia.

Topics: Acetophenones; Adolescent; Adult; Animals; Antioxidants; CD4-Positive T-Lymphocytes; Cells, Cultured; Disease Models, Animal; Female; Humans; Hypertension; Ischemia; Muscle, Smooth, Vascular; Oxidative Stress; Peroxidase; Placenta; Pre-Eclampsia; Pregnancy; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Young Adult

By combining easy and fast leukocyte enrichment with aminophenyl-fluorescein (APF) staining we developed a method to quickly and specifically address the halogenating activity of the immunological relevant blood heme peroxidases myeloperoxidase and eosinophil peroxidase, respectively. For leukocyte enrichment a two-fold hypotonic lysis procedure of the blood with Millipore water was chosen which represents a cheap, fast and reliable method to diminish the amount of erythrocytes in the samples. This procedure is shown to be suitable both to human and murine blood micro-samples, making it also applicable to small animal experiments with recurring blood sampling. As all types of leukocytes are kept in the sample during the preparation, they can be analysed separately after discrimination during the flow cytometry analysis. This also holds for all heme peroxidase-containing cells, namely neutrophils, eosinophils and monocytes. Moreover additional parameters (e.g. antibody staining) can be combined with the heme peroxidase activity determination to gain additional information about the different immune cell types. Based on previous results we applied APF for specifically addressing the halogenating activity of leukocyte peroxidases in blood samples. This dye is selectively oxidized by the MPO and EPO halogenation products hypochlorous and hypobromous acid. This approach may provide a suitable tool to gain more insights into the immune-physiological role of the halogenating activity of heme peroxidases.

Topics: Aniline Compounds; Animals; Asthma; Bromates; Cell Separation; Disease Models, Animal; Eosinophil Peroxidase; Eosinophils; Female; Flow Cytometry; Fluoresceins; Halogenation; Humans; Hypochlorous Acid; Mice; Mice, Inbred BALB C; Monocytes; Neutrophils; Peroxidase; Primary Cell Culture

Rutin, one of the most abundant flavonoids in nature, has been shown to exert intestinal antiinflammatory effects in experimental models of colitis. Our aim was to study the antiinflamatory effect of rutin in the CD4+ CD62L+ T cell transfer model of colitis, one of the closest to the human disease. Colitis was induced by transfer of CD4+ CD62L+ T cells to Rag1(-/-) mice. Rutin was administered by gavage as a postreatment. Treatment with rutin improved colitis at the dose of 57mg/kg/day, while no effect was noted with 28.5mg/kg/day. Therapeutic benefit was evidenced by a reduced disease activity index, weight loss and damage score, plus a 36% lower colonic myeloperoxidase and a 54% lower alkaline phosphatase activity. In addition, a decreased secretion of proinflammatory cytokines (IFNγ and TNFα) by mesenteric lymph node cells was observed ex vivo. The colonic expression of proinflammatory genes, including IFNγ, TNFα, CXCL1, S100A8 and IL-1β, was significantly reduced by more than 80% with rutin as assessed by RT-qPCR. Flavonoid treated mice exhibited decreased activation of splenic CD4+ cells (STAT4 phosphorylation and IFNγ expression) and reduced plasma cytokine levels. This effect was also apparent in mucosal lymphocytes based on reduced STAT4 phosphorylation. The protective effect was comparable to that of 3mg/kg/day budesonide. Rutin had no effect on splenocytes or murine T cells in vitro, while its aglycone, quercetin, exhibited a concentration dependent inhibition of proinflammatory cytokines, including IFNγ. Rutin but not quercetin showed vectorial basolateral to apical transport in IEC18 cells, associated with reduced biotransformation. We conclude that rutin exerts intestinal antiinflammatory activity in chronic, T lymphocyte dependent colitis via quercetin release and actions involving mucosal and lymph node T cells. Our results suggest that rutin may be useful in the management of inflammatory bowel disease in appropriate dosage conditions.

Topics: Alkaline Phosphatase; Animals; Anti-Inflammatory Agents; Cell Line; Cells, Cultured; Colitis; Cytokines; Disease Models, Animal; Female; Homeodomain Proteins; Intestine, Large; Lymph Nodes; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B; Peroxidase; Quercetin; Rats, Wistar; RNA, Messenger; Rutin; Spleen; STAT4 Transcription Factor; T-Lymphocytes

Endoplasmic reticulum (ER) stress in the intestine is closely associated with the development of inflammatory bowel disease (IBD). However, the role of the protein kinase RNA-like ER kinase in this disease is not fully known. We studied whether an inhibitor of the dephosphorylation of eukaryotic initiation factor 2α, salubrinal, improves murine experimental colitis through the amelioration of ER stress.. Colitis was induced by the administration of 3% dextran sulfate sodium (DSS) for 5 days. Mice were injected salubrinal intraperitoneally from the commencement of DSS treatment and were sacrificed on day 10. The severity of colitis was evaluated histologically using a scoring system.Myeloperoxidase activity and the expression of proinflammatory cytokine genes in the colon were analyzed. The expression levels of ER stress-related proteins were evaluated by Western blotting.. The administration of salubrinal significantly attenuated body weight loss and improved colitis, as assessed histologically. The elevation of myeloperoxidase activity and the expression of proinflammatory cytokine genes were suppressed in salubrinal-treated mice. The expression of glucose-regulated protein 78, activating translation factor 4, and heat-shock protein 70 was elevated in mice treated with salubrinal.. The amelioration of ER stress may be a therapeutic target for the treatment of IBD.

Topics: Animals; Cinnamates; Colitis; Colon; Dextran Sulfate; Disease Models, Animal; DNA-Binding Proteins; eIF-2 Kinase; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Eukaryotic Initiation Factor-2; Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Injections, Intraperitoneal; Interleukins; Male; Mice; Mice, Inbred C57BL; Peroxidase; Regulatory Factor X Transcription Factors; RNA, Messenger; Thiourea; Transcription Factors; Tumor Necrosis Factor-alpha; Weight Loss

Foodborne diseases caused by Salmonella enterica serovar Enteritidis (S. Enteritidis) are a significant health problem. Pregnancy, state of immunological tolerance, is a predisposing condition for the development of infections with intracellular pathogens. Salmonella species can cause pregnancy complications such as chorioamnionitis, transplacental fetal infection, pre term labor, abortions, neonatal and maternal septicemia. However, the specific mechanisms by which Salmonella infections trigger these alterations are not clear. In the present work, using a self-limiting enterocolitis murine model, we show that the ingestion of a low dose of S. Enteritidis at late stages of pregnancy (day 15 of gestation) is sufficient to induce massive maternal infection. We found that Salmonella infection leads to 40% of pre term delivery, 33% of abortion and fetal growth restriction. Placental dysfunction during S. Enteritidis enterocolitis was confirmed through cellular infiltration and hypoxia markers (MPO activity and COX-1 and COX-2 expression, respectively). Apoptosis in placental tissue due to Salmonella infection was also evident at day 18 of gestation when investigated by morphometric procedure, DNA fragmentation and Fas/FasL expression. Also, the expression of IFN-γ, TNF-α, IL-17 and IL-10 was up regulated in response to Salmonella not only in placenta, but also in amniotic fluid and maternal serum. Altogether, our results demonstrate that S. Enteritidis enterocolitis during late stages of gestation causes detrimental effect on pregnancy outcome.

Topics: Animals; Apoptosis; Bacterial Load; Cyclooxygenase 1; Cyclooxygenase 2; Cytokines; Disease Models, Animal; Female; Fetal Growth Retardation; Gene Expression; Gestational Age; Inflammation Mediators; Male; Mice; Peroxidase; Placenta; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Outcome; Salmonella enteritidis; Salmonella Infections, Animal

Endogenous carbon monoxide (CO) has been shown to modulate inflammation and inhibit cytokine production both in vivo and in vitro. The aim of this study was to examine whether exogenous carbon monoxide could suppress the vitality of Escherichia coli (E coli) and improve the survival rate in an E coli-induced murine sepsis model.. ICR mice were infected with E coli, and immediately injected intravenously with carbon monoxide releasing molecule-2 (CORM-2, 8 mg/kg) or inactive CORM-2 (8 mg/kg). The survival rate was monitored 6 times daily for up to 36 h. The blood samples, liver and lung tissues were collected at 6 h after the infection. Bacteria in peritoneal lavage fluid, blood and tissues were enumerated following culture. Tissue iNOS mRNA expression was detected using RT-PCR. NF-κB expression was detected with Western blotting.. Addition of CORM-2 (200 and 400 μmol/L) into culture medium concentration-dependently suppressed the growth of E coli and decreased the colony numbers, but inactive CORM-2 had no effect. Treatment of the infected mice with CORM-2 significantly increased the survival rate to 55%, while all the infected mice treated with inactive CORM-2 died within 36 h. E coli infection caused severe pathological changes in liver and lungs, and significantly increased serum transaminases, lipopolysaccharide, TNF-α and IL-1β levels, as well as myeloperoxidase activity, TNF-α and IL-1β levels in the major organs. Meanwhile, E coli infection significantly increased the number of colonies and the expression of iNOS mRNA and NF-κB in the major organs. All these abnormalities were significantly attenuated by CORM-2 treatment, while inactive CORM-2 was ineffective.. In addition directly suppressing E coli, CORM-2 protects the liver and lungs against E coli-induced sepsis in mice, thus improving their survival.

Topics: Animals; Biomarkers; Carbon Monoxide; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Escherichia coli; Escherichia coli Infections; Inflammation Mediators; Injections, Intravenous; Lipopolysaccharides; Liver; Lung; Male; Mice, Inbred ICR; NF-kappa B; Nitric Oxide Synthase Type II; Organometallic Compounds; Peroxidase; RNA, Messenger; Sepsis; Time Factors

Imbalances in the dietary n-6 and n-3 polyunsaturated fatty acids have been implicated in the increased prevalence of inflammatory bowel disease. This study investigated the effects of substitution of linoleic acid with long chain n-3 polyunsaturated fatty acids and hence decreasing n-6:n-3 fatty acid ratio on inflammatory response in dextran sulfate sodium induced colitis. Male weanling Sprague Dawley rats were fed diets with n-6:n-3 fatty acid in the ratios of 215,50,10 or 5 for 3 months and colitis was induced by administration of dextran sulfate sodium in drinking water during last 11 days. Decreasing the dietary n-6:n-3 fatty acid ratio to 10 and 5 significantly attenuated the severity of colitis as evidenced by improvements in clinical symptoms, reversal of shortening of colon length, reduced severity of anemia, preservation of colonic architecture as well as reduced colonic mucosal myeloperoxidase activity. This protection was associated with suppression of colonic mucosal proinflammatory mediators such as TNFα, IL-1β and nitric oxide. These findings suggest that long chain n-3 polyunsaturated fatty acids at a level of 3.0 g/kg diet (n-6:n-3 ratio of 10) prevents dextran sulfate sodium induced colitis by suppressing the proinflammatory mediators.

Topics: Animals; Colitis; Colon; Dextran Sulfate; Dietary Fats; Disease Models, Animal; Fatty Acids, Omega-3; Interleukin-1beta; Intestinal Mucosa; Linoleic Acid; Male; Nitric Oxide; Peroxidase; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

To study the anti-inflammatory actions of electroacupuncture (EAc) on an experimental colitis model in mice.. Thirty-eight male Swiss mice, divided in five groups, were subjected to induction of colitis by TNBS in 50% ethanol. Saline (SAL) and ethanol (ETNL) groups served as controls. TNBS+EAc and TNBS+ dexamethasone subgroups were treated with EAc 100Hz and dexamethasone (DEXA) 1 mg/Kg/day, respectively. After three days, a colon segment was obtained for quantification of myeloperoxidase (MPO) activity, immunohistochemistry for iNOS, malondialdehyde (MDA) and cytokines (IL-1β and IL-10).. Neutrophilic activity, assayed as MPO activity, was significantly higher in the TNBS colitis group than that in the saline control group. TNBS+EAc group showed suppression of IL-10 in the colon. EAc treatment significantly reduced the concentration of MDA and the expression of iNOS, as compared to the other groups.. Electroacupuncture 100Hz applied to acupoint ST-36 promotes an anti-inflammatory action on the TNBS-induced colitis, mediated by increase of IL-10 and decrease of iNOS expression.

Topics: Acupuncture Points; Animals; Anti-Inflammatory Agents; Colitis; Colon; Disease Models, Animal; Electroacupuncture; Immunohistochemistry; Inflammatory Bowel Diseases; Interleukin-10; Interleukin-1beta; Male; Malondialdehyde; Mice; Nitric Oxide Synthase Type II; Peroxidase; Random Allocation; Trinitrobenzenesulfonic Acid

To investigate the effects of terminal ileostomy on bacterial translocation (BT) and systemic inflammation after intestinal ischemia/reperfusion (I/R) injury in rats.. Thirty-two rats were assigned to either the sham-operated group, I/R group, I/R + resection and anastomosis group, or the I/R + ileostomy group. The superior mesenteric artery was occluded for 60 min. After 4 h, tissue samples were collected for analysis. BT was assessed by bacteriologic cultures, intestinal permeability and serum levels of endotoxin; systemic inflammation was assessed by serum levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-10, as well as by the activity of myeloperoxidase (MPO) and by intestinal histopathology.. Intestinal I/R injury not only caused morphologic damage to ileal mucosa, but also induced BT, increased MPO activity and promoted the release of TNF-α, IL-6, and IL-10 in serum. BT and ileal mucosa injuries were significantly improved and levels of TNF-α and IL-6 in serum were decreased in the I/R + ileostomy group compared with the I/R + resection and anastomosis group.. Terminal ileostomy can prevent the detrimental effects of intestinal I/R injury on BT, intestinal tissue, and inflammation.

Topics: Animals; Bacterial Translocation; Biomarkers; Disease Models, Animal; Ileostomy; Ileum; Inflammation; Inflammation Mediators; Interleukin-10; Interleukin-6; Male; Permeability; Peroxidase; Rats, Sprague-Dawley; Reperfusion Injury; Time Factors; Tumor Necrosis Factor-alpha

Preclinical in vivo research on inflammatory bowel diseases requires proper animal models and techniques allowing longitudinal monitoring of colonic inflammation without the need to kill animals. We evaluated colonoscopy and μ-positron emission tomography/computed tomography (μPET/CT) as monitoring tools in a model for chronic colitis in mice.. Colitis was induced by adoptive transfer of CD4(+)CD25(-)CD62L(+) T cells in immunocompromised severe combined immunodeficient mice. Three study protocols were designed. In study 1, colonoscopy and µPET/CT were performed once, 4 weeks after transfer. In study 2 and study 3, colitis was sequentially followed up through colonoscopy (study 2) or colonoscopy plus µPET/CT (study 3). Each study included postmortem evaluation of colonic inflammation (macroscopy, microscopy, and myeloperoxidase activity).. In study 1, both colonoscopy and µPET/CT detected colitis 4 weeks after transfer. Study 2 showed a gradual increase in colonoscopic score from week 2 (1.4 ± 0.6) to week 8 (6.0 ± 1.1). In study 3, colitis was detected 2 weeks after transfer by µPET/CT (2.0 ± 0.4) but not by colonoscopy, whereas both techniques detected inflammation 4 and 6 weeks after transfer. Colonoscopy correlated with µPET/CT (r = 0.812, 0.884, and 0.781, respectively) and with postmortem analyses in all 3 studies.. Adoptive transfer of CD4(+)CD25(-)CD62L(+) T cells in severe combined immunodeficient mice results in a moderate chronic colitis. Evolution of colitis could be monitored over time by both colonoscopy and µPET/CT. µPET/CT seems to detect inflammation at an earlier time point than colonoscopy. Both techniques represent reliable and safe methods without the need to kill animals.

Topics: Adoptive Transfer; Animals; CD4-Positive T-Lymphocytes; Colitis; Colonoscopy; Disease Models, Animal; Female; Inflammation; Mice; Mice, Inbred BALB C; Mice, SCID; Peroxidase; Positron-Emission Tomography; Tomography, X-Ray Computed

Our aim was to explore the therapeutic effects of peripheral blood-derived endothelial progenitor cells (PB-EPC) in cardiac ischemia-reperfusion infarction models in rats and in in vitro culture systems.. Rat models of ischemia reperfusion and myocardial infarction were developed using male, Sprague-Dawley rats. Cardiomyocyte and endothelial cell cultures were also established. Therapeutic effects of PB-EPCs were examined in vivo and in vitro in both models. Rats underwent either cardiac ischemia-reperfusion (n = 40) or infarction (n = 56) surgeries and were transplanted with genetically modified EPCs. Treatment efficacy in the ischemia-reperfusion group was measured by infarct size, myocardial contraction velocity, and myeloperoxidase activity after transplantation. Cardiomyocyte survival and endothelial cell apoptosis were investigated in vitro. Vascular growth-associated protein expression and cardiac function were evaluated in the myocardial infarction group by western blot and echocardiography, respectively.. Infarct size and myeloperoxidase activity were significantly decreased in the ischemia-reperfusion group, whereas myocardial contractility was significantly increased in the EPC and Tβ4 groups compared with that in the control group. In contrast, no differences were found between EPC + shRNA Tβ4 and control groups. Rates of cardiomyocyte survival and endothelial cell apoptosis were significantly higher and lower, respectively, in the EPC and Tβ4 groups than in the control group, whereas no differences were found between the EPC + shRNA Tβ4 and control group. Four weeks after myocardial infarction, cardiac function was significantly better in the EPC group than in the control group. Expressions of PDGF, VEGF, and Flk-1 were significantly higher in EPC group than in control group.. Study findings suggest that PB-EPCs are able to protect cardiomyocytes from ischemia-reperfusion or infarction-induced damage via a Tβ4-mediated mechanism. EPCs may also provide protection through increased expression of proteins involved in mediating vascular growth. Autologous peripheral-blood-derived EPCs are readily available for efficient therapeutic use without the concerns of graft rejection.

Topics: Analysis of Variance; Animals; Apoptosis; Blotting, Western; Cell Survival; Disease Models, Animal; Endothelial Cells; Hematopoietic Stem Cells; Hemodynamics; Infarction; Intercellular Signaling Peptides and Proteins; Male; Myocardial Contraction; Myocytes, Cardiac; Peroxidase; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Stem Cell Transplantation; Thymosin

The aim of the study was to investigate the effect of ozone on oxidative/nitrosative stress and bladder injury caused by Escherichia coli in rat bladder.. Twenty-one Wistar-Albino-type female rats included in the study were divided into three groups of equal number: (1) sham operation (control), (2) E. coli-only (EC), (3) EC + ozone. After ozone therapy for 3 days, urine and tissue samples were obtained for biochemical, microbiological, and histopathological analysis.. Tissue malondialdehyde (MDA), myeloperoxidase (MPO), and nitric oxide (NO) level were increased, whereas superoxide dismutase (SOD) and glutathione peroxidase (GPx) activity was decreased in the EC group. MDA, MPO, and NO levels were decreased, whereas SOD, GPx activity was increased in the ozone-treated group. Also, there was no bacterial translocation in this group.. The results of the present study suggest that ozone may be used as an agent to protect the bladder from oxidative/nitrosative stress occurring in cystitis.

Topics: Animals; Anti-Bacterial Agents; Bacterial Translocation; Cystitis; Disease Models, Animal; Escherichia coli; Escherichia coli Infections; Female; Glutathione Peroxidase; Malondialdehyde; Nitric Oxide; Oxidative Stress; Ozone; Peroxidase; Rats; Rats, Wistar; Superoxide Dismutase; Urinary Bladder; Urinary Tract Infections

Topics: Alleles; Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Disease Models, Animal; Genotype; Glomerulonephritis; Humans; Immunoglobulin G; Mice; Mice, Inbred Strains; Myeloblastin; Neutrophils; Peroxidase; Quantitative Trait Loci; Rats; Rats, Inbred WKY

The cholinergic anti-inflammatory system and α7 nicotinic receptors in macrophages have been proposed to play a role in neuroimmunomodulation and in the etiology of ulcerative colitis. We investigated the ability of a cholinesterase (ChE) inhibitor rivastigmine, to improve the pathology of ulcerative colitis by increasing the concentration of extracellular acetylcholine in the brain and periphery. In combination with carbachol (10 µM), rivastigmine (1 µM) significantly decreased the release of nitric oxide, TNF-α, IL-1β and IL-6 from lipopolysaccharide-activated RAW 264.7 macrophages and this effect was abolished by α7 nicotinic receptor blockade by bungarotoxin. Rivastigmine (1 mg/kg) but not (0.5 mg/kg), injected subcutaneously once daily in BALB/c mice with colitis induced by 4% dextran sodium sulphate (DSS), reduced the disease activity index (DAI) by 60% and damage to colon structure. Rivastigmine (1 mg/kg) also reduced myeloperoxidase activity and IL-6 by >60%, and the infiltration of CD11b expressing cells by 80%. These effects were accompanied by significantly greater ChE inhibition in cortex, brain stem, plasma and colon than that after 0.5 mg/kg. Co-administration of rivastigmine (1 mg/kg) with the muscarinic antagonist scopolamine significantly increased the number of CD11b expressing cells in the colon but did not change DAI compared to those treated with rivastigmine alone. Rivastigmine 1 and 2 mg given rectally to rats with colitis induced by rectal administration of 30 mg dintrobezene sulfonic acid (DNBS) also caused a dose related reduction in ChE activity in blood and colon, the number of ulcers and area of ulceration, levels of TNF-α and in MPO activity. The study revealed that the ChE inhibitor rivastigmine is able to reduce gastro-intestinal inflammation by actions at various sites at which it preserves ACh. These include ACh released from vagal nerve endings that activates alpha7 nicotinic receptors on circulating macrophages and in brainstem neurons.

Topics: Animals; Anti-Inflammatory Agents; Brain; CD11b Antigen; Cell Line; Cholinesterases; Colitis, Ulcerative; Colon; Crohn Disease; Dextran Sulfate; Dinitrofluorobenzene; Disease Models, Animal; Lipopolysaccharides; Macrophages, Peritoneal; Male; Mice; Nitric Oxide; Peroxidase; Phenylcarbamates; Rats; Rivastigmine; Thiobarbituric Acid Reactive Substances; Tumor Necrosis Factor-alpha

Hyperglycemia exacerbates renal ischemia-reperfusion (IR) injury via aggravated inflammatory response and excessive production of reactive oxygen species. This study aimed to investigate the ability of propofol, a known antioxidant, to protect kidneys against IR injury in hyperglycemic rats in comparison with normoglycemic rats.. Sixty rats were randomly assigned to four groups: normoglycemia-etomidate, normoglycemia-propofol, hyperglycemia-etomidate, and hyperglycemia-propofol. Anesthesia was provided with propofol or etomidate depending on the group. Also, the rats received 1.2 g/kg dextrose or the same volume of normal saline depending on the group. Renal ischemia was induced for 25 min. The rats were killed, and samples were collected 65 min after starting intravenous anesthetics (sham) and 15 min and 24 h after reperfusion injury to compare the histologic degree of renal tubular damage and levels of inflammatory markers and enzymes related to reactive oxygen species.. Compared with etomidate, propofol significantly attenuated tubular damage after reperfusion in hyperglycemic rats. Also, tubular damage was greater under hyperglycemia compared with normoglycemia in the etomidate group, whereas it was similar in the propofol group. Propofol preserved superoxide dismutase level and attenuated the increase in levels of myeloperoxidase, interlukin-1β, and tumor necrosis factor-α after reperfusion compared with etomidate especially in hyperglycemic rats. Propofol also attenuated the production of inducible nitric oxide synthase and phosphorylation of inhibitor of κB and nuclear factor-κB after reperfusion, which were more prominent under hyperglycemia.. Propofol conveyed renoprotection against IR injury by preserved antioxidation ability and attenuated inflammatory response, which were more prominent under hyperglycemia.

Topics: Anesthetics, Intravenous; Animals; Antioxidants; Comorbidity; Disease Models, Animal; Etomidate; Hyperglycemia; Interleukin-1beta; Kidney; Kidney Tubules; Male; NF-kappa B; Peroxidase; Propofol; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Reperfusion Injury; Superoxide Dismutase; Tumor Necrosis Factor-alpha

This study investigated the expression pattern of PTEN and its effect on carcinogenesis of ulcerative colitis-associated colorectal cancer, leading to insights into the underlying molecular mechanism.. We established a mouse model of ulcerative colitis-associated colorectal cancer by treating the animals with azoxymethane (AOM) and dextran sulphate sodium (DSS), and investigated the inflammation-dysplasia-carcinoma sequence. Expression patterns of PTEN, p-Akt and Ki-67 were shown by immunohistochemistry; western blotting techniques were used to detect protein expression of PTEN, p-Akt and caspase 3; TUNEL assay was used to measure apoptosis in colon epithelial cells; and colorimetric analysis was able to determine MPO activity in colon tissues.. During the inflammation-dysplasia-carcinoma sequence, PTEN expression gradually decreased, while p-Akt expression increased; PTEN and p-Akt levels were negatively correlated. Compared to the AOM-DSS and Ad-0 groups, Ad-PTEN mice had longer colons, fewer tumours (P < 0.01) and smaller tumour sizes (P < 0.05). After injecting Ad-PTEN, expression of p-Akt, Ki-67 and MPO activity decreased dramatically, whereas PTEN increased. The TUNEL assay showed increased apoptotic cells and caspase 3 expression in the Ad-PTEN group.. PTEN plays an important role in the inflammation-dysplasia-carcinoma sequence and may be a new molecular target in preventing and treating ulcerative colitis-associated colorectal cancer.

Topics: Adenoviridae; Animals; Apoptosis; Body Weight; Cell Proliferation; Colitis, Ulcerative; Colon; Colorectal Neoplasms; Disease Models, Animal; Down-Regulation; Female; Genetic Therapy; Mice; Mice, Inbred BALB C; Peroxidase; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Up-Regulation

In hemorrhagic shock with subsequent resuscitation (H/R), increased pro-inflammatory changes contribute to tissue injury and mortality in rodent models. Ethanol (EtOH) is assumed to modulate the inflammatory response and the subsequent organ injury after H/R. Therefore, we determined the contribution of acute ethanol gavage on intestinal inflammation and injury as well as survival after H/R in rats.. Fourteen hours before H/R, female LEWIS rats were gavaged with single dose of EtOH or saline (5 g/kg, 30% EtOH, H/R_EtOH group or H/R_ctrl group). Then, rats were hemorrhaged to a mean arterial blood pressure of 30 ± 2 mmHg for 60 min and resuscitated. Control groups underwent surgical procedures and gavage without H/R (sham_ctrl group and sham_EtOH group). Tissue was harvested 2 h after resuscitation. Mortality was assessed 72 h after H/R.. Ethanol gavage increased survival after H/R from 20% to 80%, but amplified plasma alanineaminotransferase (ALT) release compared to saline gavage (2847 ± 406 vs. 1159 ± 200 IU/L, p < 0.05). Intestinal mucosal damage index, intestinal permeability, ileal myeloperoxidase levels as indicators of polymorphonuclear leukocyte (PMNL) infiltration and systemic IL-6 levels as well as ileal IL-6 and TNF gene expressions after H/R were reduced and partly restored after ethanol gavage when compared to the saline gavaged group after H/R.. Taken together, we propose that acute ethanol gavage prior to H/R 1) did not enhance intestinal mucosa injury after H/R and 2) suppressed the H/R-induced inflammatory response. Both findings seem to contribute to the ethanol-induced survival benefit after H/R in our model.

Topics: Alanine Transaminase; Animals; Central Nervous System Depressants; Disease Models, Animal; Ethanol; Female; Inflammation; Interleukin-6; Intestinal Mucosa; Intestines; Neutrophils; Peroxidase; Rats; Rats, Inbred Lew; Resuscitation; Shock, Hemorrhagic; Sodium Chloride; Treatment Outcome; Tumor Necrosis Factor-alpha

Perinatal asphyxia is an important cause of injury to fetal tissues such as the brain, heart, liver and gastrointestinal system. Fetal skin has also been shown to be vulnerable to intrauterine injury after intrauterine ischaemia/reperfusion (I/R) injury.. To examine the effect of dexamethasone on fetal skin in intrauterine I/R injury in rats.. The response of rat fetal skin to I/R injury and maternal dexamethasone treatment were assessed by determining thiobarbituric acid reactive substances (TBARS), and myeloperoxidase (MPO) and nitric oxide (NO) metabolites. We also examined the ultrastructural changes of fetal skin. Bilateral utero-ovarian artery clamping was performed to produce ischaemia for 30 min in rats at day 19 of pregnancy, and reperfusion was achieved by removing the clamps for 60 min before fetal tissue was collected. The treatment group was given dexamethasone intraperitoneally 20 min before I/R was performed.. TBARS, MPO and NO all increased significantly in fetal rat skin after I/R injury. Levels of TBARS, MPO and NO were significantly lower in the dexamethasone-treated group than in the I/R-only group. I/R injury produced ultrastructural damage in the epidermis. Oedema and mitochondrial damage were less severe in the dexamethasone-treated group.. Maternal treatment with dexamethasone may have a protective effect on fetal skin in cases of I/R injury.

Topics: Animals; Anti-Inflammatory Agents; Dexamethasone; Disease Models, Animal; Female; Fetal Diseases; Ischemia; Nitric Oxide; Peroxidase; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Skin

The aim of this study was to investigate the mechanisms that contribute to hyperalgesia and edema induced by TRPA1 activation. The injection of allyl isothiocyanate (AITC, 50, 100, or 300 µg/paw) into the rat's hind paw induced dose and time-dependent hyperalgesia and edema, which were blocked by the selective TRPA1 antagonist, HC 030031 (1,200 µg/paw), or by treatment with antisense oligodeoxynucleotide (four daily intrathecal injections of 5 nmol). These results demonstrate that the hyperalgesia and edema induced by AITC depend on TRPA1 activation. AITC-induced hyperalgesia and edema were significantly reduced by treatment with neurokinin 1 (L-703,606, 38 µg/paw) or calcitonin gene-related peptide (CGRP8-37 , 5 µg/paw) receptor antagonists, with a mast cell degranulator (compound 48/80, four daily injections of 1, 3, 10, and 10 µg/paw) or with H1 (pyrilamine, 400 µg/paw), 5-HT1A (wAy-100,135, 450 µg/paw) or 5-HT3 (tropisetron, 450 µg/paw) receptor antagonists. Pre-treatment with a selectin inhibitor (fucoidan, 20 mg/kg) significantly reduced AITC-induced hyperalgesia, edema, and neutrophil migration. Finally, a cyclooxygenase inhibitor (indomethacin, 100 µg/paw), a β1 (atenolol, 6 µg/paw) or a β2 (ICI 118, 551, 1.5 µg/paw) adrenoceptor antagonist also significantly reduced AITC-induced hyperalgesia and edema. Together, these results demonstrate that TRPA1 mediates some of the key inflammatory mechanisms, suggesting a key role of this receptor in pain and inflammation.

Topics: Acetanilides; Analysis of Variance; Animals; Calcitonin Gene-Related Peptide; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Extremities; Gene Expression Regulation; Hyperalgesia; Male; Oligodeoxyribonucleotides, Antisense; Peptide Fragments; Peroxidase; Piperazines; Purines; Quinuclidines; Rats; Rats, Wistar; Serotonin Antagonists; TRPA1 Cation Channel; TRPC Cation Channels

The purpose of this study was to elucidate the possible beneficial effects of adiponectin (APN) on acute lung injury in a rat model of sepsis.. We subjected male Sprague-Dawley rats to cecal ligation and puncture (CLP) to establish sepsis models. We randomly animals divided into four groups: control (C), model (CLP), preemptive APN administration (APN plus CLP), and delayed APN administration (CLP plus APN). We killed the animals 24 h after CLP and collected blood samples to determine PaO2 and PaCO2. Lung samples were taken for histologic assessment and measurement of myeloperoxidase activity. We measured neutrophil and macrophage count and cytokine production (tumor necrosis factor-α and macrophage inflammatory protein-2) in bronchoalveolar lavage fluid.. Histology findings and lung injury score analysis revealed acute lung injury in rats in the CLP group, whereas those in the APN-treated group had mild lung injury. The effects of sepsis on the increasing cell number in bronchoalveolar lavage fluid as well as the wet/dry weight ratio, neutrophil infiltration, and myeloperoxidase activity of lung tissue were significantly attenuated by APN administration. Adiponectin also significantly alleviated hypoxemia and hypercapnia resulting from the development of lung injury. In addition, in APN-treated rats, the levels of pulmonary inflammatory molecule (macrophage inflammatory protein-2) and cytokine (tumor necrosis factor-α) were down-regulated compared with the CLP group.. Adiponectin administration ameliorates acute lung injury in a rat model of sepsis induced by CLP, no matter whether it is administrated before or after the onset of sepsis.

Topics: Acute Lung Injury; Adiponectin; Animals; Cecum; Cytokines; Disease Models, Animal; Ligation; Lung; Macrophages; Male; Neutrophils; Peroxidase; Punctures; Rats; Rats, Sprague-Dawley; Sepsis

Reflux laryngitis is a common clinic complication of nasogastric intubation (NSGI). Since there is no report concerning the effects of low level laser therapy (LLLT) on reflux laryngitis, this study aimed to analyze the protective effect of single and combined therapies with low level laser at the doses of 2.1J and 2.1+1.2 J with a total irradiation time of 30s and 30+30 s, respectively, on a model of neurogenic reflux laryngitis. NSGI was performed in Wistar rats, assigned into groups: NGI (no treatment), NLT17.5 (single therapy), and NLT17.5/10.0 (combined therapy, applied sequentially). Additional non-intubated and non-irradiated rats were use as controls (CTR). Myeloperoxidase (MPO) activity was assessed by colorimetric method after the intubation period (on days 1, 3, 5, and 7), whereas paraffin-embedded laryngeal specimens were used to carry out histopathological analysis of the inflammatory response, granulation tissue, and collagen deposition 7 days after NSGI. Significant reduction in MPO activity (p<0.05) and in the severity of the inflammatory response (p<0.05), and improvement in the granulation tissue (p<0.05) was observed in NLT17.5/10.0 group. Mast cells count was significantly decreased in NGI and NLT17.5 groups (p<0.001), whereas no difference was observed between NLT17.5/10.0 and CTR groups (p>0.05). NLT17.5/10.0 group also showed better collagenization pattern, in comparison to NGI and NLT17.5 groups. This study suggests that the combined therapy successfully modulated the inflammatory response and collagenization in experimental model of NSGI-induced neurogenic laryngitis.

Topics: Animals; Anti-Inflammatory Agents; Cell Count; Disease Models, Animal; Laryngitis; Larynx; Low-Level Light Therapy; Male; Mast Cells; Peroxidase; Rats; Rats, Wistar

Visceral afferents expressing transient receptor potential (TRP) channels TRPV1 and TRPA1 are thought to be required for neurogenic inflammation and development of inflammatory hyperalgesia. Using a mouse model of chronic pancreatitis (CP) produced by repeated episodes (twice weekly) of caerulein-induced AP (AP), we studied the involvement of these TRP channels in pancreatic inflammation and pain-related behaviors. Antagonists of the two TRP channels were administered at different times to block the neurogenic component of AP. Six bouts of AP (over 3 wks) increased pancreatic inflammation and pain-related behaviors, produced fibrosis and sprouting of pancreatic nerve fibers, and increased TRPV1 and TRPA1 gene transcripts and a nociceptive marker, pERK, in pancreas afferent somata. Treatment with TRP antagonists, when initiated before week 3, decreased pancreatic inflammation and pain-related behaviors and also blocked the development of histopathological changes in the pancreas and upregulation of TRPV1, TRPA1, and pERK in pancreatic afferents. Continued treatment with TRP antagonists blocked the development of CP and pain behaviors even when mice were challenged with seven more weeks of twice weekly caerulein. When started after week 3, however, treatment with TRP antagonists was ineffective in blocking the transition from AP to CP and the emergence of pain behaviors. These results suggest: (1) an important role for neurogenic inflammation in pancreatitis and pain-related behaviors, (2) that there is a transition from AP to CP, after which TRP channel antagonism is ineffective, and thus (3) that early intervention with TRP channel antagonists may attenuate the transition to and development of CP effectively.

Topics: Amidines; Analgesics, Opioid; Analysis of Variance; Animals; Antigens, Differentiation; Calcitonin Gene-Related Peptide; Calcium; Ceruletide; Disease Models, Animal; Disease Progression; Exploratory Behavior; Extracellular Signal-Regulated MAP Kinases; Ganglia, Spinal; Gene Expression Regulation; Injections, Intraperitoneal; Male; Mice; Mice, Inbred C57BL; Monocytes; Morphine; Neutrophil Infiltration; Nodose Ganglion; Oximes; Pain; Pain Measurement; Pancreas; Pancreatitis, Chronic; Peroxidase; Pyridines; RNA, Messenger; Sensory Receptor Cells; Time Factors; Transient Receptor Potential Channels; TRPA1 Cation Channel; TRPV Cation Channels

The aim of this study was to investigate the protective effects of taurine (Tau) on experimental acute pancreatitis (AP) in a rat model by measuring cytokines and oxidant stress markers. Forty rats were randomly divided into four groups: sham, AP, Tau and AP + Tau. AP was induced with sodium taurocholate. No treatment was given to the AP. All rats were killed 5 days later. Pancreatic tissues of rats and blood samples were obtained. Tau treatment significantly decreased serum amylase activity (p < 0.001), total injury score (p < 0.001), malondialdehyde levels (p < 0.001) and myeloperoxidase (MPO) activity (p < 0.001). There was no significant difference between the Tau and AP + Tau groups in serum and pancreatic tumor necrosis factor-α, interleukin (IL)-1β and IL-6 levels (p = 1.000). Histopathologic scores in the AP + Tau and Tau groups were significantly lower compared with the AP group (both p < 0.001). These results showed that Tau reduces lipid peroxidation, amylase and MPO activities and the concentrations of proinflammatory cytokines secondary to AP and also increases superoxide dismutase and glutathione peroxidase activities in rats with sodium taurocholate-induced AP. It also has a marked ameliorative effect at histopathologic lesions. With these effects, Tau protects the cells from oxidative damage, reduces inflammation and promotes regression of pancreatic damage.

Topics: Acute Disease; Animals; Disease Models, Animal; Interleukin-1beta; Interleukin-6; Male; Pancreatitis; Peroxidase; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Superoxide Dismutase; Taurine; Tumor Necrosis Factor-alpha

Renal ischemia-reperfusion (I/R) injury is a primary cause of acute renal failure that results in high mortality. This study aimed to investigate the effect of osthole, a natural coumarin derivative, on renal I/R injury in a rat model.. Rats were randomly allocated to the sham operation + vehicle, I/R + vehicle, and I/R + osthole groups. Renal I/R injury was induced by clamping the left renal artery for 45 min followed by 12 h of reperfusion and a contralateral nephrectomy. Osthole (40 mg/kg) was intraperitoneally injected 30 min before inducing I/R. Renal function and histological damage were determined subsequently. Myeloperoxidase activity, monocyte/macrophage infiltration, as well as tumor necrosis factor-α, IL-1β, and activated p38 mitogen-activated protein kinase expression in kidneys were also assessed.. Osthole treatment significantly ameliorated I/R-induced renal functional and morphological injuries. Moreover, osthole treatment attenuated myeloperoxidase activity, monocyte/macrophage infiltration, and tumor necrosis factor-α, IL-1β, and activated p38 mitogen-activated protein kinase expression in kidneys.. Osthole treatment ameliorates renal I/R injury by inhibiting inflammatory responses in kidneys. Thus, osthole may represent a novel practical strategy to prevent renal I/R injury.

Topics: Acute Kidney Injury; Animals; Calcium Channel Blockers; Coumarins; Disease Models, Animal; Gene Expression Regulation, Enzymologic; Inflammation; Interleukin-1beta; Kidney; Male; Monocytes; p38 Mitogen-Activated Protein Kinases; Peroxidase; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Tumor Necrosis Factor-alpha

The potential edematogenic effect and the pharmacological characterization of a glucose-mannose-binding lectin from Dioclea violacea (DvL) were investigated.. Paw edema was induced with DvL in control animals, and in animals pretreated with glucocorticoid or with blockers of histamine, nitric oxide synthase, cyclooxygenase, platelet activating factor (PAF), bradykinin and lipoxygenase.. DvL-induced paw edema paralleled with an increase in vascular permeability and myeloperoxidase (MPO) activity. DvL-induced edema could be prevented by pre-treatment with the lectin-binding sugar α-D-methyl mannoside. Dexamethasone, meclizine and Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME) inhibited this effect.. DvL induces edema, increase in vascular permeability and neutrophil infiltration. The edematogenic activity involves the lectin mannose-binding sites and is associated with histamine, cytokines and nitric oxide, since it could be treated with meclizine, dexamethasone and L-NAME.

Topics: Animals; Anti-Inflammatory Agents; Binding Sites; Cytokines; Dexamethasone; Dioclea; Disease Models, Animal; Edema; Female; Histamine; Mannose-Binding Lectin; Meclizine; Neutrophil Infiltration; Neutrophils; NG-Nitroarginine Methyl Ester; Nitric Oxide; Peroxidase; Rats; Rats, Wistar

The present study evaluated the effects of curcumin on epithelial cell apoptosis, the immunoreactivity of the phospho-c-Jun N-terminal kinase (JNK) and phospho-p38 mitogen-activated protein kinases (MAPKs) in inflamed colon mucosa, and oxidative stress in a rat model of ulcerative colitis induced by acetic acid. Rats were randomly divided into three groups: control, acetic acid, and acetic acid+curcumin. Curcumin (100 mg/kg per day, intragastrically) was administered 10 days before the induction of colitis and was continued for two additional days. Acetic acid-induced colitis caused a significant increase in the macroscopic and microscopic tissue ranking scores as well as an elevation in colonic myeloperoxidase (MPO) activity, malondialdehyde (MDA) levels, and the number of apoptotic epithelial cells in colon tissue compared to controls. In the rat colon, immunoreactivity of phospho-p38 MAPK was increased, whereas the phospho-JNK activity was decreased following the induction of colitis. Curcumin treatment was associated with amelioration of macroscopic and microscopic colitis sores, decreased MPO activity, and decreased MDA levels in acetic acid-induced colitis. Furthermore, oral curcumin supplementation clearly prevented programmed cell death and restored immunreactivity of MAPKs in the colons of colitic rats. The results of this study suggest that oral curcumin treatment decreases colon injury and is associated with decreased inflammatory reactions, lipid peroxidation, apoptotic cell death, and modulating p38- and JNK-MAPK pathways.

Topics: Acetic Acid; Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Colitis, Ulcerative; Colon; Curcuma; Curcumin; Dietary Supplements; Disease Models, Animal; Inflammation; Intestinal Mucosa; JNK Mitogen-Activated Protein Kinases; Male; Malondialdehyde; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Peroxidase; Phytotherapy; Plant Extracts; Rats; Rats, Wistar; Signal Transduction

The endoribonuclease RNase-L is a type-I interferon (IFN)-regulated component of the innate immune response that functions in antiviral, antibacterial, and antiproliferative activities. RNase-L produces RNA agonists of RIG-I-like receptors, sensors of cytosolic pathogen-associated RNAs that induce cytokines including IFN-β. IFN-β and RIG-I-like receptors signaling mediate protective responses against experimental colitis and colitis-associated cancer and contribute to gastrointestinal homeostasis. Therefore, we investigated a role for RNase-L in murine colitis and colitis-associated cancer and its association with RIG-I-like receptors signaling in response to bacterial RNA.. Colitis was induced in wild type-deficient and RNase-L-deficient mice (RNase-L⁻/⁻) by administration of dextran sulfate sodium (DSS). Colitis-associated cancer was induced by DSS and azoxymethane (AOM). Histological analysis and immunohistochemistry were performed on colon tissue to analyze immune cell infiltration and tissue damage after induction of colitis. Expression of cytokines was measured by quantitative real-time-PCR and ELISA.. DSS-treated RNase-L⁻/⁻ mice exhibited a significantly higher clinical score, delayed leukocyte infiltration, reduced expression of IFN-β, tumor necrosis factor α, interleukin-1β, and interleukin-18 at early times post-DSS exposure, and increased mortality as compared with wild-type mice. DSS/AOM-treated RNase-L⁻/⁻ mice displayed an increased tumor burden. Bacterial RNA triggered IFN-β production in an RNase-L-dependent manner and provided a potential mechanism by which RNase-L contributes to the gastrointestinal immune response to microbiota and protects against experimental colitis and colitis-associated cancer.. RNase-L promotes the innate immune response to intestinal damage and ameliorates murine colitis and colitis-associated cancer. The RNase-L-dependent production of IFN-β stimulated by bacterial RNA may be a mechanism to protect against gastrointestinal inflammatory disease.

Topics: Animals; Azoxymethane; Blotting, Western; Carcinogens; Colitis; Colonic Neoplasms; Cytokines; Dextran Sulfate; Disease Models, Animal; Endoribonucleases; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Immunity, Innate; Immunoenzyme Techniques; Interferon Type I; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Peroxidase; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction

The experimental model of aortocaval fistula is a useful model of cardiac hypertrophy in response to volume overload. In the present study it has been used to investigate the pathologic subendocardial remodeling associated with the development of heart failure during the early phases (day 1, 3, and 7) following volume overload. Compared with sham treated rats, aortocaval fistula rats showed lower systemic blood pressure and higher left ventricular end-diastolic pressure This resulted in lower coronary driving pressure and left ventricular systolic and diastolic dysfunction. Signs of myocyte necrosis, leukocyte cell infiltration, fibroplasia and collagen deposition appeared sequentially in the subendocardium where remodeling was more prominent than in the non-subendocardium. Accordingly, increased levels of TNF-alpha, IL-1 beta, and IL-6, and enhanced MMP-2 activity were all found in the subendocardium of rats with coronary driving pressure ≤ 60 mmHg. The coronary driving pressure was inversely correlated with MMP-2 activity in subendocardium in all time-points studied, and blood flow in this region showed positive correlation with systolic and diastolic function at day 7. Thus the predominant subendocardial remodeling that occurs in response to low myocardial perfusion pressure during the acute phases of aortocaval fistula contributes to early left ventricular dysfunction.

Topics: Acute Disease; Animals; Aorta, Abdominal; Arteriovenous Fistula; Blood Pressure; Coronary Circulation; Disease Models, Animal; Hemodynamics; Interleukins; Male; Matrix Metalloproteinase 2; Peroxidase; Pulsatile Flow; Rats; Rats, Wistar; Vena Cava, Inferior; Ventricular Function, Left; Ventricular Remodeling

High-frequency oscillatory ventilation (HFOV) at higher frequencies minimizes the tidal volume. However, whether increased frequencies during HFOV can reduce ventilator-induced lung injury remains unknown.. After the induction of acute respiratory distress syndrome in the model by repeated lavages, 24 adult sheep were randomly divided into four groups (n = 6): three HFOV groups (3, 6, and 9 Hz) and one conventional mechanical ventilation (CMV) group. Standard lung recruitments were performed in all groups until optimal alveolar recruitment was reached. After lung recruitment, the optimal mean airway pressure or positive end-expiratory pressure was determined with decremental pressure titration, 2 cm H2O every 10 min. Animals were ventilated for 4 h.. After lung recruitment, sustained improvements in gas exchange and compliance were observed in all groups. Compared with the HFOV-3 Hz and CMV groups, the transpulmonary pressure and tidal volumes were statistically significantly lower in the HFOV-9 Hz group. The lung injury scores and wet/dry weight ratios were significantly reduced in the HFOV-9 Hz group compared with the HFOV-3 Hz and CMV groups. Expression of interleukin-1β and interleukin-6 in the lung tissue, decreased significantly in the HFOV-9 Hz group compared with the HFOV-3 Hz and CMV groups. Malondialdehyde expression and myeloperoxidase activity in lung tissues in the HFOV-9 Hz group decreased significantly, compared with the HFOV-3 Hz and CMV groups.. The use of HFOV at 9 Hz minimizes lung stress and tidal volumes, resulting in less lung injury and reduced levels of inflammatory mediators compared with the HFOV-3 Hz and CMV conditions.

Topics: Animals; Disease Models, Animal; High-Frequency Ventilation; Interleukin-1beta; Interleukin-6; Male; Malondialdehyde; Peroxidase; Positive-Pressure Respiration; Respiration, Artificial; Respiratory Distress Syndrome; Sheep; Tidal Volume; Ventilator-Induced Lung Injury

After spinal cord injury (SCI), a series of complex pathophysiological processes follows the initial injury. Because inflammation plays a key role in this secondary pathology damage, anti-inflammatory drug treatment may reduce secondary damage and protect neurons after SCI. Though nordihydroguaiaretic acid (NDGA) can inhibit inflammatory responses, its potential roles in neuroprotection and anti- inflammation in an SCI model have not been studied. In this study, we investigated the anti-inflammatory effects of NDGA in SCI. First, histopathological alterations were evaluated with hematoxylin/eosin (HE) and Nissl staining, showing an increased number of neurons after NDGA administration. Additionally, the extent of secondary damage was assessed by TUNEL assay and measurement of astrocyte proliferation. The data showed that the numbers of apoptotic cells and the proliferative extent of astrocytes were significantly decreased by the use of NDGA. The anti-inflammatory effect of NDGA was evaluated by measuring myeloperoxidase (MPO) levels as an indicator of neutrophil activity, macrophage/microglia numbers, and expression of inflammatory cytokines including IL-1β and TNF-α. NDGA treatment significantly decreased the MPO level and the number of macrophages/microglia. In addition, NDGA also suppressed the expression of IL-1β and TNF-α after SCI. These data suggest that anti-inflammatory action by NDGA can reduce secondary damage after SCI.

Topics: Animals; Anti-Inflammatory Agents; Astrocytes; Cell Death; Cell Proliferation; Disease Models, Animal; Gene Expression Regulation; Glial Fibrillary Acidic Protein; In Situ Nick-End Labeling; Inflammation; Interleukin-6; Male; Masoprocol; Peroxidase; Rats; Rats, Wistar; Spinal Cord Injuries; Tumor Necrosis Factor-alpha

Platelet-derived CD40L is known to regulate neutrophil recruitment and lung damage in sepsis. However, the mechanism regulating shedding of CD40L from activated platelets is not known. We hypothesized that matrix metalloproteinase (MMP)-9 might cleave surface-expressed CD40L and regulate pulmonary accumulation of neutrophils in sepsis.. Abdominal sepsis was induced by cecal ligation and puncture (CLP) in wild-type and MMP-9-deficient mice. Edema formation, CXC chemokine levels, myeloperoxidase levels, neutrophils in the lung and plasma levels of CD40L and MMP-9 were quantified.. CLP increased plasma levels of MMP-9 but not MMP-2. The CLP-induced decrease in platelet surface CD40L and increase in soluble CD40L levels were significantly attenuated in MMP-9 gene-deficient mice. Moreover, pulmonary myeloperoxidase (MPO) activity and neutrophil infiltration in the alveolar space, as well as edema formation and lung injury, were markedly decreased in septic mice lacking MMP-9. In vitro studies revealed that inhibition of MMP-9 decreased platelet shedding of CD40L. Moreover, recombinant MMP-9 was capable of cleaving surface-expressed CD40L on activated platelets. In human studies, plasma levels of MMP-9 were significantly increased in patients with septic shock as compared with healthy controls, although MMP-9 levels did not correlate with organ injury score.. Our novel data propose a role of MMP-9 in regulating platelet-dependent infiltration of neutrophils and tissue damage in septic lung injury by controlling CD40L shedding from platelets. We conclude that targeting MMP-9 may be a useful strategy to limit acute lung injury in abdominal sepsis.

Topics: Animals; Blood Platelets; Case-Control Studies; CD40 Ligand; Disease Models, Animal; Humans; Lung; Lung Injury; Male; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophil Infiltration; Peroxidase; Platelet Activation; Pulmonary Edema; Sepsis; Time Factors

Nowadays, treatments for cholestasis remain largely nonspecific and often ineffective. Recent studies showed that inflammatory injuries and oxidative stress occur in the liver with cholestasis. In this study, we would use corilagin to treat the animal model of acute cholestasis in order to define the activity to interfere with inflammation-related and oxidative stress pathway in cholestatic pathogenesis.. Rats were administrated with alpha-naphthylisothiocyanate to establish model of cholestasis and divided into corilagin, ursodeoxycholic acid, dexamethasone, model and normal groups with treatment of related agent. At 24h, 48h and 72h time points after administration, living condition, serum markers of liver damage, pathological changes of hepatic tissue, nuclear factor (NF)-kappaB, myeloperoxidase (MPO), malondialdehyde (MDA), superoxide dismutase (SOD) and nitric oxide (NO) were examined and observed.. Compared to model group, corilagin had remarkable effect on living condition, pathological manifestation of liver tissue, total bilirubin, direct bilirubin, (P<0.01), but no effect on alanine aminotransferase (ALT) and aspartate aminotransferase (AST). With corilagin intervention, levels of MPO, MDA and translocation of NF-κB were notably decreased, and levels of SOD and NO were markedly increased (P<0.05 or P<0.01).. It is shown that corilagin is a potential component to relieve cholestasis through inflammation-related and oxidation-related pathway.

Topics: Acute Disease; Alanine Transaminase; Analysis of Variance; Animals; Anti-Inflammatory Agents; Aspartate Aminotransferases; Bilirubin; Cholagogues and Choleretics; Cholestasis; Dexamethasone; Disease Models, Animal; Glucosides; Hydrolyzable Tannins; Liver; Male; Malondialdehyde; NF-kappa B; Nitric Oxide; Oxidative Stress; Peroxidase; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Ursodeoxycholic Acid

To assess the protective effect of exogenous hydrogen sulfide (H₂S) against myocardial injury after skeletal muscle ischemia/reperfusion (IR) in rats and explore the mechanism.. Thirty-one Wistar rats were randomized into normal control (n=8), IR group (n=8, with a 4-h reperfusion following a 4-h ischemia of the bilateral hindlimbs induced using a tourniquet), NaHS group (n=8, with IR and intraperitoneal injection of 14 µmol/kg NaHS), and DL-propargylglycine (PPG) group (n=7, with IR and intraperitoneal injection of 50 mg/kg PPG). The plasma levels of CK-MB and the levels of MPO, TNF-α, MDA, T-SOD, and CuZn-SOD in the plasma and myocardial tissues were measured. The expression of TNF-α in the myocardium was examined using immunohistochemistry. RESULTS Skeletal muscle IR induced significantly increased plasma CK-MB level (P<0.05) and the levels of MPO, TNF-α, and MDA in the plasma and myocardium, and significantly decreased plasma and myocardial levels of T-SOD and CuZn-SOD (P<0.05). NaHS treatment significantly decreased plasma CK-MB level (P<0.05), reduced plasma and myocardial levels of MPO, TNF-α, and MDA, and increased plasma and myocardial T-SOD and CuZn-SOD in rats with IR (P<0.05), whereas PPG treatment did not produce any obvious responses (P>0.05). Immunohistochemistry showed an obviously reduced expression of TNF-α in the myocardium in rats with NaHS treatment compared with those in IR group.. H₂S treatment can alleviate myocardial injury induced by skeletal muscle IR in rats by inhibiting the inflammatory cytokines and oxidative stress.

Topics: Animals; Creatine Kinase, MB Form; Disease Models, Animal; Hydrogen Sulfide; Ischemia; Male; Malondialdehyde; Muscle, Skeletal; Myocardial Reperfusion Injury; Oxidative Stress; Peroxidase; Rats; Rats, Wistar; Superoxide Dismutase; Tumor Necrosis Factor-alpha

The onset of oral candidiasis is accompanied by inflammatory symptoms such as pain in the tongue, edema or tissue damage and lowers the quality of life (QOL) of the patient. In a murine oral candidiasis model, the effects were studied of terpinen-4-ol (T-4-ol), one of the main constituents of tea tree oil, Melaleuca alternifolia, on inflammatory reactions. When immunosuppressed mice were orally infected with Candida albicans, their tongues showed inflammatory symptoms within 24 h after the infection, which was monitored by an increase of myeloperoxidase activity and macrophage inflammatory protein-2 in their tongue homogenates. Oral treatment with 50 µL of 40 mg/mL terpinen-4-ol 3h after the Candida infection clearly suppressed the increase of these inflammatory parameters. In vitro analysis of the effects of terpinen-4-ol on cytokine secretion of macrophages indicated that 800 µg/mL of this substance significantly inhibited the cytokine production of the macrophages cultured in the presence of heat-killed C. albicans cells. Based on these findings, the role of the anti-inflammatory action of T-4-ol in its therapeutic activity against oral candidiasis was discussed.

Topics: Animals; Anti-Inflammatory Agents; Candidiasis, Oral; Chemokine CXCL2; Colony Count, Microbial; Disease Models, Animal; Macrophages; Mice; Peroxidase; Tea Tree Oil; Terpenes; Tongue; Tumor Necrosis Factor-alpha

We tested the hypothesis that the order of exposure to maternal betamethasone and intra-amniotic (IA) lipopolysaccharide (LPS) will differentially modulate inflammation in the chorioamnion.. Time-mated Merino ewes with singleton fetuses received saline alone, IA LPS alone, maternal betamethasone before LPS, or betamethasone after LPS. We assessed inflammatory markers in the chorioamnion and the amniotic fluid.. Inflammatory cell infiltration, expression of myeloperoxidase, serum amyloid A3 (acute phase reactant) in the chorioamnion, and levels of interleukin (IL)-8 in the amniotic fluid increased 7 days after LPS exposure. Betamethasone prior to LPS decreased infiltration of the inflammatory cells, CD3+ T cells, and decreased the levels of IL-1β and IL-8 in the amniotic fluid.. Betamethasone 7 days prior to LPS exposure suppressed LPS-induced inflammation. The markers of inflammation largely had returned to the baseline 14 days after LPS exposure.

Topics: Amnion; Amniotic Fluid; Animals; Anti-Inflammatory Agents; Betamethasone; CD3 Complex; Chorioamnionitis; Cytokines; Disease Models, Animal; Drug Administration Schedule; Female; Glucocorticoids; Inflammation Mediators; Lipopolysaccharides; Maternal-Fetal Exchange; Peroxidase; Pregnancy; RNA, Messenger; Serum Amyloid A Protein; Sheep; T-Lymphocytes; Time Factors

To explore the role of myeloperoxidase (MPO) and tumor necrosis factor-α (TNF-α) in myocardial injury induced by hind-limb ischemia-reperfusion (IR) in rats.. Rat models of bilateral hindlimb IR established using a tourniquet were randomized into 9 groups, including a normal control group normal, 2 ischemic groups with hindlimb ischemia for 2 and 4 h, and 6 IR groups with a 4-h ischemia followed by reperfusion for 0.5, 2, 4, 6, 12, and 24 h. The plasma and myocardial levels of MPO and TNF-α in each group were measured, and the myocardial expression of TNF-α was determined with immunohistochemistry.. Compared with the normal control group, the rats with a 2-h ischemia showed significantly increased levels of MPO and TNF-α in the plasma and myocardium. Compared with those in rats with a 4-h ischemia, the plasma and myocardial MPO levels increased significantly at 0.5 and 2 h of reperfusion, respectively; the plasma TNF-α level increased significantly at 4 h of reperfusion and myocardial TNF-α level decreased obviously at 12 h; plasma levels of MPO and TNF-α both significantly decreased at 24 h. The plasma MPO and TNF-α and myocardial TNF-α reached the peak levels at 4 h of reperfusion, and the peak myocardial MPO level occurred at 6 h. Immunohistochemistry showed that TNF-α positivity moderately increased after hindlimb ischemia, and further increased at 4 h of reperfusion but obviously reduced at 24 h.. The activation of systemic and local neutrophils and inflammatory cytokines may play an important role in myocardial injury induced by hindlimb IR in rats.

Topics: Animals; Disease Models, Animal; Hindlimb; Ischemia; Male; Myocardium; Peroxidase; Rats; Rats, Wistar; Reperfusion Injury; Tumor Necrosis Factor-alpha

Quorum sensing (QS) in Pseudomonas aeruginosa regulates the production of many virulence factors and plays an important role in the pathogenesis of P. aeruginosa infection. N-acyl homoserine lactones (AHL) are major QS signal molecules. Recently, a novel AHL-lactonase enzyme, AiiM, has been identified. The aim of this study was to evaluate the effect of AiiM on the virulence of P. aeruginosa in a mouse model of acute pneumonia. We developed a P. aeruginosa PAO1 strain harboring an AiiM-expressing plasmid. The production of several virulence factors by the AiiM-expressing strain was examined. Mice were intratracheally infected with an AiiM-expressing PAO1 strain. Lung histopathology, bacterial burden, and bronchoalveolar lavage (BAL) fluid were assessed at 24 h postinfection. AiiM expression in PAO1 reduced production of AHL-mediated virulence factors and attenuated cytotoxicity against human lung epithelial cells. In a mouse model of acute pneumonia, AiiM expression reduced lung injury and greatly improved the survival rates. The levels of proinflammatory cytokines and myeloperoxidase activity in BAL fluid were significantly lower in mice infected with AiiM-expressing PAO1. Thus, AiiM can strongly attenuate P. aeruginosa virulence in a mammalian model and is a potential candidate for use as a therapeutic agent against P. aeruginosa infection.

Topics: Animals; Bacterial Load; Bacterial Proteins; Bronchoalveolar Lavage Fluid; Carboxylic Ester Hydrolases; Cell Line, Tumor; Disease Models, Animal; Drug Evaluation, Preclinical; Enzyme Activation; Epithelial Cells; Humans; Interleukins; Lung; Male; Mice; Pancreatic Elastase; Peroxidase; Plasmids; Pneumonia, Bacterial; Pseudomonas aeruginosa; Pyocyanine; Quorum Sensing; Survival Analysis; Virulence Factors

Histone deacetylase inhibitors (HDACIs) interfere with the epigenetic process of histone acetylation and are known to have analgesic properties in models of chronic inflammatory pain. The aim of this study was to determine whether these compounds could also affect neuropathic pain. Different class I HDACIs were delivered intrathecally into rat spinal cord in models of traumatic nerve injury and antiretroviral drug-induced peripheral neuropathy (stavudine, d4T). Mechanical and thermal hypersensitivity was attenuated by 40% to 50% as a result of HDACI treatment, but only if started before any insult. The drugs globally increased histone acetylation in the spinal cord, but appeared to have no measurable effects in relevant dorsal root ganglia in this treatment paradigm, suggesting that any potential mechanism should be sought in the central nervous system. Microarray analysis of dorsal cord RNA revealed the signature of the specific compound used (MS-275) and suggested that its main effect was mediated through HDAC1. Taken together, these data support a role for histone acetylation in the emergence of neuropathic pain.

Topics: Animals; Anti-Retroviral Agents; Benzamides; Disease Models, Animal; Dose-Response Relationship, Drug; Histone Deacetylase Inhibitors; Hyperalgesia; Male; Neuralgia; Pain Measurement; Pyridines; Pyrimidines; Rats; Rats, Wistar; Time Factors

Ischaemia/reperfusion injury is a common problem in hepatic surgery. An appreciation of the role of sevoflurane dose in preconditioning and subsequent hepatoprotection against ischaemia/reperfusion injury would be useful.. The aim of current study was to investigate the protective effect of sevoflurane preconditioning at different doses on hepatic ischaemia/reperfusion injury in rats.. Randomised, controlled, laboratory study.. The Department of Anaesthesiology, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, China.. Fifty male Sprague-Dawley rats weighing 200 to 250 g, randomly assigned to five groups.. Control group (sham surgery, no ischaemia/reperfusion), I/R group (ischaemia/reperfusion but no sevoflurane pretreatment), S1 [1 minimum alveolar concentration (MAC) = 2.4%], S2 (1.5 MAC = 3.6%) and S3 (2 MAC = 4.8%) groups with sevoflurane pretreatment, respectively, followed by 60 min ischaemia and 120 min reperfusion.. At the end of reperfusion, serum levels of alanine aminotransferase and aspartate aminotransferase as well as superoxide dismutase activity, myeloperoxidase and malondialdehyde content in the liver were determined. Histological examination of the liver was also performed.. Serum levels of aspartate aminotransferase and alanine aminotransferase in the sevoflurane groups were significantly reduced compared to the elevated levels seen in the I/R group (P < 0.05). In the liver, the I/R-induced increase in myeloperoxidase activity and malondialdehyde level were significantly reduced by all sevoflurane concentrations (P < 0.05). The decrease in superoxide dismutase activity induced by I/R was prevented by all sevoflurane pretreatments (P < 0.05). No significant differences between the S1, S2 and S3 groups were seen in any of the above variables.. Sevoflurane pretreatment exerts a protective effect on hepatic ischaemia/reperfusion injury but there is no significant dose-response relationship in the concentration range used. It is possible that a dose-response relationship might exist at lower concentrations.

Topics: Alanine Transaminase; Anesthetics, Inhalation; Animals; Aspartate Aminotransferases; Biomarkers; Cytoprotection; Disease Models, Animal; Dose-Response Relationship, Drug; Liver; Male; Malondialdehyde; Methyl Ethers; Peroxidase; Protective Factors; Rats, Sprague-Dawley; Reperfusion Injury; Sevoflurane; Superoxide Dismutase; Time Factors

Quantum dots (QDs) are unique semi-conductor fluorescent nanoparticles with potential uses in a variety of biomedical applications. However, concerns exist regarding their potential toxicity, specifically their capacity to induce oxidative stress and inflammation. In this study we synthesized CdSe/ZnS core/shell QDs with a tri-n-octylphosphine oxide, poly(maleic anhydride-alt-1-tetradecene) (TOPO-PMAT) coating and assessed their effects on lung inflammation in mice. Previously published in vitro data demonstrated these TOPO-PMAT QDs cause oxidative stress resulting in increased expression of antioxidant proteins, including heme oxygenase, and the glutathione (GSH) synthesis enzyme glutamate cysteine ligase (GCL). We therefore investigated the effects of these QDs in vivo in mice deficient in GSH synthesis (Gclm +/- and Gclm -/- mice). When mice were exposed via nasal instillation to a TOPO-PMAT QD dose of 6 µg cadmium (Cd) equivalents/kg body weight, neutrophil counts in bronchoalveolar lavage fluid (BALF) increased in both Gclm wild-type (+/+) and Gclm heterozygous (+/-) mice, whereas Gclm null (-/-) mice exhibited no such increase. Levels of the pro-inflammatory cytokines KC and TNFα increased in BALF from Gclm +/+ and +/- mice, but not from Gclm -/- mice. Analysis of lung Cd levels suggested that QDs were cleared more readily from the lungs of Gclm -/- mice. There was no change in matrix metalloproteinase (MMP) activity in any of the mice. However, there was a decrease in whole lung myeloperoxidase (MPO) content in Gclm -/- mice, regardless of treatment, relative to untreated Gclm +/+ mice. We conclude that in mice TOPO-PMAT QDs have in vivo pro-inflammatory properties, and the inflammatory response is dependent on GSH synthesis status. Because there is a common polymorphism in humans that influences GCLM expression, these findings imply that humans with reduced GSH synthesis capabilities may be more susceptible to the pro-inflammatory effects of QDs.

Topics: Animals; Bronchoalveolar Lavage Fluid; Cadmium Compounds; Cytokines; Disease Models, Animal; Enzyme Activation; Glutamate-Cysteine Ligase; Glutathione; Inflammation Mediators; Keratinocytes; Lung; Male; Matrix Metalloproteinases; Mice; Mice, Knockout; Neutrophil Infiltration; Peroxidase; Pneumonia; Polymers; Quantum Dots; RNA, Messenger; Selenium Compounds; Stress, Physiological; Tumor Necrosis Factor-alpha; Zinc Sulfate

To investigate the antioxidant and anti-inflammatory effects of Shengmai San (SMS) and its ethyl acetate extract (SEa), n-butanol extract (SBu), and aqueous extract (SWe), and clarify the material base of SMS and the roles played by its fractions.. A mouse model of transient forebrain ischemia/reperfusion (I/R) by means of common carotid artery occlusion (CCAO) was used to investigate the effects of SMS and its three fractions. Histopathological damage, blood-brain barrier disruption, and antioxidant and inflammation-related parameters, including malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx), myeloperoxidase (MPO), nitric oxide (NO), tumor necrosis factor-α (TNF-α) were measured. The chemical constituents of each fraction were identified by LC-MS.. Eighteen lignans in SEa, and thirteen steroidal glycosides and ginsenosides in SBu were determined. SMS significantly inhibited I/R induced formation of histological injury and cerebral MPO activity. SMS showed the strongest antioxidant and anti-inflammatory effects against the I/R-caused injuries. SEa showed higher antioxidant activity than the other two fractions and SBu has a slightly stronger inhibition on the productions of NO and TNF-α.. SMS as a whole had the most effective protection against cerebral I/R-caused injuries compared with its fractions, which inferred that it contains different groups of compounds that contribute together to its protective effect.

Topics: Animals; Chromatography, High Pressure Liquid; Disease Models, Animal; Drugs, Chinese Herbal; Glutathione Peroxidase; Humans; Male; Malondialdehyde; Nitric Acid; Oxidative Stress; Peroxidase; Protective Agents; Rats; Reperfusion Injury; Superoxide Dismutase

To investigate the effect of hydrogen inhalation on acute lung injury after hemorrhagic shock in rats.. Twenty-four adult male Sprague-Dawley (SD) rats were equally randomized into three groups: sham operation group, model group and hydrogen-treatment group. Pressure-controlled hemorrhagic shock and resuscitation model was reproduced by blood-letting for 1 hour followed by fluid replacement for 2 hours. The rats in model group received a mixture of 50% oxygen-50% nitrogen during the process. The rats in hydrogen-treatment group received inhalation of a mixture of 2% hydrogen-48% nitrogen-50% oxygen 10 minutes before fluid replacement till the end of resuscitation. The arterial blood samples were collected for the measurement of arterial partial pressure of oxygen (PaO₂) before exsanguination, 1 hour after shock, 1 hour and 2 hours after fluid replacement. Blood and lung tissues were collected at the end of experiment, and tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels in plasma, lung wet/dry weight ratio (W/D), malondialdehyde (MDA) content, superoxide dismutase (SOD) and myeloperoxidase (MPO) activity in the lung tissue were determined. The lung tissue was subjected to pathological examination.. At the end of fluid replacement, compared with model group, hydrogen could significantly reduce pulmonary edema (lung W/D ratio: 4.72 ± 0.12 vs. 4.94 ± 0.14, P<0.05), inhibit oxidative stress (MDA: 0.55 ± 0.09 nmol/mg vs. 0.72 ± 0.08 nmol/mg, P<0.05), enhance antioxidant activity (SOD activity: 79.53 ± 14.33 U/mg vs. 59.55 ± 9.07 U/mg, P<0.05), reduce the release of pro-inflammatory cytokines (TNF-α: 55.58 ± 10.06 ng/L vs. 66.58 ± 5.17 ng/L; IL-6: 23.00 ± 2.77 ng/L vs. 27.09 ± 2.46 ng/L, both P<0.05) and inhibit neutrophil infiltration (MPO: 1.05 ± 0.18 U/g vs. 1.40 ± 0.14 U/g, P<0.05). It alleviated the damage to lung tissue, and then improved the lung function (PaO₂: 146.3 ± 22.1 mm Hg vs. 123.6 ± 16.0 mm Hg, P<0.05).. Hydrogen treatment can alleviate acute lung injury as a result of hemorrhagic shock and resuscitation.

Topics: Acute Lung Injury; Animals; Disease Models, Animal; Hydrogen; Interleukin-6; Lung; Male; Malondialdehyde; Peroxidase; Rats; Rats, Sprague-Dawley; Shock, Hemorrhagic; Superoxide Dismutase; Tumor Necrosis Factor-alpha

To investigate gastric antisecretory and gastroprotective activity of bovine hemoglobin (B-Hb) in rats.. Adult Albino-Wistar rats were divided into groups of 6 animals each. B-Hb in doses of 100, 300 and 900 mg/kg body weight was tested for gastric acid secretion and antiulcer activity. Gastric secretions were measured 6 h after pylorus ligation in rats pretreated with B-Hb. The acidity was measured by titrating gastric contents against 0.01 mol/L NaOH to pH 7. Indomethacin ulcers were produced by oral administration of 30 mg/kg bw in the rats pretreated with B-Hb one hour before indomethacin. Six hours after indomethacin stomach removed and ulcer index was recorded. Ethanol ulcer were produced by 1 mL of ethanol in the rats pretreated with B-Hb 30 min before the ethanol. One hour after ethanol stomach were cut open to score ulcers. Histological examination and analysis of gastric wall mucus, non-protein sulfhydryl groups (NP-SH), and myeloperoxidase (MPO) were carried in gastric tissue following ethanol administration.. In control rats pylorus ligation for 6 h resulted in the accumulation of 8.1 ± 0.61 mL of gastric secretion. The treatment of the rats with 100, 300 and 900 mg/kg of B-Hb produced a significant decrease in the volume of gastric secretion 5.6 ± 0.63, 5.5 ± 0.75 and 4.7 ± 0.58 mL respectively as compared to the control group [analysis of variance (ANOVA) F = 4.77, P < 0.05]. The lesion area in the control group was found to be 22.4 ± 3.2 mm(2) six hours after the administration of indomethacin. Treatment of rats with B-Hb at doses of 100 mg/kg (24.3 ± 3.29 mm(2)), 300 mg/kg (16.2 ± 1.45 mm(2)) and 900 mg/kg (12.6 ± 1.85 mm(2)) produced a dose dependent decreased the lesion scores (ANOVA F = 4.50, P < 0.05). The ulcer index following one hour after 1 mL ethanol was 7.1 ± 0.31. Pretreatment of rats with B-Hb at the doses of 100 mg/kg (2.5 ± 0.42), 300 mg/kg (2.1 ± 0.4) and 900 mg/kg (0.7 ± 0.21) significantly inhibited the formation of gastric lesions (ANOVA F = 63.26, P < 0.0001). Histological examination of gastric mucosa following ethanol showed significant lesions in the form of gastric pits with detachment of the surface epithelium; vacuolation of epithelial cells and elongation of microvessels. The changes were dose-dependently attenuated by B-Hb. The treatment of rats with ethanol significantly decreased the Alcian blue binding capacity of gastric wall mucus (480 ± 25.6 μg Alcian blue/g of tissue) as compared to control rats (667 ± 25.8 μg). Pretreatment of rats with B-Hb at the doses of 100 mg/kg (516 ± 31.6 μg/g), 300 mg/kg (558 ± 28.8 μg/g) and 900 mg/kg (654 ± 33.8 μg/g) significantly attenuated ethanol induced depletion of gastric wall mucus (ANOVA F = 8.05, P < 0.005). A significant and dose dependent increase of gastric mucosal NP-SH (ANOVA F = 19.62, P < 0.001) and decrease in MPO activity (ANOVA F = 3.1, P < 0.05) was observed in B-Hb treated rats.. B-Hb possesses significant gastric antisecretory and gastroprotective activity against experimentally induced gastric lesion. The gastroprotective effects of B-Hb are accompanied by inhibition of neutrophils activity, reduction of oxidative stress and maintenance of mucosal integrity.

Topics: Animals; Anti-Ulcer Agents; Cattle; Cytoprotection; Disease Models, Animal; Dose-Response Relationship, Drug; Ethanol; Female; Gastric Acid; Gastric Mucosa; Hemoglobins; Indomethacin; Male; Neutrophils; Oxidative Stress; Peroxidase; Rats; Rats, Wistar; Stomach Ulcer; Sulfhydryl Compounds; Time Factors

The natural hormone uroguanylin regulates intestinal fluid homeostasis and bowel function through activation of guanylate cyclase-C (GC-C), resulting in increased intracellular cyclic guanosine-3',5'-monophosphate (cGMP). We report the effects of uroguanylin-mediated activation of the GC-C/cGMP pathway in vitro on extracellular cGMP transport and in vivo in rat models of inflammation- and stress-induced visceral hypersensitivity. In vitro exposure of intestinal Caco-2 cells to uroguanylin stimulated bidirectional, active extracellular transport of cGMP into luminal and basolateral spaces. cGMP transport was significantly and concentration dependently decreased by probenecid, an inhibitor of cGMP efflux pumps. In ex vivo Ussing chamber assays, uroguanylin stimulated cGMP secretion from the basolateral side of rat colonic epithelium into the submucosal space. In a rat model of trinitrobenzene sulfonic acid (TNBS)-induced visceral hypersensitivity, orally administered uroguanylin increased colonic thresholds required to elicit abdominal contractions in response to colorectal distension (CRD). Oral administration of cGMP mimicked the antihyperalgesic effects of uroguanylin, significantly decreasing TNBS- and restraint stress-induced visceromotor response to graded CRD in rats. The antihyperalgesic effects of cGMP were not associated with increased colonic spasmolytic activity, but were linked to significantly decreased firing rates of TNBS-sensitized colonic afferents in rats in response to mechanical stimuli. In conclusion, these data suggest that the continuous activation of the GC-C/cGMP pathway along the intestinal tract by the endogenous hormones guanylin and uroguanylin results in significant reduction of gastrointestinal pain. Extracellular cGMP produced on activation of GC-C is the primary mediator in this process via modulation of sensory afferent activity.

Topics: Acetylcholine; Acetylglucosamine; Adenocarcinoma; Animals; Cell Differentiation; Cell Line, Tumor; Colitis; Colon; Colorectal Neoplasms; Cyclic GMP; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Electric Stimulation; Female; Gastrointestinal Diseases; Gene Expression Regulation, Neoplastic; Guanylate Cyclase; Humans; Hyperalgesia; Intestinal Mucosa; Male; Mast Cells; Morphine; Multidrug Resistance-Associated Proteins; Natriuretic Peptides; Organic Anion Transporters, Sodium-Independent; Peroxidase; Rats; Rats, Sprague-Dawley; Rats, Wistar; Restraint, Physical; RNA, Messenger; Signal Transduction; Trinitrobenzenesulfonic Acid; Visceral Pain

Transplantation of mesenchymal stem cells (MSCs) has been shown to enhance the recovery of brain functions following ischemic injury. Although immune modulation has been suggested to be one of the mechanisms, the molecular mechanisms underlying improved recovery has not been clearly identified. Here, we report that MSCs secrete transforming growth factor-beta (TGF-β) to suppress immune propagation in the ischemic rat brain. Ischemic stroke caused global death of resident cells in the infarcted area, elevated the monocyte chemoattractant protein-1 (MCP-1) level, and evoked massive infiltration of circulating CD68+ immune cells through the impaired blood-brain barrier. Transplantation of MSCs at day 3 post-ischemia blocked the subsequent upregulation of MCP-1 in the ischemic area and the infiltration of additional CD68+ immune cells. MSC-conditioned media decreased the migration and MCP-1 production of freshly isolated immune cells in vitro, and this effect was blocked by an inhibitor of TGF-β signaling or an anti-TGF-β neutralizing antibody. Finally, transplantation of TGF-β1-silenced MSCs failed to attenuate the infiltration of CD68+ cells into the ischemic brain, and was associated with only minor improvements in motor function. These results indicate that TGF-β is key to the ability of MSCs to beneficially attenuate immune reactions in the ischemic brain. Our findings offer insight into the interactions between allogeneic MSCs and the host immune system, reinforcing the prospective clinical value of using MSCs in the treatment of neurological disorders involving inflammation-mediated secondary damage.

Topics: Animals; Antigens, CD; Blood-Brain Barrier; Brain Infarction; Calcium-Binding Proteins; Cell Movement; Cells, Cultured; Chemokine CCL2; Disease Models, Animal; Encephalitis; Gene Expression Regulation; Infarction, Middle Cerebral Artery; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Microfilament Proteins; Peroxidase; Rats; Rats, Sprague-Dawley; Time Factors; Transforming Growth Factor beta

Sheng-Mai-San (SMS) has been used for the treatment of cardiovascular disease for many years in China.. This study investigated the protective effects and active ingredients of SMS on myocardial injury (MI) in mice.. SMS and n-butanol extraction of SMS (SMS-Bu) were prepared and administered to ISO-treated mice once a day for 7 consecutive days. The doses were equivalent to the raw medicinal herbs of SMS 5.72, 2.86 and 1.43 g/kg/d, respectively. Propranolol was used as positive control. Serum biomarkers, histopathological and electrocardiographic were evaluated.. Serum lactate dehydrogenase, creatine kinase and myeloperoxidase increased to 4473.6 ± 322.5, 950.0 ± 35.0 and 90.4 ± 12.2 U/L in the model group. SMS and SMS-Bu groups showed a decrease from 10 to 29% for lactate dehydrogenase and from 17 to 42% for creatine kinase, respectively. Both SMS and SMS-Bu significantly attenuated the myeloperoxidase activities (from 42 to 56%) and malondialdehyde levels (from 25 to 45%) compared with the model group. Decreased superoxide dismutase activities in ISO-treated mice were elevated from 19 to 59% when treated with SMS and SMS-Bu. These biochemical results were supported by electrocardiogram (ECG) and histopathological observations. Furthermore, 8 ginsenosides and 16 lignans were identified in SMS-Bu.. These findings suggested that SMS-Bu was the mainly active fraction of SMS which exerted its beneficial effects on MI mainly through protecting myocardial tissue and reducing oxidative damage, and the ginsenosides and lignans may serve as active ingredients of SMS for the treatment of MI.

Topics: Animals; Biomarkers; Cardiovascular Agents; Chromatography, Liquid; Creatine Kinase; Cytoprotection; Disease Models, Animal; Drug Combinations; Drugs, Chinese Herbal; Isoproterenol; L-Lactate Dehydrogenase; Malondialdehyde; Mice; Mice, Inbred ICR; Myocardial Infarction; Myocardium; Peroxidase; Phytotherapy; Plants, Medicinal; Superoxide Dismutase; Tandem Mass Spectrometry

Pentoxifylline, a methylxanthine derivative with significant hemorheologic properties, is used for claudication in patients with peripheral vascular disease, and experimentally for ischemic injury to organs because of its antioxidant and antiinflammatory effects. We used a rat model of severe small intestinal ischemia and reperfusion to determine the ability of pentoxifylline in improving survival, molecular response, and pathological protection.. We used 6 groups of male Wistar rats (n=25 each). The superior mesenteric artery was occluded for 120 minutes. Laboratory and tissue studies were done on 5 animals, 1 hour after reperfusion, and animal survival was assessed at 7 days. There were 2 control groups that received normal saline, either before ischemia or during reperfusion. The 4 treated groups received pentoxifylline 1 or 10 mg/kg at the same times mentioned above. Laboratory studies included measuring serum lactic acid dehydrogenase, tumor necrosis factor-α, interleukin-1β, and interleukin-6.Intestinal tissue malondialdehyde and myeloperoxidase in small intestine tissue also were measured. Histology and laser vascular blood flow at baseline and reperfusion were obtained, and survival was determined 7 days after ischemia.. A significant survival benefit in the animals treated with 10 mg/kg of pentoxifylline at reperfusion was noted. This coincided with a reduction in biochemical markers of cell damage - specifically, serum lactic acid dehydrogenase, and tissue malondialdehyde, ischemia, and reperfusion. Additionally, we saw decreased levels of tumor necrosis factor-α, interleukin-1β, and interleukin-6. Improved postreperfusion blood flow shown by laser Doppler technology also was seen in the treated groups. Histologically, we observed less neutrophil infiltration in the intestine of ischemic-treated rats. Also seen in the control animals were increased necrotic lesions in the microvilli with a higher presence of lysozyme in the Paneth cells. Survival was significantly better at 7 days (70% vs 40%) when we compared the pentoxifylline group treated at reperfusion (10 mg/kg) to the ischemic controls.. Pentoxifylline had a significant protective effect on severely ischemic bowel when administered during reperfusion at a dosage of 10 mg/kg. Better survival, improved histology, and molecular response should urge consideration of the consideration of applying these findings in some general surgery and transplant conditions.

Topics: Animals; Biomarkers; Blood Flow Velocity; Cytoprotection; Disease Models, Animal; Inflammation Mediators; Interleukin-1beta; Interleukin-6; Intestine, Small; L-Lactate Dehydrogenase; Laser-Doppler Flowmetry; Male; Malondialdehyde; Mesenteric Vascular Occlusion; Neutrophil Infiltration; Pentoxifylline; Peroxidase; Protective Agents; Rats; Rats, Wistar; Reperfusion Injury; Splanchnic Circulation; Time Factors; Tumor Necrosis Factor-alpha

Impaired gut barrier function and acute lung injury (ALI) are significant components of the multiorgan dysfunction syndrome that accompanies severe burns. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) has been shown to reduce inflammation, preserve gut barrier function, and protect the lungs from acute injury in several models of intestinal injury; however, comparable effects of HB-EGF after burn injury have never been investigated. The present studies were based on the hypothesis that HB-EGF would reduce the severity of ALI and multiorgan dysfunction after scald burns in mice.. Mice were randomized to sham, burn (25% of total body surface area with full thickness dorsal scald), and burn + HB-EGF groups. The HB-EGF group was pretreated with two enteral doses of HB-EGF (1200 μg/kg/dose). Mice were resuscitated after injury and sacrificed at 8 h later. Their lungs were harvested for determination of pulmonary myeloperoxidase activity, wet:dry ratios, and terminal deoxynucleotidyl transferase dUTP nick end label and cleaved caspase 3 immunohistochemistry. Lung function was assessed using the SCIREQ Flexivent. Splenic apoptosis was quantified by Western blot for cleaved caspase 3, and intestinal permeability was measured using the everted gut sac method.. Mice subjected to scald burn injury had increased lung myeloperoxidase levels, increased pulmonary and splenic apoptosis, elevated airway resistance and bronchial reactivity, and increased intestinal permeability compared with sham mice. These abnormalities were significantly attenuated in mice that were subjected to scald burn injury but treated with enteral HB-EGF.. These data suggest that HB-EGF protects mice from ALI after scald burn and attenuates the severity of postburn multiorgan dysfunction.

Topics: Acute Lung Injury; Animals; Apoptosis; Burns; Disease Models, Animal; Heparin-binding EGF-like Growth Factor; Intercellular Signaling Peptides and Proteins; Intestines; Lung; Male; Mice; Mice, Inbred C57BL; Multiple Organ Failure; Peroxidase; Pulmonary Edema; Random Allocation; Severity of Illness Index; Spleen

We and others have shown that the dipeptide cotransporter PepT1 is expressed in immune cells, including macrophages that are in close contact with the lamina propria of the small and large intestines. In the present study, we used PepT1-knockout (KO) mice to explore the role played by PepT1 in immune cells during dextran sodium sulfate (DSS)-induced colitis. DSS treatment caused less severe body weight loss, diminished rectal bleeding, and less diarrhea in PepT1-KO mice than in wild-type (WT) animals. A histological examination of colonic sections revealed that the colonic architecture was less disrupted and the extent of immune cell infiltration into the mucosa and submucosa following DSS treatment was reduced in PepT1-KO mice compared with WT animals. Consistent with these results, the DSS-induced colitis increase in colonic myeloperoxidase activity was significantly less in PepT1-KO mice than in WT littermates. The colonic levels of mRNAs encoding the inflammatory cytokines CXCL1, interleukin (IL)-6, monocyte chemotactic protein-1, IL-12, and interferon-γ were significantly lower in DSS-treated PepT1-KO mice than in DSS-treated WT animals. Colonic immune cells from WT had significantly higher level of proinflammatory cytokines then PepT1 KO. In addition, we observed that knocking down the PepT1 expression decreases chemotaxis of immune cells recruited during intestinal inflammation. Antibiotic treatment before DSS-induced colitis eliminated the differential expression of inflammatory cytokines between WT and PepT1-KO mice. In conclusion, PepT1 in immune cells regulates the secretion of proinflammatory cytokines triggered by bacteria and/or bacterial products, and thus has an important role in the induction of colitis. PepT1 may transport small bacterial products, such as muramyl dipeptide and the tripeptide L-Ala-gamma-D-Glu-meso-DAP, into macrophages. These materials may be sensed by members of the nucleotide-binding site-leucine-rich repeat family of intracellular receptors, ultimately resulting in altered homeostasis of the intestinal microbiota.

Topics: Animals; Anti-Bacterial Agents; Colitis; Colon; Cytokines; Dextran Sulfate; Disease Models, Animal; Female; Gene Expression; Gene Knockdown Techniques; Homeostasis; Immunity, Cellular; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Peptide Transporter 1; Peroxidase; RNA, Messenger; Symporters

Myeloperoxidase-specific anti-neutrophil cytoplasmic antibody (MPO-ANCA) is associated with rapidly progressive glomerulonephritis (RPGN) and glomerular crescent formation. Pathogenic factors in RPGN were analyzed by using SCG/Kj mice, which spontaneously develop MPO-ANCA-associated RPGN. The serum concentration of soluble IL-6R was determined by using ELISA and those of another 23 cytokines and chemokines by Bio-Plex analysis. Sections of frozen kidney tissue were examined by fluorescence microscopy and the CD3(+) B220(+) T cell subset in the spleen determined by a flow cytometry. Concentrations of IL-6 and monocyte chemotactic protein-1 were significantly correlated with the percentages of crescent formation. Anti-IL-6R antibody, which has been effective in patients with rheumatoid arthritis, was administered to SCG/Kj mice to elucidate the role of IL-6 in the development of RPGN. MPO-ANCA titers decreased after administration of anti-IL-6R antibody, but not titers of mizoribine, which is effective in Kawasaki disease model mice. These results suggest that IL-6-mediated signaling is involved in the production of MPO-ANCA.

Topics: Animals; Antibodies; Antibodies, Antineutrophil Cytoplasmic; Chemokine CCL2; Disease Models, Animal; Female; Glomerulonephritis; Humans; Interleukin-6; Mice; Mice, Inbred C57BL; Peroxidase; Receptors, Interleukin-6; Ribonucleosides; T-Lymphocyte Subsets

This study compared the effects of hydroxyethyl starch 130/0.4, hydroxyethyl starch 200/0.5, and succinylated gelatin on oxidative stress and the inflammatory response in a rodent hemorrhagic shock model.. Sodium pentobarbital-anesthetized adult male Wistar rats (200 g to 220 g) were subjected to a severe volume-controlled hemorrhage using arterial blood withdrawal (30 mL/kg to 33 mL/kg) and resuscitated with a colloid solution at the same volume as blood withdrawal (hydroxyethyl starch 130/0.4, hydroxyethyl starch 200/0.5, or succinylated gelatin). Arterial blood gas parameters were monitored. Malondialdehyde (MDA) content and myeloperoxidase (MPO) activity in the liver, lungs, intestine, and brain were measured two hours after resuscitation. The levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 in the intestine were also measured.. Infusions of hydroxyethyl starch 130/0.4, but not hydroxyethyl starch 200/0.5 or succinylated gelatin, significantly reduced MDA levels and MPO activity in the liver, intestine, lungs and brain, and it also inhibited the production of TNF-α in the intestine two hours after resuscitation. However, no significant difference between hydroxyethyl starch 200/0.5 and succinylated gelatin was observed.. Hydroxyethyl starch 130/0.4, but not hydroxyethyl starch 200/0.5 or succinylated gelatin, treatment after hemorrhagic shock ameliorated oxidative stress and the inflammatory response in this rat model. No significant differences were observed after hydroxyethyl starch 200/0.5 or succinylated gelatin administration at doses of approximately 33 mL/kg.

Topics: Animals; Blood Gas Analysis; Colloids; Disease Models, Animal; Gelatin; Hydroxyethyl Starch Derivatives; Inflammation; Interleukin-6; Intestinal Mucosa; Lipid Peroxidation; Male; Malondialdehyde; Neutrophils; Oxidative Stress; Peroxidase; Rats, Wistar; Shock, Hemorrhagic; Succinates; Tumor Necrosis Factor-alpha

Magnesium lithospermate B (MLB), an active polyphenol acid of Danshen [Radix Salviae miltiorrhizae (Labiatae)], showed renoprotective, neuroprotective and myocardial salvage effects. Previous studies demonstrated that MLB could effectively suppress the production of cytokines and their associated signaling pathways in activated human T cells.. The purpose of this study was to examine the beneficial effects of MLB on myocardial ischemia/reperfusion (MI/R) injury and to explore its potential mechanisms related to anti-inflammation.. Sprague-Dawley rats were grouped as sham group, model group and MLB-treated (15, 30 and 60 mg/kg) groups. Animals were subjected to MI/R injury by the occlusion of left anterior descending artery for 30 min followed by reperfusion for 3 h. At the end of reperfusion, blood samples were collected to determine the serum levels of cardiac troponin (cTnI), creatine kinase-MB (CK-MB), tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β) and interleukin 6 (IL-6). Hearts were harvested to assess infarct size, histopathological changes and the activity of myeloperoxidase (MPO). The expression of phosphor-IkB-α and phosphor-nuclear factor kappa B (NF-κB) were assayed by western blot.. MLB administration significantly (p < 0.05) reduced: (1) ST-segment elevation (0.23 mv), (2) the infarct size (22.5%), (3) histological scores of myocardial injury (1.67 score), (4) myocardial injury marker enzymes: cTnI (5.64 ng/ml) and CK-MB (49.57 ng/ml) levels, (5) pro-inflammatory cytokines: TNF-α (97.36 pg/ml), IL-1β (93.35 pg/ml) and IL-6 (96.84 pg/ml) levels, (6) MPO activity (1.82 U/mg), (7) phosphor-NF-κB (0.87) and phosphor-IkB-α (0.96) expression.. Our study provided evidence that MLB ameliorated the inflammatory process associated with MI/R injury via NF-κB inactivation.

Topics: Animals; Anti-Inflammatory Agents; Biomarkers; Creatine Kinase, MB Form; Cytokines; Disease Models, Animal; Drugs, Chinese Herbal; Electrocardiography; I-kappa B Proteins; Inflammation; Inflammation Mediators; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; NF-kappa B; NF-KappaB Inhibitor alpha; Peroxidase; Phosphorylation; Rats; Rats, Sprague-Dawley; Signal Transduction; Time Factors; Troponin I

Loss of the tumor suppressor SMAD4 correlates with progression of colorectal cancer (CRC). In mice, colon tumors that express CCL9 recruit CCR1(+) myeloid cells, which facilitate tumor invasion and metastasis by secreting matrix metalloproteinase 9.. We used human CRC cell lines to investigate the ability of SMAD4 to regulate expression of CCL15, a human ortholog of mouse CCL9. We used immunohistochemistry to compare levels of CCL15 and other proteins in 141 samples of human liver metastases.. In human CRC cell lines, knockdown of SMAD4 increased CCL15 expression, and overexpression of SMAD4 decreased it. SMAD4 bound directly to the promoter region of the CCL15 gene to negatively regulate its expression; transforming growth factor-β increased binding of SMAD4 to the CCL15 promoter and transcriptional repression. In livers of nude mice, SMAD4-deficient human CRC cells up-regulated CCL15 to recruit CCR1(+) cells and promote metastasis. In human tumor samples, there was a strong inverse correlation between levels of CCL15 and SMAD4; metastases that expressed CCL15 contained 3-fold more CCR1(+) cells than those without CCL15. Patients with CCL15-expressing metastases had significantly shorter times of disease-free survival than those with CCL15-negative metastases. CCR1(+) cells in the metastases expressed the myeloid cell markers CD11b and myeloperoxidase, and also matrix metalloproteinase 9.. In human CRC cells, loss of SMAD4 leads to up-regulation of CCL15 expression. Human liver metastases that express CCL15 contain higher numbers CCR1(+) cells; patients with these metastases have shorter times of disease-free survival. Reagents designed to block CCL15 recruitment of CCR1(+) cells could prevent metastasis of CRC to liver.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Animals; CD11b Antigen; Cell Line, Tumor; Chemokines, CC; Colorectal Neoplasms; Disease Models, Animal; Disease Progression; Female; Gene Expression Regulation, Neoplastic; Heterografts; Humans; Liver Neoplasms; Macrophage Inflammatory Proteins; Male; Matrix Metalloproteinase 9; Mice; Mice, Nude; Middle Aged; Myeloid Cells; Neoplasm Metastasis; Peroxidase; Receptors, CCR1; Retrospective Studies; Smad4 Protein; Survival Rate

This study aims to investigate the influence of clotrimazol (CLTZ) on acute necrotizing pancreatitis (ANP) induced by glycodeoxycholic acid in rats. Rats were divided into five groups as sham + saline, sham + CLTZ, sham + polyethylene glycol, ANP + saline, and ANP + CLTZ. ANP in rats was induced by glycodeoxycholic acid. The extent of acinar cell injury, mortality, systemic cardiorespiratory variables, functional capillary density (FCD), renal/hepatic functions, and changes in some enzyme markers for pancreatic and lung tissue were investigated during ANP in rats. The use of CLTZ after the induction of ANP resulted in a significant decrease in the mortality rate, pancreatic necrosis, and serum activity of amylase, alanine aminotransferase, interleukin-6, lactate dehydrogenase in bronchoalveolar lavage fluid, serum concentration of urea, and tissue activity of myeloperoxidase, and malondialdehyde in the pancreas and lung and a significant increase in concentrations of calcium, blood pressure, urine output, pO2, and FCD. This study showed that CLTZ demonstrated beneficial effect on the course of ANP in rats. Therefore, it may be used in the treatment of acute pancreatitis.

Topics: 14-alpha Demethylase Inhibitors; Alanine Transaminase; Amylases; Animals; Blood Pressure; Bronchoalveolar Lavage Fluid; Calcium; Clotrimazole; Disease Models, Animal; Glycodeoxycholic Acid; Interleukin-6; L-Lactate Dehydrogenase; Lung; Male; Malondialdehyde; Pancreas; Pancreatitis, Acute Necrotizing; Peroxidase; Rats; Rats, Sprague-Dawley; Urea

In vitro and in vivo data have shown that retinoid treatment promotes an anti-inflammatory milieu with few adverse effects toward the gastrointestinal tract. The in vivo studies reported here further evaluate retinoid effects in 2 mouse models of inflammatory bowel disease.. Chronic dextran sulfate sodium colitis was induced in age- and weight-matched C57Bl/6 mice by 4 cycles of dextran sulfate sodium administration (6-8 animals/group). At cycle 4, animals were administered 13-cis-retinoic acid (isotretinoin, 30 mg/kg) or vehicle (oral gavage) or 4-oxo-13-cis-retinoic acid (15 mg/kg, intraperitoneal) daily. T-cell transfer colitis was induced in CB17 SCID mice by transfer of naive CD4CD62L T cells and treated by transfer of regulatory CD4CD25 T cells (4-6 animals/group); isolated from BALB/c mice after treatment with isotretinoin or vehicle, as above, for 2 weeks. Assessments included endoscopic and histological scores, myeloperoxidase activity, serum cytokines, and plasma isotretinoin levels.. Retinoid-treated animals with colitis showed comparable changes in myeloperoxidase activity, and endoscopic and histological scores, versus untreated animals with colitis. Modest and comparable changes were seen in body weight and colon length in animals injected with naive T cells from isotretinoin-treated donors versus those injected with T cells from vehicle-treated donors. Retinoid treatment was consistently associated with lower interleukin-12 levels, which, after the transfer of naive T cells from isotretinoin-treated donors, supported isotretinoin-mediated predisposition of naive T cells toward reduced proinflammatory cytokine expression. Colitis had no effect on isotretinoin exposure.. Retinoids attenuate the proinflammatory cytokine response in vivo, with only modest effects on body weight and parameters of gastrointestinal morphology.

Topics: Animals; CD4-Positive T-Lymphocytes; Colitis; Cytokines; Dermatologic Agents; Dextran Sulfate; Disease Models, Animal; Female; Flow Cytometry; Gastrointestinal Tract; Isotretinoin; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, SCID; Peroxidase; T-Lymphocytes, Regulatory

Formononetin has shown a variety of pharmacologic properties including anti-inflammatory effect. In the present study, we analyzed the role of formononetin in acute lung injury induced by lipopolysaccharide (LPS) in mice. The cell counting in the bronchoalveolar lavage fluid (BALF) was measured. The animal lung edema degree was evaluated by wet/dry weight ratio. The superoxidase dismutase (SOD) activity and myeloperoxidase (MPO) activity was assayed by SOD and MPO kits, respectively. The levels of inflammatory mediators, tumor necrosis factor-α (TNF-α) and IL-6,were assayed by enzyme-linked immunosorbent assay method. Pathological changes of hung tissues were observed by HE staining. Peroxisome proliferator-activated receptor (PPAR)-γ gene expression was measured by real-time PCR. The data showed that treatment with the formononetin group markedly attenuated inflammatory cell numbers in the BALF, increased PPAR-γ gene expression and improved SOD activity and inhibited MPO activity. The histological changes of the lungs were also significantly improved by formononetin compared to LPS group. The results indicated that formononetin has a protective effect on LPS-induced acute lung injury in mice.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Edema; Inflammation; Interleukin-6; Isoflavones; Lipopolysaccharides; Lung; Male; Mice; Mice, Inbred BALB C; Peroxidase; Phytoestrogens; PPAR gamma; Pulmonary Edema; Superoxide Dismutase; Tumor Necrosis Factor-alpha

To determine the effect of saturated hydrogen saline on lipopolysaccharide (LPS)-induced acute liver dysfunction, rats were divided into control, LPS, and LPS plus saturated hydrogen saline (LPS+H(2)) groups. Treatment with saturated hydrogen saline prolonged the median survival time and reduced liver dysfunction. Moreover, saturated hydrogen saline significantly reduced pathological alterations in liver tissues, the number of ballooned hepatocytes, serum tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 levels, and myeloperoxidase (MPO) and malondialdehyde (MDA) levels in liver tissues (P<0.05). Cell apoptosis was detected in liver tissues after LPS treatment, and attenuated by saturated hydrogen saline treatment. Saturated hydrogen saline also decreased phosphorylated extracellular signal-regulated kinase (p-ERK), phosphorylated Jun kinase (p-JNK), nuclear factor-kappa B (NF-kappaB), and second mitochondria-derived activator of caspase (Smac) levels, and increased p38 activation (P<0.05). Thus, saturated hydrogen saline may attenuate LPS-induced acute liver dysfunction in rats, possibly by reducing inflammation and cell apoptosis. Mitogen-activated protein kinase (MAPK), NF-kappaB, and Smac may contribute to saturated hydrogen saline-mediated liver protection.

Topics: Animals; Apoptosis; Apoptosis Regulatory Proteins; Biomarkers; Carrier Proteins; Disease Models, Animal; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Hydrogen; Interleukin-6; JNK Mitogen-Activated Protein Kinases; Lipopolysaccharides; Liver; Liver Diseases; Male; Malondialdehyde; Mitochondrial Proteins; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Peroxidase; Phosphorylation; Rats; Rats, Sprague-Dawley; Sodium Chloride; Tumor Necrosis Factor-alpha

Inflammation is a fundamental aspect of many human diseases. In this video report, we demonstrate non-invasive bioluminescence imaging techniques that distinguish acute and chronic inflammation in mouse models. With tissue damage or pathogen invasion, neutrophils are the first line of defense, playing a major role in mediating the acute inflammatory response. As the inflammatory reaction progresses, circulating monocytes gradually migrate into the site of injury and differentiate into mature macrophages, which mediate chronic inflammation and promote tissue repair by removing tissue debris and producing anti-inflammatory cytokines. Intraperitoneal injection of luminol (5-amino-2,3-dihydro-1,4-phthalazinedione, sodium salt) enables detection of acute inflammation largely mediated by tissue-infiltrating neutrophils. Luminol specifically reacts with the superoxide generated within the phagosomes of neutrophils since bioluminescence results from a myeloperoxidase (MPO) mediated reaction. Lucigenin (bis-N-methylacridinium nitrate) also reacts with superoxide in order to generate bioluminescence. However, lucigenin bioluminescence is independent of MPO and it solely relies on phagocyte NADPH oxidase (Phox) in macrophages during chronic inflammation. Together, luminol and lucigenin allow non-invasive visualization and longitudinal assessment of different phagocyte populations across both acute and chronic inflammatory phases. Given the important role of inflammation in a variety of human diseases, we believe this non-invasive imaging method can help investigate the differential roles of neutrophils and macrophages in a variety of pathological conditions.

Topics: Acute Disease; Animals; Chronic Disease; Disease Models, Animal; Inflammation; Luminescent Measurements; Luminol; Mice; Mice, Inbred C57BL; Mice, Nude; Neutrophils; Peroxidase; Superoxides

Wound healing effects of 50% ethanol extract of dried whole plant of Bacopa monniera (BME) was studied on wound models in rats. BME (25 mg/kg) was administered orally, once daily for 10 days (incision and dead space wound models) or for 21 days or more (excision wound model) in rats. BME was studied for its in vitro antimicrobial and in vivo wound breaking strength, WBS (incision model), rate of contraction, period of epithelization, histology of skin (excision model), granulation tissue free radicals (nitric oxide and lipid peroxidation), antioxidants (catalase, superoxide dismutase, and reduced glutathione), acute inflammatory marker (myeloperoxidase), connective tissue markers (hydroxyproline, hexosamine, and hexuronic acid), and deep connective tissue histology (dead space wound). BME showed antimicrobial activity against skin pathogens, enhanced WBS, rate of contraction, skin collagen tissue formation, and early epithelization period with low scar area indicating enhanced healing. Healing effect was further substantiated by decreased free radicals and myeloperoxidase and enhanced antioxidants and connective tissue markers with histological evidence of more collagen formation in skin and deeper connective tissues. BME decreased myeloperoxidase and free radical generated tissue damage, promoting antioxidant status, faster collagen deposition, other connective tissue constituent formation, and antibacterial activity.

Topics: Animals; Antioxidants; Bacopa; Bacteria; Disease Models, Animal; Free Radicals; Granulation Tissue; Hexosamines; Hexuronic Acids; Hydroxyproline; Microbial Sensitivity Tests; Peroxidase; Phytotherapy; Plant Extracts; Rats; Skin; Vitamin E; Wound Healing; Wounds and Injuries

We evaluated the effects of sodium alginate (AL-Na) on dextran sulfate sodium (DSS)- and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice. DSS was added to the drinking water for 7 days. In another experiment, DSS was added to the drinking water for 5 days and DSS-free water was provided thereafter. In a separated study, colitis was induced by intrarectally administered TNBS. AL-Na, 5-aminosalicylic acid, or prednisolone was orally administered. These colitis models exhibited colonic damage and produced noticeable inflammatory responses and aggravated goblet cell damage. AL-Na significantly ameliorated DSS- and TNBS-induced experimental colitis and prevented goblet cell damage. Prednisolone also suppressed colitis but caused loss of body and spleen weight. In contrast, AL-Na did not provoke these symptoms. These data suggest that AL-Na may be a possible therapeutic agent for the treatment of inflammatory bowel disease.

Topics: Alginates; Animals; Colitis; Colon; Dextran Sulfate; Disease Models, Animal; Glucuronic Acid; Hexuronic Acids; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Peroxidase; Protective Agents; Serum Amyloid A Protein; Trinitrobenzenes

Despite extensive studies, there is no effective treatment currently available other than pirfenidone for idiopathic pulmonary fibrosis. A protective effect of pantothenic acid and its derivatives on cell damage produced by oxygen radicals has been reported, but it has not been tested in bleomycin (BLM)--induced pulmonary fibrosis in rats. Therefore, we aimed to investigate the preventive effect of dexpanthenol (Dxp) on pulmonary fibrosis. Thirty-two rats were assigned to four groups as follows: (1) control group, (2) dexpanthenol (Dxp) group; 500 mg/kg Dxp continued intraperitoneally for 14 days, (3) bleomycin (BLM) group; a single intratracheal injection of BLM (2.5 mg/kg body weight in 0.25-ml phosphate buffered saline), and (4) BLM + Dxp-treated group; 500 mg/kg Dxp was administered 1 h before the intratracheal BLM injection and continued for 14 days i.p. The histopathological grades of lung inflammation and collagen deposition, tissue levels of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and myeloperoxidase (MPO) were measured. BLM provoked inflammation and collagen deposition (p < 0.0001), with a marked increase in myeloperoxidase (MPO) activity resembling increased inflammatory activity (p < 0.0001), which was prevented by Dxp (p < 0.0001, p = 0.02). BLM reduced tissue activities of SOD, GPx, and CAT compared to controls (p = 0.01, 0.03, 0.009). MDA was increased with BLM (p = 0.003). SOD (p = 0.001) and MDA (p = 0.016) levels were improved in group 4. The CAT levels in the BLM + Dxp group were close to those in the control group (p > 0.05). We showed that Dxp significantly prevents BLM-induced lung fibrosis in rats. Further studies are required to evaluate the role of Dxp in the treatment of lung fibrosis.

Topics: Animals; Antioxidants; Bleomycin; Catalase; Collagen; Cytoprotection; Disease Models, Animal; Drug Administration Schedule; Female; Glutathione Peroxidase; Injections, Intraperitoneal; Lung; Malondialdehyde; Pantothenic Acid; Peroxidase; Pulmonary Fibrosis; Rats; Rats, Wistar; Superoxide Dismutase; Time Factors

The study goal was to use membrane voltage changes during neurohypophysial action potential (AP) propagation as an index of nerve function to evaluate the role that circulating microparticles (MPs) play in causing central nervous system injury in response to decompression stress in a murine model. Mice studied 1 h following decompression from 790 kPa air pressure for 2 h exhibit a 45% broadening of the neurohypophysial AP. Broadening did not occur if mice were injected with the MP lytic agent polyethylene glycol telomere B immediately after decompression, were rendered thrombocytopenic, or were treated with an inhibitor of nitric oxide synthase-2 (iNOS) prior to decompression, or in knockout (KO) mice lacking myeloperoxidase or iNOS. If MPs were harvested from control (no decompression) mice and injected into naive mice, no AP broadening occurred, but AP broadening was observed with injections of equal numbers of MPs from either wild-type or iNOS KO mice subjected to decompression stress. Although not required for AP broadening, MPs from decompressed mice, but not control mice, exhibit NADPH oxidase activation. We conclude that inherent differences in MPs from decompressed mice, rather than elevated MPs numbers, mediate neurological injury and that a component of the perivascular response to MPs involves iNOS. Additional study is needed to determine the mechanism of AP broadening and also mechanisms for MP generation associated with exposure to elevated gas pressure.

Topics: Action Potentials; Animals; Cell-Derived Microparticles; Decompression; Decompression Sickness; Disease Models, Animal; Enzyme Activation; Enzyme Inhibitors; Kinetics; Mice; Mice, Knockout; NADPH Oxidases; Nitric Oxide; Nitric Oxide Synthase Type II; Peroxidase; Pituitary Diseases; Pituitary Gland, Posterior; Polyethylene Glycols; Thrombocytopenia

The conventional method for the real-time assessment of murine colitis requires a large number of animals. The (13)C-butyrate breath test could be useful for evaluating disease activity and the amelioration of human ulcerative colitis non-invasively. The purpose of this study was to investigate whether this test can be used to assess the phase of inflammation in murine colitis. We investigated the excretion of (13)CO2 measured by the (13)C-butyrate breath test after rectal instillation of butyrate in the DSS colitis model. The colon length, MPO activity, and histological damage were analyzed as parameters. The efficacy of salicylazosulfa-pyridine (SASP) on (13)CO2 excretion was also studied. The (13)CO2 excretion curves in the 0.5% DSS- and 0.75% DSS-treated groups were significantly lower than those in the normal group (P < 0.01, P < 0.01). Good correlation between the results of the breath test and the inflammation parameters was observed. The (13)CO2 excretion curve in DSS murine colitis after the administration of SASP was significantly higher than in the normal group (P < 0.01). The (13)C-butyrate breath test can be used to evaluate the inflammatory phase of DSS murine colitis, and it may be a new non-invasive method for assessing murine colitis.

Topics: Administration, Rectal; Animals; Biomarkers; Breath Tests; Butyrates; Carbon Dioxide; Carbon Isotopes; Colitis, Ulcerative; Colon; Dextran Sulfate; Disease Models, Animal; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mustard Plant; Peroxidase; Plant Oils; Sulfasalazine

To test the hypothesis that restoration of antithrombin plasma concentrations attenuates vascular leakage by inhibiting neutrophil activation through syndecan-4 receptor inhibition in an established ovine model of acute lung injury.. Randomized controlled laboratory experiment.. University animal research facility.. Eighteen chronically instrumented sheep.. Following combined burn and smoke inhalation injury (40% of total body surface area, third-degree flame burn; 4 × 12 breaths of cold cotton smoke), chronically instrumented sheep were randomly assigned to receive an IV infusion of 6 IU/kg/hr recombinant human antithrombin III or normal saline (n = 6 each) during the 48-hour study period. In addition, six sham animals (not injured, continuous infusion of vehicle) were used to obtain reference values for histological and immunohistochemical analyses.. Compared to control animals, recombinant human antithrombin III reduced the number of neutrophils per hour in the pulmonary lymph (p < 0.01 at 24 and 48 hr), alveolar neutrophil infiltration (p = 0.04), and pulmonary myeloperoxidase activity (p = 0.026). Flow cytometric analysis revealed a significant reduction of syndecan-4-positive neutrophils (p = 0.002 vs control at 24 hr). Treatment with recombinant human antithrombin III resulted in a reduction of pulmonary nitrosative stress (p = 0.002), airway obstruction (bronchi: p = 0.001, bronchioli: p = 0.013), parenchymal edema (p = 0.044), and lung bloodless wet-to-dry-weight ratio (p = 0.015). Clinically, recombinant human antithrombin III attenuated the increased pulmonary transvascular fluid flux (12-48 hr: p ≤ 0.001 vs control each) and the deteriorated pulmonary gas exchange (12-48 hr: p < 0.05 vs control each) without increasing the risk of bleeding.. The present study provides evidence for the interaction between antithrombin and neutrophils in vivo, its pathophysiological role in vascular leakage, and the therapeutic potential of recombinant human antithrombin III in a large animal model of acute lung injury.

Topics: Acute Lung Injury; Airway Obstruction; Animals; Antithrombin III; Antithrombins; Burns; Capillary Permeability; Cell Movement; Disease Models, Animal; Edema; Female; Lung; Neutrophil Activation; Neutrophils; Peroxidase; Pulmonary Gas Exchange; Random Allocation; Receptors, G-Protein-Coupled; Recombinant Proteins; Sheep; Smoke Inhalation Injury; Syndecan-4

The aim of this study was to evaluate the effect of telmisartan (TELM) on inflammation, oxidation and the expression of matrix metalloproteinases (MMPs) and the expression RANKL/RANK/OPG in the periodontal tissue of a rat model for ligature-induced periodontitis.. Male Wistar albino rats were randomly divided into five groups of 10 rats each: (i) non-ligated, given water; (ii) ligated, given water; (iii) ligated, given 1 mg/kg TELM; (iv) ligated, given 5 mg/kg TELM; and (v) ligated, given 10 mg/kg TELM. All groups were treated with saline or TELM for 10 days. Periodontal tissue was analysed by histopathology; by the immunohistochemical examination of COX-2, MMP-2, MMP-9 and the RANKL/RANK/OPG pathway; and by ELISA analysis of the levels of IL-1β, IL-10, TNF-α, myeloperoxidase (MPO), malonaldehyde (MDA) and glutathione (GSH).. Treatment with 10 mg/kg TELM resulted in reduced concentrations of MPO, MDA (p < 0.05) and the pro-inflammatory cytokine IL-1β (p < 0.05); reduced expression of MMP-2, MMP-9, RANK, RANKL and COX-2; and an increase in OPG. The levels of TNF-α were significantly reduced in all TELM-treated groups.. These findings confirm the involvement of TELM in reducing the inflammatory response, oxidative stress and bone loss in ligature-induced periodontitis in rats.

Topics: Alveolar Bone Loss; Animals; Anti-Inflammatory Agents; Antioxidants; Benzimidazoles; Benzoates; Cyclooxygenase 2; Disease Models, Animal; Down-Regulation; Glutathione; Interleukin-10; Interleukin-1beta; Male; Malondialdehyde; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Osteoprotegerin; Oxidative Stress; Periodontitis; Peroxidase; Random Allocation; RANK Ligand; Rats; Rats, Wistar; Receptor Activator of Nuclear Factor-kappa B; Telmisartan; Tumor Necrosis Factor-alpha

Pomegranate (Punica granatum L.; Lythraceae) has traditionally been used for the treatment of various inflammatory diseases, including ulcerative colitis (UC). Because its fruits and extracts are rich in ellagitannins, which release ellagic acid when hydrolyzed, consumption of pomegranate products is currently being widely promoted for their potential health effects, including the prevention of inflammatory diseases and cancer. To evaluate the anti-inflammatory effects of ellagic acid on dextran sulfate sodium (DSS)-induced acute and chronic experimental colitis in two different strains of mice and to elucidate its possible mechanisms of action.. In the acute UC model, female Balb/C mice were treated with DSS (5%) for seven days while concomitantly receiving a dietary supplement of ellagic acid (2%). In the chronic UC model, female C57BL/6 mice received four week-long cycles of DSS (1% and 2%) interspersed with week-long recovery periods along with a diet supplemented with ellagic acid (0.5%).. In acute model of UC, ellagic acid ameliorated disease severity slightly as observed both macroscopically and through the profile of inflammatory mediators (IL-6, TNF-α, and IFN-γ). In the chronic UC model, ellagic acid significantly inhibited the progression of the disease, reducing intestinal inflammation and decreasing histological scores. Moreover, mediators such as COX-2 and iNOS were downregulated and the signaling pathways p38 MAPK, NF-κB, and STAT3 were blocked.. Our study reinforces the hypothetical use of ellagic acid as an anti-inflammatory complement to conventional UC treatment in chronic UC patients and could be considered in the dietary prevention of intestinal inflammation and related cancer development.

Topics: Animals; Anti-Inflammatory Agents; Colitis; Colon; Cytokines; Dextran Sulfate; Disease Models, Animal; Ellagic Acid; Female; I-kappa B Proteins; Intestinal Mucosa; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; NF-kappa B; NF-KappaB Inhibitor alpha; p38 Mitogen-Activated Protein Kinases; Peroxidase; STAT3 Transcription Factor

Ischemia-reperfusion lung injury is a common cause of acute morbidity and mortality in lung transplant recipients and has been associated with subsequent development of bronchiolitis obliterans syndrome. Recognition of endogenous ligands released during cellular injury (damage-associated molecular patterns; DAMPs) by Toll-like receptors (TLRs), especially TLR4, has increasingly been recognized as a mechanism for inflammation resulting from tissue damage. TLR4 is implicated in the pathogenesis of ischemia-reperfusion injury of multiple organs including heart, liver, kidney and lung. Additionally, activation of TLRs other than TLR4 by DAMPs has been identified in tissues other than the lung. Because all known TLRs, with the exception of TLR3, signal via the MyD88 adapter protein, we hypothesized that lung ischemia-reperfusion injury was mediated by MyD88-dependent signaling. To test this hypothesis, we subjected C57BL/6 wildtype, Myd88(-/-), and Tlr4(-/-) mice to 1 hr of left lung warm ischemia followed by 4 hr of reperfusion. We found that Myd88(-/-) mice had significantly less MCP-1/CCL2 in the left lung following ischemia-reperfusion as compared with wildtype mice. This difference was associated with dramatically reduced lung permeability. Interestingly, Tlr4(-/-) mice had only partial protection from ischemia-reperfusion as compared to Myd88(-/-) mice, implicating other MyD88-dependent pathways in lung injury following ischemia-reperfusion. We also found that left lung ischemia-reperfusion caused remote inflammation in the right lung. Finally, using chimeric mice with MyD88 expression restricted to either myeloid or non-myeloid cells, we found that MyD88-dependent signaling in myeloid cells was necessary for ischemia-reperfusion induced lung permeability. We conclude that MyD88-dependent signaling through multiple receptors is important in the pathogenesis of acute lung inflammation and injury following ischemia and reperfusion.

Topics: Acute Lung Injury; Animals; Chemokine CCL2; Cytokines; Disease Models, Animal; HEK293 Cells; Humans; Ligands; Lung; Mice; Mice, Knockout; Myeloid Cells; Myeloid Differentiation Factor 88; Permeability; Peroxidase; Pulmonary Alveoli; Reperfusion Injury; Time Factors; Toll-Like Receptor 4

Mucosal healing (MH) decreases the relapse risk in patients with inflammatory bowel disease, but the role of dietary supplementation in this process has been poorly investigated. Here, we investigated the effect of an amino acid mixture supplement on rat MH.. Colitis was induced using 5% of dextran sodium sulfate for 6 days. Then, rats received a mixture of threonine (0.50 g/d), methionine (0.31 g/d), and monosodium glutamate (0.57 g/d) or an isonitrogenous amount of alanine (control group). Colons were recovered after colitis induction and after dietary supplementation for measuring colon characteristics, myeloperoxidase, cytokine gene expression, glutathione content, protein synthesis rate, and for histological analysis. Short-chain fatty acids were measured in the colonic content.. Colitis induction resulted in anorexia, thickening and shortening of the colon, and ulceration. Colonic cytokine expression and neutrophil infiltration were increased. An increased amount of water and a decreased amount of butyrate, propionate, and acetate were measured in the colonic content. Supplementation with the amino acid mixture coincided with a reduced protein synthesis rate in the colon compatible with the observed increased colonic MH. Mucosal regeneration/re-epithelialization was visible within 3 days after colitis induction at a time when mucosal inflammation was severe. Histological analysis revealed an increased regeneration/re-epithelialization after 10-day supplementation. In contrast, the spontaneous resolution of inflammation was not affected by the supplementation.. Amino acid supplementation ameliorates colonic MH but not mucosal inflammatory status. Our data sustain the use of adjuvant dietary intervention on initiated intestinal MH.

Topics: Amino Acids; Animals; Colitis; Colon; Dextran Sulfate; Disease Models, Animal; Glutathione; Immunoenzyme Techniques; Intestinal Mucosa; Male; Peroxidase; Rats; Rats, Wistar

Acute intestinal ischaemia/reperfusion injury (AII/R) is an adaptive physiologic response during critical illness, involving mesenteric vasoconstriction and hypoperfusion. Prevention of AII/R in high risk patient populations would have a significant impact on morbidity and mortality. The purpose of this study was to investigate the protective effects of VSL#3 probiotic treatment in a murine model of AII/R. Adult 129/SvEv mice were subjected to an experimental AII/R model using superior mesenteric artery occlusion. Animals were pre-treated with either three days or two weeks of VSL#3 probiotics. Local tissue injury markers were assessed by levels of myeloperoxidase and activation of nuclear factor kappa B (NFкB). Systemic and local cytokines, including interleukin (IL)-1β, IL- 10, TNFα, and interferon gamma were measured by ELISA and multiplex fluorescent detection. VSL#3 probiotics reduced local tissue inflammation and injury due to AII/R. A two-week course of VSL#3 was more effective than a shorter three-day course. The reduction in local inflammation from the two-week course of VSL#3 is correlated to a significant reduction in levels of active IL-1β, and tissue levels of myeloperoxidase. Levels of active NFкB were significantly elevated in the vehicle-fed AII/R mice, corroborating with tissue inflammation, which were attenuated by VSL#3 administrations. VSL#3 did not cause any systemic inflammation or lung injury. VSL#3 probiotics are effective in reducing local tissue injury from AII/R by down-regulating pro-inflammatory mediators and immune cell recruitment. This study highlights a potential role for VSL#3 in management of patients at high risk for AII/R.

Topics: Animals; Cytokines; Disease Models, Animal; Intestinal Diseases; Ischemia; Mice; NF-kappa B; Peroxidase; Probiotics; Reperfusion Injury; Treatment Outcome

Rosmarinus officinalis, also named rosemary, is a native plant from the Mediterranean region that is useful for the treatment of inflammatory diseases. Studies using experimental models and/or in vitro tests have shown the important biological effects of rosemary. In this context, the mechanism of the anti-inflammatory activity of rosemary must be investigated to support the discovery of new substances with anti-inflammatory effects. The aim of the present study was to investigate the anti-inflammatory effects of crude extract oil free obtained from the leaves of rosemary in an animal model of inflammation, thus evaluating its medicinal use for the treatment of inflammatory conditions. Also its ethanol, hexane, and ethyl acetate fractions, as well as its isolated compounds carnosol and rosmarinic acid were analyzed. Swiss mice were used for the in vivo experiments. The effect of this herb on the inhibition of the leukocytes, exudation, myeloperoxidase, and adenosine-deaminase activities, nitrite/nitrate, interleukin 17A, and interleukin 10 levels and mRNA expression was determined. The crude extract and its derived fractions, in addition to its isolated compounds, inhibited leukocytes and decreased exudation and myeloperoxidase and adenosine-deaminase activities, as well as nitrite/nitrate and interleukin 17A levels and mRNA expression, besides increasing interleukin 10 levels and mRNA expression. Rosemary showed important anti-inflammatory activity by inhibiting leukocytes and decreasing exudation. These effects were associated with a decrease in the proinflammatory parameters (myeloperoxidase, adenosine-deaminase, nitrite/nitrate, and interleukin 17A) and an increase in the anti-inflammatory cytokine (interleukin 10). This study confirms the anti-inflammatory properties of rosemary and validates its use in folk medicine to treat inflammatory diseases such as rheumatism and asthma.

Topics: Abietanes; Adenosine Deaminase; Animals; Anti-Inflammatory Agents; Carrageenan; Cinnamates; Cytokines; Depsides; Disease Models, Animal; Inflammation; Inflammation Mediators; Leukocytes; Mice; Mice, Inbred Strains; Nitrates; Nitrites; Peroxidase; Phytotherapy; Plant Extracts; Plant Leaves; Pleurisy; RNA, Messenger; Rosmarinic Acid; Rosmarinus

Hemorrhagic cystitis (HC) is a common side effect of cyclophosphamide therapy, which deserves new therapeutic strategies, such as those based on natural products. The ethanol extract of the inner bark of Caesalpinia pyramidalis (Tul.) (EECp) possesses anti-inflammatory, antinociceptive, and antioxidant activities as previously showed by our group. We have investigated the effect of EECp on the cyclophosphamide-induced HC. Cystitis was induced in male Wistar rats by the injection of cyclophosphamide. These animals were pretreated with EECp (100-400 mg/kg), vehicle, or mesna. Myeloperoxidase activity and malondialdehyde formation were measured in urinary bladder and other tissues. Bladder edema and histopathological alterations and serum nitric oxide metabolites concentration NOx- were also evaluated. Treatment with EECp (100-400 mg/kg) or mesna impaired the increase of myeloperoxidase activity in urinary bladder and the serum NOx- induced by cyclophosphamide but did not reduce edema in this tissue, as did mesna. Total histological score was reduced by EECp (100 mg/kg). Lung myeloperoxidase activity, which was increased by cyclophosphamide, was decreased significantly by EECp (400 mg/kg). EECp also diminished the malondialdehyde formation in bladder, lung, and spleen, although these parameters were not affected by cyclophosphamide. These results indicate that EECp reduced urinary bladder damage during cyclophosphamide-induced HC in rats.

Topics: Animals; Anti-Inflammatory Agents; Caesalpinia; Cyclophosphamide; Cystitis; Disease Models, Animal; Enzyme Activation; Hemorrhage; Leukocyte Count; Lipid Peroxidation; Male; Malondialdehyde; Nitric Oxide; Peroxidase; Plant Bark; Plant Extracts; Rats; Urinary Bladder

The present study evaluated the anti-inflammatory effects of 4-methylcyclopentadecanone (4-MCPC) on edema models in mice and aimed to determine the safety of 4-MCPC after acute exposure. The acute toxicity of 4-MCPC was evaluated by oral administration to rats of single doses of 0, 5, 50, 500 and 5000 mg/kg. Toxic symptoms were observed for 14 days. The anti-inflammatory activity was evaluated in xylene-induced mouse ear edema and carrageenan-induced mouse paw edema. The animals were treated with 4-MCPC once every day for seven consecutive days. Edema index, % inhibition, IL-1β, TNF-α, PGE2 and MPO levels in paws were detected after the treatment with xylene or carrageenan. Our results indicated that the LD50 value of 4-MCPC in rats is greater than 5000 mg/kg. The ED50 of 4-MCPC in xylene-induced mouse ear edema model was 7.5 mg/kg. 4-MCPC (8 or 16 mg/kg) remarkably inhibited carrageenan-induced mouse paw edema. Further study revealed that 4-MCPC treatment also decreased IL-1β, TNF-α, PGE2 and MPO levels in mice paws. Intragastric administration of 4-MCPC exhibited more significant anti-inflammatory activity than muscone at a dose of 16 mg/kg. Taken together, our results suggest that 4-MCPC has potent anti-inflammatory activity and the mechanisms might be related to the decreases of the levels of IL-1β, TNF-α, PGE2 and MPO in inflamed paws.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Carrageenan; Dinoprostone; Disease Models, Animal; Edema; Interleukin-1beta; Ketones; Macrocyclic Compounds; Male; Mice; Peroxidase; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha; Xylenes

Melanin-concentrating hormone (MCH), an evolutionarily conserved appetite-regulating neuropeptide, has been recently implicated in the pathogenesis of inflammatory bowel disease (IBD). Expression of MCH is upregulated in inflamed intestinal mucosa in humans with colitis and MCH-deficient mice treated with trinitrobenzene-sulfonic acid (TNBS) develop an attenuated form of colitis compared to wild type animals. Zebrafish have emerged as a new animal model of IBD, although the majority of the reported studies concern zebrafish larvae. Regulation MCH expression in the adult zebrafish intestine remains unknown.. In the present study we induced enterocolitis in adult zebrafish by intrarectal administration of TNBS. Follow-up included survival analysis, histological assessment of changes in intestinal architecture, and assessment of intestinal infiltration by myeloperoxidase positive cells and cytokine transcript levels.. Treatment with TNBS dose-dependently reduced fish survival. This response required the presence of an intact microbiome, since fish pre-treated with vancomycin developed less severe enterocolitis. At 6 hours post-challenge, we detected a significant influx of myeloperoxidase positive cells in the intestine and upregulation of both proinflammatory and anti-inflammatory cytokines. Most importantly, and in analogy to human IBD and TNBS-induced mouse experimental colitis, we found increased intestinal expression of MCH and its receptor in TNBS-treated zebrafish.. Taken together these findings not only establish a model of chemically-induced experimental enterocolitis in adult zebrafish, but point to effects of MCH in intestinal inflammation that are conserved across species.

Topics: Administration, Rectal; Animals; Cell Movement; Cytokines; Disease Models, Animal; Enterocolitis; Fish Proteins; Gene Expression Regulation; Humans; Hypothalamic Hormones; Intestinal Mucosa; Intestines; Male; Melanins; Microbiota; Peroxidase; Pituitary Hormones; Receptors, Pituitary Hormone; Survival Analysis; Trinitrobenzenesulfonic Acid; Vancomycin; Zebrafish

Dihydrocorynantheol (DHC) is an alkaloid compound isolated from Esenbeckia leiocarpa Engl. that has demonstrated anti-inflammatory properties in experimental models. The aim of this study was to investigate whether the modification of the chemical structure of DHC could alter its anti-inflammatory effect in a mouse model of pleurisy induced by carrageenan.. DHC was isolated from Esenbeckia leiocarpa Engl. Capillary electrophoresis, physical characteristics, spectral data produced by infrared analysis and nuclearmagnetic resonance ((1)H and (13)C), and mass spectrometry analysis were used to identify and elucidate DHC structure. The DHC compound was subjected to chemical structural modifications by nucleophilic substitution reactions, yielding five analogous compounds: acetyl (1), p-methylbenzoyl (2), benzoyl (3), p-methoxybenzoyl (4) and p-chlorobenzoyl (5). Swiss mice were used throughout the experiments. Pro-inflammatory parameters leukocyte migration, exudate concentrations and myeloperoxidase (MPO) activity were quantified in the fluid leakage from the mouse pleural cavities at 4 h after pleurisy induction.. DHC and its analogues acetyl, p-methylbenzoyl, benzoyl, p-methoxybenzoyl and p-chlorobenzoyl inhibited total and differential leukocyte migration and MPO activity (p < 0.05). Only DHC significantly decreased the exudate concentrations (p < 0.01).. DHC was more effective than its analogues as an anti-inflammatory agent in the mouse model of pleurisy induced by carrageenan. We did not determine what physicochemical modifications altered the anti-inflammatory effect of DHC, but this effect may be due to the modifications on the hydroxyl group at carbon 17 of the DHC.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents; Carrageenan; Chemotaxis, Leukocyte; Disease Models, Animal; Dose-Response Relationship, Drug; Exudates and Transudates; Female; Male; Mice; Molecular Structure; Neutrophil Infiltration; Peroxidase; Phytotherapy; Plant Bark; Plant Extracts; Plants, Medicinal; Pleura; Pleurisy; Rutaceae; Structure-Activity Relationship

To evaluate the potential effectiveness of hydroxynaphthoquinone mixture (HM) in rats with 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis.. Colitis was induced by intracolonic administration of TNBS (80 mg/kg, dissolved in 50% ethanol). Rats were treated daily for 7 d with HM (2.5, 5, 10 mg/kg) and mesalazine 100 mg/kg 24 h after TNBS instillation. Disease progression was monitored daily by observation of clinical signs and body weight change. At the end of the experiment, macroscopic and histopathologic lesions of rats were scored, and myeloperoxidase (MPO) activity was determined. We also determined inflammatory cytokine tumor necrosis factor (TNF)-α level by ELISA, Western blotting and immunochemistry to explore the potential mechanisms of HM.. After intracolonic instillation of TNBS, animals developed colitis associated with soft stool, diarrhea and marked colonic destruction. Administration of HM significantly attenuated clinical and histopathologic severity of TNBS-induced colitis in a dose-dependent manner. It abrogated body weight loss, diarrhea and inflammation, decreased macroscopic damage score, and improved histological signs, with a significant reduction of inflammatory infiltration, ulcer size and the severity of goblet cell depletion (all P < 0.05 vs TNBS alone group). HM could reduce MPO activity. In addition, it also decreased serum TNF-α level and down-regulated TNF-α expression in colonic tissue. This reduction was statistically significant when the dose of HM was 10 mg/kg (P < 0.05 vs TNBS alone group), and the effect was comparable to that of mesalazine and showed no apparent adverse effect. The underlying mechanism may be associated with TNF-α inhibition.. These findings suggest that HM possesses favourable therapeutic action in TNBS-induced colitis, which provides direct pharmacological evidence for its clinical application.

Topics: Animals; Anti-Inflammatory Agents; Boraginaceae; Colitis, Ulcerative; Colon; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Gastrointestinal Agents; Goblet Cells; Inflammation Mediators; Male; Mesalamine; Naphthoquinones; Peroxidase; Phytotherapy; Plant Extracts; Plants, Medicinal; Rats; Rats, Sprague-Dawley; Time Factors; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

Formaldehyde exposure during the menstrual cycle is known to affect the course of allergic lung inflammation. Because our previous data demonstrated that formaldehyde combined with an ovariectomy reduced allergic lung inflammation, we investigated the putative role of ovary removal and progesterone treatment when considering the effect of formaldehyde on allergic lung inflammation.. Ovariectomized rats and their matched controls were exposed to formaldehyde (1%, 3 days, 90 min/day) or vehicle, and immediately after exposure, the rats were sensitized to ovalbumin by a subcutaneous route. After 1 week, the rats received a booster by the same route, and after an additional week, the rats were challenged with ovalbumin (1%) by an aerosol route. The leukocyte numbers, interleukin-10 (IL-10) release, myeloperoxidase activity, vascular permeability, ex vivo tracheal reactivity to methacholine and mast cell degranulation were determined 24 h later.. Our results showed that previous exposure to formaldehyde in allergic rats decreased lung cell recruitment, tracheal reactivity, myeloperoxidase activity, vascular permeability and mast cell degranulation while increasing IL-10 levels. Ovariectomy only caused an additional reduction in tracheal reactivity without changing the other parameters studied. Progesterone treatment reversed the effects of formaldehyde exposure on ex vivo tracheal reactivity, cell influx into the lungs and mast cell degranulation.. In conclusion, our study revealed that formaldehyde and ovariectomy downregulated allergic lung inflammation by IL-10 release and mast cell degranulation. Progesterone treatment increased eosinophil recruitment and mast cell degranulation, which in turn may be responsible for tracheal hyperreactivity and allergic lung inflammation.

Topics: Animals; Cell Degranulation; Disease Models, Animal; Female; Formaldehyde; Interleukin-10; Leukocyte Count; Lung; Mast Cells; Ovalbumin; Ovariectomy; Peroxidase; Pneumonia; Progesterone; Random Allocation; Rats; Rats, Wistar; Respiratory Hypersensitivity; Time Factors

There is a strong male predominance of oesophageal adenocarcinoma, which might be related to the higher prevalence of precursor lesions such as erosive reflux oesophagitis in men compared with women. This experiment investigated the gender difference in a reflux oesophagitis model of rats and explored the potential role of oestrogen in controlling oesophageal tissue damage.. An acid-reflux oesophagitis model was surgically produced in male and female rats, and ascorbic acid in the diet and sodium nitrite in the drinking water were administered to half of either group to provoke luminal exogenous nitric oxide (NO) as an exacerbating agent. Seven days after the surgery, the oesophagus was excised, and the injury area, myeloperoxidase activity and pro-inflammatory cytokine levels were measured. Furthermore, 17β-oestradiol was administered to ovariectomised female rats or male rats, which then underwent reflux oesophagitis surgery.. While there was no gender difference in oesophageal damage in the baseline model, oesophageal damage was more intensively observed in males than in females in the presence of exogenous NO administration. While oesophageal damage was increased in ovariectomised rats compared with sham ovariectomised, exacerbated oesophageal damage was attenuated by the replacement of 17β-oestradiol. In addition, exacerbated oesophageal damage in male rats was suppressed by 17β-oestradiol.. This is the first study showing the prominent gender difference in the severity of oesophageal tissue damage in a gastro-oesophageal reflux disease-related animal model, highlighting the critical involvement of oestrogen in controlling gastro-oesophageal reflux disease-related oesophageal epithelial injury.

Topics: Animals; Ascorbic Acid; Biomarkers; Chronic Disease; Cytokines; Disease Models, Animal; Esophagitis, Peptic; Esophagus; Estradiol; Estrogens; Female; Gastroesophageal Reflux; Male; Mucous Membrane; Nitric Oxide; Ovariectomy; Peroxidase; Random Allocation; Rats; Rats, Wistar; Severity of Illness Index; Sex Factors; Sodium Nitrite; Stomach

The objective of the present study was to evaluate the protective effects of halofuginone against renal ischemia/reperfusion (I/R) injury.. Male Wistar albino rats were unilaterally nephrectomized and the left renal pedicles were occluded for 45 min to induce ischemia and then reperfused for 6 h (early) or for 72 h (late). The rats were treated intraperitoneally with either halofuginone (100 μg/kg/day) or saline 30 min prior to ischemia and the dose was repeated in the late reperfusion groups. In the sham groups, rats underwent unilateral nephrectomy and were treated at similar time points. The animals were decapitated at either 6 h or 72 h of reperfusion and trunk blood and kidney samples were obtained.. I/R injury increased renal malondialdehyde levels, myeloperoxidase activity and reactive oxygen radical levels, and decreased the renal glutathione content. Halofuginone treatment was found to reduce oxidative I/R injury and improve renal function in the rat kidney, as evidenced by reduced generation of reactive oxygen species, depressed lipid peroxidation and myeloperoxidase activity, and increased glutathione levels.. The present findings demonstrate the anti-inflammatory and antioxidant effects of halofuginone in renal I/R injury, supporting its potential use where renal I/R injury is inevitable.

Topics: Animals; Blood Urea Nitrogen; Creatinine; Disease Models, Animal; Fibrosis; Glutathione; Kidney Diseases; L-Lactate Dehydrogenase; Lipid Peroxidation; Male; Nephrectomy; Oxidative Stress; Peroxidase; Piperidines; Protein Synthesis Inhibitors; Quinazolinones; Rats; Rats, Wistar; Reperfusion Injury

We sought to elucidate whether minocycline, a broad-spectrum tetracycline antibiotic with potent anti-inflammation capacity, could mitigate inflammatory response and organ dysfunction in the lungs and liver induced by hemorrhagic shock/resuscitation (HS) plus abdominal compartment syndrome (ACS).. Adult male rats were randomized to receive HS plus ACS or HS plus ACS plus minocycline (denoted as the HS/A and HS/A-M group, respectively; n = 12). Sham-instrumentation groups were employed to serve as the controls. Hemorrhagic shock/resuscitation was induced by blood drawing (mean arterial pressure: 40-45 mm Hg for 60 min) followed by shed blood/saline mixture reinfusion. Subsequently, intra-abdominal pressure (IAP) was increased to 25 mm Hg by injecting air into the preplaced intraperitoneal latex balloon to induce ACS. Minocycline (20 mg/kg) was intravenously administered immediately after resuscitation. IAP was maintained at 25 mm Hg for 6 h. Then, all rats were euthanized.. The levels of polymorphonuclear leukocyte infiltration, the wet/dry weight ratio, and the concentrations of inflammatory molecules (e.g., chemokine, cytokine, and prostaglandin E2) in lung and liver tissues of the HS/A group were significantly higher than those of the HS/A-M groups (all P < 0.05). Moreover, the levels of lung dysfunction (assayed by arterial blood gas) and liver dysfunction (assayed by plasma concentrations of bilirubin, aspartate aminotransferase, and alaninine aminotransferase) of the HS/A group were significantly higher than those of the HS/A-M group (all P < 0.05).. Minocycline ameliorates inflammatory response and organ dysfunction in the lungs and liver induced by hemorrhagic shock/resuscitation plus abdominal compartment syndrome.

Topics: Alanine Transaminase; Animals; Anti-Bacterial Agents; Aspartate Aminotransferases; Disease Models, Animal; Hemodynamics; Intra-Abdominal Hypertension; Liver; Lung; Male; Minocycline; Peroxidase; Rats; Rats, Sprague-Dawley; Shock, Hemorrhagic

Oxygen-induced lung injury is believed to lead to the development of bronchopulmonary dysplasia in premature infants. We have evaluated the beneficial effects of Nigella sativa oil (NSO) on rats with hyperoxia-induced lung injury.. Thirty newborn Sprague-Dawley rats were randomly divided into 3 groups as hyperoxia (95% O(2)), hyperoxia+NSO and control (21% O(2)). Pups in the hyperoxia+NSO group were administered intraperitoneal NSO at a dose of 4ml/kg daily during the study period. Histopathologic, immunochemical, and biochemical evaluations (superoxide dismutase [SOD], glutathione peroxidase [GSH-Px], malonaldehyde [MDA] and myeloperoxidase [MPO]) were performed.. In the histopathologic and immunochemical evaluation, severity of lung damage was significantly lower in the hyperoxia+NOS group (P<.05). Tissue GSH-Px and SOD levels were significantly preserved, and MDA, MPO levels were significantly lower in the hyperoxia+NSO group (P<.05).. NSO significantly reduced the severity of lung damage due to hyperoxia.

Topics: Acute Lung Injury; Animals; Animals, Newborn; Disease Models, Animal; Drug Evaluation, Preclinical; Glutathione Peroxidase; Hyperoxia; Inflammation; Injections, Intraperitoneal; Lung; Malondialdehyde; Nigella sativa; Oxygen Inhalation Therapy; Peroxidase; Phytotherapy; Plant Oils; Random Allocation; Rats; Rats, Sprague-Dawley; Severity of Illness Index; Single-Blind Method; Superoxide Dismutase

Recent advances have established a fundamental role for inflammation in mediating all stages of atherosclerosis, from initiation through progression. Quercetin may be a powerful bioactive constituent of the human diet, as a free radical scavenging agent and through interactions with various endogenous proteins. The present study focused on the effect of quercetin on inflammation induced by a hypercholesterolemic diet (HCD) in rabbits.. The animals were subjected to two different experiments, atherosclerotic progression and regression. In the atherosclerotic progression study, quercetin (25 mg/kg of body weight) was administered with the HCD for 90 d. In the atherosclerotic regression study, the animals were fed with the HCD for 90 d and then supplemented with quercetin (25 mg/kg of body weight) for another 90 d. The inflammatory enzyme activities were examined and a histopathologic examination of the aorta was performed.. In the atherosclerotic progression study, quercetin coadministered with the HCD significantly decreased the activities of inflammatory enzymes such as cyclooxygenase, lipoxygenases (LOX) such as 5-LOX and 12-LOX in monocytes, nitric oxide synthase activity in the plasma, myeloperoxidase activity in the aorta, and the level of C-reactive protein in serum. In the regression study, quercetin administration significantly decreased the increased activities of inflammatory mediators such as cyclooxygenase, 5-LOX, 12-LOX, myeloperoxidase, and nitric oxide synthase and the serum level of C-reactive protein in HCD-fed rabbits compared with regression control rabbits. This effect was confirmed by histopathologic examination of the aorta.. This study demonstrates that quercetin modulates the deleterious inflammatory effects induced by an HCD in vivo in rabbits, suggesting its beneficial effect in decreasing inflammation in atherosclerotic progression and regression.

Topics: Animals; Aorta; Atherosclerosis; C-Reactive Protein; Cells, Cultured; Cholesterol, Dietary; Dietary Supplements; Disease Models, Animal; Disease Progression; Female; Free Radical Scavengers; Humans; Inflammation; Inflammation Mediators; Lipids; Lipoproteins, LDL; Lipoxygenases; Nitric Oxide Synthase; Peroxidase; Prostaglandin-Endoperoxide Synthases; Quercetin; Rabbits

The peroxisome proliferator-activated receptor-α (PPAR-α) has attracted considerable attention for its anti-inflammatory properties; however, Toll-like receptor (TLR) pathways have an essential proinflammatory role in acute pancreatitis (AP). This study aimed to evaluate the attenuation of inflammation by PPAR-α and to investigate the interaction between PPAR-α and TLR pathways in AP.. Acute pancreatitis was induced in rats by administration of cerulein. The PPAR-α agonist WY14643 and/or antagonist MK886 was administered. The severity of AP was determined by measuring serum amylase, lipase, Ca(2+), pathological changes, myeloperoxidase activity, serum levels of interleukin (IL)-6, and intercellular adhesion molecule-1 (ICAM-1). The TLR2 and TLR4 messenger RNA (mRNA) and proteins were determined by real-time reverse transcriptase polymerase chain reaction and Western blotting, respectively. The mRNA expressions of target molecules of TLR pathways, including IL-6, IL-10, ICAM-1, and tumor necrosis factor α were also measured.. Treatment with WY14643 significantly decreased amylase, lipase, myeloperoxidase activity, pathological scores, IL-6, and ICAM-1 levels. The TLR2 and TLR4 mRNA and proteins were markedly decreased after treatment with WY14643, along with IL-6, ICAM-1, and tumor necrosis factor α mRNA levels. However, these effects were completely reversed by the coadministration of MK886.. Activation of PPAR-α played a protective role in AP, partially mediated by modulation of TLR pathways.

Topics: Amylases; Animals; Anti-Inflammatory Agents; Biomarkers; Blotting, Western; Calcium; Ceruletide; Cytokines; Disease Models, Animal; Gene Expression Regulation; Indoles; Intercellular Adhesion Molecule-1; Lipase; Male; Neutrophil Infiltration; Pancreas; Pancreatitis; Peroxidase; PPAR alpha; Pyrimidines; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Time Factors; Toll-Like Receptor 2; Toll-Like Receptor 4; Toll-Like Receptor 9; Toll-Like Receptors

The anti-inflammatory effects of O-1602 and cannabidiol (CBD), the ligands of G protein-coupled receptor 55 (GPR55), on experimental acute pancreatitis (AP) were investigated.. Acute pancreatitis was induced in C57BL mice by intraperitoneal injection of 50 μg/kg cerulein hourly, with a total of 6 times. Drugs (O-1602, 10 mg/kg, or CBD, 0.5 mg/kg) were given by intraperitoneal injection 2 times at 30 minutes before the first injection and immediately before the fifth cerulein injection. At 3 hours after the last injection, the blood, the lungs, and the pancreas were harvested for the pancreatic enzyme activity, myeloperoxidase activity, and pro-inflammatory cytokines measurement; and the expressions of GPR55 mRNA and protein in the pancreas were detected.. Cannabidiol or O-1602 treatment significantly improved the pathological changes of mice with AP and decreased the enzyme activities, IL-6 and tumor necrosis factor α; levels, and the myeloperoxidase activities in plasma and in the organ tissues. G protein-coupled receptor 55 mRNA and protein expressed in the pancreatic tissue, and the expressions were decreased in the mice with AP, and either CBD or O-1602 attenuated these changes to a certain extent.. Cannabidiol and O-1602 showed anti-inflammatory effects in mice with AP and improved the expression of GPR55 in the pancreatic tissue as well.

Topics: Acute Disease; Amylases; Animals; Anti-Inflammatory Agents; Blotting, Western; Cannabidiol; Ceruletide; Disease Models, Animal; Immunohistochemistry; Inflammation Mediators; Injections, Intraperitoneal; Interleukin-6; Lipase; Lung; Mice; Mice, Inbred C57BL; Pancreas; Pancreatitis; Peroxidase; Real-Time Polymerase Chain Reaction; Receptors, Cannabinoid; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors; Tumor Necrosis Factor-alpha

The present study was designed to evaluate whether CP was beneficial in alleviating myocardial fibrosis following I/R injury.. Sprague-Dawley rats were subjected to 30 minutes occlusion of the LADCA, followed by reperfusion. CP (0.4 or 0.8 g/kg) was daily administered starting from three hour after reperfusion until day 6. Coronary venular diameter, RBC velocity, albumin leakage, MBF, heart function, myocardial infarction and fibrosis size, myocardium ultrastructure, MPO activity, and MDA level were evaluated. The expression of MCP-1, RP S19, TGF-β1, P-Smad3, Smad4, MMP-9 and α-SMA, and the infiltration of leukocytes were examined.. CP post-treatment ameliorated I/R-induced myocardial RBC velocity reduction, MBF decrease, cardiac dysfunction, and albumin leakage increase. Moreover, myocardial infarction and fibrosis size, MPO activity, MDA level, the expression of RP S19, TGF-β1, P-Smad3, Smad4, MMP-9 and α-SMA, the number of CD68-positive cells increased significantly after I/R, and myocardium collagen deposition was observed on day 6 after reperfusion. All the alterations after I/R were significantly ameliorated by CP.. Post-treatment with CP ameliorates I/R-induced myocardial fibrosis, suggesting that CP may be applied as an option for preventing cardiac remodeling after I/R injury.

Topics: Actins; Animals; Camphanes; Cardiotonic Agents; Chemokine CCL2; Coronary Circulation; Disease Models, Animal; Drugs, Chinese Herbal; Fibrosis; Hemodynamics; Male; Malondialdehyde; Matrix Metalloproteinase 9; Microcirculation; Microscopy, Electron, Transmission; Monocytes; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Panax notoginseng; Peroxidase; Phytotherapy; Rats; Rats, Sprague-Dawley; Salvia miltiorrhiza; Transforming Growth Factor beta1; Ventricular Remodeling

The cytoprotective enzyme heme oxygenase 1 (HO-1) is highly up-regulated in acute pancreatitis (AP). In this study, we tested its metabolites as potential therapeutic agents for AP in rats.. Acute necrotizing pancreatitis was induced by retrograde intraductal injection of sodium taurocholate in rats. Biliverdin hydrochloride (BV HCl) (50 μmol/kg subcutaneously), the carbon monoxide, donor methylene chloride (MC) (500 mg/kg orally), or iron-chelating desferrioxamine (DFO) (125 mg/kg subcutaneously) were administered in a therapeutic manner starting with the first dose 4 hours after taurocholate injection to mimic the effects of HO-1 metabolites.. Administration of BV HCl, MC, or DFO showed significant reduction of inflammatory activity in comparison to controls leading to lower myeloperoxidase activity in the pancreas, less edema, lower ascites volumes, and preservation of tissue integrity (P < 0.05). Administration of either BV HCl or MC markedly increased 5-day survival rate (70% and 75% vs 40%; P < 0.05), whereas DFO had no significant effect on survival (60%). When given in therapeutic manner, all 3 substances led to diminished nuclear factor κB activity in the pancreas (P < 0.05).. Therapeutic use of BV HCl and MC led to marked reduction of mortality in experimental pancreatitis. Thus, HO-1 metabolites may present a novel therapeutic approach in AP treatment.

Topics: Animals; Anti-Inflammatory Agents; Ascites; Biliverdine; Carbon Monoxide; Deferoxamine; Disease Models, Animal; Edema; Heme Oxygenase (Decyclizing); Injections, Subcutaneous; Iron Chelating Agents; Male; Methylene Chloride; NF-kappa B; Pancreas; Pancreatitis, Acute Necrotizing; Peroxidase; Rats; Rats, Wistar; Taurocholic Acid; Time Factors; Up-Regulation

Recent studies have revealed that aberrant vitamin A signaling may lead to memory deficits in rodents. Present study investigates the potential of all-trans-retinoic acid (ATRA) an agonist at retinoid acid family of receptors, in cognitive dysfunctions associated with experimental dementia. Streptozotocin (STZ) [3 mg/kg, intracerebroventricularly (i.c.v)] was administered on alternate days (day 1 and day 3) to induce dementia in Swiss albino mice. STZ mice were administered ATRA (10 mg/kg; 20 mg/kg, p.o.) for a total of 19 days following second i.c.v injection of STZ [day 4 to day 22]. Morris water maze (MWM) test was performed on days 19, 20, 21, 22 and 23 to assess learning and memory of the animals. Following MWM test, the animals were sacrificed for biochemical and histopathological studies. Extent of oxidative stress was measured by estimating the levels of brain reduced glutathione (GSH) and thiobarbituric acid reactive species (TBARS). Brain acetylcholinestrase (AChE) activity and serum cholesterol levels were also estimated. The brain level of myeloperoxidase (MPO) was measured as a marker of inflammation. STZ produced a marked decline in MWM performance of the animals, reflecting impairment of learning and memory. STZ treated mice showed marked accentuation of AChE activity, TBARS and MPO levels along with fall in GSH level. Further the stained micrographs of STZ-treated mice indicated pathological changes, severe neutrophilic infiltration and amyloid deposition. ATRA treatment significantly attenuated STZ-induced memory deficits, biochemical and histopathological alterations. The findings demonstrate that the memory restorative ability of ATRA may be attributed to its anti-cholinesterase, anti-oxidative and anti-inflammatory potential.

Topics: Alzheimer Disease; Animals; Brain; Dementia; Disease Models, Animal; Female; Glutathione; Male; Maze Learning; Memory Disorders; Mice; Peroxidase; Reactive Oxygen Species; Streptozocin; Thiobarbiturates; Tretinoin

Granulocyte colony stimulating factor (GCSF) is important in mobilising neutrophils from the bone marrow but also has a range of proinflammatory effects. We therefore decided to investigate the role of GCSF in antineutrophil cytoplasmic antibody (ANCA) vasculitis.. We measured GCSF levels in the serum of 38 patients with active ANCA vasculitis compared with 31 age-matched controls, and assessed the effect of GCSF priming on the response of human neutrophils to ANCA. We also examined the effect of exogenous GCSF administration in a murine model of antimyeloperoxidase (anti-MPO) vasculitis, and the effect of GCSF on murine neutrophil activation.. The serum levels of GCSF in patients with active ANCA vasculitis were significantly higher than those of age matched healthy controls (mean 38.04 vs 18.35 pg/ml, p<0.001). Furthermore, we demonstrated that GCSF primed human neutrophils in vitro for a respiratory burst in response to anti-MPO ANCA. In an anti-MPO antibody transfer model, mice given GCSF had more crescents (mean 29.1% vs 5.8% per glomerular cross section, p<0.05), more macrophages (mean 3.2 vs 1.2 per glomerular cross-section, p<0.01), higher serum creatines (mean 13.6 vs 8.3 μmol/l, p<0.05) and more haematuria (p<0.05) compared with controls. In vivo administration of GCSF with lipopolysaccharide (LPS), but not LPS alone, led to upregulation of CD11c on murine neutrophils.. These data suggest that GCSF, which is raised in patient serum, may play an important role in exacerbating disease in ANCA vasculitis. In addition, GCSF therapy for neutropenia should be used with caution in these patients.

Topics: Aged; Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Case-Control Studies; Disease Models, Animal; Disease Progression; Female; Glomerulonephritis; Granulocyte Colony-Stimulating Factor; Humans; Male; Mice; Neutrophil Activation; Neutrophils; Peroxidase

Oxidative stress and inflammation play an integral role in the pathogenesis of cerebral ischemia that leads to a cascade of events culminating in the death of neurons and their supporting structures. The signaling pathways that link these events are not fully understood. Recent studies have demonstrated a close link between the nuclear factor-κB (NF-κB) signaling pathway and cerebral ischemia/reperfusion (I/R)-induced inflammation. Flavonoids have been suggested to exert human health benefits by anti-oxidant and anti-inflammatory mechanisms. In this study we undertook a pharmacological approach to investigate the ability of naringenin, a potent flavonoid, to prevent oxidative stress and NF-κB-mediated inflammatory brain damage in the rat model of focal cerebral I/R injury. To test this hypothesis, male Wistar rats were pretreated with naringenin once daily for 21 days and then subjected to 1h of middle cerebral artery occlusion followed by 23 h of reperfusion. Naringenin treatment successfully upregulates the antioxidant status, decreases the infarct size and lowers the levels of myeloperoxidase, nitric oxide and cytokines, besides functional recovery returned close to the baseline. Moreover, immunohistochemical and Western blot analyses clearly demonstrated that naringenin treatment limits glial activation and downregulates the NF-κB expression level and their target genes. These results show, prophylactic treatment with naringenin improved functional outcomes and abrogated the ischemic brain injury by suppressing NF-κB-mediated neuroinflammation. The present study suggests that naringenin may be used as a potential neuroprotectant in patients at high risk of ischemic stroke.

Topics: Animals; Brain Infarction; Cytokines; Disease Models, Animal; Flavanones; Glial Fibrillary Acidic Protein; Glutathione; Hand Strength; Infarction, Middle Cerebral Artery; Lipid Peroxidation; Male; Motor Activity; Nervous System Diseases; Neuroprotective Agents; NF-kappa B; Nitric Oxide; Peroxidase; Peroxisome Proliferator-Activated Receptors; Psychomotor Performance; Rats; Rats, Wistar; Reperfusion; Signal Transduction; Thiobarbituric Acid Reactive Substances

context: Stems and leaves of Pittocaulon spp. (Asteraceae) are used in Mexican traditional medicine as an anti-inflammatory substance and for the treatment of skin injuries.. This study evaluated the antioxidant activity of methanol (MeOH) and dichloromethane (DC) extracts of five Pittocaulon species.. DC and MeOH extracts from flowers, roots, and stems of Pittocaulon praecox (Cav.) H. Rob. & Brettell, P. bombycophole (Bullock) H. Rob. & Brettell, P. filare (Mc Vaugh) H. Rob. & Brettell, P. velatum (Greenm.) Rob. & Brettell and P. hintonii H. Rob. & Brettell.. In the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, the flower extracts obtained with MeOH were the most active with IC(50) values ranging from 51.83 ± 4.08 to 154.19 ± 8.39 ppm. In the thiobarbituric acid reactive substances (TBARS) model, the best activity was shown by DC extracts of roots with IC(50) values ranging from 55.54 ± 1.28 to 160.82 ± 5.37 ppm. The MeOH extract of flowers of P. bombycophole had the highest IC(50) value in both DPPH (51.83 ± 4.08 ppm) and TBARS (39.78 ± 1.97 ppm). The samples with the best values in the antioxidant activity assays were evaluated in the anti-inflammatory tests. The DC root extract of P. velatum at a dose of 1 mg/ear produced the greatest reduction (84.96%) of the 2-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse ear edema. This extract also reduced the activity of the enzyme myeloperoxidase (MPO) (73.65%) at the same dose. In contrast, DC root extract of this species did not show significant inhibition of the increase in paw edema induced by carrageenan at the doses tested (100 mg/kg).. These results support the traditional use of these plants as anti-inflammatory. DC extracts of P. velatum and MeOH extracts of P. bombycophole may be a potential resource of natural anti-inflammatory and antioxidant compounds, respectively. Additional studies must be done to identify the compounds responsible of the activity on these plants and to establish the mechanism of action.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Asteraceae; Biphenyl Compounds; Brain; Carrageenan; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Enzyme Inhibitors; Flowers; Lipid Peroxidation; Male; Methanol; Methylene Chloride; Mexico; Mice; Peroxidase; Picrates; Plant Extracts; Plant Roots; Plant Stems; Plants, Medicinal; Rats; Rats, Wistar; Solvents; Tetradecanoylphorbol Acetate; Thiobarbituric Acid Reactive Substances

Jatropha isabellei Müll Arg. (Euphorbiaceae) is a medicinal plant that has been used in South American folk medicine for the treatment of arthritic diseases, particularly gout.. This study was designed to verify the antinociceptive, anti-inflammatory and hypouricemic potential of Jatropha isabellei.. Rats were orally administered with the crude extract (100-300 mg/kg) or a fraction that is rich in alkaloids (0.15 mg/kg) of Jatropha isabellei. An intra-articular (i.a.) injection of 50 μl of monosodium urate (MSU) crystals (1.25mg/site) was used to generate the gout model to assess the effect of the treatment on nociception (thermal and mechanical hyperalgesia) and inflammation (oedema and neutrophil infiltration). The effect of Jatropha isabellei on the serum levels of uric acid was evaluated in a model of hyperuricaemia induced by the intraperitoneal injection of potassium oxonate (250 mg/kg). The side effects were analysed using an open-field test, gastric lesion assessment and by measuring the levels of the ALT and AST enzymes.. Our study demonstrated that the crude extract of Jatropha isabellei and a fraction rich in alkaloids were able to prevent the thermal hyperalgesia, mechanical allodynia, oedema and neutrophil infiltration induced by intra-articular MSU injection in rats. On the other hand, treatment with Jatropha isabellei did not alter the uric acid levels increased by potassium oxonate in the hyperuricaemia model. In addition, Jatropha isabellei did not induce gastric lesions or liver damage and did not alter spontaneous locomotor activity.. The crude extract of Jatropha isabellei and its fraction rich in alkaloid presents antinociceptive and anti-inflammatory effects in a rat gout model, similar to that observed after treatment with colchicine, supporting the traditional use of this plant in gouty patients.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents; Arthritis, Gouty; Biomarkers, Pharmacological; Disease Models, Animal; Edema; Hyperalgesia; Hyperuricemia; Jatropha; Male; Motor Activity; Neutrophil Infiltration; Oxonic Acid; Peroxidase; Phytotherapy; Plant Extracts; Rats; Stomach Ulcer; Uric Acid; Xanthine Oxidase

The endocannabinoid system has been shown to mediate beneficial effects on gastrointestinal inflammation via cannabinoid receptors 1 (CB(1)) and 2 (CB(2)). These receptors have also been reported to activate the MAP kinases p38 and c-Jun NH(2)-terminal kinase (JNK), which are involved in early acinar events leading to acute pancreatitis and induction of proinflammatory cytokines. Our aim was to examine the role of cannabinoid receptor activation in an experimental model of acute pancreatitis and the potential involvement of MAP kinases. Cerulein pancreatitis was induced in wild-type, CB(1)-/-, and MK2-/- mice pretreated with selective cannabinoid receptor agonists or antagonists. Severity of pancreatitis was determined by serum amylase and IL-6 levels, intracellular activation of pancreatic trypsinogen, lung myeloperoxidase activity, pancreatic edema, and histological examinations. Pancreatic lysates were investigated by Western blotting using phospho-specific antibodies against p38 and JNK. Quantitative PCR data, Western blotting experiments, and immunohistochemistry clearly show that CB(1) and CB(2) are expressed in mouse pancreatic acini. During acute pancreatitis, an upregulation especially of CB(2) on apoptotic cells occurred. The unselective CB(1)/CB(2) agonist HU210 ameliorated pancreatitis in wild-type and CB(1)-/- mice, indicating that this effect is mediated by CB(2). Furthermore, blockade of CB(2), not CB(1), with selective antagonists engraved pathology. Stimulation with a selective CB(2) agonist attenuated acute pancreatitis and an increased activation of p38 was observed in the acini. With use of MK2-/- mice, it could be demonstrated that this attenuation is dependent on MK2. Hence, using the MK2-/- mouse model we reveal a novel CB(2)-activated and MAP kinase-dependent pathway that modulates cytokine expression and reduces pancreatic injury and affiliated complications.

Topics: Amylases; Animals; Anti-Inflammatory Agents; Apoptosis; Blotting, Western; Cannabinoids; Ceruletide; Disease Models, Animal; Dronabinol; Edema; Enzyme Activation; Immunohistochemistry; Interleukin-6; Intracellular Signaling Peptides and Proteins; Lung; Mice; Mice, Inbred C57BL; Mice, Knockout; p38 Mitogen-Activated Protein Kinases; Pancreas, Exocrine; Pancreatitis; Peroxidase; Phosphorylation; Polymerase Chain Reaction; Protein Serine-Threonine Kinases; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Trypsinogen

Neutrophils have been shown to be involved in all stages of human and experimental abdominal aortic aneurysm (AAA) development. The initial processes of neutrophil rolling and trapping in the intraluminal thrombus (ILT) are mediated mainly by P-selectin expressed by activated platelets. In the present study, we propose to evaluate the beneficial effect of fucoidan, a competitive binding agent of P-selectin, on aneurysmal growth in a rat model of aortic aneurysm with neutrophil enrichment of the ILT induced by repeated episodes of weak bacteremia.. Sixty Lewis rats with experimental AAAs, developed from decellularized aortic xenografts, were divided into four groups. Two groups were used as controls: group fucoidan control (FC) was treated with 200 mg of fucoidan (F) delivered by 2 mL, 4-week osmotic pumps placed intraperitoneally before closing the abdomen, and group C received saline instead of fucoidan. Two more groups were injected weekly with Porphyromonas gingivalis (P. gingivalis [Pg]): group F+Pg received 200 mg of intraperitoneal fucoidan and group Pg received saline. AAAs were harvested after 4 weeks and peripheral blood was sampled at that time. Cell-free DNA (cf-DNA) and myeloperoxydase (MPO) antigen concentrations were determined in plasma and in AAA-conditioned media. Histology and P-selectin immunostaining were performed on AAA tissue samples.. Comparing rats injected with Pg, those receiving fucoidan presented reduced aneurysmal diameter. Histologic analysis of AAAs showed that fucoidan reduced the ILT thickness in Pg-injected rats, with fewer trapped neutrophils, and with signs of a healing process, as observed in control group C. Immunohistological analysis revealed a substantial decrease in P-selectin immunostaining at the luminal surface of aneurysms in fucoidan-treated rats compared to the other groups, suggesting an interaction between fucoidan and P-selectin. A significant decrease in MPO concentrations in both plasma and conditioned medium was induced by fucoidan treatment in Pg-injected rats, reflecting a pacification of the ILT biological activity. This effect was associated with a reduction in neutrophil activation and apoptosis, reflected by a significant decrease in cf-DNA concentration in both plasma and conditioned medium of fucoidan-treated rats.. Our results suggest that fucoidan has a beneficial effect on experimental aneurysmal degeneration by decreasing neutrophil activation in the ILT enhanced by weak pathogen contamination. This effect seems to be related to its interaction with P-selectin, which may decrease the trapping of neutrophils into the ILT. Fucoidan could represent a therapeutic option in AAAs to decrease the neutrophil activation involved in the degenerative process of aneurysmal expansion and rupture.

Topics: Aneurysm, Infected; Animals; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Apoptosis; Bacteroidaceae Infections; Biomarkers; Disease Models, Animal; DNA; Guinea Pigs; Immunohistochemistry; Infusions, Parenteral; Neutrophil Activation; Neutrophils; P-Selectin; Peroxidase; Polysaccharides; Porphyromonas gingivalis; Rats; Rats, Inbred Lew; Time Factors

The dextran sulfate sodium (DSS)-induced model of colitis is a commonly used model of inflammatory bowel disease (IBD) in animals. However, there were few studies on the therapeutic efficacy of drugs for IBD after the onset of colitis in this model. We established a semi-chronic model of DSS-induced colitis in mice and used it to assess the therapeutic efficacy of agents for IBD.. Colitis was induced by administration of 3% DSS in drinking water to mice for 7days followed by 5days of normal drinking water.. Ulcerative colitis (UC)-like symptoms including diarrhea, bloody stools and body-weight loss were observed from days 3 to 5, and continued until day 12 after DSS administration. Persistent colitis was associated with sustained local production of cytokines and was characterized by infiltration of inflammatory cells, crypt loss and erosion in the distal colon. These features are similar to those found in patients with UC. In this model, anti-tumor necrosis factor (TNF)-α antibody or anti-interleukin (IL)-12/23p40 antibody significantly ameliorated colitis when administered after the onset of colitis. However, treatment with FK506, prednisolone or sulfasalazine provided limited therapeutic benefit.. The DSS-induced colitis established here showed similar symptomatic and histopathological features to those seen in human UC. This model may be available for predicting the clinical efficacy of candidate compounds for UC.

Topics: Animals; Anti-Inflammatory Agents; Antibodies; Colitis; Cytokines; Dextran Sulfate; Disease Models, Animal; Female; Gastrointestinal Agents; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mice; Mice, Inbred C57BL; Peroxidase; Prednisolone; Sulfasalazine; Tacrolimus

Ischemia-reperfusion injury is an important factor in the development of lower urinary tract symptoms (LUTS) that is partly mediated by the generation of free radicals. We investigate the effect of the phytotherapeutic agent Eviprostat, a treatment for benign prostatic hyperplasia (BPH) that has antioxidant and anti-inflammatory activity, on urinary bladder blood flow (BBF), and function in a rat model of bladder overdistension and emptying (OE).. For 8 days before surgery, OE rats received daily oral Eviprostat (36 mg/kg/day) or vehicle, while sham-operated animals received vehicle. The bladder was distended by infusion of saline over a period of 2 hr (overdistension) and then emptied. After 24 hr, BBF was measured with a laser speckle blood flow imager. The oxidative-stress marker malondialdehyde (MDA), proinflammatory cytokines, and myeloperoxidase were determined in the isolated bladder, and histological analysis was performed. Functional contractile responses of bladder strips to electrical field stimulation, carbachol, and KCl were measured.. Twenty-four hours after bladder OE, a significant decrease in BBF and significant increases in bladder weight, malondialdehyde, proinflammatory cytokines, and myeloperoxidase were observed. Eviprostat almost completely prevented these changes. Histological analysis of the bladder of OE rats showed hemorrhage, accumulation of leukocytes, desquamation of epithelium, and edema, and Eviprostat suppressed these changes. The reduction in functional contractile forces in the bladder of OE rats was also prevented by Eviprostat.. Eviprostat-mediated suppression of increased bladder oxidative stress and inflammation caused by bladder OE may contribute to the improvement of BBF and bladder function by Eviprostat.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Blood Flow Velocity; Cytokines; Disease Models, Animal; Drug Combinations; Ethamsylate; Female; Inflammation Mediators; Laser-Doppler Flowmetry; Malondialdehyde; Muscle Contraction; Oxidative Stress; Peroxidase; Phytotherapy; Plant Extracts; Plants, Medicinal; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Time Factors; Urinary Bladder; Urinary Bladder Neck Obstruction

Combretum leprosum is a species that is popularly used in Brazil as a healing agent to treat skin problems and lesions. In this study we investigated the possible potential of this extract to treat inflammatory and hyperproliferative skin conditions.. Classical models of skin inflammation such as TPA- and croton oil-induced mouse ear oedema were applied in order to verify the potential topical anti-inflammatory activity of the ethanolic extract from flowers of Combretum leprosum.. Topical application of ethanolic extract promoted a dose-dependent inhibition of phorbol ester-induced ear oedema, reduced myeloperoxidase activity and IL-6 tissue levels with inhibition comparable to dexamethasone (positive control). Histological and immunohistochemical analysis revealed that ethanolic extract also suppressed cell infiltration. Ethanolic extract altered inflammatory parameters on a chronic skin inflammation model induced by repeated applications of croton oil, decreasing ear oedema, epidermal hyperproliferation and cell infiltration. In addition, immunohistochemical analysis showed that the extract decreased PCNA expression on the epidermis.. Taken together, these results suggest that the extract from flowers of Combretum leprosum could be considered as a new potential tool for the treatment of several skin inflammatory diseases since it reversed the skin inflammatory and hyperproliferative process in a very significant manner. Further investigations are needed in order to verify the cellular mechanism and safety of Combretum leprosum extract.

Topics: Acetylglucosaminidase; Animals; Anti-Inflammatory Agents; Arachidonic Acid; Cell Line; Cell Proliferation; Combretum; Croton Oil; Dermatitis, Contact; Disease Models, Animal; Dose-Response Relationship, Drug; Ear; Edema; Ethanol; Female; Flowers; Interleukin-6; Mice; Peroxidase; Phytotherapy; Plant Extracts; Proliferating Cell Nuclear Antigen; Skin; Tetradecanoylphorbol Acetate

The aim of this study was to examine whether administration of ulinastatin inhibits pro-inflammatory mediators and ameliorate visceral vasopermeability both in a rat model of major burn, and also in rat cultured endothelial cells stimulated with permeability-evoking mediators.. Plasma levels of tumor necrosis factor-alpha (TNF-α), C-reactive protein (CRP), myeloperoxidase (MPO), microvascular permeability, and water content of organ tissues were evaluated in a rodent model of a 55% TBSA full-thickness scald injury. Microvascular permeability was also evaluated with a cultured pulmonary microvascular endothelial cells (PMECs) monolayer after stimulation with trypsin, bradykinin, histamine, prostaglandin E2 and burn serum.. We found that the plasma levels of TNF-α, CRP, MPO, vascular permeability and water content of heart, lung, kidney, and small intestine tissues were significantly increased in animals after scald injury, and administration of ulinastatin lowered the levels TNF-α, CRP, MPO, vascular permeability and water content of those organ tissues. In vitro, ulinastatin lowered the levels of TNF-α, interleukin-6 (IL-6) and attenuated permeability in PMEC monolayers after being stimulated with burn serum or trypsin, but not by bradykinin, histamine or prostaglandin E2.. These results indicate that ulinastatin attenuates the systemic inflammatory response and visceral vasopermeability both in vivo and vitro, and may serve as a therapeutic agent for prevention of systemic inflammatory response and leakage of fluid into tissue after major burn.

Topics: Animals; Biomarkers; Burns; C-Reactive Protein; Capillary Permeability; Disease Models, Animal; Glycoproteins; Inflammation; Inflammation Mediators; Interleukin-6; Intestine, Small; Kidney; Lung; Male; Peroxidase; Rats; Trypsin Inhibitors; Tumor Necrosis Factor-alpha; Water

Acute lung injury (ALI) presents high mortality and morbidity clinically and by far no effective preventive strategy has been established. Extract of Ginkgo biloba leaves, EGb 761, is a complex mixture that possesses several clinical beneficial effects such as anti-oxidation, anti-inflammation, anti-tumor, and cardioprotective property. With EGb 761 pretreatment, both lipopolysaccharide (LPS)-induced protein leakage and neutrophil infiltration, and LPS-induced inflammatory responses including increased myeloperoxidase (MPO) activity, lipid peroxidation, and metalloproteinase (MMP)-9 activity, were inhibited; LPS-suppressed activation of antioxidative enzymes (AOE) were reversed; and not only the phosphorylation of NF-κB but also the degradation of its inhibitor, IκB, were suppressed. These results suggested that the protection mechanism of EGb 761 is by inhibition of NFκB activation, possibly via the up-regulation of antioxidative enzymes. More studies are needed to further evaluate whether EGb 761 is a suitable candidate as an effective dietary strategy to reduce the incidence of endotoxin-induced ALI.

Topics: Acute Lung Injury; Animals; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Drug Evaluation, Preclinical; Enzyme Activation; Ginkgo biloba; Lipopolysaccharides; Lung; Male; Matrix Metalloproteinase 9; Mice; Mice, Inbred ICR; NF-kappa B p50 Subunit; Oxidative Stress; Peroxidase; Phytotherapy; Plant Extracts

The aim of this study was to analyze the effects of cryotherapy on the biochemical and morphological changes in ischemic and reperfused (I/R) gastrocnemius muscle of rats. Forty male Wistar rats were divided into control and I/R groups, and divided based on whether or not the rats were submitted to cryotherapy. Following the reperfusion period, biochemical and morphological analyses were performed. Following cryotherapy, a reduction in thiobarbituric acid-reactive substances and dichlorofluorescein oxidation levels were observed in I/R muscle. Cryotherapy in I/R muscle also minimized effects such as decreased cellular viability, levels of non-protein thiols and calcium ATPase activity as well as increased catalase activity. Cryotherapy also limited mitochondrial dysfunction and decreased the presence of neutrophils in I/R muscle, an effect that was corroborated by reduced myeloperoxidase activity in I/R muscle treated with cryotherapy. The effects of cryotherapy are associated with a reduction in the intensity of the inflammatory response and also with a decrease in mitochondrial dysfunction.

Topics: Analysis of Variance; Animals; Biomarkers; Cell Survival; Cryotherapy; Disease Models, Animal; Ischemia; Male; Mitochondria, Muscle; Muscle, Skeletal; Oxidative Stress; Peroxidase; Rats; Rats, Wistar; Reperfusion Injury

Curcumin is a widely used spice with anti-inflammatory and anticancer properties. It has been reported to have beneficial effects in experimental colitis. This study explored whether curcumin improves colonic inflammation in a rat colitis model through inhibition of the TLR4/NF-κB signaling pathway and IL-27 expression. After induction of colitis with 2,4,6-trinitrobenzene sulfonic acid, rats were intragastrically administered with curcumin or sulfasalazine daily for one week. Rat intestinal mucosa was collected for evaluation of the disease activity index, colonic mucosa damage index, and histological score. Myeloperoxidase activity was detected by immunohistochemistry, and mRNA and protein expression levels of TLR4, NF-κB, and IL-27 in colonic mucosa were detected by RT-PCR and Western blot. Compared with the untreated colitis group, the curcumin-treated group showed significant decreases in the disease activity index, colonic mucosa damage index, histological score, myeloperoxidase activity, and expressions of NF-κB mRNA, IL-27 mRNA, TLR4 protein, NF-κB p65 protein, and IL-27 p28 protein (p < 0.05). TLR4 mRNA expression did not differ between groups. Disease activity index decreased more rapidly in the curcumin-treated group than in the sulfasalazine-treated group (p < 0.05). There was no significant difference in TLR4, NF-κB, and IL-27 mRNA and proteins between curcumin-treated and sulfasalazine-treated groups. Curcumin shows significant therapeutic effects on 2,4,6-trinitrobenzene sulfonic acid-induced colitis that are comparable to sulfasalazine. The anti-inflammatory actions of curcumin on colitis may involve inhibition of the TLR4/NF-κB signaling pathway and of IL-27 expression.

Topics: Animals; Anti-Inflammatory Agents; Colitis; Colon; Curcumin; Disease Models, Animal; Gastrointestinal Agents; Inflammation; Interleukins; Intestinal Mucosa; Male; NF-kappa B; Peroxidase; Random Allocation; Rats; Signal Transduction; Sulfasalazine; Toll-Like Receptor 4; Transcription Factor RelA; Trinitrobenzenesulfonic Acid

The aim of the present study is to evaluate pathologic changes in the pancreatic parenchyma in an experimental model of acute pancreatitis (AP) following bilio-pancreatic duct ligation. An effort was made to clarify the role of apigenin, a substance that is well-known for its antioxidant and anti-inflammatory role and its likely beneficial activity to the pancreatic parenchyma following AP in rats.. One hundred twenty-six male Wistar rats 3-4 mo old and weighing 220-350 g were used. At time 0, the following groups were randomly assigned: group sham: rats were subjected to virtual surgery; group control: rats were subjected to surgery for induction of AP, by ligation of the bilio-pancreatic duct; group apigenin: rats were subjected to surgery for induction of AP and enteral feeding with apigenin. Pathologic changes of the pancreatic parenchymal and myeloperoxidase activity were measured at predetermined time intervals 6, 12, 24, 48, and 72 h.. From the pathologic reports, by comparing the control group with the apigenin group, an improvement of pancreatic tissue architecture following apigenin administration was observed. Inflammatory infiltration, edema, ductal dilation, and necrosis were reduced following apigenin administration over time (P = 0.049, P = 0.228, P = 0.387, P = 0.046). Treatment with apigenin significantly reduced the bilio-pancreatic duct ligation and evoked an increase in pancreatic myeloperoxidase activity (P = 0.030).. Oral apigenin administration in rats, following experimentally induced pancreatitis, seems to protect the pancreatic tissue. Thus, apigenin administration to humans could potentially ameliorate the damages to the pancreas.

Topics: Animals; Apigenin; Disease Models, Animal; Drug Evaluation, Preclinical; Edema; Ligation; Male; Necrosis; Pancreas; Pancreatitis, Acute Necrotizing; Peroxidase; Rats; Rats, Wistar

Myeloid-derived suppressor cells (MDSCs) are a group of myeloid cells expressing CD11b and Gr-1 marker in mice and comprise at least two subsets: granulocytic MDSCs (G-MDSCs) and monocytic MDSCs (M-MDSCs). This study aimed to evaluate the therapeutic efficacy of transplantation of G-MDSC subsets from normal mice to colitis mice.. Murine colitis model was induced by the intrarectal administration of 2,4,6-trinitrobenzenesulfonic acid (TNBS). The mice were divided into four groups: control group, TNBS-induced colitis, TNBS-induced colitis plus normal saline injection and TNBS-induced colitis plus bone marrow-derived G-MDSCs injection (transplantation group). G-MDSCs were sorted and enriched via magnetic-activated cell sorting (MACS) program, the purity of the sorted cells was then identified using flow cytometry analysis. Sex cross-transplantation of dominant G-MDSCs was applied from normal mice to colitis models using i.v. injection. Changes of body weight, survival rate, myeloperoxidase (MPO) activity were monitored and macroscopic and microscopic injury scores are calculated. Donor cell Y chromosomes were assessed by in situ hybridization to assess reconstitutions.. After the transplantation of bone marrow-derived G-MDSCs from normal mice to colitis models, recipient mice showed increased survival rate, decreased macroscopic and microscopic injury scores and MPO activity, as well as lowered concentration of serum interleukin-6. Y chromosomes staining displayed colonization of donor cells of liver, spleen and colon tissues.. Bone marrow-derived G-MDSCs are effective in the improvement of murine colitis, but its effect in human needs further investigation.

Topics: Animals; Body Weight; Colitis; Cytokines; Disease Models, Animal; Female; Graft Survival; Granulocytes; Inflammation Mediators; Male; Mice; Mice, Inbred BALB C; Myeloid Cells; Peroxidase; Trinitrobenzenesulfonic Acid

In Brazilian traditional medicine, Arctium lappa (Asteraceae), has been reported to relieve gastrointestinal symptoms.. In the present study, we investigated the effects of the lactone sesquiterpene onopordopicrin enriched fraction (ONP fraction) from Arctium lappa in an experimental colitis model induced by 2,4,6 trinitrobenzene sulfonic acid and performed experiments to elucidate the underlying action mechanisms involved in that effect.. ONP fraction (25 and 50 mg/kg/day) was orally administered 48, 24 and 1 h prior to the induction of colitis and 24 h after. The inflammatory response was assessed by gross appearance, myeloperoxidase (MPO) activity, tumor necrosis factor alpha (TNF-α) levels and a histological study of the lesions. We determined cyclooxygenase (COX)-1 and -2 protein expressions by western blotting and immunohistochemistry assays.. TNBS group was characterized by increased colonic wall thickness, edema, diffuse inflammatory cell infiltration, increased MPO activity and TNF-α levels. On the contrary, ONP fraction (25 and 50 mg/kg) treatment significantly reduced the macroscopic inflammation scores (p<0.05 and p<0.01, respectively) and morphological alterations associated with an increase in the mucus secretion. Similarly, the degree of neutrophil infiltration and the cytokine levels were significantly ameliorated. Moreover, COX-2 expression was up regulated in TNBS-treated rats. In contrast, ONP fraction (50 mg/kg) administration reduced COX-2 overexpression.. We have shown that the ONP fraction obtained from Arctium lappa exert marked protective effects in acute experimental colitis, confirming and justifying, at least in part, the popular use of this plant to treat gastrointestinal diseases.

Topics: Animals; Anti-Inflammatory Agents; Arctium; Colitis; Cyclooxygenase 2; Disease Models, Animal; Male; Peroxidase; Phytotherapy; Plant Extracts; Plant Leaves; Rats; Rats, Wistar; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

Conventional medical therapies for ulcerative colitis (UC) are still limited due to the adverse side effects like dose-dependent diarrhoea and insufficient potency to keep in remission for long-term periods. So, new alternatives that provide more effective and safe therapies for ulcerative colitis are constantly being sought. In the present study, probiotic LaBb Dahi was selected for investigation of its therapeutic effect on DSS-induced colitis model in mice. LaBb Dahi was prepared by co-culturing Dahi culture of Lactococci along with selected strain of Lactobacillus acidophilus LaVK2 and Bifidobacterium bifidum BbVK3 in buffalo milk. Four groups of mice (12 each) were fed for 17 d with buffalo milk (normal control), buffalo milk plus DSS (Colitis control), Dahi plus DSS, and LaBb Dahi plus DSS, respectively, with basal diet. The disease activity scores, weight loss, organ weight, colon length, myeloperoxidase (MPO) and β-glucoronidase activity was assessed, and the histopathological picture of the colon of mice was studied. All colitis control mice evidenced significant increase in MPO, β-glucoronidase activity and showed high disease activity scores along with histological damage to colonic tissue. Feeding with LaBb Dahi offered significant reduction in MPO activity, β-glucoronidase activity and improved disease activity scores. We found significant decline in length of colon, organ weight and body weight in colitis induced controls which were improved significantly by feeding LaBb Dahi. The present study suggests that LaBb Dahi can be used as a potential nutraceutical intervention to combat UC related changes and may offer effective adjunctive treatment for management of UC.

Topics: Animals; Bifidobacterium; Body Weight; Buffaloes; Colitis, Ulcerative; Colon; Dextran Sulfate; Dietary Supplements; Disease Models, Animal; Glucuronidase; Lactobacillus acidophilus; Male; Mice; Milk; Peroxidase; Probiotics

Thymosin β4 (Tβ4) was recently found at high concentration in the bronchoalveolar lavage fluid (BALF) of scleroderma patients with lung involvement. It has been hypothesized that Tβ4 may exert a cyto-protective effect during lung injury because lower Tβ4 levels were associated with interstitial lung disease progression. Moreover, Tβ4 treatment prevented profibrotic gene expression in cardiac cells in vitro and in vivo.. In this study, we explored a putative Tβ4 protective role in lung damage by utilizing a well-known in vivo model of lung fibrosis. C57BL/6 mice were treated with bleomycin (BLEO, 1 mg/kg) in the absence or presence of Tβ4 (6 mg/kg delivered intraperitoneally on the day of BLEO treatment and for two additional doses). After sacrifice 1 week later, measurement of fluid and collagen content in the lung, BALF analysis, myeloperoxidase (MPO) activity assay, lung histology and IHC were performed.. Compared with BLEO-treated mice, BLEO-treated mice who received Tβ4 did not lose as much weight and had a higher survival rate. Moreover, BLEO-induced inflammation and lung damage were substantially reduced by Tβ4 treatment, as demonstrated by the significant reduction in oedema, total collagen content, lung infiltration by leucocytes, MPO activity in lung homogenates, and histological evidence of the ongoing lung fibrosis. Results of IHC show a strong reactivity for Tβ4 in the lung tissue of Tβ4-treated mice.. This is the first report that shows a Tβ4 protective role in lung toxicity associated with BLEO in a mouse model. Future studies are needed to assess its putative antifibrotic properties.

Topics: Animals; Antibiotics, Antineoplastic; Bleomycin; Bronchoalveolar Lavage Fluid; Collagen; Disease Models, Animal; Lung Injury; Male; Mice; Mice, Inbred C57BL; Peroxidase; Protective Agents; Pulmonary Edema; Pulmonary Fibrosis; Random Allocation; Thymosin; Weight Loss

The beneficial effects of kolaviron, a natural biflavonoid from the seeds of Garcinia kola, have been attributed mainly to its antioxidant and anti-inflammatory effects. This study investigated these effects on dextran sulphate sodium (DSS)-induced ulcerative colitis in rats. Sulfasalazine served as standard reference in this study. Kolaviron and sulfasalazine were separately co-administered orally at 200 mg/kg and 500 mg/kg, respectively, to dextran sulphate sodium-exposed rats for 5 days. The result indicated that kolaviron or sulfasalazine significantly prevented DSS-induced body weight loss as well as the incidence of diarrhoea and bleeding in DSS-exposed rats. Kolaviron suppressed the DSS-mediated increase in colonic nitric oxide concentration and myeloperoxidase activity and significantly prevented the increase in inflammatory mediators, interleukin-1β and tumour necrosis factor alpha, in the colon of DSS-treated rats. The significant depletion in colonic antioxidant status in rats exposed to DSS alone was evident by marked reduction in colonic catalase and glutathione S-transferase activities as well as glutathione content, leading to elevated hydrogen peroxide and lipid peroxidation levels. Histopathologically, DSS alone resulted in severe epithelial erosion, total absence of goblet cells, destruction of the crypts, necrotic and distorted glands, accompanied by marked cellular mononuclear cells infiltration. However, administration of kolaviron and sulfasalazine ameliorated DSS-induced colitis by increasing the antioxidant status decreased hydrogen peroxide and lipid peroxidation levels and attenuated the adverse effect of DSS on colon architecture. In conclusion, the anti-colitis effect of kolaviron is related to its intrinsic anti-inflammatory and anti-oxidative properties.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Colitis, Ulcerative; Dextran Sulfate; Disease Models, Animal; Flavonoids; Garcinia; Inflammation Mediators; Male; Nitric Oxide; Organ Size; Peroxidase; Rats; Rats, Wistar; Seeds; Sulfasalazine

Quercetin (1) is an anti-inflammatory and antioxidant flavonoid. However, the oral administration of 1 did not lead to beneficial effects in experimental animal colitis models, which involve cytokines and oxidative stress. A possible explanation is that the absorption profile of 1 prevents its activity. Therefore, it was reasoned that the controlled release of 1 would improve its therapeutic effect. Thus, the therapeutic effect and mechanisms of 1-loaded microcapsules in acetic acid-induced colitis in mice were evaluated. Microcapsules were prepared using pectin/casein polymer and 1. The oral administration of 1-loaded microcapsules decreased neutrophil recruitment, attenuated histological alterations, and reduced macroscopical damage, edema, and IL-1β and IL-33 production in the colon samples. Microcapsules loaded with 1 also prevented the reduction of anti-inflammatory cytokine IL-10 and the antioxidant capacity of the colon. These preclinical data indicate that pectin/casein polymer microcapsules loaded with 1 improved the anti-inflammatory and antioxidant effects of 1 compared to the nonencapsulated drug. Therefore, quercetin seems to be a promising active molecule in inflammatory bowel disease if provided with adequate controlled release.

Topics: Acetic Acid; Administration, Oral; Animals; Anti-Inflammatory Agents; Antioxidants; Capsules; Colitis; Disease Models, Animal; Drug Delivery Systems; Edema; Interleukin-1beta; Interleukin-33; Interleukins; Male; Mice; Molecular Structure; Neutrophils; Peroxidase; Quercetin

Septic shock is a systemic inflammatory response syndrome, and it is the leading cause of death in intensive care units. Mycophenolate mofetil (MMF) is an immunosuppressant that has been shown to be effective in the treatment of various inflammatory diseases. In this study, the anti-inflammatory effect of MMF in a mouse model of acute lung injury (ALI) induced by lipopolysaccharide (LPS) was evaluated. ALI was induced by intrapleural injection of LPS (250 ng/cavity). The leukocyte migration, exudation, myeloperoxidase and adenosine deaminase activities, nitric oxide products, tumor necrosis factor alpha (TNF-α), and interleukin 1 beta (IL-1β) levels, as well as mRNA expression of TNF-α and IL-1β, were evaluated. This study showed that MMF significantly decreased all parameters studied in a manner comparable to treatment with dexamethasone. In conclusion, MMF has important anti-inflammatory effects that may be useful as an auxiliary treatment for septic shock.

Topics: Acute Lung Injury; Adenosine Deaminase; Animals; Anti-Inflammatory Agents; Cell Movement; Dexamethasone; Disease Models, Animal; Immunosuppressive Agents; Inflammation; Interleukin-1beta; Leukocytes; Lipopolysaccharides; Lung; Mice; Mycophenolic Acid; Nitric Oxide; Peroxidase; RNA, Messenger; Shock, Septic; Tumor Necrosis Factor-alpha

Adipose-derived stem cells (ASCs) have emerged as important regulators of inflammatory/immune responses in vitro and in vivo and represent attractive candidates for cell-based therapies for diseases that involve excessive inflammation. Acute lung injury (ALI) is an inflammatory condition for which treatment is mainly supportive due to lack of effective therapies. In this study, the therapeutic effects of ASC-based therapy were assessed in vivo by comparison of the anti-inflammatory properties of both human and murine ASCs in a mouse model of lipopolysaccharide (LPS)-induced ALI.. Human ASCs (hASCs) or mouse ASCs (mASCs) were delivered to C57Bl/6 mice (7.5 × 105 total cells/mouse) by oropharyngeal aspiration (OA) four hours after the animals were challenged with lipopolysaccharide (15 mg/kg). Mice were sacrificed 24 and 72 hours after LPS exposure, and lung histology examined for evaluation of inflammation and injury. Bronchoalveolar lavage fluid (BALF) was analyzed to determine total and differential cell counts, total protein and albumin concentrations, and myeloperoxidase (MPO) activity. Cytokine expression in the injured lungs was measured at the steady-state mRNA levels and protein levels for assessment of the degree of lung inflammation.. Both human and mouse ASC treatments provided protective anti-inflammatory responses. There were decreased levels of leukocyte (for example neutrophil) migration into the alveoli, total protein and albumin concentrations in BALF, and MPO activity after the induction of ALI following both therapies. Additionally, cell therapy with both cell types effectively suppressed the expression of proinflammatory cytokines and increased the anti-inflammatory cytokine interleukin 10 (IL-10). Overall, the syngeneic mASC therapy had a more potent therapeutic effect than the xenogeneic hASC therapy in this model.. Treatment with hASCs or mASCs significantly attenuated LPS-induced acute lung injury in mice. These results suggest a potential benefit for using an ASC-based therapy to treat clinical ALI and may possibly prevent the development of acute respiratory distress syndrome (ARDS).

Topics: Acute Lung Injury; Adipose Tissue; Animals; Bronchoalveolar Lavage Fluid; Cell- and Tissue-Based Therapy; Disease Models, Animal; Female; Humans; Interleukin-10; Leukocytes; Lipopolysaccharides; Lung; Mice; Mice, Inbred C57BL; Mice, Transgenic; Peroxidase; Pneumonia; Respiratory Distress Syndrome; Stem Cells

Chronic lung diseases cause serious morbidity and mortality, and effective treatments are limited. Induced pluripotent stem cells (iPSCs) lacking the reprogramming factor c-Myc (3-gene iPSCs) can be used as ideal tools for cell-based therapy because of their low level of tumorigenicity. In this study, we investigated whether 3-gene iPSC transplantation could rescue bleomycin-induced pulmonary fibrosis. After the induction of pulmonary inflammation and fibrosis via intratracheal delivery of bleomycin sulfate, mice were i.v. injected with 3-gene iPSCs or conditioned medium (iPSC-CM) at 24 h after bleomycin treatment. Administration of either 3-gene iPSCs or iPSC-CM significantly attenuated collagen content and myeloperoxidase activity, diminished neutrophil accumulation, and rescued pulmonary function and recipient survival after bleomycin treatment. Notably, both treatments reduced the levels of inflammatory cytokines and chemokines, including interleukin 1 (IL-1), IL-2, IL-10, tumor necrosis factor-α, and monocyte chemotactic protein 1 yet increased the production of the antifibrotic chemokine interferon-γ-induced protein 10 (IP-10) in bleomycin-injured lungs. Furthermore, IP-10 neutralization via treatment with IP-10-neutralizing antibodies ameliorated the reparative effect of either 3-gene iPSCs or iPSC-CM on collagen content, neutrophil and monocyte accumulation, pulmonary fibrosis, and recipient survival. Intravenous delivery of 3-gene iPSCs/iPSC-CM alleviated the severity of histopathologic and physiologic impairment in bleomycin-induced lung fibrosis. The protective mechanism was partially mediated by the early moderation of inflammation, reduced levels of cytokines and chemokines that mediate inflammation and fibrosis, and an increased production of antifibrotic IP-10 in the injured lungs.

Topics: Animals; Bleomycin; Chemokine CXCL10; Culture Media, Conditioned; Cytokines; Disease Models, Animal; Genes, myc; Induced Pluripotent Stem Cells; Mice; Mice, Inbred C57BL; Neutrophil Infiltration; Peroxidase; Pneumonia; Pulmonary Fibrosis

To investigate the protective effects of pentoxifylline against lung injury observed after dorsal scald in aged animals.. Adult (eight months old) and aged (20 months old) rats were subjected to thermal injury or sham procedure. The six hours post-trauma animals received pentoxifylline and after 24 hours were euthanatized and lung tissue samples collected. The bronchoalveolar lavage fluid was evaluated for total protein content and tumor necrosis factor-alpha cytokine. Malondialdehyde and myeloperoxidase activity in the lung homogenate were measured and a histological lung examination was undertaken.. Burn injury induced oxidative stress in lung homogenate was higher in elderly-burned rats compared to adult-burned rats (p<0.001). Total protein and cytokine in bronchoalveolar lavage increased in the elderly-burned group when compared to the adult-burned group (p<0.001). All parameters decreased in both groups treated with pentoxifylline (p<0.05).. The injury was augmented in elderly rats when compared to adult rats. Damage was reduced with the use of pentoxifylline, however further studies are needed to evaluate the dose-response of the drug.

Topics: Age Factors; Animals; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; Burns; Disease Models, Animal; Free Radical Scavengers; Inflammation Mediators; Lung Injury; Malondialdehyde; Oxidative Stress; Pentoxifylline; Peroxidase; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

Local delivery to bowel tissue through oral administration is a challenging but a desirable goal to treat diseases like inflammatory bowel disease (IBD). Colon specific drug delivery system should be capable of protecting the drug en route colon.. Liposomes have shown potential to specific accumulation at inflammation site thus reduce toxicity; hence it can be used for effective treatment of IBD.. Liposomes prepared using thin film hydration method. Statistical design was used for optimization. Colitis was induced using acetic acid. Inverted sac method was used as ex vivo model for IBD. Myeloperoxidase (MPO) activity and histopathology comparative study was carried out. Liposomes were formulated in enteric coated capsules to deliver the liposome specifically in initial segment of colon.. Particle size and entrapment efficiency were between 200 and 300 nm and 40 and 60%, respectively. In vivo and ex vivo study indicates higher accumulation of liposomes in colonic region as compared to pure drug. Enteric coated capsules delivered the drug after 5 h lag time.. Low particle size is attributed to low lipid content and stabilization due to surfactant. At higher cholesterol level, vesicles cannot reshuffle into smaller vesicles due to rigidization. Study shows higher accumulation of liposomes due to its lipoidal nature as compared to pure drug due to membrane transfer mechanism of drug thus MPO significantly lowers as compared to standard group (p < 0.05).. Higher accumulation of liposomal drug in inflammatory area and specific release of liposomes by enteric coated capsules provide better option for the treatment of colonic disease.

Topics: Animals; Anti-Inflammatory Agents; Budesonide; Calorimetry, Differential Scanning; Colon; Disease Models, Animal; Drug Carriers; Drug Compounding; Drug Design; Drug Stability; Inflammatory Bowel Diseases; Liposomes; Male; Microscopy, Electron, Scanning; Particle Size; Peroxidase; Rats; Rats, Wistar; Solubility; Spectroscopy, Fourier Transform Infrared; Surface Properties

To study the effects of combined early fluid resuscitation and hydrogen inhalation on septic shock-induced lung and intestine injuries.. Wistar male rats were randomly divided into four groups: control group (Group A, n = 15); septic shock group (Group B, n = 15); early fluid resuscitation-treated septic shock group (Group C, n = 15); and early fluid resuscitation and inhalation of 2% hydrogen-treated septic shock group (Group D, n = 15). The activity of hydroxyl radicals, myeloperoxidase (MPO), superoxide dismutase (SOD), diamine oxidase (DAO), and the concentration of malonaldehyde (MDA) in the lung and intestinal tissue were assessed according to the corresponding kits. Hematoxylin and eosin staining was carried out to detect the pathology of the lung and intestine. The expression levels of interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-α in lung and intestine tissue were detected by enzyme-linked immunosorbent assay method. The expression levels of Fas and Bcl2 in lung tissues were determined by immunohistochemistry and Western blotting.. Septic shock elicited a significant increase in the levels of MDA (10.17 ± 1.12 nmol/mg protein vs 2.98 ± 0.64 nmol/mg protein) and MPO (6.79 ± 1.02 U/g wet tissue vs 1.69 ± 0.14 U/g wet tissue) in lung tissues. These effects were not significantly decreased by Group C pretreatment, but were significantly reduced by Group D pretreatment (MDA: 4.45 ± 1.13 nmol/mg protein vs 9.56 ± 1.37 nmol/mg protein; MPO: 2.58 ± 0.21 U/g wet tissue vs 6.02 ± 1.16 U/g wet tissue). The activity of SOD (250.32 ± 8.56 U/mg protein vs 365.78 ± 10.26 U/mg protein) in lung tissues was decreased after septic shock, and was not significantly increased by Group C pretreatment, but was significantly enhanced by Group D pretreatment (331.15 ± 9.64 U/mg protein vs 262.98 ± 5.47 U/mg protein). Histological evidence of lung hemorrhage, neutrophil infiltration and overexpression of IL-6, IL-8, and TNF-α was observed in lung tissues, all of which were attenuated by Group C and further alleviated by Group D pretreatment. Septic shock also elicited a significant increase in the levels of MDA, MPO and DAO (6.54 ± 0.68 kU/L vs 4.32 ± 0.33 kU/L) in intestinal tissues, all of which were further increased by Group C, but significantly reduced by Group D pretreatment. Increased Chiu scoring and overexpression of IL-6, IL-8 and TNF-α were observed in intestinal tissues, all of which were attenuated by Group C and further attenuated by Group D pretreatment.. Combined early fluid resuscitation and hydrogen inhalation may protect the lung and intestine of the septic shock rats from the damage induced by oxidative stress and the inflammatory reaction.

Topics: Acute Lung Injury; Administration, Inhalation; Amine Oxidase (Copper-Containing); Animals; Combined Modality Therapy; Cytokines; Disease Models, Animal; Fluid Therapy; Gases; Hydrogen; Hydroxyl Radical; Inflammation Mediators; Intestinal Diseases; Intestine, Small; Lung; Male; Malondialdehyde; Oxidative Stress; Peroxidase; Rats; Rats, Wistar; Resuscitation; Shock, Septic; Superoxide Dismutase; Time Factors

Different species from genus Phlomis, frequently native from the the eastern Mediterranean zone, have been used in traditional medicine as an anti-inflammatory remedy. Among other constituents, they contain polyphenols that show antioxidant properties, which are interesting for the treatment of inflammatory pathologies associated with oxidative stress in humans, such as inflammatory bowel disease (IBD). The aim of this study was to evaluate the intestinal anti-inflammatoy effect of hydroalcoholic extracts of Phlomis lychnitis and P. purpurea in the trinitrobenzenesulphonic acid (TNBS) model of rat colitis, a well characterized experimental model with some resemblance to human IBD.. Hydroalcoholic extracts of both plants were characterized by determining their polyphenolic content and then assayed in the TNBS model of rat colitis. For this purpose, female Wistar rats were assigned to seven groups (n=10): healthy control, untreated TNBS-colitis and five TNBS- colitis groups treated with Phlomis lychnitis (10 and 20mg/kg), P. purpurea (10 and 25mg/kg) and sulphasalazine (200mg/kg), as a positive control. Treatments started the same day of TNBS colitis induction, and rats were sacrificed one week later. Colonic inflammation was evaluated both histologically and biochemically.. The histological (macroscopic and microscopic) analysis of colonic samples revealed that both extracts showed an anti-inflammatory effect, which was confirmed biochemically by a decreased colonic MPO activity, a maker of neutrophil infiltration, an increased colonic glutathione content, which counteracts the oxidative status associated with the inflammatory process, and a down-regulated iNOS expression. However, only the extract of P. purpurea reduced the expression of the proinflammatory cytokines IL-1β and IL-17, the chemokines CINC-1 and MCP-1, as well as the adhesion molecule ICAM-1, ameliorating the altered immune response associated with the colonic inflammation. Furthermore, both P. lychnitis and P. purpurea extracts were able to significantly increase the expression of markers of epithelial integrity such as MUC-2, MUC-3 and villin, thus revealing an improvement in the altered colonic permeability that characterizes colonic inflammation.. Both extracts showed intestinal anti-inflammatory activity in the TNBS model of rat colitis, thus confirming their traditional use in digestive inflammatory complaints. In addition to their antioxidant properties, other mechanisms can contribute to this beneficial effect, like an improvement in the intestine epithelial barrier and a downregulation of the immune response.

Topics: Animals; Anti-Inflammatory Agents; Colitis; Colon; Cytokines; Disease Models, Animal; Female; Glutathione; Intestinal Mucosa; Mucins; Necrosis; Peroxidase; Phlomis; Plant Components, Aerial; Plant Extracts; Rats; Rats, Wistar; Trinitrobenzenesulfonic Acid

Ischemia-reperfusion injury contributes significantly to morbidity and mortality in lung transplant patients. Currently, no therapeutic agents are clinically available to prevent ischemia-reperfusion injury, and treatment strategies are limited to maintaining oxygenation and lung function. Adenosine can modulate inflammatory activity and injury by binding to various adenosine receptors; however, the role of the adenosine A1 receptor in ischemia-reperfusion injury and inflammation is not well understood. The present study tested the hypothesis that selective, exogenous activation of the A1 receptor would be anti-inflammatory and attenuate lung ischemia-reperfusion injury.. Wild-type and A1 receptor knockout mice underwent 1 hour of left lung ischemia and 2 hours of reperfusion using an in vivo hilar clamp model. An A1 receptor agonist, 2-chloro-N6-cyclopentyladenosine, was administered 5 minutes before ischemia. After reperfusion, lung function was evaluated by measuring airway resistance, pulmonary compliance, and pulmonary artery pressure. The wet/dry weight ratio was used to assess edema. The myeloperoxidase and cytokine levels in bronchoalveolar lavage fluid were measured to determine the presence of neutrophil infiltration and inflammation.. In the wild-type mice, 2-chloro-N6-cyclopentyladenosine significantly improved lung function and attenuated edema, cytokine expression, and myeloperoxidase levels compared with the vehicle-treated mice after ischemia-reperfusion. The incidence of lung ischemia-reperfusion injury was similar in the A1 receptor knockout and wild-type mice; and 2-chloro-N6-cyclopentyladenosine had no effects in the A1 receptor knockout mice. In vitro treatment of neutrophils with 2-chloro-N6-cyclopentyladenosine significantly reduced chemotaxis.. Exogenous A1 receptor activation improves lung function and decreases inflammation, edema, and neutrophil chemotaxis after ischemia and reperfusion. These results suggest a potential therapeutic application for A1 receptor agonists for the prevention of lung ischemia-reperfusion injury after transplantation.

Topics: Adenosine; Analysis of Variance; Animals; Bronchoalveolar Lavage Fluid; Chemotaxis; Cytokines; Disease Models, Animal; Lung Transplantation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophil Infiltration; Peroxidase; Random Allocation; Receptor, Adenosine A1; Reperfusion Injury; Respiratory Function Tests

Ulcerative colitis (UC) is a chronic inflammatory autoimmune disease with limited treatment modalities. The animal model of colitis induced by treatment with trinitrobenzene sulfonic acid (TNBS-colitis) is commonly used to test new therapies of this disease. In our previous work we found that epicutaneous (EC) immunization with protein antigen induced a state of profound immunosuppression that inhibited inflammatory response in contact sensitivity, in experimental autoimmune encephalomyelitis (EAE) and in allogeneic skin graft rejection.. TNBS-induced colitis was used as an experimental model.. In our current work, we showed that EC immunization with TNP-conjugated mouse immunoglobulin (TNP-Ig) prior to induction of TNBS-colitis alleviates disease severity what was determined by the body weight, the length and the weight of the colon, the histological activity index (HAI) and myeloperoxidase activity (MPO). Observed amelioration of the disease in TNP-Ig patched mice was accompanied with decreased production of IFN-γ and IL-17A by splenocytes. Additionally, spleen cells isolated from mice EC immunized with TNP-Ig prior to colitis induction showed increased production of IL-10 suggesting that this cytokine might be involved in inhibiting inflammatory response in the colon.. This work shows that EC immunization with protein antigen prior to TNBS-colitis induction ameliorates disease and observed suppression of inflammatory response in the colon might be mediated by IL-10.

Topics: Administration, Cutaneous; Animals; Biomarkers; Cells, Cultured; Colitis; Colon; Desensitization, Immunologic; Disease Models, Animal; Female; Immunoglobulins; Inflammation Mediators; Interferon-gamma; Interleukin-10; Interleukin-17; Mice; Neutrophils; Peroxidase; Severity of Illness Index; Skin; Spleen; Time Factors; Transdermal Patch; Trinitrobenzenes; Trinitrobenzenesulfonic Acid

To elucidate the ameliorative effect of hydroalcoholic extract of leaves of Hibiscus rosa sinensis (HRS) in acetic acid induced experimental colitis in male wistar rats.. The animals were administered with 2 mL acetic acid (4%) via intra rectal. The animals were divided into various treatment groups (n=6). Prednisolone was used as standard drug and HRS was administered at a dose of 50, 100 and 200 mg/kg p.o. The control group of animals received 1 mL of vehicle (distilled water). Ulcer area, ulcer index, spleen weight, colon weight to length ratio, macroscopic score, haematological parameters, colonic superoxide dismutase (SOD), glutathione (GSH), myeloperoxidase (MPO), malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), nitric oxide (NO) and histological changes were recorded after the treatment regimen of 11 days.. Intrarectal instillation of acetic acid caused enhanced ulcer area, ulcer index, spleen weight, colon weight to length ratio, colonic MPO, MDA, NO and TNF-α It caused significant decreased level of SOD and GSH. Pretreatment with HRS for 7 days exhibited significant effect in lowering of oxidative stress, colonic NO, TNF-α and elevation of SOD and GSH at a dose of 100 and 200 mg/kg in acetic acid induced colitis.. The present investigation demonstrates HRS is of potent therapeutic value in the amelioration of experimental colitis in laboratory animals by inhibiting the proinflammatory mediator like NO and TNF-α.

Topics: Acetic Acid; Animals; Colitis; Colon; Disease Models, Animal; Glutathione; Hibiscus; Male; Malondialdehyde; Nitric Oxide; Organ Size; Oxidative Stress; Peroxidase; Phytotherapy; Plant Leaves; Plant Preparations; Rats; Rats, Wistar; Superoxide Dismutase; Tumor Necrosis Factor-alpha

The aim of this trial was to study the role of glucagon-like peptide-2 in reducing bacterial translocation by virtue of its anti-inflammatory effects and ability to decrease intestinal permeability in rat models of inflammatory bowel diseases. On the basis of our results and those of other recent studies, we suggest a new treatment modality for colitis. To our knowledge, this is the first study of the effectiveness of glucagon-like peptide-2 on bacterial translocation, in treating an experimental colitis model.. Rats were randomized into 3 groups of 7 rats each-the control group, colitis group, and treatment group. On the 7 th day after induction of colitis, the levels of tissue myeloperoxidase, serum tumor necrosis factor-alpha, and plasma endotoxin were measured. Tissue samples were obtained from the liver, spleen, and mesenteric lymph nodes for evaluating bacterial translocation.. Bacterial translocation in samples of the liver, spleen, mesenteric lymph nodes, and portal and systemic blood obtained from the treatment group was lower than that in samples obtained from the colitis group (p < 0.05). The levels of tissue myeloperoxidase, serum tumor necrosis factor-alpha, and plasma endotoxin in the treatment group were significantly lower than those in the colitis group (p < 0.05).. In experimental colitis models, which were induced using trinitrobenzene sulfonic acid in ethanol, glucagon-like peptide-2 treatment reduced inflammation and bacterial translocation from the intestinal mucosa. Our results indicate that glucagon-like peptide-2 is a potential agent for treating colitis; however, extensive trials are needed to confirm our results.

Topics: Animals; Bacterial Translocation; Colitis; Colon; Disease Models, Animal; Endotoxins; Glucagon-Like Peptide 2; Male; Peroxidase; Random Allocation; Rats; Rats, Wistar; Treatment Outcome; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

The aim of this study was to investigate the anti-inflammatory efficacy of rosiglitazone (ROSI) in a pleurisy model of carrageenan-induced inflammation. Efficacy was monitored in the mouse pleural cavity by evaluating leukocyte migration, exudate concentration, and myeloperoxidase (MPO) and adenosine deaminase (ADA) activities concomitantly with nitrate/nitrite (NOx), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-17A (IL-17A), and vascular endothelial growth factor-alpha (VEGF-α) levels 4 and 48 h after pleurisy induction. In both phases (4 and 48 h) of pleurisy, ROSI inhibited all the inflammation parameters that were tested (p<0.05). These results provide evidence that ROSI was efficacious in inhibiting pro-inflammatory mediators. These anti-inflammatory effects are assumed to mainly result from the inhibition of products released from activated leukocytes, such as MPO, ADA, NOx, TNF-α, IL-1β, IL-17A, and VEGF-α.

Topics: Adenosine Deaminase; Animals; Carrageenan; Cell Movement; Disease Models, Animal; Inflammation; Inflammation Mediators; Interleukin-17; Interleukin-1beta; Leukocytes, Mononuclear; Mice; Peroxidase; Pleurisy; PPAR gamma; Rosiglitazone; Thiazolidinediones; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

Successful resuscitation after cardiac arrest is typically associated with cerebral and myocardial ischemia/reperfusion (I/R)-injury. Recently, we have demonstrated effects of therapeutic hypothermia (HT) and postconditioning with the volatile anesthetic sevoflurane (SEV) on I/R-mediated mechanisms in the heart and brain [Meybohm et al., PLoS One, 2009; Meybohm et al., Crit Care, 2010]. As the intestine is also highly susceptible to I/R-injury, we investigated the influence of HT and SEV on intestinal I/R-mediated events induced by cardiac arrest and successful resuscitation.. Effects of I/R, HT (12h, 33°C) and a combination of HT with SEV (12h, 2.0vol%) were evaluated in a pig model of cardiac arrest and successful cardiopulmonary resuscitation. Western blotting, ELISA, caspase-3/7 assays, myeloperoxidase (MPO) quantifications and gelatine zymography were performed using intestinal tissue derived 24h after return of spontaneous circulation.. Compared to the normothermia control, HT and HT+SEV resulted in a significant increase in intestinal HIF-1α protein expression (P<0.05). Tissue concentrations of IL-1β were significantly reduced in the HT and HT+SEV group (P<0.05), whereas a reduction of IL-10 levels was only detected in the intestine of animals treated with HT+SEV (P<0.05). A statistically significant increase of intestinal MPO activity was found in the HT+SEV group (P<0.01). Activities of caspase-3 and 7 or matrixmetalloproteinase-2 were not changed in any of the groups investigated, the activity of matrixmetalloproteinase-9 was, however, significantly increased in the HT+SEV group (P<0.05).. HT and postconditioning with SEV influence the expression and activity of several small intestinal proteins that are possibly involved in intestinal I/R-mediated events following successful cardiopulmonary resuscitation.

Topics: Anesthesia, Inhalation; Anesthetics, Inhalation; Animals; Biomarkers; Blotting, Western; Cardiopulmonary Resuscitation; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Heart Arrest; Hypothermia, Induced; Intestine, Small; Male; Methyl Ethers; Peroxidase; Reperfusion Injury; Sevoflurane; Swine; Treatment Outcome

Taurine (Tau) is reported to have a key role in the regulation of the innate immune response and thus reduce tissue damage induced by bacterial infection. In this study, the effects of Tau on a rat model of mastitis induced by Streptococcus uberis (S. uberis) and the changes of T regulatory cells (Tregs) were assessed. Starting on gestation day 14 and continuing until parturition, 100 mg/kg of taurine (group TS) or an equal volume of physiological saline (group CS) was administered daily, per os. Seventy-two hours after parturition, rats were infused with approximately 100 cfu of S. uberis into each of two mammary glands. The results showed that the resultant inflammation, evidenced by swelling, secretory epithelial cell degeneration, increased adipose tissue and neutrophil (PMN) infiltration were evident in mammary tissue following injection with S. uberis. Pre-treatment with Tau attenuated these morphologic changes, the expression of interleukin (IL)-2, interferon (INF)-γ mRNA, myeloperoxidase (MPO) activity and N-acetyl-β-D-glucosaminidase (NAGase) in mammary tissue. The percentages of Foxp3+CD25+CD4+/lymphocytes (Tregs) were dramatically increased after the S. uberis challenge. Significant differences (P<0.05) were observed at 24, and 72 h post S. uberis-injection (PI) in CS. Pre-treatment further increased the percentage of Tregs and a significant difference between CS and TS (P<0.05) was apparent at 24 h PI. Our data indicate that in rats, Tau can be used to regulate the immune response following infection by S. uberis and consequently prevent mammary tissue damage by increasing Tregs.

Topics: Acetylglucosaminidase; Animals; Anti-Inflammatory Agents, Non-Steroidal; CD4 Lymphocyte Count; Disease Models, Animal; Female; Inflammation; Interferon-gamma; Interleukin-2; Mammary Glands, Animal; Mastitis; Parturition; Peroxidase; Pregnancy; Rats; Streptococcus; T-Lymphocytes, Regulatory; Taurine

Implant associated osteomyelitis (OM) is difficult to treat with antibiotics, and outcomes remain poor. Some reports suggest that hyperbaric oxygen treatment is a safe and effective means of treating OM. We tested this hypothesis in a murine model. Clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, and Klebsiella pneumoniae were used. The mice were infected with each of the three pathogens, treated with 100% oxygen at high pressure, hyperbaric oxygen (HBO), and monitored for the ability of HBO to prevent and/or clear the OM infection. Assessments included bacterial burden of the tibias and lesion scores, as well as receptor activator of NF-κB ligand (RANKL) and myeloperoxidase (MPO) concentrations. HBO resulted in more severe lesion scores and higher RANKL and MPO concentrations for MRSA. A significant positive correlation was found between RANKL concentration and lesion score. No significant difference was found with HBO in P. aeruginosa infections and K. pneumoniae seems to either not infect bone well or get cleared before establishing an infection. The model is useful for studying OM infections caused by MRSA and P. aeruginosa, but HBO does not appear to be an efficacious treatment of an implant-associated OM infection.

Topics: Animals; Disease Models, Animal; Hyperbaric Oxygenation; Klebsiella Infections; Male; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred C57BL; Osteomyelitis; Peroxidase; Prostheses and Implants; Pseudomonas Infections; RANK Ligand; Staphylococcal Infections; Tibia

Hemorrhagic shock activates cellular stress signals and can lead to systemic inflammatory response, organ injury, and death. We have previously shown that treatment with histone deacetylase inhibitors (HDACIs) significantly improves survival in lethal models (60% blood loss) of hemorrhage. The aim of the current study was to examine whether these protective effects were due to attenuation of mitogen activated protein kinase (MAPK) signaling pathways, which are known to promote inflammation and apoptosis.. Wistar-Kyoto rats (250-300 g) were subjected to 40% blood loss and randomized to treatment with: (1) HDACI valproic acid (VPA 300 mg/kg i.v.; volume = 0.75 mL/kg), or (2) vehicle control (0.75 mL/kg of 0.9% saline). Animals were sacrificed at 1, 4, and 20 h (n = 3-4/group/timepoint), and lung samples were analyzed by Western blotting for expression of active (phosphorylated) and inactive forms of c-Jun N-terminal Kinase (JNK) and p38 MAPK. Myeloperoxidase (MPO) activity was measured in lung tissue 20 h after hemorrhage as a marker of neutrophil infiltration. Normal animals (n = 3) served as shams.. Hemorrhaged animals demonstrated significant increases in phosphorylated p38 at 1 h, phosphorylated JNK at 4 h, and increased MPO activity at 20 h (P < 0.05 compared with sham). VPA treatment significantly (P < 0.05) attenuated all of these changes.. Hemorrhagic shock activates pro-inflammatory MAPK signaling pathways and promotes pulmonary neutrophil infiltration, affects that are significantly attenuated by VPA treatment. This may represent a key mechanism through which HDACIs decrease organ damage and promote survival in hemorrhagic shock.

Topics: Animals; Apoptosis; Disease Models, Animal; Histone Deacetylase Inhibitors; Lung; Male; Mitogen-Activated Protein Kinase Kinases; p38 Mitogen-Activated Protein Kinases; Peroxidase; Phosphorylation; Pneumonia; Proto-Oncogene Proteins c-jun; Rats; Rats, Inbred WKY; Shock, Hemorrhagic; Signal Transduction; Valproic Acid

S-nitrosoglutathione (GSNO) is a nitric oxide donor that may exert antioxidant, anti-inflammatory, and microbicidal actions and is thus a potential drug for the topical treatment of periodontitis. In this study, the effect of intragingival injections of GSNO-containing polyvinylpyrrolidone (PVP) formulations is evaluated in a rat model of periodontitis.. Periodontal disease was induced by placing a sterilized nylon (000) thread ligature around the cervix of the second left upper molar of the animals, which received intragingival injections of PVP; saline; or PVP/GSNO solutions which corresponded to GSNO doses of 25, 100, and 500 nmol; 1 hour before periodontitis induction, and thereafter, daily for 11 days.. PVP/GSNO formulations at doses of 25 and/or 100, but not 500 nmol caused significant inhibition of alveolar bone loss, increase of bone alkaline phosphatase, decrease of myeloperoxidase activity, as well as significant reduction of inflammatory and oxidative stress markers when compared to saline and PVP groups. These effects were also associated with a decrease of matrix metalloproteinases 1 and 8, inducible nitric oxide synthase, and nuclear factor-κB immunostaining in the periodontium.. Local intragingival injections of GSNO reduces inflammation and bone loss in experimental periodontal disease.

Topics: Alkaline Phosphatase; Alveolar Bone Loss; Alveolar Process; Animals; Anti-Inflammatory Agents; Biomarkers; Bone Resorption; Disease Models, Animal; Gingiva; Injections; Interleukin-1beta; Lipid Peroxidation; Matrix Metalloproteinase Inhibitors; NF-kappa B; Nitric Oxide Donors; Nitric Oxide Synthase Type II; Oxidative Stress; Periodontitis; Peroxidase; Pharmaceutic Aids; Povidone; Rats; Rats, Wistar; S-Nitrosoglutathione; Sodium Chloride; Tumor Necrosis Factor-alpha

Antiinflammatory cytokines such as interleukin-10 (IL-10) have been used to modulate and terminate inflammation and provide neuroprotection. Recently, we reported that the modular recombinant transfection vector NLSCt is an efficient tool for transgene overexpression in vivo, which induces neuroprotection as a result of its RGD-mediated integrin-interacting capacity. We here sought to evaluate the putative synergic neuroprotective action exerted by IL-10 overexpression using NLSCt as a transfection vector after an excitotoxic injury to the postnatal rat brain. For this purpose, lesion volume, neurodegeneration, astroglial and microglial responses, neutrophil infiltration, and proinflammatory cytokine production were analyzed at several survival times after intracortical NMDA injection in postnatal day 9 rats, followed by injection of NLSCt combined with the IL-10 gene, a control transgene, or saline vehicle solution. Our results show no combined neuroprotective effect between RGD-interacting vectors and IL-10 gene therapy; instead, IL-10 overexpression using NLSCt as transfection vector increased lesion volume and neuronal degeneration at 12 hr and 3 days postlesion. In parallel, NLSCt/IL-10 treated animals displayed increased density of neutrophils and microglia/macrophages, and a reduced astroglial content of GFAP and vimentin. Moreover, NLSCt/IL-10 treated animals did not show any variation in interleukin-1β or tumor necrosis factor-α expression but a slight increase in interleukin-6 content at 7 days postlesion. In conclusion, overexpression of IL-10 by using NLSCt transfection vector did not synergistically neuroprotect the excitotoxically damaged postnatal rat brain but induced changes in the astroglial and microglial and inflammatory cell response.

Topics: Analysis of Variance; Animals; Animals, Newborn; CD11b Antigen; Cell Death; Cytokines; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Fluoresceins; Gene Expression Regulation; Genetic Vectors; Glial Fibrillary Acidic Protein; Histidine; Interleukin-10; Macrophages; Male; N-Methylaspartate; Neuroglia; Neuroprotective Agents; Neurotoxicity Syndromes; Neutrophils; Oligopeptides; Organic Chemicals; Peroxidase; Plant Lectins; Rats; Rats, Long-Evans; Transduction, Genetic; Vimentin

We explored the putative anti-inflammatory effects of nicotinamide against experimental stroke.. Prospective laboratory study.. Research laboratory in a university teaching hospital.. Adult male Sprague-Dawley rats (250-300 g).. The antioxidant, radical scavenging, and anti-inflammatory actions of nicotinamide were evaluated using a panel of acellular assays and lipopolysaccharide-stimulated RAW 264.7 and BV2 cells. Animals were subjected to transient middle cerebral artery occlusion for 90 mins. Nicotinamide (500 mg/kg) or vehicle was given intravenously at reperfusion onset.. Nicotinamide effectively inhibited nuclear factor-κB translocation and binding activity as well as the production of tumor necrosis factor-α, nitrite/nitrate, and interleukin-6 in the lipopolysaccharide-stimulated RAW 264.7 and BV2 cells (p < .05, respectively) but exhibited weak antioxidant and radical-scavenging actions. Relative to controls, nicotinamide-treated animals had significant reductions in neutrophil and macrophage/activated microglial infiltration in the ischemic brain by 53% and 77% (p < .05, respectively). Additionally, nicotinamide significantly attenuated phosphorylation of nuclear factor-κB's inhibitory protein, nuclear factor-κB translocation and binding activity, and the synthesis of inducible nitric oxide in the ischemic brain (p < .05, respectively). Consequently, nicotinamide effectively reduced brain infarction and improved neurobehavioral outcome by 43% and 50% (p < .05, respectively).. Nicotinamide effectively attenuated postischemic nuclear factor-kappa]B activation and exhibited robust anti-inflammatory actions against ischemic stroke.

Topics: Animals; Behavior, Animal; Confidence Intervals; Disease Models, Animal; Electrophoresis, Gel, Two-Dimensional; Immunoblotting; Immunohistochemistry; Interleukin-6; Ischemic Attack, Transient; Lipid Peroxidation; Male; NF-kappa B; Niacinamide; Peroxidase; Random Allocation; Rats; Rats, Sprague-Dawley; Reference Values; Statistics, Nonparametric; Tumor Necrosis Factor-alpha

Human neutrophil peptide (HNP)-1, HNP-2, and HNP-3 (HNP-1-3) are useful biomarkers for ulcerative colitis (UC). The precise roles of these peptides in UC are poorly understood, however. The aim of this study was to determine whether HNP-1 affects disease activity in mice with experimental colitis.. Experimental colitis was induced in BALB/c or severe combined immunodeficiency (SCID) mice using dextran sulfate sodium (DSS). Mice were subsequently treated intraperitoneally with HNP-1 (100 μg/day) or phosphate-buffered saline (PBS) from day 4 to day 6. The severity of colitis was evaluated based on a disease activity index, histologic score, and cytokine expression.. Body weight and colon length significantly decreased and the disease activity index score, histologic score, and myeloperoxidase activity significantly increased in HNP-1-treated BALB/c mice compared with PBS-treated mice. Interferon-γ and tumor necrosis factor-α levels in colon culture supernatants-derived HNP-1-treated mice were also significantly higher, and interleukin (IL)-1β levels tended to increase in response to HNP-1. In addition, treating SCID mice with HNP-1 aggravated DSS-induced colitis and IL-1β levels in colon culture supernatants from these mice were significantly higher than in cultures obtained from control mice. Furthermore, in both BALB/c and SCID mice increased recruitment of F4/80-positive macrophages was observed in the inflamed colonic mucosa following HNP-1 injections.. High concentrations of HNP-1 aggravate DSS-induced colitis, including upregulated expression of such macrophage-derived cytokines as IL-1β. These results indicate that high concentrations of HNP-1-3 in patients with UC may exacerbate disease activity via increased cytokine production.

Topics: alpha-Defensins; Animals; Cells, Cultured; Colitis; Colon; Dextran Sulfate; Disease Models, Animal; Humans; Interferon-gamma; Interleukin-1beta; Intestinal Mucosa; Macrophages; Male; Mice; Mice, Inbred BALB C; Mice, SCID; Peroxidase; Severity of Illness Index; Tumor Necrosis Factor-alpha; Up-Regulation

Salvinorin A (SA) has a potent inhibitory action on mouse gastrointestinal (GI) motility and ion transport, mediated primarily by kappa-opioid receptors (KOR). The aim of the present study was to characterize possible antiinflammatory and antinociceptive effects of SA in the GI tract of mice.. Colonic damage scores and myeloperoxidase activity were determined after intraperitoneal (i.p.), intracolonic (i.c.), and oral (p.o.) administration of SA using the trinitrobenzene sulfonic acid (TNBS) and dextran sodium sulfate (DSS) models of colitis in mice. Additionally, KOR, cannabinoid (CB)1, and CB2 western blot analysis of colon samples was performed. The antinociceptive effect of SA was examined based on the number of behavioral responses to i.c. instillation of mustard oil (MO).. The i.p. (3 mg/kg, twice daily) and p.o. (10 mg/kg, twice daily) administration of SA significantly attenuated TNBS and DSS colitis in mice. The effect of SA was blocked by KOR antagonist nor-binaltorphimine (10 mg/kg, i.p.). Western blot analysis showed no influence of SA on KOR, CB1, or CB2 levels. SA (3 mg/kg, i.p. and 10 mg/kg, i.c.) significantly decreased the number of pain responses after i.c. instillation of MO in the vehicle- and TNBS-treated mice. The antinociceptive action of SA was blocked by KOR and CB1 antagonists. The analgesic effect of i.c. SA was more potent in TNBS-treated mice compared to controls.. Our results suggest that the drugs based on the structure of SA have the potential to become valuable antiinflammatory or analgesic therapeutics for the treatment of GI diseases.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Blotting, Western; Colitis; Colon; Dextran Sulfate; Disease Models, Animal; Diterpenes, Clerodane; Gastrointestinal Motility; Male; Mice; Naltrexone; Pain; Peroxidase; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Receptors, Opioid, kappa; Salvia; Trinitrobenzenesulfonic Acid

Inflammation and oxidative stress are linked to the deleterious effects of cigarette smoke in producing chronic obstructive pulmonary disease (COPD). Myeloperoxidase (MPO), a neutrophil and macrophage product, is important in bacterial killing, but also drives inflammatory reactions and tissue oxidation.. To determine the role of MPO in COPD.. We treated guinea pigs with a 2-thioxanthine MPO inhibitor, AZ1, in a 6-month cigarette smoke exposure model, with one group receiving compound from Smoking Day 1 and another group treated after 3 months of smoke exposure.. At 6 months both treatments abolished smoke-induced increases in lavage inflammatory cells, largely ameliorated physiological changes, and prevented or stopped progression of morphologic emphysema and small airway remodeling. Cigarette smoke caused a marked increase in immunohistochemical staining for the myeloperoxidase-generated protein oxidation marker dityrosine, and this effect was considerably decreased with both treatment arms. Serum 8-isoprostane, another marker of oxidative stress, showed similar trends. Both treatments also prevented muscularization of the small intrapulmonary arteries, but only partially ameliorated smoke-induced pulmonary hypertension. Acutely, AZ1 prevented smoke-induced increases in expression of cytokine mediators and nuclear factor-κB binding.. We conclude that an MPO inhibitor is able to stop progression of emphysema and small airway remodeling and to partially protect against pulmonary hypertension, even when treatment starts relatively late in the course of long-term smoke exposure, suggesting that inhibition of MPO may be a novel and useful therapeutic treatment for COPD. Protection appears to relate to inhibition of oxidative damage and down-regulation of the smoke-induced inflammatory response.

Topics: Airway Remodeling; Animals; Dinoprost; Disease Models, Animal; Disease Progression; Enzyme Inhibitors; Female; Guinea Pigs; Hypertension, Pulmonary; Inflammation; Lung; Oxidative Stress; Peroxidase; Pulmonary Disease, Chronic Obstructive; Purines; Smoking; Thiones; Thioxanthenes; Tyrosine

To determine the contribution of programmed death receptor (PD)-1 in the morbidity and mortality associated with the development of indirect-acute lung injury.. The immune cell interaction(s) leading to indirect-acute lung injury are not completely understood. In this respect, we have recently shown that the murine cell surface coinhibitory receptor, PD-1, has a role in septic morbidity/mortality that is mediated in part through the effects on the innate immune arm. However, it is not know if PD-1 has a role in the development of indirect-acute lung injury and how this may be mediated at a cellular level.. PD-1 -/- mice were used in a murine model of indirect-acute lung injury (hemorrhagic shock followed 24 hours after with cecal ligation and puncture-septic challenge) and compared to wild type controls. Groups were initially compared for survival and subsequently for markers of pulmonary inflammation, influx of lymphocytes and neutrophils, and expression of PD-1 and its ligand-PD-L1. In addition, peripheral blood leukocytes of patients with indirect-acute lung injury were examined to assess changes in cellular PD-1 expression relative to mortality.. PD-1 -/- mice showed improved survival compared to wild type controls. In the mouse lung, CD4+, CD11c+, and Gr-1+ cells showed increased PD-1 expression in response to indirect-acute lung injury. However, although the rise in bronchial alveolar lavage fluid protein concentrations, lung IL-6, and lung MCP-1 were similar between PD-1 -/- and wild type animals subjected to indirect acute lung injury, the PD-1 -/- animals that were subjected to shock/septic challenge had reduced CD4:CD8 ratios, TNF-α levels, MPO activity, and Caspase 3 levels in the lung. Comparatively, we observed that humans, who survived their acute lung injury, had significantly lower expression of PD-1 on T cells.. PD-1 expression contributes to mortality after the induction of indirect-acute lung injury and this seems to be associated with modifications in the cellular and cytokine profiles in the lung.

Topics: Acute Lung Injury; Adult; Aged; Animals; Antigens, Differentiation; Bronchoalveolar Lavage Fluid; Caspase 3; CD4-CD8 Ratio; Disease Models, Animal; Female; Gene Expression; Humans; Interleukin-6; Leukocytes; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Peroxidase; Programmed Cell Death 1 Receptor; Shock, Septic; Survival Rate; T-Lymphocytes; Tumor Necrosis Factor-alpha

Cytokine activation and the ensuing spread of damage to distant organs play a central role in sepsis caused by generalized peritonitis, which accompanies surgical conditions such as gastrointestinal perforation. Anti-inflammatory properties have been discovered in endogenous substances such as vitamin E; we evaluated, in a rat model of peritonitis-induced sepsis, the newly synthetic vitamin E derivative E-Ant-S-GS, in which the endogenous substances vitamin E, glutathione, 5-OH-anthranilic acid, and succinic acid are chemically linked.. We used a model of sepsis in male Wistar rats with the cecal ligation and puncture (CLP) method. To evaluate the anti-inflammatory effects of E-Ant-S-GS, we measured serum interleukin-6 (IL-6) levels at various times after CLP. To assess the effects of E-Ant-S-GS in acute lung injury, we evaluated histologically lung tissue 12 hours after CLP by hematoxylin-eosin staining. In addition, myeloperoxidase (MPO) activity and expression of protease-activated receptor 1 (PAR1) and high mobility group box 1 (HMGB1) in the lung were determined.. Serum IL-6 levels increased progressively after the CLP procedure; this cytokine induction was attenuated by E-Ant-S-GS. Increased MPO activity in lung tissue and marked changes in lung histology caused by CLP-induced sepsis were also ameliorated by E-Ant-S-GS. In addition, E-Ant-S-GS suppressed the upregulation of PAR1 and HMGB1 in the lungs after CLP.. The newly synthetic vitamin E derivative E-Ant-S-GS showed anti-inflammatory actions and organ-protective effects in a rat model of sepsis, suggesting its potential clinical use as a therapeutic agent against systemic inflammation.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cecum; Disease Models, Animal; HMGB1 Protein; Interleukin-6; Ligation; Male; Peritonitis; Peroxidase; Punctures; Rats; Rats, Wistar; Receptor, PAR-1; Sepsis; Up-Regulation; Vitamin E

The objective of this study was to investigate the effects of the c-Jun N-terminal kinase (JNK) signaling pathway on rats' acute pancreatitis-associated lung injury (APALI).. Seventy-two Sprague-Dawley rats were randomly divided into 3 groups, namely, the sham operation (SO) group, the severe acute pancreatitis (SAP) group, and the SP600125 group. The SAP model was established by injection of 5% sodium taurocholate into the pancreatic duct. The samples were taken at 3, 6, 12, and 24 hours. Serum amylase, pathologic lesions of the pancreas and lung tissues, wet-to-dry weight ratio of the lung, myeloperoxidase (MPO) activity of the lung, tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), intercellular adhesion molecule 1 (ICAM-1), and p-JNK of lung tissues were detected.. The wet-to-dry weight ratio, MPO activity, and IL-1β, TNF-α, ICAM-1, and p-JNK levels in the SAP group significantly increased compared with those in the SO group. The scores of lung pathologic injury significantly increased, consistent with the APALI. The wet-to-dry weight ratio, MPO activity, IL-1β, TNF-α, ICAM-1, p-JNK expressions, and lung pathologic injury scores in the SP600125 group decreased compared with those in the SAP group. p-JNK was closely correlated with MPO activity, IL-1β, ICAM-1, and total scores of lung injury.. The JNK signaling pathway plays a critical role in APALI. On the other hand, application of a specific JNK inhibitor can contribute to alleviation of APALI.

Topics: Acute Disease; Amylases; Animals; Anthracenes; Disease Models, Animal; Intercellular Adhesion Molecule-1; Interleukin-1; JNK Mitogen-Activated Protein Kinases; Lung; Lung Injury; Male; Pancreas; Pancreatitis; Peroxidase; Phosphorylation; Protein Kinase Inhibitors; Rats; Rats, Sprague-Dawley; Signal Transduction; Taurocholic Acid; Time Factors; Tumor Necrosis Factor-alpha

Supplementation studies of glutamine, arginine, and docosahexaenoic acid (DHA) have established the safety of each of these nutrients in neonates; however, the potential for a more stable and soluble dipeptide, arginyl-glutamine (Arg-Gln) or DHA with anti-inflammatory properties, to exert benefits on hyperoxia-induced intestinal injury has not been investigated. Arg-Gln dipeptide has been shown to prevent retinal damage in a rodent model of oxygen-induced injury. The objective of the present study was to investigate whether Arg-Gln dipeptide or DHA could also attenuate markers of injury and inflammation to the small intestine in this same model.. Seven-day-old mouse pups were placed with their dams in 75% oxygen for 5 days. After 5 days of hyperoxic exposure (P7-P12), pups were removed from hyperoxia and allowed to recover in atmospheric conditions for 5 days (P12-P17). Mouse pups received Arg-Gln (5g·kg·day) or DHA (5g·kg·day) or vehicle orally started on P12 through P17. Distal small intestine (DSI) histologic changes, myeloperoxidase (MPO), lactate dehydrogenase (LDH), inflammatory cytokines, and tissue apoptosis were evaluated.. Hyperoxic mice showed a greater distortion of overall villus structure and with higher injury score (P<0.05). Arg-Gln dipeptide and DHA supplementation groups were more similar to the room air control group. Supplementation of Arg-Gln or DHA reduced hyperoxia-induced MPO activity (P<0.05). Supplementation of Arg-Gln or DHA returned LDH activity to the levels of control. Hyperoxia induced apoptotic cell death in DSIs, and both Arg-Gln and DHA reversed this effect (P<0.05).. Supplementation with either Arg-Gln or DHA may limit some inflammatory and apoptotic processes involved in hyperoxic-induced intestinal injury in neonatal mice.

Topics: Animals; Animals, Newborn; Apoptosis; Arginine; Dietary Supplements; Dipeptides; Disease Models, Animal; Docosahexaenoic Acids; Female; Glutamine; Hyperoxia; Intestinal Mucosa; Intestine, Small; L-Lactate Dehydrogenase; Mice; Mice, Inbred C57BL; Peroxidase

Lysosomal membrane protein 2 (LAMP-2) is a target of antineutrophil cytoplasmic autoantibodies (ANCA) in addition to the more commonly known targets proteinase 3 and myeloperoxidase. The prevalence of anti-LAMP-2 antibodies and their relationship to disease in ANCA glomerulonephritis are not well described. We measured anti-LAMP-2 reactivity in 680 sera samples (two academic centers) from patients with ANCA glomerulonephritis (n=329); those with ANCA-negative glomerulonephritis (n=104); those with fimbriated, gram-negative Escherichia coli urinary tract infection (n=104); disease controls (n=19); and healthy volunteers (n=124). With levels in healthy controls used to define a reference range, anti-LAMP-2 reactivity was present in 21% of ANCA sera from two of the centers; reactivity was present in 16% of the control group with urinary tract infection. Western blotting and immunofluorescence microscopy did not verify positivity. Titers of anti-myeloperoxidase and anti-proteinase 3 antibodies were 1500-fold and 10,000-fold higher than anti-LAMP-2 titers, respectively. There was no correlation between anti-LAMP-2 antibodies and disease activity. Furthermore, Wistar Kyoto rats injected with anti-LAMP-2 antibodies did not develop glomerulonephritis. In conclusion, antibodies that react with LAMP-2 may exist at very low titers in a minority of patients with ANCA disease. These data do not support a mechanistic relationship between anti-LAMP-2 antibodies and ANCA glomerulonephritis.

Topics: Adult; Aged; Animals; Antibodies, Anti-Idiotypic; Antibodies, Antineutrophil Cytoplasmic; Case-Control Studies; Disease Models, Animal; Escherichia coli Infections; Female; Glomerulonephritis; HEK293 Cells; Humans; Kidney; Lysosomal-Associated Membrane Protein 2; Male; Middle Aged; Myeloblastin; Peroxidase; Prevalence; Rats; Rats, Inbred WKY; Sensitivity and Specificity; Urinary Tract Infections

Acute lung injury is still a significant clinical problem with a high mortality rate and there are few effective therapies in clinic. Here, we studied the inhibitory effect of ruscogenin, an anti-inflammatory and anti-thrombotic natural product, on lipopolysaccharide (LPS)-induced acute lung injury in mice basing on our previous studies. The results showed that a single oral administration of ruscogenin significantly decreased lung wet to dry weight (W/D) ratio at doses of 0.3, 1.0 and 3.0 mg/kg 1 h prior to LPS challenge (30 mg/kg, intravenous injection). Histopathological changes such as pulmonary edema, coagulation and infiltration of inflammatory cells were also attenuated by ruscogenin. In addition, ruscogenin markedly decreased LPS-induced myeloperoxidase (MPO) activity and nitrate/nitrite content, and also downregulated expression of tissue factor (TF), inducible NO synthase (iNOS) and nuclear factor (NF)-κB p-p65 (Ser 536) in the lung tissue at three doses. Furthermore, ruscogenin reduced plasma TF procoagulant activity and nitrate/nitrite content in LPS-induced ALI mice. These findings confirmed that ruscogenin significantly attenuate LPS-induced acute lung injury via inhibiting expressions of TF and iNOS and NF-κB p65 activation, indicating it as a potential therapeutic agent for ALI or sepsis.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Disease Models, Animal; Lipopolysaccharides; Male; Mice; Mice, Inbred ICR; NF-kappa B; Nitrates; Nitric Oxide Synthase Type II; Nitrites; Peroxidase; Spirostans; Thromboplastin

The purpose of our study was to evaluate the protective effect of the strong antioxidant and anti-inflammatory agent, lycopene, on oxidative stress in a rat model of cerulein-induced acute edematous pancreatitis.. Sprague-Dawley rats were pretreated with lycopene (50 mg/kg, i.p.) or saline 15 min before cerulein was given 20 μg/kg (i.p.) at 1-h intervals within 4 h. Twelve hours after cerulein or saline injections, the animals were killed by decapitation. Blood samples were collected to analyze amylase, lipase, and proinflammatory cytokines (TNF-α and IL-1ß). Pancreatic tissues were taken for the determination of tissue glutathione (GSH) and malondialdehyde (MDA) levels, Na(+)/K(+)-ATPase, and myeloperoxidase (MPO) activities. Tissue samples were also examined histologically.. Acute pancreatitis caused significant decrease in tissue GSH levels and Na(+)/K(+)-ATPase activity, while pancreatic MDA levels and MPO activity were increased. Furthermore, TNF-α, IL-1ß, and amylase lipase levels were also significantly increased. On the other hand, lycopene pretreatment reserved all these biochemical indices as well as histopathologic alterations that were induced by cerulein.. According to the results, lycopene protects the pancreatic tissues from oxidative damage induced by cerulein, and this effect possibly involves the inhibition of neutrophil infiltration and lipid peroxidation. These results suggest that high dietary intake of tomatoes may have protective effects against acute pancreatitis.

Topics: Acute Disease; Amylases; Animals; Antioxidants; Carotenoids; Ceruletide; Cytokines; Disease Models, Animal; Female; Glutathione; Lipase; Lipid Peroxidation; Lycopene; Male; Malondialdehyde; Oxidative Stress; Pancreatitis; Peroxidase; Rats; Rats, Sprague-Dawley

The present study aimed at isolating and elucidating the structure of the main components of Pistacia khinjuk L. and exploring its potential anti-inflammatory effect in different experimental models. The extract was evaluated for anti-inflammatory activity by measuring paw volume in three experimental models. Then, prostaglandin E₂ (PGE₂) level, ear edema, tissue myeloperoxidase (MPO) activity, histopathology, nitric oxide (NO) level, and tumor necrosis factor-α (TNF-α) level were assessed. Seven phenolic compounds, mainly flavonoids and galloylated compounds, were isolated from the aqueous methanol extract: gallic acid (1), methyl gallate (2), quercetin-3-O-β-D-⁴C₁-galactopyranoside (hyperin) (3), myricetin-3-O-α-L-¹C₄-rhamnopyranoside (myricitrin) (4), 1,6-digalloyl-β-D-glucose (5), 1,4-digalloyl-β-D-glucopyranoside (6), and 2,3-di-O-galloyl-(α/β)-⁴C₁-glucopyranose (nilocitin) (7). The anti-inflammatory activity was evidenced by decreased carrageenan-induced rat paw edema and PGE₂ elevation. In the croton oil-induced ear edema model, MPO activity was significantly inhibited, and inflammatory histopathological changes were ameliorated. In the rat air pouch model, NO generation and TNF-α release were significantly inhibited. The isolation and nuclear magnetic resonance spectral data of compound 6 from the genus Pistacia are revealed for the first time. Also, P. khinjuk L. aqueous methanol extract possesses anti-inflammatory activity in several experimental models.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Dinoprostone; Disease Models, Animal; Drug Discovery; Edema; Exudates and Transudates; Flavonoids; Gallic Acid; Glycosides; Male; Mediterranean Region; Molecular Structure; Nitric Oxide; Peroxidase; Pistacia; Plant Extracts; Plant Leaves; Rats; Rats, Sprague-Dawley; Skin; Tumor Necrosis Factor-alpha

Extracts of the mushroom Agaricus blazei (A. blazei) have been described as possessing immunomodulatory and potentially cancer-protective activities. However, these effects of A. blazei as a functional food have not been fully investigated in vivo.. Using apolipoprotein E-deficient (ApoE(-/-)) mice, an experimental model of atherosclerosis, we evaluated the effects of 6 or 12 weeks of A. blazei supplementation on the activation of immune cells in the spleen and blood and on the development of atherosclerosis.. Food intake, weight gain, blood lipid profile, and glycemia were similar between the groups. To evaluate leukocyte homing and activation, mice were injected with (99m)Tc-radiolabeled leukocytes, which showed enhanced leukocyte migration to the spleen and heart of A. blazei-supplemented animals. Analysis of the spleen showed higher levels of activation of neutrophils, NKT cells, and monocytes as well as increased production of TNF-α and IFN-γ. Circulating NKT cells and monocytes were also more activated in the supplemented group. Atherosclerotic lesion areas were larger in the aorta of supplemented mice and exhibited increased numbers of macrophages and neutrophils and a thinner fibrous cap. A. blazei-induced transcriptional upregulation of molecules linked to macrophage activation (CD36, TLR4), neutrophil chemotaxy (CXCL1), leukocyte adhesion (VCAM-1), and plaque vulnerability (MMP9) were seen after 12 weeks of supplementation.. This is the first in vivo study showing that the immunostimulatory effect of A. blazei has proatherogenic repercussions. A. blazei enhances local and systemic inflammation, upregulating pro-inflammatory molecules, and enhancing leukocyte homing to atherosclerosis sites without affecting the lipoprotein profile.

Topics: Agaricus; Animals; Aorta; Apolipoproteins E; Atherosclerosis; CD36 Antigens; Cell Adhesion; Chemokine CXCL1; Dietary Supplements; Disease Models, Animal; Fruiting Bodies, Fungal; Immunologic Factors; Inflammation; Interferon-gamma; Leukocytes; Liver; Macrophage Activation; Matrix Metalloproteinase 9; Mice; Mice, Knockout; Monocytes; Natural Killer T-Cells; Neutrophils; Peroxidase; RNA, Messenger; Spleen; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha; Up-Regulation; Vascular Cell Adhesion Molecule-1

Chafuroside A (CFA), a poorly water-soluble flavone C-glycoside, was firstly isolated from oolong tea, and it acts as a potent anti-inflammatory agent. The present study was undertaken to develop a water-soluble formulation of CFA using a self-assembled micellar (SAM) system, with the aim of improved dissolution behavior and potent anti-inflammatory effects. The SAM formulation of CFA (CFA/SAM) was characterized in terms of its morphology, particle size distribution, crystallinity, and dissolution behavior. In dissolution testing, the CFA/SAM exhibited marked improvement in dissolution behavior when compared with crystalline CFA, and then, nano-micellar particles were constituted with a mean diameter of 84 nm. The therapeutic potential of the crystalline CFA and CFA/SAM was assessed using an experimental asthma/chronic obstructive pulmonary disease (COPD)-like model. Orally-administered CFA at 0.5mg/kg or higher could attenuate inflammatory symptoms in a dose-dependent manner, as evidenced by decreases of infiltrated granulocytes, including macrophages and neutrophils, and myeloperoxidase, a specific biomarker for neutrophilia. Biomarker profiling demonstrated that the CFA/SAM at 0.1mg CFA/kg was equipotent to CFA at 1.0mg/kg in ameliorating antigen-induced airway inflammation, suggesting the better pharmacological effect of CFA/SAM due to improved dissolution behavior. From these observations, the SAM formulation might be an efficacious approach for enhancing the therapeutic potential of CFA for treatment of inflammatory diseases.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Asthma; Biomarkers; Bronchoalveolar Lavage Fluid; Cell Count; Chemical Phenomena; Disease Models, Animal; Dose-Response Relationship, Drug; Flavones; Glycosides; Granulocytes; Heterocyclic Compounds, 4 or More Rings; Male; Micelles; Nanostructures; Peroxidase; Phagocytes; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Sprague-Dawley; Solubility

Spinal cord injury (SCI) is a traumatic event that causes a secondary and extended inflammation characterized by infiltration of immune cells, including T lymphocytes, release of pro-inflammatory mediators in the lesion site, and tissue degeneration. Current therapeutic approaches for SCI are limited to glucocorticoids (GC) due to their potent anti-inflammatory activity. GC efficacy resides, in part, in the capability to inhibit NF-κB, T lymphocyte activation, and the consequent cytokine production. In this study, we performed experiments aimed to test the susceptibility of glucocorticoid-induced leucine zipper (GILZ) transgenic (GILZ(TG)) mice, in which GILZ is selectively over-expressed in T lymphocytes, to SCI induction. Consistent with a decreased inflammatory response, GILZ(TG) were less susceptible to SCI as compared to wild-type littermates. Notably, inhibition of NF-κB activation and nuclear translocation, diminished T lymphocytes activation and tissue infiltration, as well as decreased release of cytokines were evident in GILZ(TG) as compared to wild-type mice. Moreover, GILZ(TG) showed a reduced tumor necrosis factor-α, IL-1β, Inductible nitric oxide synthase (iNOS) and nytrotyrosine production, apoptosis, and neuronal tissue damage. Together these results indicate that GILZ mimics the anti-inflammatory effect of GC and represents a potential pharmacological target for modulation of T lymphocyte-mediated immune response in inflammatory disorders, such as SCI.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Cyclin D1; Cytokines; Dinoprostone; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Glial Fibrillary Acidic Protein; In Situ Nick-End Labeling; Inflammation; Mice; Mice, Transgenic; Nitric Oxide Synthase Type II; Peroxidase; Signal Transduction; Spinal Cord Injuries; T-Lymphocytes; Transcription Factors

T-helper (Th) cells play a major role in initiating and shaping the pathologic response in inflammatory bowel disease (IBD). Glutamine (GLN) is a nutrient with immune-modulating effects. This study investigated the effect of GLN on cytokine expressions and inflammatory responses of three subsets of Th cells in dextran sulfate sodium (DSS)-induced IBD. There were one normal control (NC) and two DSS groups. Mice in the DSS groups drank distilled water containing 3% DSS for 5 days, whereas the NC group received distilled water. Mice in the G-DSS group were given intraperitoneal injection of 0.5 g GLN/kg/d for 3 days before receiving DSS water. The other DSS group (C-DSS) received an identical amount of amino acid solution without GLN. After induction of IBD, the mice were allowed to recover for 3 days and then were sacrificed. Blood and colon samples were collected for further analysis. The C-DSS group had higher percentages of blood interleukin (IL)-17A, IL-17F, IL-22, IL-4 and interferon-γ than the NC group. The G-DSS group had lower Th1/Th17/Th2 cytokine expressions, which showed no differences from the NC group. Plasma haptoglobin, colon immunoglobin G and chemokine levels and myeloperoxidase activities were higher in the DSS groups than the NC group. These parameters were significantly lower in the G-DSS than the C-DSS group. These results suggest that pretreatment with GLN suppressed Th-associated cytokine expressions and may consequently reduce inflammatory mediator production and leukocyte infiltration into tissues, thus ameliorating the severity of acute DSS-induced colitis.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Colitis; Colitis, Ulcerative; Colon; Cytokines; Dextran Sulfate; Dipeptides; Disease Models, Animal; Down-Regulation; Haptoglobins; Inflammatory Bowel Diseases; Injections, Intraperitoneal; Intestinal Mucosa; Male; Mice; Mice, Inbred C57BL; Peroxidase; Severity of Illness Index; T-Lymphocytes, Helper-Inducer

To investigate whether a physiologic effect of "glycosaminoglycan (GAG) replenishment therapy" altered recruitment of inflammatory cells in an acute bladder damage model. Replacement of the GAG layer with intravesically administered GAGs is an effective therapy for interstitial cystitis in at least some patients. Intravesically administered chondroitin sulfate was previously shown to bind to and restore the impermeability of surface-damaged ("leaky") urothelium to small ions.. Rat bladders were damaged with 10 mM HCl. Negative control bladders were treated with phosphate-buffered saline. On the following day, the animal bladders were treated with 20 mg/mL chondroitin sulfate in phosphate-buffered saline, and the negative and positive controls were treated with phosphate-buffered saline alone. At 2 and 4 days after treatment with chondroitin sulfate, the rats were killed, and sections of their bladders were analyzed using toluidine blue staining for mast cell immunohistochemical labeling using antibodies against CD45 for lymphocytes and myeloperoxidase for neutrophils.. Chondroitin sulfate treatment reduced the recruitment, in a statistically significant manner, of inflammatory cells, including neutrophils and mast cells to the suburothelial space but did not alter recruitment of CD45-positive lymphocytes.. For the first time, we have demonstrated that intravesical GAG replenishment therapy also produces a physiologic effect of decreasing recruitment of inflammatory cells in an acute model of the damaged bladder. These findings support the use of intravesically administered GAG for bladder disorders that result from a loss of impermeability, including interstitial, radiation, and chemical cystitis, and possibly others as well.

Topics: Animals; Burns, Chemical; Chemotaxis, Leukocyte; Chondroitin Sulfates; Cystitis; Disease Models, Animal; Drug Evaluation, Preclinical; Edema; Hydrochloric Acid; Leukocyte Common Antigens; Lymphocytes; Mast Cells; Neutrophils; Permeability; Peroxidase; Rats; Rats, Sprague-Dawley

Activation of nuclear factor-kappa B (NF-κB), which controls transcription of various pro-inflammatory cytokine genes, has been shown to play a critical role in the pathogenesis of ulcerative colitis (UC). Parthenolide, a sesquiterpene lactone compound isolated from extracts of the herb Feverfew (Tanacetum parthenium), has been demonstrated to be a potent inhibitor of NF-κB activation. This study was designed to investigate the effects of parthenolide on an experimental murine colitis model.. Experimental colitis was induced by dextran sulfate sodium (DSS), and mice were divided into 3 groups: normal control, DSS+saline, and DSS+parthenolide. The disease activity index (DAI) and histological score were observed. The tumor necrosis factor (TNF)-α and interleukin (IL)-1β levels were measured by enzyme-linked immunosorbent assay. Phospho-IκBα, IκBα and phospho-NF-κB p65 expression were assessed by western blot analysis. Myeloperoxidase (MPO) activity was determined by using MPO assay kit.. Administration of parthenolide significantly reduced the severity of DSS-induced colitis as assessed by DAI and histological score, and resulted in downregulation of MPO activity and phospho-NF-κB p65 expression by the blockade of phosphorylation and subsequent degradation of IκB protein, strikingly reduced the production of TNF-α and IL-1β.. Parthenolide exerts beneficial effects in experimental colitis and may therefore provide a useful therapeutic approach for the treatment of UC.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Colitis, Ulcerative; Dextran Sulfate; Disease Models, Animal; I-kappa B Proteins; Male; Mice; Mice, Inbred BALB C; NF-kappa B; NF-KappaB Inhibitor alpha; Peroxidase; Sesquiterpenes

Multiple system atrophy (MSA) is a rare and fatal α-synucleinopathy characterized by a distinctive oligodendrogliopathy with glial cytoplasmic inclusions and associated neuronal multisystem degeneration. The majority of patients presents with a rapidly progressive parkinsonian disorder and atypical features such as early autonomic failure and cerebellar ataxia. We have previously reported that complete MSA pathology can be modeled in transgenic mice overexpressing oligodendroglial α-synuclein under conditions of oxidative stress induced by 3-nitropropionic acid (3-NP) including striatonigral degeneration, olivopontocerebellar atrophy, astrogliosis, and microglial activation. Here, we show that myeloperoxidase (MPO), a key enzyme involved in the production of reactive oxygen species by phagocytic cells, is expressed in both human and mouse MSA brains. We also demonstrate that in the MSA mouse model, MPO inhibition reduces motor impairment and rescues vulnerable neurons in striatum, substantia nigra pars compacta, cerebellar cortex, pontine nuclei, and inferior olives. MPO inhibition is associated with suppression of microglial activation but does not affect 3-NP induced astrogliosis in the same regions. Finally, MPO inhibition results in reduced intracellular aggregates of α-synuclein. This study suggests that MPO inhibition may represent a novel candidate treatment strategy against MSA-like neurodegeneration acting through its anti-inflammatory and anti-oxidative properties.

Topics: Aged; alpha-Synuclein; Animals; Brain; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Gliosis; Humans; Male; Mice; Mice, Transgenic; Microglia; Middle Aged; Motor Activity; Multiple System Atrophy; Nerve Degeneration; Peroxidase; Pyrimidinones; Pyrroles

In sepsis, extracellular ATP, secreted by activated platelets and leukocytes, may contribute to the crosstalk between hemostasis and inflammation. Previously, we showed that, in addition to their role in platelet activation, ATP-gated P2X(1) ion channels are involved in promoting neutrophil chemotaxis.. To elucidate the contribution of P2X(1) ion channels to sepsis and the associated disturbance of hemostasis.. We used P2X(1) (-/-) mice in a model of lipopolysaccharide (LPS)-induced sepsis. Hemostasis and inflammation parameters were analyzed together with outcome. Mechanisms were further studied ex vivo with mouse and human blood or isolated neutrophils and monocytes.. P2X(1) (-/-) mice were more susceptible to LPS-induced shock than wild-type mice, despite normal cytokine production. Plasma levels of thrombin-antithrombin complexes were higher, thrombocytopenia was worsened, and whole blood coagulation time was markedly reduced, pointing to aggravated hemostasis disturbance in the absence of P2X(1). However, whole blood platelet aggregation occurred normally, and P2X(1) (-/-) macrophages displayed normal levels of total tissue factor activity. We found that P2X(1) (-/-) neutrophils produced higher amounts of reactive oxygen species. Increased amounts of myeloperoxidase were released in the blood of LPS-treated P2X(1) (-/-) mice, and circulating neutrophils and monocytes expressed higher levels of CD11b. Neutrophil accumulation in the lungs was also significantly augmented, as was lipid peroxidation in the liver. Desensitization of P2X(1) ion channels led to increased activation of human neutrophils and enhanced formation of platelet-leukocyte aggregates.. P2X(1) ion channels play a protective role in endotoxemia by negatively regulating systemic neutrophil activation, thereby limiting the oxidative response, coagulation, and organ damage.

Topics: Adenosine Triphosphate; Animals; Blood Coagulation; Blood Platelets; CD11b Antigen; Cells, Cultured; Cytokines; Disease Models, Animal; Endotoxemia; Humans; Ion Channel Gating; Lipopolysaccharides; Liver; Lung; Mice; Mice, Inbred C57BL; Mice, Knockout; Monocytes; Neutrophil Activation; Neutrophil Infiltration; Neutrophils; Peroxidase; Platelet Adhesiveness; Reactive Oxygen Species; Receptors, Purinergic P2X1; Sepsis; Time Factors

In our previous study, the remarkable analgesic and anti-inflammatory effects of the combination of sodium ferulate (SF) and oxymatrine (OMT) had been found. In this study, we investigated the effect of the combination of SF and OMT on acute lung injury using lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model. The cell counting and the protein concentration in the bronchoalveolar lavage fluid (BALF) were measured. The animal lung edema degree was evaluated by wet/dry weight (W/D) ratio. The superoxidase dismutase (SOD) activity and myeloperoxidase (MPO) activity was assayed by SOD and MPO kits, respectively. The levels of inflammatory mediators including C-reactive protein (CRP) and tumor necrosis factor-α (TNF-α) were assayed by enzyme-linked immunosorbent assay method. The data showed that treatment with the combination of SF and OMT markedly attenuated inflammatory cell numbers and protein concentration in the BALF and improved SOD activity and inhibited MPO activity compared to LPS group. Moreover, the combination significantly inhibited the production of CRP and TNF-α in lung homogenate. The histological changes of the lungs were also more significantly improved by the combination. At the same dose, the obvious protective effect was not found in SF or OMT-treated alone group except that the protein concentration slightly decreased in SF group. The results indicated that the combination SF and OMT had a protective effect on LPS-induced ALI in mice, and the effect was much better than that of SF or OMT used alone.

Topics: Acute Lung Injury; Alkaloids; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bronchoalveolar Lavage Fluid; C-Reactive Protein; Coumaric Acids; Disease Models, Animal; Drug Combinations; Edema; Inflammation; Lipopolysaccharides; Lung; Mice; Peroxidase; Quinolizines; Random Allocation; Superoxide Dismutase; Tumor Necrosis Factor-alpha

The pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated necrotizing crescentic GN (NCGN) is incompletely understood. Dipeptidyl peptidase I (DPPI) is a cysteine protease required for the activation of neutrophil serine proteases (NSPs) cathepsin G, neutrophil elastase, and proteinase 3, which are enzymes that modulate inflammation. We used a mouse model of anti-myeloperoxidase (MPO) antibody-induced NCGN to determine whether active NSPs contribute to its pathogenesis. MPO-deficient animals immunized with murine MPO, irradiated, and transplanted with wild-type bone marrow developed NCGN. In contrast, transplantation with bone marrow that lacked DPPI or lacked both neutrophil elastase and proteinase 3 protected mice from NCGN induced by anti-MPO antibody. The kidneys of mice reconstituted with DPPI-deficient bone marrow generated significantly less IL-1β than did those of mice reconstituted with wild-type bone marrow; similarly, in vitro, DPPI-deficient monocytes produced significantly less IL-1β in response to anti-MPO antibody than did wild-type monocytes. This reduction in IL-1β was NSP dependent; exogenous addition of PR3 restored IL-β production in DPPI-deficient monocytes. Last, the IL-1 receptor antagonist anakinra protected animals against anti-MPO antibody-induced NCGN (16.7%±6.0% versus 2.4%±1.7% crescents), suggesting that IL-1β is a critical inflammatory mediator in this model. These data suggest that the development of anti-MPO antibody-induced NCGN requires NSP-dependent IL-1β generation and that these processes may provide therapeutic targets for ANCA-mediated diseases in humans.

Topics: Animals; Antibodies, Anti-Idiotypic; Antibodies, Antineutrophil Cytoplasmic; Bone Marrow Transplantation; Cathepsin C; Cell Movement; Disease Models, Animal; Female; Glomerulonephritis; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-1beta; Kidney; Kidney Cortex Necrosis; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Monocytes; Neutrophils; Peroxidase; Receptors, Interleukin-1; Serine Proteases

Proline-rich tyrosine kinase 2 (Pyk2) is essential in neutrophil degranulation and chemotaxis in vitro. However, its effect on the process of lung inflammation and edema formation during LPS induced acute lung injury (ALI) remains unknown. The goal of the present study was to determine the effect of inhibiting Pyk2 on LPS-induced acute lung inflammation and injury in vivo.. C57BL6 mice were given either 10 mg/kg LPS or saline intratracheally. Inhibition of Pyk2 was effected by intraperitoneal administration TAT-Pyk2-CT 1 h before challenge. Bronchoalveolar lavage analysis of cell counts, lung histology and protein concentration in BAL were analyzed at 18 h after LPS treatment. KC and MIP-2 concentrations in BAL were measured by a mouse cytokine multiplex kit. The static lung compliance was determined by pressure-volume curve using a computer-controlled small animal ventilator. The extravasated Evans blue concentration in lung homogenate was determined spectrophotometrically.. Intratracheal instillation of LPS induced significant neutrophil infiltration into the lung interstitium and alveolar space, which was attenuated by pre-treatment with TAT-Pyk2-CT. TAT-Pyk2-CT pretreatment also attenuated 1) myeloperoxidase content in lung tissues, 2) vascular leakage as measured by Evans blue dye extravasation in the lungs and the increase in protein concentration in bronchoalveolar lavage, and 3) the decrease in lung compliance. In each paradigm, treatment with control protein TAT-GFP had no blocking effect. By contrast, production of neutrophil chemokines MIP-2 and keratinocyte-derived chemokine in the bronchoalveolar lavage was not reduced by TAT-Pyk2-CT. Western blot analysis confirmed that tyrosine phosphorylation of Pyk2 in LPS-challenged lungs was reduced to control levels by TAT-Pyk2-CT pretreatment.. These results suggest that Pyk2 plays an important role in the development of acute lung injury in mice and that pharmacological inhibition of Pyk2 might provide a potential therapeutic strategy in the pretreatment for patients at imminent risk of developing acute lung injury.

Topics: Acute Lung Injury; Animals; Bronchoalveolar Lavage Fluid; Chemokine CXCL2; Chemokines; Disease Models, Animal; Female; Focal Adhesion Kinase 2; Lipopolysaccharides; Lung; Mice; Mice, Inbred C57BL; Neutrophil Infiltration; Peroxidase; Pneumonia; Recombinant Fusion Proteins

In this study, the therapeutic and protective effects of montelukast against cisplatin (CP)-induced acute renal damage were investigated.. Thirty-five female rats were divided into five groups as follows: (1) control, (2) montelukast (10 mg/kg daily for 10 days per-oral (p.o.), (3) CP (single dose 7 mg/kg intraperitoneally (i.p.)), (4) CP + montelukast (10 mg/kg daily for 10 days p.o., after 3 days of the injection of CP), (5) montelukast (10 mg/kg daily for 10 days p.o.) + CP (single dose 7 mg/kg i.p., after the last dose of montelukast). At the end of the experiment, malondialdehyde (MDA), a lipid peroxidation product, myeloperoxidase (MPO), and reduced glutathione (GSH) levels were determined in the renal tissue. Also, blood urea nitrogen (BUN) and creatinine (Cr) levels were assayed from the trunk blood samples.. CP treatment caused a significant elevation of MDA, MPO, BUN, and Cr levels when compared with the control group. Also, GSH levels were found to be reduced due to the CP treatment. Montelukast administration after CP injection ameliorated all of these parameters. Our histopathological findings (marked swelling of epithelial cells, tubular dilatation, tubular desquamation, and loss of brush border in the kidney) were consistent with the biochemical results.. Montelukast treatment after CP injection exerted therapeutic effects against CP-induced acute kidney damage.

Topics: Acetates; Acute Kidney Injury; Animals; Blood Urea Nitrogen; Cisplatin; Creatinine; Cyclopropanes; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Glutathione; Injections, Intraperitoneal; Kidney; Leukotriene Antagonists; Malondialdehyde; Oxidative Stress; Peroxidase; Quinolines; Rats; Rats, Wistar; Spectrophotometry; Sulfides; Treatment Outcome

Acute lung injury is an inflammatory condition for which treatment is mainly supportive because effective therapies have not been developed. Cannabidiol, a non-psychotropic cannabinoid component of marijuana (Cannabis sativa), has potent immunosuppressive and anti-inflammatory properties. Therefore, we investigated the possible anti-inflammatory effect of cannabidiol in a murine model of acute lung injury. Analysis of total inflammatory cells and differential in bronchoalveolar lavage fluid was used to characterize leukocyte migration into the lungs; myeloperoxidase activity of lung tissue and albumin concentration in the bronchoalveolar lavage fluid were analyzed by colorimetric assays; cytokine/chemokine production in the bronchoalveolar lavage fluid was also analyzed by Cytometric Bead Arrays and Enzyme-Linked Immunosorbent Assay (ELISA). A single dose of cannabidiol (20mg/kg) administered prior to the induction of LPS (lipopolysaccharide)-induced acute lung injury decreases leukocyte (specifically neutrophil) migration into the lungs, albumin concentration in the bronchoalveolar lavage fluid, myeloperoxidase activity in the lung tissue, and production of pro-inflammatory cytokines (TNF and IL-6) and chemokines (MCP-1 and MIP-2) 1, 2, and 4days after the induction of LPS-induced acute lung injury. Additionally, adenosine A(2A) receptor is involved in the anti-inflammatory effects of cannabidiol on LPS-induced acute lung injury because ZM241385 (4-(2-[7-Amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol) (a highly selective antagonist of adenosine A(2A) receptor) abrogated all of the anti-inflammatory effects of cannabidiol previously described. Thus, we show that cannabidiol has anti-inflammatory effects in a murine model of acute lung injury and that this effect is most likely associated with an increase in the extracellular adenosine offer and signaling through adenosine A(2A) receptor.

Topics: Acute Lung Injury; Adenosine A2 Receptor Antagonists; Animals; Anti-Inflammatory Agents; Bone Marrow Cells; Bronchoalveolar Lavage Fluid; Cannabidiol; Cannabinoids; Capillary Permeability; Chemokines; Cytokines; Disease Models, Animal; Drug Evaluation, Preclinical; Leukocytes; Male; Mice; Mice, Inbred C57BL; Peroxidase; Receptor, Adenosine A2A; Triazines; Triazoles

The formation of oxidative stress in the lung and activation of neutrophils are major determinants in the development of respiratory failure after acute lung injury and sepsis. However, the time changes of these pathogenic factors have not been sufficiently described. Twenty-four chronically instrumented sheep were subjected to cotton smoke inhalation injury and instillation of live Pseudomonas aeruginosa into both lungs. The sheep were euthanized at 4, 8, 12, 18, and 24 h after injury. Additional sheep received sham injury and were euthanized after 24 h. Pulmonary function was assessed by determination of oxygenation index and pulmonary shunt fraction. In addition, lung tissue was harvested at the respective time points for the measurement of malondialdehyde, interleukin 6, poly(ADP ribose), myeloperoxidase, and alveolar polymorphonuclear neutrophil score. The injury induced severe respiratory failure that was associated with an early increase in lipid peroxidation and interleukin 6 expression. The injury further led to an increase in poly(ADP ribose) activity that reached its peak at 12 h after injury and declined afterward. In addition, progressive increases in markers of neutrophil accumulation in the lung were observed. The peak of neutrophil accumulation in the lung was associated with a severe depletion of circulating neutrophils. The results from our model may enhance the understanding of the pathophysiological alterations after acute lung injury and sepsis and thus be useful in exploring therapeutic interventions directed at modifying the expression or activation of inflammatory mediators.

Topics: Acute Lung Injury; Animals; Disease Models, Animal; Gene Expression Regulation; Inflammation Mediators; Interleukin-6; Lung; Malondialdehyde; Neutrophil Activation; Neutrophils; Oxidative Stress; Peroxidase; Poly Adenosine Diphosphate Ribose; Pseudomonas aeruginosa; Pseudomonas Infections; Sheep; Smoke Inhalation Injury; Time Factors

Histone deacetylase (HDAC) inhibitors are efficacious in models of hypertension-induced left ventricular heart failure. The consequences of HDAC inhibition in the context of pulmonary hypertension with associated right ventricular cardiac remodeling are poorly understood.. This study was performed to assess the utility of selective small-molecule inhibitors of class I HDACs in a preclinical model of pulmonary hypertension.. Rats were exposed to hypobaric hypoxia for 3 weeks in the absence or presence of a benzamide HDAC inhibitor, MGCD0103, which selectively inhibits class I HDACs 1, 2, and 3. The compound reduced pulmonary arterial pressure more dramatically than tadalafil, a standard-of-care therapy for human pulmonary hypertension that functions as a vasodilator. MGCD0103 improved pulmonary artery acceleration time and reduced systolic notching of the pulmonary artery flow envelope, which suggests a positive impact of the HDAC inhibitor on pulmonary vascular remodeling and stiffening. Similar results were obtained with an independent class I HDAC-selective inhibitor, MS-275. Reduced pulmonary arterial pressure in MGCD0103-treated animals was associated with blunted pulmonary arterial wall thickening because of suppression of smooth muscle cell proliferation. Right ventricular function was maintained in MGCD0103-treated animals. Although the class I HDAC inhibitor only modestly reduced right ventricular hypertrophy, it had multiple beneficial effects on the right ventricle, which included suppression of pathological gene expression, inhibition of proapoptotic caspase activity, and repression of proinflammatory protein expression.. By targeting distinct pathogenic mechanisms, isoform-selective HDAC inhibitors have potential as novel therapeutics for pulmonary hypertension that will complement vasodilator standards of care.

Topics: Animals; Benzamides; Blood Pressure; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Heart Ventricles; Histone Deacetylase Inhibitors; Histone Deacetylases; Hypertension, Pulmonary; Hypoxia; Muscle, Smooth, Vascular; Pyridines; Pyrimidines; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Ventricular Remodeling

Hepatic ischemia/reperfusion injury (IRI) occurs in multiple clinical settings, including liver transplantation. The cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) pathway inhibits hepatocellular apoptosis and regulates toll-like receptor 4-triggered inflammation responses in vitro. Here we examined the function and therapeutic potential of cAMP-PKA activation in a murine (C57/BL6) model of liver warm ischemia (90 minutes) followed by reperfusion. Liver IRI triggered cAMP-PKA activation, whereas the administration of its specific inhibitor, H89, exacerbated hepatocellular damage. Conversely, forskolin therapy, which activates PKA by elevating cAMP levels, protected livers from IRI; this was evidenced by diminished serum alanine aminotransferase levels and well-preserved tissue architecture. Liver protection due to cAMP-PKA stimulation was accompanied by diminished neutrophil and macrophage infiltration/activation, reduced hepatocyte necrosis/apoptosis, and increased cAMP response element-binding protein (CREB) expression and augmented interleukin-10 (IL-10) expression. The neutralization of IL-10 restored liver damage in otherwise ischemia/reperfusion-resistant, forskolin-treated mice. In vitro, cAMP-PKA activation diminished macrophage tumor necrosis factor α, IL-6, and IL-12 in an IL-10-dependent manner and prevented necrosis/apoptosis in primary mouse hepatocyte cultures. Our novel findings in a mouse model of liver IRI document the importance of cAMP-PKA signaling in hepatic homeostasis and cytoprotection in vivo. The activation of cAMP-PKA signaling differentially regulates local inflammation and prevents hepatocyte death, and this provides a rationale for novel therapeutic approaches to combating liver IRI in transplant recipients.

Topics: Animals; Apoptosis; Cells, Cultured; Colforsin; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Disease Models, Animal; Enzyme Inhibitors; Hepatocytes; Interleukin-10; Isoquinolines; Liver; Liver Transplantation; Macrophages; Male; Mice; Mice, Inbred C57BL; Necrosis; Peroxidase; Reperfusion Injury; Signal Transduction; Sulfonamides; Temperature