piperidines and Inflammation

Autoimmune diseases and acute inflammation like sepsis cause significant morbidity and disability globally, and new targeted therapies are urgently needed. DNA repair and reactive oxygen species (ROS) pathways have long been investigated as targets for cancer treatment, but their role in immunological research has been limited. In this MiniReview, we discuss the DNA repair enzymes MTH1 and OGG1 as targets to treat both T cell-driven diseases and acute inflammation. The MiniReview is based on a PhD thesis where both enzymes were investigated with cell and animal models. For MTH1, we found that its inhibition selectively kills activated T cells without being toxic to resting cells or other tissues. MTH1 inhibition also had an alleviating role in disease models of psoriasis and multiple sclerosis. We further identified a novel MTH1

Topics: Animals; Benzimidazoles; DNA Glycosylases; DNA Repair; DNA Repair Enzymes; Inflammation; Mice; Phosphoric Monoester Hydrolases; Piperidines; Reactive Oxygen Species

The present study aimed to assess the prevalence of symptoms of anxiety and depression among health professionals in the three most affected regions in Cameroon.. The study was a descriptive cross-sectional type. Participants were health care professionals working in the three chosen regions of Cameroon. The non_probability convinient sample technique and that of the snowball were valued via a web questionnaire. The non-exhaustive sample size was 292. The diagnosis of anxiety and depression was made by the HAD (Hospital Anxiety and Depression scale).. Les auteurs rapportent que le secteur médical est classé à un plus grand risque de contracter le COVID-19 et de le propager potentiellement à d’autres. Le nombre sans cesse croissant de cas confirmés et suspects, la pression dans les soins, l’épuisement des équipements de protection individuelle et le manque de médicaments spécifiques peuvent contribuer à un vécu anxio-dépressif significatif. La présente étude s’est donnée pour ambition d’évaluer la prévalence des symptômes de l’anxiété et de la dépression chez les professionnels de santé dans les trois Régions les plus concernées au Cameroun.. Le choix des trois Régions du Cameroun se justifie non seulement par le fait qu’elles totalisent 95,8 % des cas de coronavirus au pays depuis le début de la pandémie, mais aussi parce qu’elles disposent de plus de la moitié des personnels de santé (56 %). Il s’agit d’une étude transversale, descriptive et analytique. Les participants sont des professionnels de la santé en service dans les Régions du Centre, Littoral et de l’Ouest du Cameroun. La méthode d’échantillonnage non probabiliste de convenance couplée à celle de boule de neige via un web questionnaire a été adoptée. La collecte des données a duré du 5 au 19 avril 2020, intervalle de temps après lequel on n’avait plus eu de répondants. À la fin de cette période, la taille de l’échantillon non exhaustive était de 292 professionnels. Le diagnostic de l’état anxio-dépressive était posé via l’échelle de HAD (Hospital Anxiety and Depression scale). Dans le HAD, chaque réponse cotée évalue de manière semi-quantitative l’intensité du symptôme au cours de la semaine écoulée. Un score total est obtenu ainsi que des scores aux deux sous-échelles : le score maximal est de 42 pour l’échelle globale et de 21 pour chacune des sous-échelles. Le coefficient alpha de Cronbach est de 0,70 pour la dépression et de 0,74 pour l’anxiété. Certains auteurs après plusieurs travaux ont proposé qu’une note inférieure ou égale à 7 indique une absence d’anxiété ou de dépression ; celle comprise entre 8 et 10 suggère une anxiété ou une dépression faible à bénigne ; entre 11 et 14, pour une anxiété ou une dépression modérée ; enfin, une note comprise entre 15 et 21 est révélatrice d’une anxiété sévère. Le logiciel Excel 2013 et Epi Info version 7.2.2.6 ont été utilisés pour les traitements statistiques. Les liens entre les variables ont été considérées significatifs pour une valeur de. L’amélioration des conditions de travail et notamment la fourniture d’équipement de protection, la mise en place des cellules spéciales d’écoute pour le personnel de santé pourraient être proposées.. Taken together with satisfactory selectivity index (SI) values, the acetone and methanol extracts of. During a mean follow-up period of 25.6 ± 13.9 months, 38 (18.4%) VAs and 78 (37.7%) end-stage events occurred. Big ET-1 was positively correlated with NYHA class (. In primary prevention ICD indication patients, plasma big ET-1 levels can predict VAs and end-stage events and may facilitate ICD-implantation risk stratification.. Beyond age, cognitive impairment was associated with prior MI/stroke, higher hsCRP, statin use, less education, lower eGFR, BMI and LVEF.. These data demonstrate that even a short period of detraining is harmful for elderly women who regularly participate in a program of strength training, since it impairs physical performance, insulin sensitivity and cholesterol metabolism.. Exposure to PM. Respiratory sinus arrhythmia is reduced after PVI in patients with paroxysmal AF. Our findings suggest that this is related to a decrease in cardiac vagal tone. Whether and how this affects the clinical outcome including exercise capacity need to be determined.. BDNF and leptin were not associated with weight. We found that miR-214-5p exerted a protective role in I/R injured cardiac cells by direct targeting FASLG. The results indicated that the MGO injection reduced all CCl. The hepatoprotective effects of MGO might be due to histopathological suppression and inflammation inhibition in the liver.. OVEO showed moderate antifungal activity, whereas its main components carvacrol and thymol have great application potential as natural fungicides or lead compounds for commercial fungicides in preventing and controlling plant diseases caused by. PF trajectories were mainly related to income, pregestational BMI, birth weight, hospitalisation due to respiratory diseases in childhood, participant's BMI, report of wheezing, medical diagnosis and family history of asthma, gestational exposure to tobacco and current smoking status in adolescence and young adult age.. In chronic pain patients on opioids, administration of certain benzodiazepine sedatives induced a mild respiratory depression but paradoxically reduced sleep apnoea risk and severity by increasing the respiratory arousal threshold.. Quantitative measurements of sensory disturbances using the PainVision. The serum level of 20S-proteasome may be a useful marker for disease activity in AAV.. The electrophysiological data and MD simulations collectively suggest a crucial role of the interactions between the HA helix and S4-S5 linker in the apparent Ca. Invited for the cover of this issue are Vanesa Fernández-Moreira, Nils Metzler-Nolte, M. Concepción Gimeno and co-workers at Universidad de Zaragoza and Ruhr-Universität Bochum. The image depicts the reported bimetallic bioconjugates as planes directing the gold fragment towards the target (lysosomes). Read the full text of the article at 10.1002/chem.202002067.. The optimal CRT pacing configuration changes during dobutamine infusion while LV and RV activation timing does not. Further studies investigating the usefulness of automated dynamic changes to CRT pacing configuration according to physiologic condition may be warranted.

Topics: 3' Untranslated Regions; 5'-Nucleotidase; A549 Cells; Accidental Falls; Acetylcholinesterase; Acrylic Resins; Actinobacillus; Acute Disease; Acute Kidney Injury; Adaptor Proteins, Signal Transducing; Adenosine; Adenosine Triphosphate; Administration, Inhalation; Administration, Oral; Adolescent; Adult; Advance Care Planning; Africa, Northern; Age Factors; Aged; Aged, 80 and over; Air Pollutants; Air Pollution; Air Pollution, Indoor; Albendazole; Aluminum Oxide; Anastomosis, Surgical; Ancylostoma; Ancylostomiasis; Androstadienes; Angiogenesis Inhibitors; Angiotensin II; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antibodies, Bispecific; Antibodies, Viral; Anticoagulants; Antihypertensive Agents; Antinematodal Agents; Antineoplastic Agents; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antiporters; Antiviral Agents; Apoptosis; Aptamers, Nucleotide; Aromatase Inhibitors; Asian People; Astrocytes; Atrial Fibrillation; Auditory Threshold; Aurora Kinase B; Australia; Autophagy; Autophagy-Related Protein 5; Autotrophic Processes; Bacillus cereus; Bacillus thuringiensis; Bacterial Proteins; Beclin-1; Belgium; Benzene; Benzene Derivatives; Benzhydryl Compounds; beta Catenin; beta-Arrestin 2; Biliary Tract Diseases; Biofilms; Biofuels; Biomarkers; Biomarkers, Tumor; Biomass; Biomechanical Phenomena; Bioreactors; Biosensing Techniques; Biosynthetic Pathways; Bismuth; Blood Platelets; Bone and Bones; Bone Regeneration; Bortezomib; Botulinum Toxins, Type A; Brain; Brain Injuries; Brain Ischemia; Brain Neoplasms; Breast Neoplasms; Breath Tests; Bronchodilator Agents; Calcium Phosphates; Cannabis; Carbon Dioxide; Carbon Isotopes; Carcinogenesis; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cardiac Resynchronization Therapy; Cardiac Resynchronization Therapy Devices; Cardiomyopathies; Cardiovascular Diseases; Cariostatic Agents; Case Managers; Case-Control Studies; Catalysis; Cation Transport Proteins; CD8-Positive T-Lymphocytes; Cecropia Plant; Cell Adhesion; Cell Count; Cell Differentiation; Cell Division; Cell Line; Cell Line, Tumor; Cell Membrane; Cell Movement; Cell Proliferation; Cell Self Renewal; Cell Survival; Cells, Cultured; Cellular Reprogramming; Cellulose; Charcoal; Chemical and Drug Induced Liver Injury; Chemical Phenomena; Chemokines; Chemoradiotherapy; Chemoreceptor Cells; Child; Child Abuse; Child, Preschool; China; Chlorogenic Acid; Chloroquine; Chromatography, Gas; Chronic Disease; Clinical Competence; Coated Materials, Biocompatible; Cochlea; Cohort Studies; Color; Comorbidity; Computer Simulation; Computer-Aided Design; Contraception; Contraceptive Agents, Female; Contrast Media; COP-Coated Vesicles; Coronavirus Infections; Cost of Illness; Coturnix; COVID-19; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Culex; Curriculum; Cyclic N-Oxides; Cytokines; Cytoplasm; Cytotoxicity, Immunologic; Cytotoxins; Databases, Factual; Deep Learning; Delivery, Obstetric; Denitrification; Dental Caries; Denture, Complete; Dexamethasone; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dielectric Spectroscopy; Diet, High-Fat; Dietary Fiber; Disease Models, Animal; Disease Progression; DNA; DNA Copy Number Variations; DNA, Mitochondrial; Dog Diseases; Dogs; Dopaminergic Neurons; Double-Blind Method; Down-Regulation; Doxorubicin; Drug Carriers; Drug Design; Drug Interactions; Drug Resistance, Bacterial; Drug Resistance, Neoplasm; Drug-Related Side Effects and Adverse Reactions; Drugs, Chinese Herbal; Dry Powder Inhalers; Dust; E2F1 Transcription Factor; Ecosystem; Education, Nursing; Education, Nursing, Baccalaureate; Electric Impedance; Electricity; Electrocardiography; Electrochemical Techniques; Electrochemistry; Electrodes; Electrophoresis, Polyacrylamide Gel; Endoplasmic Reticulum; Endothelial Cells; Environmental Monitoring; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Estrogen Receptor Modulators; Europe; Evoked Potentials, Auditory, Brain Stem; Exosomes; Feasibility Studies; Female; Ferricyanides; Ferrocyanides; Fibrinogen; Finite Element Analysis; Fistula; Fluorescent Dyes; Fluorides, Topical; Fluorodeoxyglucose F18; Fluticasone; Follow-Up Studies; Food Contamination; Food Microbiology; Foods, Specialized; Forensic Medicine; Frail Elderly; France; Free Radicals; Fresh Water; Fungi; Fungicides, Industrial; Galactosamine; Gastrointestinal Neoplasms; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Frequency; Genetic Predisposition to Disease; Genotype; Gingival Hemorrhage; Glioblastoma; Glioma; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Glucose; Glucose Transport Proteins, Facilitative; Glucosides; Glutamine; Glycolysis; Gold; GPI-Linked Proteins; Gram-Negative Bacteria; Gram-Positive Bacteria; Graphite; Haplotypes; HCT116 Cells; Healthy Volunteers; Hearing Loss; Heart Failure; Hedgehog Proteins; HEK293 Cells; HeLa Cells; Hemodynamics; Hemorrhage; Hepatocytes; Hippo Signaling Pathway; Histone Deacetylases; Homeostasis; Hospital Mortality; Hospitalization; Humans; Hydantoins; Hydrazines; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; Hydroxylamines; Hypoglycemic Agents; Immunity, Innate; Immunoglobulin G; Immunohistochemistry; Immunologic Factors; Immunomodulation; Immunophenotyping; Immunotherapy; Incidence; Indazoles; Indonesia; Infant; Infant, Newborn; Infarction, Middle Cerebral Artery; Inflammation; Injections, Intramuscular; Insecticides; Insulin-Like Growth Factor I; Insurance, Health; Intention to Treat Analysis; Interleukin-1 Receptor-Associated Kinases; Interleukin-6; Intrauterine Devices; Intrauterine Devices, Copper; Iron; Ischemia; Jordan; Keratinocytes; Kidney; Kidney Diseases; Kir5.1 Channel; Klebsiella Infections; Klebsiella pneumoniae; Lab-On-A-Chip Devices; Laparoscopy; Lasers; Lasers, Semiconductor; Lenalidomide; Leptin; Lethal Dose 50; Levonorgestrel; Limit of Detection; Lipid Metabolism; Lipid Metabolism Disorders; Lipogenesis; Lipopolysaccharides; Liquid Biopsy; Liver; Liver Abscess, Pyogenic; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Longevity; Lung Neoplasms; Luteolin; Lymph Nodes; Lymphocyte Activation; Macaca fascicularis; Macrophages; Mad2 Proteins; Magnetic Resonance Imaging; Male; Mammary Glands, Human; Manganese; Manganese Compounds; MAP Kinase Signaling System; Materials Testing; Maternal Health Services; MCF-7 Cells; Medicaid; Medicine, Chinese Traditional; Melanoma; Membrane Proteins; Mental Health; Mercury; Metal Nanoparticles; Metals, Heavy; Metformin; Methionine Adenosyltransferase; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Knockout; Mice, Nude; Microalgae; Microbial Sensitivity Tests; Microglia; MicroRNAs; Microscopy, Atomic Force; Microscopy, Electron, Scanning; Middle Aged; Mitochondria; Mitochondrial Proteins; Mitral Valve; Mitral Valve Insufficiency; Models, Anatomic; Molecular Structure; Molybdenum; Monocarboxylic Acid Transporters; Moths; MPTP Poisoning; Multigene Family; Multiparametric Magnetic Resonance Imaging; Multiple Myeloma; Muscle, Skeletal; Mutagens; Mutation; Myeloid Cells; Nanocomposites; Nanofibers; Nanomedicine; Nanoparticles; Nanowires; Neoadjuvant Therapy; Neomycin; Neoplasm Grading; Neoplasm Recurrence, Local; Neoplasms; Neoplastic Stem Cells; Neostriatum; Neovascularization, Pathologic; Netherlands; Neuromuscular Agents; Neurons; NF-E2-Related Factor 2; NF-kappa B; Nickel; Nitrogen Oxides; Non-alcoholic Fatty Liver Disease; Nucleosides; Nucleotidyltransferases; Nutritional Status; Obesity, Morbid; Ofloxacin; Oils, Volatile; Oligopeptides; Oncogene Protein v-akt; Optical Imaging; Organic Cation Transport Proteins; Organophosphonates; Osteoarthritis; Osteoarthritis, Hip; Osteoarthritis, Knee; Osteoblasts; Osteogenesis; Oxidation-Reduction; Oxidative Stress; Oxides; Oxygen Isotopes; Pancreas; Pancreaticoduodenectomy; Pandemics; Particle Size; Particulate Matter; Patient Acceptance of Health Care; Patient Compliance; PC-3 Cells; Peptide Fragments; Peptides; Periodontal Attachment Loss; Periodontal Index; Periodontal Pocket; Periodontitis; Peroxides; Peru; Pest Control, Biological; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Phylogeny; Pilot Projects; Piperidines; Plant Bark; Plant Extracts; Plant Leaves; Plasmids; Platelet Function Tests; Pneumonia, Viral; Podocytes; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Polyethylene Terephthalates; Polymers; Polymorphism, Single Nucleotide; Porosity; Portugal; Positron-Emission Tomography; Postoperative Complications; Postural Balance; Potassium Channels, Inwardly Rectifying; Povidone; Powders; Precancerous Conditions; Precision Medicine; Predictive Value of Tests; Pregnancy; Prenatal Care; Prognosis; Promoter Regions, Genetic; Prospective Studies; Prostatectomy; Prostatic Neoplasms; Proteasome Inhibitors; Protective Agents; Protein Binding; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Protein Transport; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-akt; Psychiatric Nursing; PTEN Phosphohydrolase; Pulmonary Embolism; Pyrimethamine; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; Rats, Wistar; Reactive Oxygen Species; Receptor, ErbB-2; Receptor, IGF Type 1; Receptors, Estrogen; Receptors, G-Protein-Coupled; Recombinational DNA Repair; Recovery of Function; Regional Blood Flow; Renal Dialysis; Renin; Renin-Angiotensin System; Reperfusion Injury; Reproducibility of Results; Republic of Korea; Respiratory Distress Syndrome; Retrospective Studies; Rhodamines; Risk Assessment; Risk Factors; RNA, Long Noncoding; RNA, Messenger; Running; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Salinity; Salmeterol Xinafoate; Sarcoma; Seasons; Shoulder Injuries; Signal Transduction; Silicon Dioxide; Silver; Sirtuin 1; Sirtuins; Skull Fractures; Social Determinants of Health; Sodium; Sodium Fluoride; Sodium Potassium Chloride Symporter Inhibitors; Sodium-Glucose Transporter 2 Inhibitors; Soil; Soil Pollutants; Spain; Spectrophotometry; Spectroscopy, Fourier Transform Infrared; Staphylococcal Protein A; Staphylococcus aureus; Stem Cells; Stereoisomerism; Stomach Neoplasms; Streptomyces; Strontium; Structure-Activity Relationship; Students, Nursing; Substance-Related Disorders; Succinic Acid; Sulfur; Surface Properties; Survival Rate; Survivin; Symporters; T-Lymphocytes; Temozolomide; Tensile Strength; Thiazoles; Thiobacillus; Thiohydantoins; Thiourea; Thrombectomy; Time Factors; Titanium; Tobacco Mosaic Virus; Tobacco Use Disorder; Toll-Like Receptor 4; Toluene; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Toxicity Tests, Acute; Toxicity Tests, Subacute; Transcriptional Activation; Treatment Outcome; Troponin I; Tumor Cells, Cultured; Tumor Escape; Tumor Hypoxia; Tumor Microenvironment; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha; Tyrosine; Ubiquitin-Protein Ligases; Ubiquitination; Ultrasonic Waves; United Kingdom; United States; United States Department of Veterans Affairs; Up-Regulation; Urea; Uric Acid; Urinary Bladder Neoplasms; Urinary Bladder, Neurogenic; Urine; Urodynamics; User-Computer Interface; Vemurafenib; Verbenaceae; Veterans; Veterans Health; Viral Load; Virtual Reality; Vitiligo; Water Pollutants, Chemical; Wildfires; Wnt Signaling Pathway; Wound Healing; X-Ray Diffraction; Xenograft Model Antitumor Assays; Xylenes; Young Adult; Zinc; Zinc Oxide; Zinc Sulfate; Zoonoses

Postoperative ileus is common and is a major clinical problem. It has been widely studied in patients and in experimental models in laboratory animals. A wide variety of treatments have been tested to prevent or modify the course of this disorder.. This review draws together information on animal studies of ileus with studies on human patients. It summarizes some of the conceptual advances made in understanding the mechanisms that underlie paralytic ileus. The treatments that have been tested in human subjects (both pharmacological and non-pharmacological) and their efficacy are summarized and graded consistent with current clinical guidelines. The review is not intended to provide a comprehensive overview of ileus, but rather a general understanding of the major clinical problems associated with it, how animal models have been useful to elucidate key mechanisms and, finally, some perspectives from both scientists and clinicians as to how we may move forward with this debilitating yet common condition.

Topics: Anesthesia, Epidural; Animals; Benzofurans; Chewing Gum; Cholinergic Agents; Contrast Media; Cyclooxygenase Inhibitors; Diatrizoate Meglumine; Digestive System Surgical Procedures; Enhanced Recovery After Surgery; Enteral Nutrition; Enteric Nervous System; Fluid Therapy; Gastrointestinal Agents; Gastrointestinal Motility; Ghrelin; Humans; Ileus; Inflammation; Intestinal Pseudo-Obstruction; Intubation, Gastrointestinal; Laparoscopy; Mast Cells; Piperidines; Postoperative Complications; Serotonin 5-HT4 Receptor Agonists; Sympathetic Nervous System; Sympatholytics

In the past few years, Bruton's tyrosine Kinase (Btk) has emerged as new target in medicinal chemistry. Since approval of ibrutinib in 2013 for treatment of different hematological cancers (as leukemias and lymphomas), two other irreversible Btk inhibitors have been launched on the market. In the attempt to overcome irreversible Btk inhibitor limitations, reversible compounds have been developed and are currently under evaluation. In recent years, many Btk inhibitors have been patented and reported in the literature. In this review, we summarized the (ir)reversible Btk inhibitors recently developed and studied clinical trials and preclinical investigations for malignancies, chronic inflammation conditions and SARS-CoV-2 infection, covering advances in the field of medicinal chemistry. Furthermore, the nanoformulations studied to increase ibrutinib bioavailability are reported.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Chemistry, Pharmaceutical; COVID-19 Drug Treatment; Drug Delivery Systems; Hematologic Neoplasms; Humans; Inflammation; Neoplasms; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrimidines; SARS-CoV-2

The mechanisms of inflammation and cancer are intertwined by complex networks of signaling pathways. Dysregulations in the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway underlie several pathogenic conditions related to chronic inflammatory states, autoimmune diseases and cancer. Historically, the potential application of JAK inhibition has been thoroughly explored, thus triggering an escalation of favorable results in this field. So far, five JAK inhibitors have been approved by the Food and Drug Administration (FDA) for the treatment of different diseases. Considering the complexity of JAK-depending processes and their involvement in multiple disorders, JAK inhibitors are the perfect candidates for drug repurposing and for the assessment of multitarget strategies. Herein we reviewed the recent progress concerning JAK inhibition, including the innovations provided by the release of JAKs crystal structures and the improvement of synthetic strategies aimed to simplify of the industrial scale-up.

Topics: Anti-Inflammatory Agents; Antineoplastic Agents; Autoimmune Diseases; Drug Approval; Drug Design; Humans; Inflammation; Janus Kinase Inhibitors; Janus Kinases; Neoplasms; Nitriles; Piperidines; Protein Binding; Protein Conformation; Pyrazoles; Pyrimidines; United States; United States Food and Drug Administration

The spread of the novel human respiratory coronavirus (SARS-CoV-2) is a global public health emergency. There is no known successful treatment as of this time, and there is a need for medical options to mitigate this current epidemic. SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) receptor and is primarily trophic for the lower and upper respiratory tract. A number of current studies on COVID-19 have demonstrated the substantial increase in pro-inflammatory factors in the lungs during infection. The virus is also documented in the central nervous system and, particularly in the brainstem, which plays a key role in respiratory and cardiovascular function. Currently, there are few antiviral approaches, and several alternative drugs are under investigation. Two of these are Idelalisib and Ebastine, already proposed as preventive strategies in airways and allergic diseases. The interesting and evolving potential of phosphoinositide 3-kinase δ (PI3Kδ) inhibitors, together with Ebastine, lies in their ability to suppress the release of pro-inflammatory cytokines, such as IL-1β, IL-8, IL-6, and TNF-α, by T cells. This may represent an optional therapeutic choice for COVID-19 to reduce inflammatory reactions and mortality, enabling patients to recover faster. This concise communication aims to provide new potential therapeutic targets capable of mitigating and alleviating SARS-CoV-2 pandemic infection.

Topics: Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antiviral Agents; Betacoronavirus; Butyrophenones; Class I Phosphatidylinositol 3-Kinases; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Drug Repositioning; Humans; Inflammation; Interleukin-6; Molecular Targeted Therapy; Pandemics; Peptidyl-Dipeptidase A; Piperidines; Pneumonia, Viral; Purines; Quinazolinones; SARS-CoV-2

Cytokines are key drivers of inflammation in RA, and anti-cytokine therapy has improved the outcome of RA. Janus Kinases (JAK) are intracellular tyrosine kinases linked to intracellular domains of many cytokine receptors. There are four JAK isoforms: JAK1, JAK2, JAK3 and TYK2. Different cytokine receptor families utilize specific JAK isoforms for signal transduction. Phosphorylation of JAK when cytokine binds to its cognate receptor leads to phosphorylation of other intracellular molecules that eventually leads to gene transcription. Oral JAK inhibitors (JAKi) have been developed as anti-cytokine therapy in RA. Two JAKi, tofacitinib and baricitinib, have been approved recently for the treatment of RA, and many JAKi are currently in development. JAKi inhibit JAK isoforms with different selectivity. This review discusses the efficacy and safety of JAKi in RA, in particular the potential clinical significance of JAKi selectivity.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Azetidines; Humans; Inflammation; Janus Kinase Inhibitors; Piperidines; Purines; Pyrazoles; Pyrimidines; Pyrroles; Sulfonamides

A disruption of the crucial balance between regulatory T-cells (Tregs) and Th17-cells was recently implicated in various autoimmune disorders. Tregs are responsible for the maintenance of self-tolerance, thus inhibiting autoimmunity, whereas pro-inflammatory Th17-cells contribute to the induction and propagation of inflammation. Distortion of the Th17/Treg balance favoring the  pro-inflammatory Th17 side is hence suspected to contribute to exacerbation of autoimmune disorders. This review aims to summarize recent data and advances in targeted therapeutic modification of the Th17/Treg-balance, as well as information on the efficacy of candidate therapeutics with respect to the treatment of autoimmune diseases.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Autoimmune Diseases; Forkhead Transcription Factors; Gene Expression Regulation; Humans; Immunologic Factors; Inflammation; Interleukin-17; Nuclear Receptor Subfamily 1, Group F, Member 3; Piperidines; Pyrimidines; Pyrroles; Signal Transduction; T-Lymphocytes, Regulatory; Th17 Cells; Ustekinumab

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antitubercular Agents; Antiviral Agents; Apolipoproteins E; Apoptosis; Arabidopsis; Arabidopsis Proteins; Arsenic; Arthritis, Rheumatoid; Asthma; Atherosclerosis; ATP-Dependent Proteases; Attitude of Health Personnel; Australia; Austria; Autophagy; Axitinib; Bacteria; Bacterial Outer Membrane Proteins; Bacterial Proteins; Bacterial Toxins; Bacterial Typing Techniques; Bariatric Surgery; Base Composition; Bayes Theorem; Benzoxazoles; Benzylamines; beta Catenin; Betacoronavirus; Betula; Binding Sites; Biological Availability; Biological Oxygen Demand Analysis; Biomarkers; Biomarkers, Tumor; Biopsy; Bioreactors; Biosensing Techniques; Birth Weight; Blindness; Blood Chemical Analysis; Blood Gas Analysis; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Blood-Brain Barrier; Blotting, Western; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Bone Resorption; Borates; Brain; Brain Infarction; Brain Injuries, Traumatic; Brain Neoplasms; Breakfast; Breast Milk Expression; Breast Neoplasms; Bronchi; Bronchoalveolar Lavage Fluid; Buffaloes; Cadherins; Calcification, Physiologic; Calcium Compounds; Calcium, Dietary; Cannula; Caprolactam; Carbon; Carbon Dioxide; Carboplatin; Carcinogenesis; Carcinoma, Ductal; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Pancreatic Ductal; Carcinoma, Renal Cell; Cardiovascular Diseases; Carps; Carrageenan; Case-Control Studies; Catalysis; Catalytic Domain; Cattle; CD8-Positive T-Lymphocytes; Cell Adhesion; Cell Cycle Proteins; Cell Death; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Phone Use; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cell Transformation, Viral; Cells, Cultured; Cellulose; Chemical Phenomena; Chemoradiotherapy; Child; Child Development; Child, Preschool; China; Chitosan; Chlorocebus aethiops; Cholecalciferol; Chromatography, Liquid; Circadian Clocks; Circadian Rhythm; Circular Dichroism; Cisplatin; Citric Acid; Clinical Competence; Clinical Laboratory Techniques; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clostridioides difficile; Clostridium Infections; Coculture Techniques; Cohort Studies; Cold Temperature; Colitis; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type XI; Color; Connective Tissue Diseases; Copper; Coronary Angiography; Coronavirus 3C Proteases; Coronavirus Infections; Cost of Illness; Counselors; COVID-19; COVID-19 Testing; Creatine Kinase; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Cryoelectron Microscopy; Cryosurgery; Crystallography, X-Ray; Cues; Cultural Competency; Cultural Diversity; Curriculum; Cyclic AMP Response Element-Binding Protein; Cyclin-Dependent Kinase Inhibitor p21; Cycloparaffins; Cysteine Endopeptidases; Cytokines; Cytoplasm; Cytoprotection; Databases, Factual; Denitrification; Deoxycytidine; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Diatoms; Diet; Diet, High-Fat; Dietary Exposure; Diffusion Magnetic Resonance Imaging; Diketopiperazines; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Disease Progression; Disease-Free Survival; DNA; DNA Damage; DNA Glycosylases; DNA Repair; DNA-Binding Proteins; DNA, Bacterial; DNA, Viral; Docetaxel; Dose Fractionation, Radiation; Dose-Response Relationship, Drug; Down-Regulation; Doxorubicin; Drosophila; Drosophila melanogaster; Drug Carriers; Drug Delivery Systems; Drug Liberation; Drug Repositioning; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Drug Therapy, Combination; Edema; Edible Grain; Education, Graduate; Education, Medical, Graduate; Education, Pharmacy; Ehlers-Danlos Syndrome; Electron Transport Complex III; Electron Transport Complex IV; Electronic Nicotine Delivery Systems; Emergency Service, Hospital; Empathy; Emulsions; Endothelial Cells; Endurance Training; Energy Intake; Enterovirus A, Human; Environment; Environmental Monitoring; Enzyme Assays; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Epoxide Hydrolases; Epoxy Compounds; Erythrocyte Count; Erythrocytes; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Esophagectomy; Estrogens; Etanercept; Ethiopia; Ethnicity; Ethylenes; Exanthema; Exercise; Exercise Test; Exercise Tolerance; Extracellular Matrix; Extracorporeal Membrane Oxygenation; Eye Infections, Fungal; False Negative Reactions; Fatty Acids; Fecal Microbiota Transplantation; Feces; Female; Femur Neck; Fermentation; Ferritins; Fetal Development; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Fibroblasts; Fibroins; Fish Proteins; Flavanones; Flavonoids; Focus Groups; Follow-Up Studies; Food Handling; Food Supply; Food, Formulated; Forced Expiratory Volume; Forests; Fractures, Bone; Fruit and Vegetable Juices; Fusobacteria; G1 Phase Cell Cycle Checkpoints; G2 Phase Cell Cycle Checkpoints; Gamma Rays; Gastrectomy; Gastrointestinal Microbiome; Gastrointestinal Stromal Tumors; Gefitinib; Gels; Gemcitabine; Gene Amplification; Gene Expression; Gene Expression Regulation; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Plant; Gene Knockdown Techniques; Gene-Environment Interaction; Genotype; Germany; Glioma; Glomerular Filtration Rate; Glucagon; Glucocorticoids; Glycemic Control; Glycerol; Glycogen Synthase Kinase 3 beta; Glycolipids; Glycolysis; Goblet Cells; Gram-Negative Bacterial Infections; Granulocyte Colony-Stimulating Factor; Graphite; Greenhouse Effect; Guanidines; Haemophilus influenzae; HCT116 Cells; Health Knowledge, Attitudes, Practice; Health Personnel; Health Services Accessibility; Health Services Needs and Demand; Health Status Disparities; Healthy Volunteers; Heart Failure; Heart Rate; Heart Transplantation; Heart-Assist Devices; HEK293 Cells; Heme; Heme Oxygenase-1; Hemolysis; Hemorrhage; Hepatitis B; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Hepatocytes; Hexoses; High-Throughput Nucleotide Sequencing; Hippo Signaling Pathway; Histamine; Histamine Agonists; Histidine; Histone Deacetylase 2; HIV Infections; HIV Reverse Transcriptase; HIV-1; Homebound Persons; Homeodomain Proteins; Homosexuality, Male; Hospice and Palliative Care Nursing; HSP70 Heat-Shock Proteins; Humans; Hyaluronan Receptors; Hydrogen; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrolysis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemia; Hypoglycemic Agents; Hypoxia; Idiopathic Interstitial Pneumonias; Imaging, Three-Dimensional; Imatinib Mesylate; Immunotherapy; Implementation Science; Incidence; INDEL Mutation; Induced Pluripotent Stem Cells; Industrial Waste; Infant; Infant, Newborn; Inflammation; Inflammation Mediators; Infliximab; Infusions, Intravenous; Inhibitory Concentration 50; Injections; Insecticides; Insulin-Like Growth Factor Binding Protein 5; Insulin-Secreting Cells; Interleukin-1; Interleukin-17; Interleukin-8; Internship and Residency; Intestines; Intracellular Signaling Peptides and Proteins; Ion Transport; Iridaceae; Iridoid Glucosides; Islets of Langerhans Transplantation; Isodon; Isoflurane; Isotopes; Italy; Joint Instability; Ketamine; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Kidney Neoplasms; Kinetics; Klebsiella pneumoniae; Knee Joint; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Lactate Dehydrogenase 5; Laparoscopy; Laser Therapy; Lasers, Semiconductor; Lasers, Solid-State; Laurates; Lead; Leukocyte L1 Antigen Complex; Leukocytes, Mononuclear; Light; Lipid Peroxidation; Lipopolysaccharides; Liposomes; Liver; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Locomotion; Longitudinal Studies; Lopinavir; Lower Urinary Tract Symptoms; Lubricants; Lung; Lung Diseases, Interstitial; Lung Neoplasms; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating; Lymphoma, Mantle-Cell; Lysosomes; Macrophages; Male; Manganese Compounds; MAP Kinase Kinase 4; Mass Screening; Maternal Health; Medicine, Chinese Traditional; Melanoma, Experimental; Memantine; Membrane Glycoproteins; Membrane Proteins; Mesenchymal Stem Cell Transplantation; Metal Nanoparticles; Metalloendopeptidases; Metalloporphyrins; Methadone; Methane; Methicillin-Resistant Staphylococcus aureus; Mexico; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Mice, Nude; Mice, SCID; Mice, Transgenic; Microarray Analysis; Microbial Sensitivity Tests; Microbiota; Micronutrients; MicroRNAs; Microscopy, Confocal; Microsomes, Liver; Middle Aged; Milk; Milk, Human; Minority Groups; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins; Models, Animal; Models, Molecular; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Epidemiology; Molecular Structure; Molecular Weight; Multilocus Sequence Typing; Multimodal Imaging; Muscle Strength; Muscle, Skeletal; Muscular Diseases; Mutation; Mycobacterium tuberculosis; Myocardial Stunning; Myristates; NAD(P)H Dehydrogenase (Quinone); Nanocomposites; Nanogels; Nanoparticles; Nanotechnology; Naphthalenes; Nasal Cavity; National Health Programs; Necrosis; Needs Assessment; Neoadjuvant Therapy; Neonicotinoids; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins; Neoplasm Recurrence, Local; Neoplasm Staging; Neoplasm Transplantation; Neoplasms; Neoplastic Stem Cells; Netherlands; Neuroblastoma; Neuroprotective Agents; Neutrophils; NF-kappa B; NFATC Transcription Factors; Nicotiana; Nicotine; Nitrates; Nitrification; Nitrites; Nitro Compounds; Nitrogen; Nitrogen Dioxide; North Carolina; Nuclear Magnetic Resonance, Biomolecular; Nuclear Proteins; Nucleic Acid Hybridization; Nucleosomes; Nutrients; Obesity; Obesity, Morbid; Oceans and Seas; Oncogene Protein v-akt; Oncogenes; Oocytes; Open Reading Frames; Osteoclasts; Osteogenesis; Osteoporosis; Osteoporosis, Postmenopausal; Outpatients; Ovarian Neoplasms; Ovariectomy; Overweight; Oxazines; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxides; Oxidoreductases; Oxygen; Oxygen Inhalation Therapy; Oxygenators, Membrane; Ozone; Paclitaxel; Paenibacillus; Pain Measurement; Palliative Care; Pancreatic Neoplasms; Pandemics; Parasympathetic Nervous System; Particulate Matter; Pasteurization; Patient Preference; Patient Satisfaction; Pediatric Obesity; Permeability; Peroxiredoxins; Peroxynitrous Acid; Pharmaceutical Services; Pharmacists; Pharmacy; Phaseolus; Phenotype; Phoeniceae; Phosphates; Phosphatidylinositol 3-Kinases; Phospholipid Transfer Proteins; Phospholipids; Phosphorus; Phosphorylation; Photoperiod; Photosynthesis; Phylogeny; Physical Endurance; Physicians; Pilot Projects; Piperidines; Pituitary Adenylate Cyclase-Activating Polypeptide; Plant Extracts; Plant Leaves; Plant Proteins; Plant Roots; Plaque, Atherosclerotic; Pneumonia; Pneumonia, Viral; Point-of-Care Testing; Polyethylene Glycols; Polymers; Polysorbates; Pore Forming Cytotoxic Proteins; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Postprandial Period; Poverty; Pre-Exposure Prophylaxis; Prediabetic State; Predictive Value of Tests; Pregnancy; Pregnancy Trimester, First; Pregnancy, High-Risk; Prenatal Exposure Delayed Effects; Pressure; Prevalence; Primary Graft Dysfunction; Primary Health Care; Professional Role; Professionalism; Prognosis; Progression-Free Survival; Prolactin; Promoter Regions, Genetic; Proof of Concept Study; Proportional Hazards Models; Propylene Glycol; Prospective Studies; Prostate; Protein Binding; Protein Biosynthesis; Protein Isoforms; Protein Kinase Inhibitors; Protein Phosphatase 2; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Protein Structure, Tertiary; Protein Transport; Proteoglycans; Proteome; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; Proto-Oncogene Proteins c-ret; Proto-Oncogene Proteins p21(ras); Proton Pumps; Protons; Protoporphyrins; Pseudomonas aeruginosa; Pseudomonas fluorescens; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Pulmonary Gas Exchange; Pulmonary Veins; Pyrazoles; Pyridines; Pyrimidines; Qualitative Research; Quinoxalines; Rabbits; Random Allocation; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Histamine H3; Receptors, Immunologic; Receptors, Transferrin; Recombinant Proteins; Recurrence; Reference Values; Referral and Consultation; Regional Blood Flow; Registries; Regulon; Renal Insufficiency, Chronic; Reperfusion Injury; Repressor Proteins; Reproducibility of Results; Republic of Korea; Research Design; Resistance Training; Respiration, Artificial; Respiratory Distress Syndrome; Respiratory Insufficiency; Resuscitation; Retinal Dehydrogenase; Retreatment; Retrospective Studies; Reverse Transcriptase Inhibitors; Rhinitis, Allergic; Ribosomal Proteins; Ribosomes; Risk Assessment; Risk Factors; Ritonavir; Rivers; RNA Interference; RNA-Seq; RNA, Messenger; RNA, Ribosomal, 16S; RNA, Small Interfering; Rosuvastatin Calcium; Rural Population; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Salivary Ducts; Salivary Gland Neoplasms; San Francisco; SARS-CoV-2; Satiation; Satiety Response; Schools; Schools, Pharmacy; Seasons; Seawater; Selection, Genetic; Sequence Analysis, DNA; Serine-Threonine Kinase 3; Sewage; Sheep; Sheep, Domestic; Shock, Hemorrhagic; Signal Transduction; Silver; Silymarin; Single Photon Emission Computed Tomography Computed Tomography; Sirolimus; Sirtuin 1; Skin; Skin Neoplasms; Skin Physiological Phenomena; Sleep Initiation and Maintenance Disorders; Social Class; Social Participation; Social Support; Soil; Soil Microbiology; Solutions; Somatomedins; Soot; Specimen Handling; Spectrophotometry, Ultraviolet; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis; Spinal Fractures; Spirometry; Staphylococcus aureus; STAT1 Transcription Factor; STAT3 Transcription Factor; Streptomyces coelicolor; Stress, Psychological; Stroke; Stroke Volume; Structure-Activity Relationship; Students, Medical; Students, Pharmacy; Substance Abuse Treatment Centers; Sulfur Dioxide; Surface Properties; Surface-Active Agents; Surveys and Questionnaires; Survival Analysis; Survival Rate; Survivin; Sweden; Swine; Swine, Miniature; Sympathetic Nervous System; T-Lymphocytes, Regulatory; Talaromyces; Tandem Mass Spectrometry; tau Proteins; Telemedicine; Telomerase; Telomere; Telomere Homeostasis; Temperature; Terminally Ill; Th1 Cells; Thiamethoxam; Thiazoles; Thiophenes; Thioredoxin Reductase 1; Thrombosis; Thulium; Thyroid Cancer, Papillary; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Time Factors; Titanium; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Transcription Factor AP-1; Transcription Factors; Transcription, Genetic; Transcriptional Activation; Transcriptome; Transforming Growth Factor beta1; Transistors, Electronic; Translational Research, Biomedical; Transplantation Tolerance; Transplantation, Homologous; Transportation; Treatment Outcome; Tretinoin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Tubulin Modulators; Tumor Microenvironment; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha; Twins; Ultrasonic Therapy; Ultrasonography; Ultraviolet Rays; United States; Up-Regulation; Uranium; Urethra; Urinary Bladder; Urodynamics; Uromodulin; Uveitis; Vasoconstrictor Agents; Ventricular Function, Left; Vero Cells; Vesicular Transport Proteins; Viral Nonstructural Proteins; Visual Acuity; Vital Capacity; Vitamin D; Vitamin D Deficiency; Vitamin K 2; Vitamins; Volatilization; Voriconazole; Waiting Lists; Waste Disposal, Fluid; Wastewater; Water Pollutants, Chemical; Whole Genome Sequencing; Wine; Wnt Signaling Pathway; Wound Healing; Wounds and Injuries; WW Domains; X-linked Nuclear Protein; X-Ray Diffraction; Xanthines; Xenograft Model Antitumor Assays; YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor, mainly secreted by endothelial cells. It acts through two types of receptors: ETA and ETB. Apart from a vasoconstrictive action, ET-1 causes fibrosis of the vascular cells and stimulates production of reactive oxygen species. It is claimed that ET-1 induces proinflammatory mechanisms, increasing superoxide anion production and cytokine secretion. A recent study has shown that ET-1 is involved in the activation of transcription factors such as NF-κB and expression of proinflammatory cytokines including TNF-α, IL-1, and IL-6. It has been also indicated that during endotoxaemia, the plasma level of ET-1 is increased in various animal species. Some authors indicate a clear correlation between endothelin plasma level and morbidity/mortality rate in septic patients. These pathological effects of ET-1 may be abrogated at least partly by endothelin receptor blockade. ET-1 receptor antagonists may be useful for prevention of various vascular diseases. This review summarises the current knowledge regarding endothelin receptor antagonists and the role of ET-1 in sepsis and inflammation.

Topics: Animals; Bosentan; Cytokines; Endothelin Receptor Antagonists; Endothelin-1; Humans; Inflammation; Lipopolysaccharides; NF-kappa B; Oligopeptides; Peptides, Cyclic; Piperidines; Pyridines; Reactive Oxygen Species; Sepsis; Signal Transduction; Sulfonamides; Superoxides; Tetrazoles

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by synovial inflammation and joint destruction. However, the combined use of synthetic disease-modifying anti-rheumatic drug (DMARD) such as methotrexate and a biological DMARD targeting tumour necrosis factor (TNF) has revolutionized treatment of RA. Clinical remission is a realistic target to treat and the maintenance of remission has produced significant improvements in structural and function outcomes. However, biological DMARDs are limited to intravenous or subcutaneous uses and orally available small but strong products have been developed. The multiple cytokines and cell surface molecules bind to receptors, resulting in the activation of various signalling, including phosphorylation of kinase proteins. Among multiple kinases, Janus kinase (JAK) plays pivotal roles in the pathological processes of RA. Tofacitinib, a small product targeting JAK, inhibits phosphorylation of JAK1 and JAK3, subsequent Stat1 and expression of Stat1-inducible genes, which contribute to efficient propagation of its anti-inflammatory effects for the treatment of RA. The primary targets of tofacitinib are dendritic cells, CD4(+) T cells such as Th1 and Th17 and activated B cells which leads to multi-cytokine targeting. Six global phase 3 studies revealed that oral administration of 5 or 10 mg tofacitinib was significantly effective than placebo with or without methotrexate in active RA patients with methotrexate-naïve, inadequately responsive to methotrexate or TNF-inhibitors. Therapeutic efficacy of tofacitinib was observed in a short term after administration and was as strong as adalimumab, a TNF-inhibitor. The most commonly observed adverse events were related to infection, hematologic, hepatic and renal disorders and association of tofacitinib with carcinogenicity and infections remains debated. Further investigation on post-marketing survey would help us understand the positioning of this drug.

Topics: Arthritis, Rheumatoid; Humans; Inflammation; Janus Kinase 1; Janus Kinase 3; Methotrexate; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; STAT1 Transcription Factor; Translational Research, Biomedical; Tumor Necrosis Factor-alpha

Cytokines are key mediators of the development and homeostasis of haematopoietic cells, critical for host defense, but also for the development of autoimmune and inflammatory diseases such as psoriasis or rheumatoid arthritis (RA). Blocking cytokines activity by interfering with the ligand-receptor association has been successfully employed to treat several immune disorders. A subgroup of cytokines signals through receptors requiring the association with a family of cytoplasmic protein tyrosine kinases known as Janus kinases (Jaks). Jaks have recently gained significant attention as therapeutic targets in inflammation and autoimmunity, and several Jak inhibitory small molecules have been developed. The first two Jak inhibitors, tofacitinib and ruxolitinib, have been approved for the treatment of RA and primary myelofibrosis, respectively. Efficacy and safety data suggest that some of these oral Jak inhibitors as well as their topical formulations may soon enter the daily clinical practice for treating patients with psoriasis, lupus erythematosus or other inflammatory skin diseases. While biologics typically target one single cytokine, these new immunomodulators can inhibit signals from multiple cytokines intra-cellularly and therefore could be useful when other therapies are ineffective. Thus, Jak inhibitors may replace some traditional immunosuppressive agents and help patients not responding to previous therapies.

Topics: Animals; Autoimmune Diseases; Cytokines; Humans; Immunosuppressive Agents; Inflammation; Janus Kinases; Mice; Nitriles; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrazoles; Pyrimidines; Pyrroles; Signal Transduction

The Janus kinases (JAKs) are a family of intracellular tyrosine kinases that play an essential role in the signaling of numerous cytokines that have been implicated in the pathogenesis of inflammatory diseases. As a consequence, the JAKs have received significant attention in recent years from the pharmaceutical and biotechnology industries as therapeutic targets. Here, we provide a review of the JAK pathways, the structure, function, and activation of the JAK enzymes followed by a detailed look at the JAK inhibitors currently in the clinic or approved for these indications. Finally, a perspective is provided on what the past decade of research with JAK inhibitors for inflammatory indications has taught along with thoughts on what the future may hold in terms of addressing the opportunities and challenges that remain.

Topics: Animals; Anti-Inflammatory Agents; Antirheumatic Agents; Autoimmune Diseases; Clinical Trials as Topic; Cytokines; Humans; Inflammation; Inflammatory Bowel Diseases; Janus Kinases; Piperidines; Protein Conformation; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Signal Transduction

BTK and ITK are cytoplasmic tyrosine kinases of crucial importance for B and T cell development, with loss-of-function mutations causing X-linked agammaglobulinemia and susceptibility to severe, frequently lethal, Epstein-Barr virus infection, respectively. Over the last few years, considerable efforts have been made in order to develop small-molecule inhibitors for these kinases to treat lymphocyte malignancies, autoimmunity or allergy/hypersensitivity. The rationale is that even if complete lack of BTK or ITK during development causes severe immunodeficiency, inactivation after birth may result in a less severe phenotype. Moreover, therapy can be transient or only partially block the activity of BTK or ITK. Furthermore, a drug-induced B cell deficiency is treatable by gamma globulin substitution therapy. The newly developed BTK inhibitor PCI-32765, recently renamed Ibrutinib, has already entered several clinical trials for various forms of non-Hodgkin lymphoma as well as for multiple myeloma. Experimental animal studies have demonstrated highly promising treatment effects also in autoimmunity. ITK inhibitors are still under the early developmental phase, but it can be expected that such drugs will also become very useful. In this study, we present BTK and ITK with their signalling pathways and review the development of the corresponding inhibitors.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Agammaglobulinemia; Antineoplastic Agents; Autoimmunity; B-Lymphocytes; Epstein-Barr Virus Infections; Gene Expression Regulation, Neoplastic; Genetic Diseases, X-Linked; Humans; Inflammation; Lymphoma; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Signal Transduction; Small Molecule Libraries; T-Lymphocytes

The aim of the present study was to conduct a meta-analysis of the effectiveness of tofacitinib, a novel oral Janus kinase inhibitor, recently approved for the treatment of active rheumatoid arthritis in patients who have failed previous treatment with methotrexate (MTX) or other disease-modifying antirheumatic drugs (DMARDs). A systematic literature search was conducted in PubMed, EMBASE, Cochrane Library, and other databases till 3 May 2013. All included studies were analyzed with the use of the Review Manager 5.1.0. software according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement protocol. Nine randomized controlled trials (RCTs) comparing tofacitinib with placebo were identified. Two of them additionally provided the comparison with adalimumab. However, only eight RCTs met the inclusion criteria for the meta-analysis. The overall results of the meta-analysis showed that tofacitinib provided a statistically significant improvement according to the response criteria (ACR20/50/70) after 12 weeks of treatment when compared to placebo (p < 0.00001). Moreover, it was demonstrated that tofacitinib was significantly superior to adalimumab in achieving the ACR50 response criteria at week 12 (p = 0.003). For the safety analysis, there were no statistically significant differences between tofacitinib-, adalimumab-, and placebo-treated patients in respect to the risk of serious adverse events or treatment discontinuation due to adverse reactions (p > 0.05). The findings of this systematic review with meta-analysis indicate that tofacitinib monotherapy or with background methotrexate provides early statistically significant and clinically important improvement in rheumatoid arthritis symptoms and has an acceptable safety profile comparable to that of placebo. The results of the present meta-analysis show that the frequency of serious adverse events was not increased after tofacitinib treatment. In addition, tofacitinib might provide an effective treatment option compared to intravenous or subcutaneous biological DMARDs, as suggested by the result of the comparison made regarding tofacitinib vs. adalimumab ACR50 response rate.

Topics: Adalimumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Inflammation; Janus Kinases; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Risk; Treatment Outcome; Tumor Necrosis Factor-alpha

Commonly used immunosuppressants possess several significant dose-limiting toxicities, prompting the search for agents whose mechanisms of action are limited to immune cells. Inhibition of Janus Kinase 3 (JAK3), a hematopoetic cell-restricted tyrosine kinase, represents an attractive target for immunosuppression owing to its limited distribution in tissue and specific role in lymphoid homeostasis. CP-690,550, a JAK3 inhibitor undergoing clinical trials for the treatment of transplant rejection and autoimmune disorders, has shown efficacy similar to comparator immunosuppressants. However, its inhibition of the more ubiquitous JAK family members, JAK1 and JAK2, is a probable cause of drug-related adverse events (e.g. overt immunosuppression, anemia). Here, we argue that CP-690,550 represents only a starting point in the search for a safer small molecule immunosuppressant, and that an isozyme-selective JAK3 inhibitor identified by rational drug design might be substantially safer.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Autoimmune Diseases; Graft Rejection; Humans; Immunosuppressive Agents; Inflammation; Isoenzymes; Janus Kinase 3; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Signal Transduction; STAT Transcription Factors

Obesity is a world wide epidemic; it is becoming more usual to be overweight or obese than to be normal weight. Obesity increases the risk of an extensive range of diseases such as cardiovascular disease, diabetes mellitus type 2, hypertension, depression and some types of cancer. Adipose tissue is more than a storage organ for surplus energy - it is also a setting for complex metabolic processes and adipose tissue releases substances that interact with other parts of the body to influence several systems including food intake and energy metabolism. The endocannabinoid system (ECS) is one of the signalling systems that control feeding behaviour. The ECS is implicated in many functions, such as pain, memory, addiction, inflammation, and feeding, and could be considered a stress recovery system. It also seems to integrate nutrient intake, metabolism and storage maintaining homeostatic balance. The ECS is a recently discovered system, and research indicates hyperactivity in obesity. The aim of this thesis is to elaborate on the relationships of this widespread system and its elements in adipose tissue in obesity. Study I is a 4 weeks rat intervention study to investigate whether weight independent effect of Rimonabant treatment exists. We found that food intake-tolerance development could be circumvented by cyclic administration of Rimonabant and implications of weight independent effects of treatment. Study II is a cross-sectional study to establish the expression of cannabinoid receptor 1 from various adipose tissue depots of lean and obese persons. In this study we conclude, that the subcutaneous adipose tissue express more CBR1 than the visceral depot in lean, but comparable levels in obese. Study III is a 10 weeks human intervention study to asses the effects on the ECS of 10% weight loss. We found reduction in the ECS in obesity that normalised with weight loss. Our results clearly show the presence of all the components of the ECS in human adipose tissue, and suggest that the ECS is reduced in adipose tissue in obesity. Our results do not support the hypothesis of hyperactivity of the ECS in human obesity. Possible future treatment of obesity with CBR1 antagonist could involve cyclic treatment of specific peripheral compounds.

Topics: Adiponectin; Adipose Tissue; Animals; Body Mass Index; Body Weight; C-Reactive Protein; Cannabinoid Receptor Modulators; Case-Control Studies; Endocannabinoids; Fatty Acids, Nonesterified; Feeding Behavior; Female; Genetic Variation; Humans; Inflammation; Male; Obesity; Piperidines; Pyrazoles; Rats; Rats, Wistar; Reference Values; Rimonabant; Risk Factors; Weight Loss

The endocannabinoid system comprises receptors, CB1 and CB2, their endogenous lipidic ligands and machinery dedicated to endocannabinoid synthesis and degradation. An overactive endocannabinoid system appears to contribute to the pathogenesis of several diseases, including liver diseases. With the increasing incidence of non-alcoholic fatty liver disease (NAFLD) in parallel with the obesity epidemic, the development of effective therapies is gaining considerable interest. Several recent experimental lines of evidence identify CB receptors as potential novel therapeutic targets in the management of NAFLD. Endogenous activation of peripheral CB1 receptors is a key mediator of insulin resistance and enhances liver lipogenesis in experimental models of NAFLD. Moreover, we have shown that adipose tissue CB2 receptors are markedly upregulated and promote fat inflammation, thereby contributing to insulin resistance and liver steatosis. Data from our group also indicate that tonic activation of CB1 receptors is responsible for progression of liver fibrosis, whereas CB2 receptors display anti-fibrogenic properties. The clinical relevance of these findings is supported by studies in patients with chronic hepatitis C indicating that daily cannabis use is an independent predictor of both fibrosis and steatosis severity. Moreover, preliminary data derived from clinical trials strongly suggest that selective CB1 antagonism improves insulin resistance and reduces liver fat. Tempering these promises, the first generation of CB1 antagonists raised concern due to an alarming rate of mood disorders and the development program of these molecules was suspended. Current research efforts are therefore focused on developing formulations of CB1 antagonists that do not enter the central nervous system, and preliminary experimental data obtained with such molecules are encouraging.

Topics: Animals; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Cannabinoid Receptor Modulators; Endocannabinoids; Fatty Liver; Humans; Hypertension, Portal; Inflammation; Insulin Resistance; Liver Cirrhosis; Piperidines; Pyrazoles; Receptors, Cannabinoid; Rimonabant

The bis (1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)-decandioate called IAC, is a new non-peptidyl low molecular weight radical scavenger able to give a fast reaction with the majority of radical species involved in the oxidative stress. This intrinsic property might be of particular interest in all the processes where it presents an over production of reactive oxygen/nitrogen species (ROS/RNS) such as inflammation. Indeed, it is well known that systemic inflammatory response is associated with the production of ROS, nitric oxide (NO), which in turn deplete the endogenous GSH, mediating cytotoxicity. It has been shown that IAC through its antioxidant activity, exerted a protective effect in vitro in islets isolated from type-2 diabetic patients, and in vivo in a non-obese diabetic mouse model and in DNBS-induced colitis in rats. The ability of IAC to protect brain from ischemia, suggests a possible use of the compound in broad range of inflammatory- related diseases. It is well known that the use of non steroidal anti-inflammatory drugs (NSAIDs) is associated with a broad spectrum of untoward side-effects such as gastrointestinal ulceration. The major pathogenetic element in the development of these effects is the depletion of prostaglandins (PGs) through inhibition of cyclooxygenase. The evidence that IAC protects gastric mucosa in an animal model of indomethacin-induced ulcer, through local increase of PGE2 levels and antioxidant activity, candidates this compound as a novel, promising, anti-inflammatory compound avoiding the major common untoward side-effects elicited by NSAID's.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Free Radical Scavengers; Free Radicals; Humans; Inflammation; Mice; Piperidines; Rats

The duration of postoperative ileus following abdominal surgery is quite variable, and prolonged postoperative ileus is an iatrogenic phenomenon with important influence on patient morbidity, hospital costs and length of stay in hospital. Adequate treatment for prolonged postoperative ileus is important to improve patient morbidity and clinical efficiency. Both clinical and pharmacological management strategies have improved rapidly over the last decade, and appropriate and timely management using multimodal techniques should be used for optimal care. In this review, we define postoperative ileus, describe the pathogenesis and briefly discuss clinical management before detailing potential pharmacologic management options.

Topics: Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Anti-Inflammatory Agents, Non-Steroidal; Bisacodyl; Cathartics; Cisapride; Dihydroergotamine; Humans; Ileus; Inflammation; Naltrexone; Neostigmine; Parasympathomimetics; Piperidines; Postoperative Complications; Propranolol; Quaternary Ammonium Compounds; Receptors, Opioid, mu; Serotonin Receptor Agonists

Vascular dementia (VaD) is a progressive neurodegenerative disease with a high prevalence. Several studies have recently reported that VaD patients present cholinergic deficits in the brain and cerebrospinal fluid (CSF) that may be closely related to the pathophysiology of cognitive impairment. Moreover, cholinergic therapies have shown promising effects on cognitive improvement in VaD patients. The precise mechanisms of these cholinergic agents are currently not fully understood; however, accumulating evidence indicates that these drugs may act through the cholinergic anti-inflammatory pathway, in which the efferent vagus nerve signals suppress pro-inflammatory cytokine release and inhibit inflammation, although regulation of oxidative stress and energy metabolism, alleviation of apoptosis may also be involved. In this paper, we provide a brief overview of the cholinergic treatment strategy for VaD and its relevant mechanisms of anti-inflammation.Acta Pharmacologica Sinica (2009) 30: 879-888; doi: 10.1038/aps.2009.82.

Topics: Acetylcholine; Alkaloids; Animals; Anti-Inflammatory Agents; Cholinergic Agents; Cholinesterase Inhibitors; Dementia, Vascular; Disease Models, Animal; Donepezil; Galantamine; Humans; Indans; Inflammation; Neuroprotective Agents; Nootropic Agents; Phenylcarbamates; Piperidines; Receptors, Cholinergic; Rivastigmine; Sesquiterpenes; Signal Transduction

Adipose tissue is an endocrine organ secreting more than 30 various adipokines which regulate wide spectrum of metabolic and immune processes. Obesity is associated with development of adipose tissue inflammation. This inflammation is characterized by infiltration with macrophages, alterations of adipokine secretion, development of insulin resistance. All these factors promote atherosclerosis. Inflammation of perivascular adipose tissue is especially important. Adipokines damage vascular endothelium via paracrine pathway. Cytokines released by macrophages as well as changes of adipokine secretion lead to endothelial dysfunction - the first stage of atherogenesis. Besides specific action curative factors used in obesity, metabolic syndrome, and diabetes mellitus also produce anti-inflammatory effect and thus diminish risk factors of cardiovascular diseases, rate of their development, and alleviate manifestations of atherosclerosis. Inflammation of adipose tissue is a connecting link between obesity and atherosclerosis. This review contains an outline of roles of various major adipokines in development of atherosclerosis as well as synopsis of anti-inflammatory and antiatherogenic effects of glytazones , metformin, rimonabant, statins, and of lowering of body weight.

Topics: Adipokines; Adipose Tissue; Atherosclerosis; Chemotaxis; Cytokines; Endothelium, Vascular; Humans; Hypoglycemic Agents; Inflammation; Insulin Resistance; Macrophages; Metformin; Obesity; Piperidines; Pyrazoles; Rimonabant; Vasoconstrictor Agents

Filamentous tau inclusions are hallmarks of Alzheimer's disease (AD) and related tauopathies, and the discovery of mutations in the tau gene in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) constitutes convincing evidence that tau proteins play a key role in the pathogenesis of neurodegenerative disorders. To investigate the pathomechanism of tauopathies, we generated and studied P301S mutant human tau transgenic mice (line PS19). Filamentous tau lesions developed in PS19 mice at 6-months of age, and progressively accumulated in association with striking neuron loss as well as hippocampal and entorhinal cortical atrophy by 9-12 months of age. Remarkably, hippocampal synapse loss and impaired synaptic function were detected in 3 month old PS19 mice before fibrillary tau tangles emerged. Prominent microglial activation and proinflammatory cytokine expressions in neurons also preceded tangle formation. Importantly, immunosuppression of young PS19 mice with FK506 attenuated tau pathology, thereby linking neuroinflammation to early progression of tauopathies. Recently, an anti-inflammatory function of acetylcholine (ACh) has been reported, suggesting that synaptic dysfunction might accelerate neuroinflammatory reaction by depletion of ACH. To investigate this, we administered donepezil (DZ), an ACh-esterase inhibitor, and trihexiphenidyl (TP), an anti-cholinergic agent to PS19 mice. Interestingly, DZ ameliorated but TP deteriorated microglial activation, tau pathology and neuronal loss, indicating the ACh level in the brain might play roles in not only neurotransmission, but also suppressing neuroinflammation in the brain.

Topics: Acetylcholine; Amyloid; Animals; Brain; Cholinesterase Inhibitors; Disease Models, Animal; Donepezil; Humans; Immunosuppressive Agents; Indans; Inflammation; Mice; Mice, Transgenic; Microglia; Mutation; Neurodegenerative Diseases; Piperidines; Synapses; Tacrolimus; tau Proteins

Topics: Amyloid beta-Peptides; Animals; Crystallography, X-Ray; Drug Design; Humans; Hypersensitivity; Inflammation; Intramolecular Oxidoreductases; Lipocalins; Molecular Chaperones; Muscular Dystrophies; Pain; Piperidines; Prostaglandin D2; Protein Conformation; Sleep

The prevalence of metabolic syndrome has increased dramatically in recent years, and the cluster of metabolic abnormalities it encompasses results in increased cardiovascular morbidity and mortality. The role of abdominal (visceral) obesity and the underlying molecular and cellular mechanisms central to this association have been the subject of intensive research in recent times. The aim of this review is to correlate data in this area, highlighting the central role of excess visceral fat and its secreted adipokines, and to review existing and emerging therapies.. Data were generated from a search of the PubMed database using the terms 'abdominal obesity', 'metabolic syndrome', 'insulin resistance', 'adipokines', 'interleukin-6 (IL-6)', 'adiponectin', 'tumour necrosis factor-alpha (TNF-alpha)' and 'cardiovascular disease'.. Metabolic syndrome is associated with a pro-inflammatory state, and the role of visceral obesity is thought to be central to this. Visceral obesity leads to alteration of the normal physiological balance of adipokines, insulin resistance, endothelial dysfunction and a pro-atherogenic state. In association with this, the presence of conventional cardiovascular risk factors such as hypertension, dyslipidaemia and smoking results in a significantly elevated cardiovascular and metabolic (cardiometabolic) risk. Better understanding of the molecular mechanisms central to this association has led to the development of potential therapeutic agents.

Topics: Cardiovascular Diseases; Fatty Acids, Nonesterified; Humans; Inflammation; Insulin Resistance; Interleukin-6; Intra-Abdominal Fat; Metabolic Syndrome; Obesity; Piperidines; Pyrazoles; Rimonabant; Risk Factors; Tumor Necrosis Factor-alpha

The current obesity epidemic is a major public health concern worldwide, in both developed and developing countries, and in adults and children alike. Obesity confers physical stress on multiple biologic processes and is associated with an increased risk of developing cardiovascular disease, type 2 diabetes mellitus, osteoarthritis, and certain forms of cancer, among other serious diseases. Therefore, it is essential that all health care providers take an active role in addressing the issue of obesity with their patients to reduce their cardiometabolic risks. Indeed, there is a 3-fold increase in the odds that a patient will attempt weight loss if it is recommended by a trusted health care professional. A reduction of only 5% to 10% of body weight improves lipid profiles, insulin sensitivity, and endothelial function, and reduces thrombosis and inflammatory markers. There is evidence, however, that humans are highly sensitive to the availability and nature of food in the environment, which presents a formidable obstacle to achieving lasting weight loss. The National Heart, Lung, and Blood Institute of the National Institutes of Health recommends lifestyle modification as the primary intervention. For individuals who do not respond or for those who also have a weight-related illness, a weight loss medication may need to be added to their treatment plan. While there are few medical options currently available, new compounds for the treatment of obesity are under investigation.

Topics: Adipocytes; Adipokines; Cardiovascular Diseases; Humans; Inflammation; Life Style; Obesity; Overweight; Piperidines; Pyrazoles; Rimonabant; Risk Assessment; Risk Factors; United States

Obesity has reached global epidemic proportions because of an increasingly obesogenic environment. This review examines the association between obesity, and in particular visceral fat, as a risk factor for cardiovascular disease and mortality.. The World Health Organization defines obesity based on the body mass index. Recently the waist-to-hip ratio has been shown to be a significantly stronger predictor of cardiovascular events than body mass index. The metabolic syndrome and its evolving definition represent a cluster of metabolic risk factors which help predict cardiovascular disease and mortality. Although insulin resistance plays a central role in the pathophysiology of the metabolic syndrome, there is limited support for therapy with insulin sensitizers, thiazolidinediones, in patients with coronary artery disease. The current anti-obesity drugs, orlistat and sibutramine, have only a modest effect on weight loss. The blockade of the endocannabinoid system with rimonabant, however, may be a promising new strategy.. Obesity is associated with significant increase in cardiovascular risk. Lifestyle modification remains the cornerstone of management although anti-obesity medications may be indicated in high risk individuals with comorbid disease.

Topics: Appetite Depressants; Body Fat Distribution; Body Mass Index; Cardiovascular Diseases; Cyclobutanes; Humans; Inflammation; Insulin Resistance; Intra-Abdominal Fat; Lactones; Life Style; Lipid Metabolism; Metabolic Syndrome; Obesity; Orlistat; Piperidines; Pyrazoles; Rimonabant; Thiazolidinediones; Waist-Hip Ratio

Stroke is the third leading cause of death and the leading cause of disability in Western countries. To date, only approximately 2% of stroke patients are eligible for thrombolysis treatment with recombinant tissue plasminogen activator. The very limited options available for stroke treatment and recent disappointing clinical trials in stroke call for novel therapeutic approaches. Inflammation represents one of the key pathophysiological mechanisms for the progression of ischaemic stroke. Recent advances in preclinical models of stroke using investigational small molecular antagonists, neutralising antibodies/proteins or genetically altered gene functions against various inflammatory mediators suggest a great therapeutic potential of anti-inflammation for ischaemic stroke. The scope of the present review is to update the evidence for a role of inflammatory pathways in stroke and to summarise the investigational drugs currently available both in preclinical and clinical development for potential treatment of ischaemic stroke.

Topics: ADAM Proteins; ADAM17 Protein; Animals; Anti-Inflammatory Agents; Brain; Brain Ischemia; Clinical Trials as Topic; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Drug Design; Enzyme Inhibitors; Humans; Inflammation; Mitogen-Activated Protein Kinases; Nitric Oxide; Nitric Oxide Synthase Type II; Piperidines; Protein Kinase Inhibitors; Quinolines; Receptors, Tumor Necrosis Factor; Tumor Necrosis Factor-alpha

Topics: Animals; Arachidonic Acids; Chemotaxis, Leukocyte; Chromones; Dogs; Guinea Pigs; Humans; Hypertension, Pulmonary; Inflammation; Ketanserin; Leukocyte Count; Leukocytes; Lung; Piperidines; Platelet Activating Factor; Pulmonary Embolism; Respiratory Distress Syndrome; Serotonin; Serotonin Antagonists; SRS-A; Thromboxane A2

Psoriatic arthritis (PsA) is an inflammatory disease characterised by synovitis, enthesitis, dactylitis and axial involvement. The prevalence of axial involvement ranges from 25% to 70% in this patient group. Treatment recommendations for axial PsA were mainly extrapolated from guidelines for axial spondyloarthritis, and the main treatment options are non-steroidal anti-inflammatory drugs and biological disease-modifying antirheumatic drugs (tumour necrosis factor, IL-17 and IL-23 inhibitors). Tofacitinib was approved for the treatment of PsA and its efficacy on axial inflammation has been demonstrated in a phase II study of ankylosing spondylitis (AS). This prospective study aims to evaluate the efficacy of tofacitinib in reducing inflammation in the sacroiliac joints (SIJs) and spine on MRI in patients with axial disease of their PsA presenting with active axial involvement compatible with axial PsA.. This is a randomised, double-blind, placebo-controlled, multicentre clinical trial in patients with axial PsA who have evidence of axial involvement, active disease as defined by a Bath AS Disease Activity Index score of ≥4 and active inflammation on MRI of the SIJs and/or spine as assessed by and independent central reader. The study includes a 6-week screening period, a 24-week treatment period, which consist of a 12-week placebo-controlled double-blind treatment period followed by a 12-week active treatment period with tofacitinib for all participants, and a safety follow-up period of 4 weeks. At baseline, 80 subjects shall be randomised (1:1) to receive either tofacitinib or matching placebo for a 12-week double-blind treatment period. At week 12, an MRI of the whole spine and SIJs will be performed to evaluate the primary study endpoint.. The study will be performed according to the ethical principles of the Declaration of Helsinki and the German drug law. The independent ethics committees of each centre approved the ethical, scientific and medical appropriateness of the study before it was conducted.. NCT04062695; ClinicalTrials.gov and EudraCT No: 2018-004254-22; European Union Clinical Trials Register.

Topics: Antirheumatic Agents; Arthritis, Psoriatic; Axial Spondyloarthritis; Double-Blind Method; Humans; Inflammation; Magnetic Resonance Imaging; Multicenter Studies as Topic; Piperidines; Prospective Studies; Pyrimidines; Randomized Controlled Trials as Topic; Treatment Outcome

The present study aimed to assess the prevalence of symptoms of anxiety and depression among health professionals in the three most affected regions in Cameroon.. The study was a descriptive cross-sectional type. Participants were health care professionals working in the three chosen regions of Cameroon. The non_probability convinient sample technique and that of the snowball were valued via a web questionnaire. The non-exhaustive sample size was 292. The diagnosis of anxiety and depression was made by the HAD (Hospital Anxiety and Depression scale).. Les auteurs rapportent que le secteur médical est classé à un plus grand risque de contracter le COVID-19 et de le propager potentiellement à d’autres. Le nombre sans cesse croissant de cas confirmés et suspects, la pression dans les soins, l’épuisement des équipements de protection individuelle et le manque de médicaments spécifiques peuvent contribuer à un vécu anxio-dépressif significatif. La présente étude s’est donnée pour ambition d’évaluer la prévalence des symptômes de l’anxiété et de la dépression chez les professionnels de santé dans les trois Régions les plus concernées au Cameroun.. Le choix des trois Régions du Cameroun se justifie non seulement par le fait qu’elles totalisent 95,8 % des cas de coronavirus au pays depuis le début de la pandémie, mais aussi parce qu’elles disposent de plus de la moitié des personnels de santé (56 %). Il s’agit d’une étude transversale, descriptive et analytique. Les participants sont des professionnels de la santé en service dans les Régions du Centre, Littoral et de l’Ouest du Cameroun. La méthode d’échantillonnage non probabiliste de convenance couplée à celle de boule de neige via un web questionnaire a été adoptée. La collecte des données a duré du 5 au 19 avril 2020, intervalle de temps après lequel on n’avait plus eu de répondants. À la fin de cette période, la taille de l’échantillon non exhaustive était de 292 professionnels. Le diagnostic de l’état anxio-dépressive était posé via l’échelle de HAD (Hospital Anxiety and Depression scale). Dans le HAD, chaque réponse cotée évalue de manière semi-quantitative l’intensité du symptôme au cours de la semaine écoulée. Un score total est obtenu ainsi que des scores aux deux sous-échelles : le score maximal est de 42 pour l’échelle globale et de 21 pour chacune des sous-échelles. Le coefficient alpha de Cronbach est de 0,70 pour la dépression et de 0,74 pour l’anxiété. Certains auteurs après plusieurs travaux ont proposé qu’une note inférieure ou égale à 7 indique une absence d’anxiété ou de dépression ; celle comprise entre 8 et 10 suggère une anxiété ou une dépression faible à bénigne ; entre 11 et 14, pour une anxiété ou une dépression modérée ; enfin, une note comprise entre 15 et 21 est révélatrice d’une anxiété sévère. Le logiciel Excel 2013 et Epi Info version 7.2.2.6 ont été utilisés pour les traitements statistiques. Les liens entre les variables ont été considérées significatifs pour une valeur de. L’amélioration des conditions de travail et notamment la fourniture d’équipement de protection, la mise en place des cellules spéciales d’écoute pour le personnel de santé pourraient être proposées.. Taken together with satisfactory selectivity index (SI) values, the acetone and methanol extracts of. During a mean follow-up period of 25.6 ± 13.9 months, 38 (18.4%) VAs and 78 (37.7%) end-stage events occurred. Big ET-1 was positively correlated with NYHA class (. In primary prevention ICD indication patients, plasma big ET-1 levels can predict VAs and end-stage events and may facilitate ICD-implantation risk stratification.. Beyond age, cognitive impairment was associated with prior MI/stroke, higher hsCRP, statin use, less education, lower eGFR, BMI and LVEF.. These data demonstrate that even a short period of detraining is harmful for elderly women who regularly participate in a program of strength training, since it impairs physical performance, insulin sensitivity and cholesterol metabolism.. Exposure to PM. Respiratory sinus arrhythmia is reduced after PVI in patients with paroxysmal AF. Our findings suggest that this is related to a decrease in cardiac vagal tone. Whether and how this affects the clinical outcome including exercise capacity need to be determined.. BDNF and leptin were not associated with weight. We found that miR-214-5p exerted a protective role in I/R injured cardiac cells by direct targeting FASLG. The results indicated that the MGO injection reduced all CCl. The hepatoprotective effects of MGO might be due to histopathological suppression and inflammation inhibition in the liver.. OVEO showed moderate antifungal activity, whereas its main components carvacrol and thymol have great application potential as natural fungicides or lead compounds for commercial fungicides in preventing and controlling plant diseases caused by. PF trajectories were mainly related to income, pregestational BMI, birth weight, hospitalisation due to respiratory diseases in childhood, participant's BMI, report of wheezing, medical diagnosis and family history of asthma, gestational exposure to tobacco and current smoking status in adolescence and young adult age.. In chronic pain patients on opioids, administration of certain benzodiazepine sedatives induced a mild respiratory depression but paradoxically reduced sleep apnoea risk and severity by increasing the respiratory arousal threshold.. Quantitative measurements of sensory disturbances using the PainVision. The serum level of 20S-proteasome may be a useful marker for disease activity in AAV.. The electrophysiological data and MD simulations collectively suggest a crucial role of the interactions between the HA helix and S4-S5 linker in the apparent Ca. Invited for the cover of this issue are Vanesa Fernández-Moreira, Nils Metzler-Nolte, M. Concepción Gimeno and co-workers at Universidad de Zaragoza and Ruhr-Universität Bochum. The image depicts the reported bimetallic bioconjugates as planes directing the gold fragment towards the target (lysosomes). Read the full text of the article at 10.1002/chem.202002067.. The optimal CRT pacing configuration changes during dobutamine infusion while LV and RV activation timing does not. Further studies investigating the usefulness of automated dynamic changes to CRT pacing configuration according to physiologic condition may be warranted.

Topics: 3' Untranslated Regions; 5'-Nucleotidase; A549 Cells; Accidental Falls; Acetylcholinesterase; Acrylic Resins; Actinobacillus; Acute Disease; Acute Kidney Injury; Adaptor Proteins, Signal Transducing; Adenosine; Adenosine Triphosphate; Administration, Inhalation; Administration, Oral; Adolescent; Adult; Advance Care Planning; Africa, Northern; Age Factors; Aged; Aged, 80 and over; Air Pollutants; Air Pollution; Air Pollution, Indoor; Albendazole; Aluminum Oxide; Anastomosis, Surgical; Ancylostoma; Ancylostomiasis; Androstadienes; Angiogenesis Inhibitors; Angiotensin II; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antibodies, Bispecific; Antibodies, Viral; Anticoagulants; Antihypertensive Agents; Antinematodal Agents; Antineoplastic Agents; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antiporters; Antiviral Agents; Apoptosis; Aptamers, Nucleotide; Aromatase Inhibitors; Asian People; Astrocytes; Atrial Fibrillation; Auditory Threshold; Aurora Kinase B; Australia; Autophagy; Autophagy-Related Protein 5; Autotrophic Processes; Bacillus cereus; Bacillus thuringiensis; Bacterial Proteins; Beclin-1; Belgium; Benzene; Benzene Derivatives; Benzhydryl Compounds; beta Catenin; beta-Arrestin 2; Biliary Tract Diseases; Biofilms; Biofuels; Biomarkers; Biomarkers, Tumor; Biomass; Biomechanical Phenomena; Bioreactors; Biosensing Techniques; Biosynthetic Pathways; Bismuth; Blood Platelets; Bone and Bones; Bone Regeneration; Bortezomib; Botulinum Toxins, Type A; Brain; Brain Injuries; Brain Ischemia; Brain Neoplasms; Breast Neoplasms; Breath Tests; Bronchodilator Agents; Calcium Phosphates; Cannabis; Carbon Dioxide; Carbon Isotopes; Carcinogenesis; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cardiac Resynchronization Therapy; Cardiac Resynchronization Therapy Devices; Cardiomyopathies; Cardiovascular Diseases; Cariostatic Agents; Case Managers; Case-Control Studies; Catalysis; Cation Transport Proteins; CD8-Positive T-Lymphocytes; Cecropia Plant; Cell Adhesion; Cell Count; Cell Differentiation; Cell Division; Cell Line; Cell Line, Tumor; Cell Membrane; Cell Movement; Cell Proliferation; Cell Self Renewal; Cell Survival; Cells, Cultured; Cellular Reprogramming; Cellulose; Charcoal; Chemical and Drug Induced Liver Injury; Chemical Phenomena; Chemokines; Chemoradiotherapy; Chemoreceptor Cells; Child; Child Abuse; Child, Preschool; China; Chlorogenic Acid; Chloroquine; Chromatography, Gas; Chronic Disease; Clinical Competence; Coated Materials, Biocompatible; Cochlea; Cohort Studies; Color; Comorbidity; Computer Simulation; Computer-Aided Design; Contraception; Contraceptive Agents, Female; Contrast Media; COP-Coated Vesicles; Coronavirus Infections; Cost of Illness; Coturnix; COVID-19; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Culex; Curriculum; Cyclic N-Oxides; Cytokines; Cytoplasm; Cytotoxicity, Immunologic; Cytotoxins; Databases, Factual; Deep Learning; Delivery, Obstetric; Denitrification; Dental Caries; Denture, Complete; Dexamethasone; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dielectric Spectroscopy; Diet, High-Fat; Dietary Fiber; Disease Models, Animal; Disease Progression; DNA; DNA Copy Number Variations; DNA, Mitochondrial; Dog Diseases; Dogs; Dopaminergic Neurons; Double-Blind Method; Down-Regulation; Doxorubicin; Drug Carriers; Drug Design; Drug Interactions; Drug Resistance, Bacterial; Drug Resistance, Neoplasm; Drug-Related Side Effects and Adverse Reactions; Drugs, Chinese Herbal; Dry Powder Inhalers; Dust; E2F1 Transcription Factor; Ecosystem; Education, Nursing; Education, Nursing, Baccalaureate; Electric Impedance; Electricity; Electrocardiography; Electrochemical Techniques; Electrochemistry; Electrodes; Electrophoresis, Polyacrylamide Gel; Endoplasmic Reticulum; Endothelial Cells; Environmental Monitoring; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Estrogen Receptor Modulators; Europe; Evoked Potentials, Auditory, Brain Stem; Exosomes; Feasibility Studies; Female; Ferricyanides; Ferrocyanides; Fibrinogen; Finite Element Analysis; Fistula; Fluorescent Dyes; Fluorides, Topical; Fluorodeoxyglucose F18; Fluticasone; Follow-Up Studies; Food Contamination; Food Microbiology; Foods, Specialized; Forensic Medicine; Frail Elderly; France; Free Radicals; Fresh Water; Fungi; Fungicides, Industrial; Galactosamine; Gastrointestinal Neoplasms; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Frequency; Genetic Predisposition to Disease; Genotype; Gingival Hemorrhage; Glioblastoma; Glioma; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Glucose; Glucose Transport Proteins, Facilitative; Glucosides; Glutamine; Glycolysis; Gold; GPI-Linked Proteins; Gram-Negative Bacteria; Gram-Positive Bacteria; Graphite; Haplotypes; HCT116 Cells; Healthy Volunteers; Hearing Loss; Heart Failure; Hedgehog Proteins; HEK293 Cells; HeLa Cells; Hemodynamics; Hemorrhage; Hepatocytes; Hippo Signaling Pathway; Histone Deacetylases; Homeostasis; Hospital Mortality; Hospitalization; Humans; Hydantoins; Hydrazines; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; Hydroxylamines; Hypoglycemic Agents; Immunity, Innate; Immunoglobulin G; Immunohistochemistry; Immunologic Factors; Immunomodulation; Immunophenotyping; Immunotherapy; Incidence; Indazoles; Indonesia; Infant; Infant, Newborn; Infarction, Middle Cerebral Artery; Inflammation; Injections, Intramuscular; Insecticides; Insulin-Like Growth Factor I; Insurance, Health; Intention to Treat Analysis; Interleukin-1 Receptor-Associated Kinases; Interleukin-6; Intrauterine Devices; Intrauterine Devices, Copper; Iron; Ischemia; Jordan; Keratinocytes; Kidney; Kidney Diseases; Kir5.1 Channel; Klebsiella Infections; Klebsiella pneumoniae; Lab-On-A-Chip Devices; Laparoscopy; Lasers; Lasers, Semiconductor; Lenalidomide; Leptin; Lethal Dose 50; Levonorgestrel; Limit of Detection; Lipid Metabolism; Lipid Metabolism Disorders; Lipogenesis; Lipopolysaccharides; Liquid Biopsy; Liver; Liver Abscess, Pyogenic; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Longevity; Lung Neoplasms; Luteolin; Lymph Nodes; Lymphocyte Activation; Macaca fascicularis; Macrophages; Mad2 Proteins; Magnetic Resonance Imaging; Male; Mammary Glands, Human; Manganese; Manganese Compounds; MAP Kinase Signaling System; Materials Testing; Maternal Health Services; MCF-7 Cells; Medicaid; Medicine, Chinese Traditional; Melanoma; Membrane Proteins; Mental Health; Mercury; Metal Nanoparticles; Metals, Heavy; Metformin; Methionine Adenosyltransferase; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Knockout; Mice, Nude; Microalgae; Microbial Sensitivity Tests; Microglia; MicroRNAs; Microscopy, Atomic Force; Microscopy, Electron, Scanning; Middle Aged; Mitochondria; Mitochondrial Proteins; Mitral Valve; Mitral Valve Insufficiency; Models, Anatomic; Molecular Structure; Molybdenum; Monocarboxylic Acid Transporters; Moths; MPTP Poisoning; Multigene Family; Multiparametric Magnetic Resonance Imaging; Multiple Myeloma; Muscle, Skeletal; Mutagens; Mutation; Myeloid Cells; Nanocomposites; Nanofibers; Nanomedicine; Nanoparticles; Nanowires; Neoadjuvant Therapy; Neomycin; Neoplasm Grading; Neoplasm Recurrence, Local; Neoplasms; Neoplastic Stem Cells; Neostriatum; Neovascularization, Pathologic; Netherlands; Neuromuscular Agents; Neurons; NF-E2-Related Factor 2; NF-kappa B; Nickel; Nitrogen Oxides; Non-alcoholic Fatty Liver Disease; Nucleosides; Nucleotidyltransferases; Nutritional Status; Obesity, Morbid; Ofloxacin; Oils, Volatile; Oligopeptides; Oncogene Protein v-akt; Optical Imaging; Organic Cation Transport Proteins; Organophosphonates; Osteoarthritis; Osteoarthritis, Hip; Osteoarthritis, Knee; Osteoblasts; Osteogenesis; Oxidation-Reduction; Oxidative Stress; Oxides; Oxygen Isotopes; Pancreas; Pancreaticoduodenectomy; Pandemics; Particle Size; Particulate Matter; Patient Acceptance of Health Care; Patient Compliance; PC-3 Cells; Peptide Fragments; Peptides; Periodontal Attachment Loss; Periodontal Index; Periodontal Pocket; Periodontitis; Peroxides; Peru; Pest Control, Biological; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Phylogeny; Pilot Projects; Piperidines; Plant Bark; Plant Extracts; Plant Leaves; Plasmids; Platelet Function Tests; Pneumonia, Viral; Podocytes; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Polyethylene Terephthalates; Polymers; Polymorphism, Single Nucleotide; Porosity; Portugal; Positron-Emission Tomography; Postoperative Complications; Postural Balance; Potassium Channels, Inwardly Rectifying; Povidone; Powders; Precancerous Conditions; Precision Medicine; Predictive Value of Tests; Pregnancy; Prenatal Care; Prognosis; Promoter Regions, Genetic; Prospective Studies; Prostatectomy; 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Skull Fractures; Social Determinants of Health; Sodium; Sodium Fluoride; Sodium Potassium Chloride Symporter Inhibitors; Sodium-Glucose Transporter 2 Inhibitors; Soil; Soil Pollutants; Spain; Spectrophotometry; Spectroscopy, Fourier Transform Infrared; Staphylococcal Protein A; Staphylococcus aureus; Stem Cells; Stereoisomerism; Stomach Neoplasms; Streptomyces; Strontium; Structure-Activity Relationship; Students, Nursing; Substance-Related Disorders; Succinic Acid; Sulfur; Surface Properties; Survival Rate; Survivin; Symporters; T-Lymphocytes; Temozolomide; Tensile Strength; Thiazoles; Thiobacillus; Thiohydantoins; Thiourea; Thrombectomy; Time Factors; Titanium; Tobacco Mosaic Virus; Tobacco Use Disorder; Toll-Like Receptor 4; Toluene; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Toxicity Tests, Acute; Toxicity Tests, Subacute; Transcriptional Activation; Treatment Outcome; Troponin I; Tumor Cells, Cultured; Tumor Escape; Tumor Hypoxia; Tumor Microenvironment; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha; Tyrosine; Ubiquitin-Protein Ligases; Ubiquitination; Ultrasonic Waves; United Kingdom; United States; United States Department of Veterans Affairs; Up-Regulation; Urea; Uric Acid; Urinary Bladder Neoplasms; Urinary Bladder, Neurogenic; Urine; Urodynamics; User-Computer Interface; Vemurafenib; Verbenaceae; Veterans; Veterans Health; Viral Load; Virtual Reality; Vitiligo; Water Pollutants, Chemical; Wildfires; Wnt Signaling Pathway; Wound Healing; X-Ray Diffraction; Xenograft Model Antitumor Assays; Xylenes; Young Adult; Zinc; Zinc Oxide; Zinc Sulfate; Zoonoses

Nonalcoholic fatty liver diseases (NAFLD) is a highly prevalent disease that is closely associated with several cardiometabolic complications. The potential anti-inflammatory role of curcuminoids that have already been reported to reduce hepatic steatosis, in patients with NAFLD was explored in this study.. This double-blind, randomized placebo-controlled trial was conducted for a period of 8 weeks in patients with NAFLD. Subjects (n = 55) were randomly allocated to receive either curcuminoids or placebo. The curcuminoids group received one capsule containing 500 mg curcuminoids (plus 5 mg piperine to increase intestinal absorption) per day for 8 weeks and the control group received matched placebo capsules for the same period. Liver ultrasonography was performed to assess the severity of hepatic steatosis at baseline and the study end. Serum levels of cytokines including interleukin-1α, interleukin-1β, interleukin-2, interleukin-4, interleukin-6, interleukin-8, interleukin-10, tumor necrosis factor-α, monocyte chemoattractant protein-1, interferon γ, vascular endothelial growth factor and epidermal growth factor were measured before and after the intervention.. The two groups were comparable in demographic features at baseline. The results showed that supplementation with curcuminoids could decrease weight compared to the placebo group (p = 0.016) in patients with NAFLD. Curcuminoids supplementation improved the severity of NAFLD according to the ultrasound results (p = 0.002). Moreover, serum concentrations of TNF-α (p = 0.024), MCP-1 (p = 0.008) and EGF (p = 0.0001) were improved by curcuminoids in NAFLD patients.. The results of our study showed that curcumin supplementation can improve serum levels of inflammatory cytokines in subjects with NAFLD and this might be at least partly responsible for the anti-steatotic effects of curcuminoids.

Topics: Adolescent; Adult; Aged; Alkaloids; Benzodioxoles; Curcumin; Diarylheptanoids; Double-Blind Method; Female; Humans; Inflammation; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Piperidines; Polyunsaturated Alkamides; Young Adult

Patients with psoriasis have an increased risk of myocardial infarction, and psoriasis is now recognized as an independent risk factor for coronary heart disease and cardiovascular mortality. To understand the effects of psoriasis medications on systemic inflammation associated with cardiovascular risks, we studied blood proteins related to inflammation and cardiovascular disease archived from a phase 3 clinical trial of tofacitinib and etanercept in adults with moderate-to-severe psoriasis. A total of 157 blood proteins were quantified by a proximity extension assay from 266 patients at baseline and week 4. Protein changes in the blood after 1 month of treatment were compared between tofacitinib (10 mg two times a day) and etanercept (50 mg biweekly), and by response status at week 12. Tofacitinib and etanercept commonly reduced IL-6, CCL20, and CXCL10, but IL-17A was significantly reduced only in responders of either treatment. Compared with etanercept, tofacitinib showed a wider spectrum of cardiovascular blood protein reduction, but the protein reduction effects of tofacitinib were strictly confined to treatment responders. Tumor necrosis factor receptor 1, E-selectin, hK11, tumor necrosis factor-related activation-induced cytokine, CHI3L1, IL-16, and matrix metalloproteinase-12 were cardiovascular proteins significantly reduced only in tofacitinib responders. Our data suggest that a short-term systemic psoriasis treatment can cause reductions in circulating inflammatory and other proteins associated with cardiovascular risks.

Topics: Adult; Aged; Cardiovascular Diseases; Cytokines; Etanercept; Female; Humans; Inflammation; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Proteomics; Psoriasis; Pyrimidines; Pyrroles; Risk Factors; Treatment Outcome; Young Adult

Curcuminoids have been shown to reduce glycemia and related complications in diabetes. In the present study, we evaluated the impact of curcuminoids plus piperine administration on glycemic, hepatic and inflammatory biomarkers in type 2 diabetes (T2D) patients.. T2D patients aged 18-65 years were enrolled in a randomized double-blind placebo-controlled trial and randomly allocated to standard-of-care treatment and dietary advises plus either curcuminoids (daily dose of 500 mg/day co-administered with piperine 5 mg/day) or placebo for a period of 3 months. Glycemic, hepatic and inflammatory parameters were measured at baseline and final conditions.. A total of 100 subjects (50 in each group) completed the 3-month period of trial. A significant reduction was found in serum levels of glucose (-9±16 mg/dL vs. -3±11 mg/dL in curcuminoids and placebo groups, respectively; p=0.048), C-peptide (-0.6±0.8 ng/mL vs. 0.02±0.6 ng/mL; p<0.001) and HbA1c (-0.9±1.1% vs. -0.2±0.5%; p<0.001) after curcuminoids supplementation versus placebo group. Additionally, participants in the intervention group showed lower serum alanine aminotransferase (-2±6 vs. -1±5; p=0.032) and aspartate aminotransferase (-3±5 vs. -0.3±4; p=0.002) levels compared with the placebo group. Finally, no significant differences in high-sensitivity C-reactive protein (hs-CRP) concentrations were observed between curcuminoids and placebo groups (p>0.05).. The results of the present trial revealed a beneficial effect of curcuminoids plus piperine supplementation on glycemic and hepatic parameters but not on hs-CRP levels in T2D patients.

Topics: Adolescent; Adult; Aged; Alanine Transaminase; Alkaloids; Antioxidants; Aspartate Aminotransferases; Benzodioxoles; Biomarkers; Blood Glucose; C-Reactive Protein; Curcumin; Diabetes Mellitus, Type 2; Dietary Supplements; Double-Blind Method; Female; Humans; Inflammation; Male; Middle Aged; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Young Adult

Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia, with profound disease-related cellular, humoral, and innate immune suppression. The objective of this study was to study the correlations between stress and disease-specific, negative prognostic cellular, cytokine, and chemokine markers in patients with CLL.. A single-group, observational design was used. Patients with relapsed/refractory CLL (N = 96) who were entering a phase 2 trial of an experimental therapy (ibrutinib) were studied. Before the first dose, a validated self-report measure of stress (the Impact of Event Scale) was completed, and blood was drawn for absolute lymphocyte counts (ALCs) and for cytokine and chemokine enzyme-linked immunosorbent assays. Multiple linear regression models tested stress as a concurrent predictor of ALCs; of cytokines (tumor necrosis factor α [TNFα], a proliferation-inducing ligand [APRIL], B-cell activating factor [BAFF], interleukin 6 [IL-6], IL-10, IL-16, and vascular endothelial growth factor [VEGF]); and of the chemokine (C-C motif) ligand 3 (CCL3).. Controlling for relevant demographic variables, comorbidities, CLL genetic risk (deletion of the short arm of chromosome 17 [del17p]), and correlates of inflammation, stress predicted higher ALCs (P < .05), and higher levels of TNFα (P < .05), IL-16 (P < .01), and CCL3 (P < .05). Stress was not associated with APRIL, BAFF, IL-6, IL-10, or VEGF.. Novel biobehavioral data from patients with relapsed/refractory CLL demonstrate that stress is related to heightened levels of cellular, cytokine, and chemokine markers associated previously with progressive disease in CLL. The current results indicate that stress is related to immune and inflammatory processes that contribute to cancer cell proliferation and survival. These data provide a first look into these processes. Cancer 2018. © 2018 American Cancer Society.

Topics: Adenine; Aged; B-Cell Activating Factor; Biomarkers, Tumor; Cell Proliferation; Female; Humans; Immunity, Innate; Inflammation; Interleukin-6; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocyte Count; Male; Middle Aged; Piperidines; Prognosis; Pyrazoles; Pyrimidines; Stress, Psychological; Tumor Necrosis Factor Ligand Superfamily Member 13; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

Animal studies suggest that cannabinoid receptor-1 (CB-1) blockade reduces inflammation and neovascularization by decreasing vascular endothelial growth factor (VEGF) levels associated with a reduction in inflammatory markers, thereby potentially reducing cardiovascular risk.. To determine the impact of CB1 antagonism by rimonabant on VEGF and inflammatory markers in obese PCOS women.. Randomized, open-labelled parallel study.. Endocrinology outpatient clinic in a referral centre.. Twenty patients with PCOS (PCOS) and biochemical hyperandrogenaemia with a body mass index of ≥30 kg/m. Post hoc review to detect VEGF and pro-inflammatory cytokines TNF-α, IL-1β, IL-1ra, IL-2, IL6, IL-8, IL-10 and MCP-1 before and after 12 weeks of treatment.. After 12 weeks of rimonabant treatment, there was a significant increase in VEGF (99·2 ± 17·6 vs 116·2 ± 15·8 pg/ml, P < 0·01) and IL-8 (7·4 ± 11·0 vs 18·1 ± 13·2 pg/ml, P < 0·05) but not after metformin (VEGF P = 0·7; IL-8 P = 0·9). There was no significant difference in the pro-inflammatory cytokines TNF-α, IL-1β, IL-1ra, IL-2, IL6, IL-8, IL-10 and MCP-1 following either treatment.. This study suggests that rimonabant CB-I blockade paradoxically raised VEGF and the cytokine IL-8 in obese women with PCOS that may have offset the potential benefit associated with weight loss.

Topics: Biomarkers; Cannabinoid Receptor Antagonists; Cytokines; Female; Humans; Hyperandrogenism; Inflammation; Interleukin-8; Metformin; Obesity; Piperidines; Polycystic Ovary Syndrome; Pyrazoles; Rimonabant; Vascular Endothelial Growth Factor A; Weight Loss

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antitubercular Agents; Antiviral Agents; Apolipoproteins E; Apoptosis; Arabidopsis; Arabidopsis Proteins; Arsenic; Arthritis, Rheumatoid; Asthma; Atherosclerosis; ATP-Dependent Proteases; Attitude of Health Personnel; Australia; Austria; Autophagy; Axitinib; Bacteria; Bacterial Outer Membrane Proteins; Bacterial Proteins; Bacterial Toxins; Bacterial Typing Techniques; Bariatric Surgery; Base Composition; Bayes Theorem; Benzoxazoles; Benzylamines; beta Catenin; Betacoronavirus; Betula; Binding Sites; Biological Availability; Biological Oxygen Demand Analysis; Biomarkers; Biomarkers, Tumor; Biopsy; Bioreactors; Biosensing Techniques; Birth Weight; Blindness; Blood Chemical Analysis; Blood Gas Analysis; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Blood-Brain Barrier; Blotting, Western; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Bone Resorption; Borates; Brain; Brain Infarction; Brain Injuries, Traumatic; Brain Neoplasms; Breakfast; Breast Milk Expression; Breast Neoplasms; Bronchi; Bronchoalveolar Lavage Fluid; Buffaloes; Cadherins; Calcification, Physiologic; Calcium Compounds; Calcium, Dietary; Cannula; Caprolactam; Carbon; Carbon Dioxide; Carboplatin; Carcinogenesis; Carcinoma, Ductal; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Pancreatic Ductal; Carcinoma, Renal Cell; Cardiovascular Diseases; Carps; Carrageenan; Case-Control Studies; Catalysis; Catalytic Domain; Cattle; CD8-Positive T-Lymphocytes; Cell Adhesion; Cell Cycle Proteins; Cell Death; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Phone Use; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cell Transformation, Viral; Cells, Cultured; Cellulose; Chemical Phenomena; Chemoradiotherapy; Child; Child Development; Child, Preschool; China; Chitosan; Chlorocebus aethiops; Cholecalciferol; Chromatography, Liquid; Circadian Clocks; Circadian Rhythm; Circular Dichroism; Cisplatin; Citric Acid; Clinical Competence; Clinical Laboratory Techniques; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clostridioides difficile; Clostridium Infections; Coculture Techniques; Cohort Studies; Cold Temperature; Colitis; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type XI; Color; Connective Tissue Diseases; Copper; Coronary Angiography; Coronavirus 3C Proteases; Coronavirus Infections; Cost of Illness; Counselors; COVID-19; COVID-19 Testing; Creatine Kinase; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Cryoelectron Microscopy; Cryosurgery; Crystallography, X-Ray; Cues; Cultural Competency; Cultural Diversity; Curriculum; Cyclic AMP Response Element-Binding Protein; Cyclin-Dependent Kinase Inhibitor p21; Cycloparaffins; Cysteine Endopeptidases; Cytokines; Cytoplasm; Cytoprotection; Databases, Factual; Denitrification; Deoxycytidine; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Diatoms; Diet; Diet, High-Fat; Dietary Exposure; Diffusion Magnetic Resonance Imaging; Diketopiperazines; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Disease Progression; Disease-Free Survival; DNA; DNA Damage; DNA Glycosylases; DNA Repair; DNA-Binding Proteins; DNA, Bacterial; DNA, Viral; Docetaxel; Dose Fractionation, Radiation; Dose-Response Relationship, Drug; Down-Regulation; Doxorubicin; Drosophila; Drosophila melanogaster; Drug Carriers; Drug Delivery Systems; Drug Liberation; Drug Repositioning; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Drug Therapy, Combination; Edema; Edible Grain; Education, Graduate; Education, Medical, Graduate; Education, Pharmacy; Ehlers-Danlos Syndrome; Electron Transport Complex III; Electron Transport Complex IV; Electronic Nicotine Delivery Systems; Emergency Service, Hospital; Empathy; Emulsions; Endothelial Cells; Endurance Training; Energy Intake; Enterovirus A, Human; Environment; Environmental Monitoring; Enzyme Assays; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Epoxide Hydrolases; Epoxy Compounds; Erythrocyte Count; Erythrocytes; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Esophagectomy; Estrogens; Etanercept; Ethiopia; Ethnicity; Ethylenes; Exanthema; Exercise; Exercise Test; Exercise Tolerance; Extracellular Matrix; Extracorporeal Membrane Oxygenation; Eye Infections, Fungal; False Negative Reactions; Fatty Acids; Fecal Microbiota Transplantation; Feces; Female; Femur Neck; Fermentation; Ferritins; Fetal Development; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Fibroblasts; Fibroins; Fish Proteins; Flavanones; Flavonoids; Focus Groups; Follow-Up Studies; Food Handling; Food Supply; Food, Formulated; Forced Expiratory Volume; Forests; Fractures, Bone; Fruit and Vegetable Juices; Fusobacteria; G1 Phase Cell Cycle Checkpoints; G2 Phase Cell Cycle Checkpoints; Gamma Rays; Gastrectomy; Gastrointestinal Microbiome; Gastrointestinal Stromal Tumors; Gefitinib; Gels; Gemcitabine; Gene Amplification; Gene Expression; Gene Expression Regulation; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Plant; Gene Knockdown Techniques; Gene-Environment Interaction; Genotype; Germany; Glioma; Glomerular Filtration Rate; Glucagon; Glucocorticoids; Glycemic Control; Glycerol; Glycogen Synthase Kinase 3 beta; Glycolipids; Glycolysis; Goblet Cells; Gram-Negative Bacterial Infections; Granulocyte Colony-Stimulating Factor; Graphite; Greenhouse Effect; Guanidines; Haemophilus influenzae; HCT116 Cells; Health Knowledge, Attitudes, Practice; Health Personnel; Health Services Accessibility; Health Services Needs and Demand; Health Status Disparities; Healthy Volunteers; Heart Failure; Heart Rate; Heart Transplantation; Heart-Assist Devices; HEK293 Cells; Heme; Heme Oxygenase-1; Hemolysis; Hemorrhage; Hepatitis B; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Hepatocytes; Hexoses; High-Throughput Nucleotide Sequencing; Hippo Signaling Pathway; Histamine; Histamine Agonists; Histidine; Histone Deacetylase 2; HIV Infections; HIV Reverse Transcriptase; HIV-1; Homebound Persons; Homeodomain Proteins; Homosexuality, Male; Hospice and Palliative Care Nursing; HSP70 Heat-Shock Proteins; Humans; Hyaluronan Receptors; Hydrogen; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrolysis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemia; Hypoglycemic Agents; Hypoxia; Idiopathic Interstitial Pneumonias; Imaging, Three-Dimensional; Imatinib Mesylate; Immunotherapy; Implementation Science; Incidence; INDEL Mutation; Induced Pluripotent Stem Cells; Industrial Waste; Infant; Infant, Newborn; Inflammation; Inflammation Mediators; Infliximab; Infusions, Intravenous; Inhibitory Concentration 50; Injections; Insecticides; Insulin-Like Growth Factor Binding Protein 5; Insulin-Secreting Cells; Interleukin-1; Interleukin-17; Interleukin-8; Internship and Residency; Intestines; Intracellular Signaling Peptides and Proteins; Ion Transport; Iridaceae; Iridoid Glucosides; Islets of Langerhans Transplantation; Isodon; Isoflurane; Isotopes; Italy; Joint Instability; Ketamine; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Kidney Neoplasms; Kinetics; Klebsiella pneumoniae; Knee Joint; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Lactate Dehydrogenase 5; Laparoscopy; Laser Therapy; Lasers, Semiconductor; Lasers, Solid-State; Laurates; Lead; Leukocyte L1 Antigen Complex; Leukocytes, Mononuclear; Light; Lipid Peroxidation; Lipopolysaccharides; Liposomes; Liver; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Locomotion; Longitudinal Studies; Lopinavir; Lower Urinary Tract Symptoms; Lubricants; Lung; Lung Diseases, Interstitial; Lung Neoplasms; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating; Lymphoma, Mantle-Cell; Lysosomes; Macrophages; Male; Manganese Compounds; MAP Kinase Kinase 4; Mass Screening; Maternal Health; Medicine, Chinese Traditional; Melanoma, Experimental; Memantine; Membrane Glycoproteins; Membrane Proteins; Mesenchymal Stem Cell Transplantation; Metal Nanoparticles; Metalloendopeptidases; Metalloporphyrins; Methadone; Methane; Methicillin-Resistant Staphylococcus aureus; Mexico; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Mice, Nude; Mice, SCID; Mice, Transgenic; Microarray Analysis; Microbial Sensitivity Tests; Microbiota; Micronutrients; MicroRNAs; Microscopy, Confocal; Microsomes, Liver; Middle Aged; Milk; Milk, Human; Minority Groups; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins; Models, Animal; Models, Molecular; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Epidemiology; 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YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

Oxidative stress and inflammation have been proposed as emerging components of metabolic syndrome (MetS). Curcuminoids are natural polyphenols with strong antioxidant and anti-inflammatory properties.. To study the effectiveness of supplementation with a bioavailable curcuminoid preparation on measures of oxidative stress and inflammation in patients with MetS. Our secondary aim was to perform a meta-analysis of data from all randomized controlled trials in order to estimate the effect size of curcuminoids on plasma C-reactive protein (CRP) concentrations.. In this randomized double-blind placebo-controlled trial, 117 subjects with MetS (according to the NCEP-ATPIII diagnostic criteria) were randomly assigned to curcuminoids (n = 59; drop-outs = 9) or placebo (n = 58; drop-outs = 8) for eight weeks. Curcuminoids were administered at a daily dose of 1 g, and were co-supplemented with piperine (10 mg/day) in order to boost oral bioavailability. Serum activities of superoxide dismutase (SOD) and concentrations of malondialdehyde (MDA) and CRP were measured at baseline and at study end. Regarding the importance of CRP as a risk marker and risk factor of cardiovascular disease, a random-effects meta-analysis of clinical trials was performed to estimate the overall impact of curcuminoid therapy on circulating concentrations of CRP. The robustness of estimated effect size was evaluated using leave-one-out sensitivity analysis.. Supplementation with curcuminoid-piperine combination significantly improved serum SOD activities (p < 0.001) and reduced MDA (p < 0.001) and CRP (p < 0.001) concentrations compared with placebo. Quantitative data synthesis revealed a significant effect of curcuminoids vs. placebo in reducing circulating CRP concentrations (weighed mean difference: -2.20 mg/L; 95% confidence interval [CI]: -3.96, -0.44; p = 0.01). This effect was robust in sensitivity analysis.. Short-term supplementation with curcuminoid-piperine combination significantly improves oxidative and inflammatory status in patients with MetS. Curcuminoids could be regarded as natural, safe and effective CRP-lowering agents.

Topics: Adult; Alkaloids; Anti-Inflammatory Agents; Antioxidants; Benzodioxoles; Biological Availability; Blood Pressure; Body Mass Index; C-Reactive Protein; Curcumin; Databases, Factual; Dietary Supplements; Double-Blind Method; Female; Humans; Inflammation; Male; Malondialdehyde; Meta-Analysis as Topic; Metabolic Syndrome; Middle Aged; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Superoxide Dismutase

Remote ischemic preconditioning (RIPC) may confer the protection in critical organs. The authors hypothesized that limb RIPC would reduce lung injury in patients undergoing pulmonary resection.. In a randomized, prospective, parallel, controlled trial, 216 patients undergoing elective thoracic pulmonary resection under one-lung ventilation with propofol-remifentanil anesthesia were randomized 1:1 to receive either limb RIPC or conventional lung resection (control). Three cycles of 5-min ischemia/5-min reperfusion induced by a blood pressure cuff served as RIPC stimulus. The primary outcome was PaO2/FIO2. Secondary outcomes included other pulmonary variables, the incidence of in-hospital complications, markers of oxidative stress, and inflammatory response.. Limb RIPC significantly increased PaO2/FIO2 compared with control at 30 and 60 min after one-lung ventilation, 30 min after re-expansion, and 6 h after operation (238 ± 52 vs. 192 ± 67, P = 0.03; 223 ± 66 vs. 184 ± 64, P = 0.01; 385 ± 61 vs. 320 ± 79, P = 0.003; 388 ± 52 vs. 317 ± 46, P = 0.001, respectively). In comparison with control, it also significantly reduced serum levels of interleukin-6 and tumor necrosis factor-α at 6, 12, 24, and 48 h after operation and malondialdehyde levels at 60 min after one-lung ventilation and 30 min after re-expansion (all P < 0.01). The incidence of acute lung injury and the length of postoperative hospital stay were markedly reduced by limb RIPC compared with control (all P < 0.05).. Limb RIPC attenuates acute lung injury via improving intraoperative pulmonary oxygenation in patients without severe pulmonary disease after lung resection under propofol-remifentanil anesthesia.

Topics: Acute Lung Injury; Aged; Analysis of Variance; Anesthesia, Intravenous; Anesthetics, Intravenous; Carcinoma, Non-Small-Cell Lung; Cytokines; Female; Humans; Inflammation; Ischemic Preconditioning; Lung; Lung Neoplasms; Male; Malondialdehyde; Middle Aged; Oxidative Stress; Pain, Postoperative; Piperidines; Propofol; Prospective Studies; Remifentanil; Respiratory Function Tests; Sample Size; Treatment Outcome

Small increases in mean serum creatinine (SCr) were observed in studies of rheumatoid arthritis patients during tofacitinib treatment. These SCr changes were investigated and potential mechanisms explored.. SCr values and renal adverse event data were pooled from five Phase 3 and two long-term extension (LTE) studies. Dose-response relationships and association with inflammation (C-reactive protein (CRP)) were explored using Phase 2 data and confirmed with Phase 3 data.. In Phase 3, least squares mean SCr differences from placebo at Month 3 were 0.02 and 0.04 mg/dl for tofacitinib 5 and 10 mg twice daily (BID) (P <0.05), respectively. During Months 0 to 3, confirmed SCr ≥33% increases over baseline were reported in 17 (1.4%; 5 mg BID) and 23 (1.9%; 10 mg BID) patients. Generally, elevations plateaued and remained within normal limits throughout Phase 3 and LTE studies. Exposure-response modeling demonstrated small, reversible effects of tofacitinib on mean SCr, and significant (P <0.05) effects of CRP on model parameters. Phase 3 data confirmed that patients with higher baseline CRP or greater CRP decreases following tofacitinib treatment had the largest increases in SCr. Across Phase 3 and LTE studies, 22 tofacitinib-treated patients had clinical acute renal failure (ARF), predominantly in the setting of concurrent serious illness.. Tofacitinib treatment was associated with small, reversible mean increases in SCr that plateaued early. The mechanism behind these SCr changes remains unknown, but may involve effects of tofacitinib on inflammation. ARF occurred infrequently, was associated with concurrent serious illness, and was unrelated to prior SCr increases.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; C-Reactive Protein; Creatinine; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Inflammation; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles

Our aim was to compare a continuous infusion of remifentanil with intermittent boluses of fentanyl as regards the perioperative hormonal stress response and inflammatory activation in coronary artery bypass graft patients under sevoflurane-based anaesthesia.. In all, 42 patients undergoing coronary artery bypass grafting with cardiopulmonary bypass were prospectively randomized to a fentanyl group (n = 21, total fentanyl dose 2.6 +/- 0.3 mg), or a remifentanil group (n = 21, infusion rate 0.25 microg kg(-1) min(-1)). Haemodynamics, plasma levels of epinephrine, norepinephrine, antidiuretic hormone, adrenocorticotropic hormone, cortisol, complement activation (C3a, C5b-9), interleukin (IL)-6, IL-8 and tumour necrosis factor-alpha were measured at T1: baseline, T2: intubation, T3: sternotomy, T4: 30 min on cardiopulmonary bypass, T5: end of surgery and T6: 8 h postoperatively. Troponin T and creatine kinase-MB were measured postoperatively.. Patients in the remifentanil group were extubated significantly earlier than fentanyl patients (240 +/- 182 min vs. 418 +/- 212 min, P = 0.006). Stress hormones 30 min after start of cardiopulmonary bypass showed higher values in the fentanyl group compared to the remifentanil group (antidiuretic hormone (ADH): 39.94 +/- 30.98 vs. 11.7 +/- 22.8 pg mL(-1), P = 0.002; adrenocorticotropic hormone: 111.5 +/- 116.8 vs. 21.81 +/- 24.71 pg mL(-1), P = 0.01; cortisol 185 +/- 86 vs. 131 +/- 82 ng mL(-1), P = 0.04). The interleukins were significantly higher at some perioperative time points in the fentanyl group compared to the remifentanil group (tumour necrosis factor: T5: 3.57 vs. 2.37; IL-6: T5: 4.62 vs. 3.73; and IL-8: T5: 4.43 vs. 2.65 and T6: 2.61 vs. 1.13). However, cardiopulmonary bypass times and aortic cross-clamp times were longer in the fentanyl group, which may to some extent account for the differences.. The perioperative endocrine stress response was attenuated in patients supplemented with continuous remifentanil infusion as compared to intermittent fentanyl.

Topics: Adrenocorticotropic Hormone; Aged; Anesthetics, Inhalation; Anesthetics, Intravenous; Coronary Artery Bypass; Female; Fentanyl; Humans; Hydrocortisone; Inflammation; Infusions, Intravenous; Injections, Intravenous; Interleukins; Male; Methyl Ethers; Middle Aged; Piperidines; Remifentanil; Sevoflurane; Stress, Physiological; Time Factors; Vasopressins

Surgery and anesthetic method have immunomodulating effects on hemodynamic response and stress. We compared the effects of 2 intraoperative analgesic regimens on patients undergoing abdominal hysterectomy.. We conducted a randomized double-blind trial in ASA 1 and 2 patients undergoing abdominal hysterectomy under balanced anesthesia. Twenty-nine patients were randomized to 2 groups. One group received analgesia by infusion of remifentanil plus morphine and nonsteroidal anti-inflammatory drugs as rescue medications; the other received conventional analgesia with bolus doses of fentanyl according to changes in hemodynamic variables. We measured levels of proinflammatory (interleukin [IL]-6) and antiinflammatory (IL-10) cytokines, cortisol, and C-reactive protein preoperatively, at incision, and at 1, 4 and 24 hours after surgery.. There were no significant differences between the 2 groups in terms of the markers studied at baseline. In each group, however, there were significant changes from baseline at the various points in time. IL-6 and IL-10 levels were significantly elevated (P < .05) at 4 hours. The changes in cortisol levels were significantly different at 1 and 4 hours. Finally, there were significant increases in C-reactive protein at 24 hours.. Unlike other clinical trials, our study detected no differences between the 2 techniques in response to surgical stress evaluated by analyzing concentrations of pro- and anti-inflammatory cytokines, cortisol, and C-reactive protein.

Topics: Aged; Anesthesia, General; Anti-Inflammatory Agents, Non-Steroidal; Biomarkers; C-Reactive Protein; Dipyrone; Double-Blind Method; Drug Administration Schedule; Female; Fentanyl; Humans; Hydrocortisone; Hysterectomy; Inflammation; Infusions, Intravenous; Injections, Intravenous; Interleukin-10; Interleukin-6; Intraoperative Complications; Kinetics; Middle Aged; Morphine; Narcotics; Pain, Postoperative; Piperidines; Postoperative Complications; Remifentanil; Stress, Physiological

To test the hypothesis that the choice of anesthesia technique for coronary artery surgery influences the degree and magnitude of the subsequent inflammatory response and its consequences.. Prospective, randomized, comparative study.. Major university teaching hospital.. Sixty patients undergoing elective surgery.. Patients were randomized into an alfentanil group, a high-dose remifentanil group, a low-dose remifentanil group, or a thoracic epidural group, in combination with a propofol target-controlled infusion. The study was blinded for the opioid, except in the epidural group. Tight control of perioperative hemodynamic parameters was maintained, and the postoperative management was strictly standardized. Bactericidal permeability-increasing protein as an indicator of the polymorphonuclear neutrophil response, interleukin-6 as an inducer of the acute-phase response, and lipopolysaccharide-binding protein and C-reactive protein as parameters of the acute phase response were determined at regular intervals. Ventilator dependency and analgesia were evaluated as clinical outcome measures.. Interleukin-6 levels increased in all groups. Plasma levels in the epidural group were significantly higher at all time points than in the other groups. The increase in the plasma levels of bactericidal permeability-increasing protein, lipopolysaccharide-binding protein, and C-reactive protein showed the same pattern in all groups, and no significant differences among the 4 groups were observed.. Supplementation of a fast-track anesthetic technique with epidural analgesia preserves hemodynamic stability and is associated with faster extubation times (p = 0.003) and less postoperative pain (p = 0.045). Thoracic epidural analgesia was associated with significantly higher levels of IL-6 throughout the study period as compared with the total intravenous anesthesia groups. The exact clinical relevance of this finding remains unclear.

Topics: Acute-Phase Proteins; Alfentanil; Analgesics, Opioid; Anesthesia; Anesthesia, Epidural; Antimicrobial Cationic Peptides; Biomarkers; Blood Bactericidal Activity; Blood Proteins; C-Reactive Protein; Cardiopulmonary Bypass; Carrier Proteins; Coronary Artery Bypass; Dose-Response Relationship, Drug; Elective Surgical Procedures; Enzyme-Linked Immunosorbent Assay; Follow-Up Studies; Humans; Inflammation; Infusions, Intravenous; Interleukin-6; Lipopolysaccharides; Membrane Glycoproteins; Membrane Proteins; Middle Aged; Myocardial Ischemia; Piperidines; Prospective Studies; Remifentanil

We tested the responsiveness of measures of hyperalgesia in a model of UVB-induced inflammatory hyperalgesia with remifentanil, gabapentin, and the combination of both drugs in a double-blinded, active placebo-controlled, 4-way-crossover design in 16 volunteers. A circular skin area was irradiated with UVB-light 20 h before the application of gabapentin (600 mg) and 2 h later remifentanil (0.08 microg.kg(-1).min(-1), 40 min). In the sunburn spots we observed stable decreases of the heat pain perception thresholds (HPPT, mean difference, 4.45 degrees C; 95% confidence interval [CI], 3.32 degrees -5.59 degrees ) and heat pain tolerance thresholds (HPTT; mean difference, 5.43 degrees C; 95% CI, 4.50 degrees -6.35 degrees ) compared with normal skin. Further, large areas of mechanical hyperalgesia to pinprick adjacent to the erythema spots developed in all subjects. Overall remifentanil increased the HPPT (mean increase, 2.47 degrees C; 95% CI, 1.86 degrees -3.09 degrees, P < 0.001) and HPTT (mean increase, 3.18 degrees C; 95% CI, 2.65 degrees -3.71 degrees, P < 0.001) and reduced the area of secondary hyperalgesia by 59% (mean decrease, 5326 mm(2); 95% CI, 4233-6419 mm(2), P < 0.001) compared with placebo. In the sunburn remifentanil markedly increased the HPTT by 86% compared with normal skin (additional increase, 2.57 degrees C; 95% CI, 1.71 degrees -3.43 degrees). This different effect was not seen in the HPPT. With the exception of a small increase of HPTT in the sunburn (P = 0.02) gabapentin had no noticeable effect on either hyperalgesia. In conclusion, opioid analgesia was reliably demonstrated in this new extended pain model.. Opioid analgesia was reliably demonstrated in a new inflammatory model of primary and secondary hyperalgesia. Gabapentin showed no antihyperalgesic and no opioid-enhancing effect in this model.

Topics: Acetates; Adult; Amines; Analgesics, Opioid; Cross-Over Studies; Cyclohexanecarboxylic Acids; Diazepam; Double-Blind Method; Drug Synergism; Excitatory Amino Acid Antagonists; Female; GABA Modulators; Gabapentin; gamma-Aminobutyric Acid; Humans; Hyperalgesia; Inflammation; Male; Pain Measurement; Pain Threshold; Physical Stimulation; Piperidines; Reaction Time; Remifentanil; Skin; Sunburn; Treatment Outcome

Postprandial hyperglycemia may be a risk factor for cardiovascular disease. We compared the effects of two insulin secretagogues, repaglinide and glyburide, known to have different efficacy on postprandial hyperglycemia, on carotid intima-media thickness (CIMT) and markers of systemic vascular inflammation in type 2 diabetic patients.. We performed a randomized, single-blind trial on 175 drug-naive patients with type 2 diabetes mellitus (93 men and 82 women), 35 to 70 years of age, selected from a population of 401 patients who participated in an epidemiological analysis assessing the relation of postprandial hyperglycemia to surrogate measures of atherosclerosis. Eighty-eight patients were randomly assigned to receive repaglinide and 87 patients to glyburide, with a titration period of 6 to 8 weeks for optimization of drug dosage and a subsequent 12-month treatment period. The effects of repaglinide (1.5 to 12 mg/d) and glyburide (5 to 20 mg/d) on CIMT were compared by using blinded, serial assessments of the far wall. After 12 months, postprandial glucose peak was 148+/-28 mg/dL in the repaglinide group and 180+/-32 mg/dL in the glyburide group (P<0.01). HbA(1c) showed a similar decrease in both groups (-0.9%). CIMT regression, defined as a decrease of >0.020 mm, was observed in 52% of diabetics receiving repaglinide and in 18% of those receiving glyburide (P<0.01). Interleukin-6 (P=0.04) and C-reactive protein (P=0.02) decreased more in the repaglinide group than in the glyburide group. The reduction in CIMT was associated with changes in postprandial but not fasting hyperglycemia.. Reduction of postprandial hyperglycemia in type 2 diabetic patients is associated with CIMT regression.

Topics: Adult; Aged; Biomarkers; Blood Glucose; Carbamates; Carotid Artery Diseases; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Fasting; Female; Glyburide; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Inflammation; Insulin; Lipids; Male; Middle Aged; Piperidines; Postprandial Period; Single-Blind Method; Tunica Intima; Tunica Media; Ultrasonography

[corrected] To study the analgesia, hemodynamic stability and inflammatory response in patients undergoing carotid endarterectomy under different types of general anesthesia.. A comparison of 80 patients randomized to 4 groups: group 1, maintenance with sevoflurane at a minimum alveolar concentration (MAC) of 1; group 2, sevoflurane at MAC 1.5; group 3, remifentanil; group 4, propofol. Variables studied were hemodynamic alterations during and after surgery, level of postoperative analgesia, differential white cell counts, levels of interleukin-6 (IL-6), and clinical signs and symptoms of systemic inflammatory response syndrome in the first 24 hours after surgery.. The incidences of episodes of intraoperative hypertension were 60% in group 1, 65% in group 2, 50% in group 3, and 60% in group 4. The incidences of episodes of intraoperative hypotension were 85% in group 1, 80% in group 2, 80% in group 3, and 75% in group 4. Patients in groups 3 and 4 had higher incidences of systemic inflammatory response syndrome (p<0.05) in the first 24 hours after surgery and higher levels of IL-6 (p<0.05). Postoperative analgesia was similar in all 4 groups.. Increased levels of IL-6 in peripheral blood and of systemic inflammatory response syndrome were found in the early postoperative period in groups that did not receive halogenated gases. Hemodynamic stability and analgesia were similar in all groups, however.

Topics: Aged; Anesthesia, General; Anesthetics, Inhalation; Anesthetics, Intravenous; Cardiovascular Diseases; Endarterectomy, Carotid; Hemodynamics; Humans; Incidence; Inflammation; Interleukin-6; Intraoperative Complications; Male; Methyl Ethers; Middle Aged; Pain, Postoperative; Piperidines; Propofol; Prospective Studies; Remifentanil; Sevoflurane

Flavopiridol is a flavonoid with antiproliferative effects mediated, in part, by inhibition of cyclin-dependent kinases. Clinical manifestations in a previous Phase I trial in patients with refractory malignancies treated with a 72-h flavopiridol infusion included a proinflammatory syndrome consisting of fever, fatigue, and "local" tumor pain with concomitant alterations in plasma acute-phase reactant proteins.. The aim of this study was to determine whether the proinflammatory syndrome observed in this trial was associated with modulation of plasma cytokines.. Patients receiving flavopiridol (n = 76) had serial plasma samples drawn preinfusion and during the infusion for evaluation of interleukin (IL)-6, IL-10, IL-12, granulocyte macrophage colony-stimulating factor, basic-fibroblast growth factor, transforming growth factor-beta, and tumor necrosis factor-alpha levels by standard ELISA assays. The Wilcoxon signed rank test was used to test the significance of the difference between the baseline (time 0) plasma cytokine levels compared with the values of each subsequent data collection time points (8, 24, 48, and 72 h).. There was a significant and sustained increase in plasma IL-6 levels at all time points when compared with baseline values. Paired values were used in the statistical analysis. Median plasma (interquartile range) values of IL-6 were elevated from 15.5 (9-52) pg/ml at baseline to 23 (4-48) pg/ml (P < 0.01) at 8 h; from 15 (2-48) pg/ml at baseline to 46 (21-105) pg/ml (P < 0.001) at 24 h; from 16 (9-52) pg/ml at baseline to 61 (32-170) pg/ml (P < 0.001) at 48 h; and from 15.5 (6-48) pg/ml to 68 (40-200) pg/ml (P < 0.001) at 72 h. Significance was maintained even when adjusted for multiple comparisons. The relative increase in IL-6 concentration was dose-dependent. Moreover, IL-6 elevation had a direct correlation with flavopiridol peak plasma concentration, flavopiridol area under the curve, and plasma C-Reactive protein levels. A significant decrease in plasma granulocyte macrophage colony-stimulating factor occurred at the 8-h sampling point: 50 pg/ml (interquartile range 10-205 pg/ml, P < 0.01) when compared with baseline plasma levels and 71 pg/ml (interquartile range 5-152 pg/ml, P < 0.01). No changes in the other pro or anti-inflammatory cytokines were observed. Immunohistochemistry studies in bone marrow aspirates from a prospective group of patients in this trial demonstrated approximately 4-fold induction of IL-6 (compared with baseline), mostly in non-T cells.. Biochemical analysis of plasma in patients undergoing infusional flavopiridol found a significant dose-dependent induction of IL-6. IL-6 elevation could be a marker for the process leading to the appearance of the proinflammatory syndrome observed in patients treated with infusional flavopiridol. The mechanism(s) underlying IL-6 induction and its significance are still unknown but may influence strategies to modulate flavopiridol's clinical effects.

Topics: Antineoplastic Agents; Bone Marrow; Cyclin-Dependent Kinases; Enzyme Inhibitors; Flavonoids; Humans; Inflammation; Infusions, Intravenous; Interleukin-6; Interleukins; Neoplasms; Piperidines

Fibrodysplasia ossificans progressive (FOP) is an ultra-rare genetic disorder that is caused by a mutation in the ACVR1 gene and provokes severe heterotopic ossification. Since flares of the disease are associated with inflammation, it is assumed that JAK inhibitors can control active FOP due to blocking multiple signaling pathways.

Topics: Humans; Inflammation; Myositis Ossificans; Patients; Piperidines; Rare Diseases

Sustained neutrophilic inflammation is detrimental for cardiac repair and associated with adverse outcomes following myocardial infarction (MI). An attractive therapeutic strategy to treat MI is to reduce or remove infiltrating neutrophils to promote downstream reparative mechanisms. CDK9 inhibitor compounds enhance the resolution of neutrophilic inflammation; however, their effects on cardiac repair/regeneration are unknown. We have devised a cardiac injury model to investigate inflammatory and regenerative responses in larval zebrafish using heartbeat-synchronised light-sheet fluorescence microscopy. We used this model to test two clinically approved CDK9 inhibitors, AT7519 and flavopiridol, examining their effects on neutrophils, macrophages and cardiomyocyte regeneration. We found that AT7519 and flavopiridol resolve neutrophil infiltration by inducing reverse migration from the cardiac lesion. Although continuous exposure to AT7519 or flavopiridol caused adverse phenotypes, transient treatment accelerated neutrophil resolution while avoiding these effects. Transient treatment with AT7519, but not flavopiridol, augmented wound-associated macrophage polarisation, which enhanced macrophage-dependent cardiomyocyte number expansion and the rate of myocardial wound closure. Using cdk9-/- knockout mutants, we showed that AT7519 is a selective CDK9 inhibitor, revealing the potential of such treatments to promote cardiac repair/regeneration.

Topics: Animals; Cyclin-Dependent Kinase 9; Flavonoids; Inflammation; Myocardium; Neutrophils; Piperidines; Pyrazoles; Regeneration; Zebrafish; Zebrafish Proteins

Topics: Cell Communication; Humans; Inflammation; Piperidines; Pyrimidines

Brain kappa-opioid receptors (KORs) are implicated in the pathophysiology of depressive and anxiety disorders, stimulating interest in the therapeutic potential of KOR antagonists. Research on KOR function has tended to focus on KOR-expressing neurons and pathways such as the mesocorticolimbic dopamine system. However, KORs are also expressed on non-neuronal cells including microglia, the resident immune cells in the brain. The effects of KOR antagonists on microglia are not understood despite the potential contributions of these cells to overall responsiveness to this class of drugs. Previous work in vitro suggests that KOR activation suppresses proinflammatory signaling mediated by immune cells including microglia. Here, we examined how KOR antagonism affects microglia function in vivo, together with its effects on physiological and behavioral responses to an immune challenge. Pretreatment with the prototypical KOR antagonist JDTic potentiates levels of proinflammatory cytokines (IL-1β, IL-6) in blood following administration of lipopolysaccharide (LPS), an immune-activating agent, without triggering effects on its own. Using magnetic-activated cell sorting (MACs), we found that KOR antagonism potentiates LPS-induced cytokine expression within microglia. This effect is accompanied by potentiation of LPS-induced hyperthermia, although reductions in body weight and locomotion were not affected. Histological analyses confirm that LPS produces visible changes in microglia morphology consistent with activation, but this effect is not altered by KOR antagonism. Considering that inflammation is increasingly implicated in depressive and anxiety disorders, these findings raise the possibility that KOR antagonist actions on microglia may detract from actions on neurons that contribute to their therapeutic potential.

Topics: Animals; Brain; Cytokines; Inflammation; Lipopolysaccharides; Locomotion; Male; Mice; Mice, Inbred C57BL; Microglia; Narcotic Antagonists; Nucleus Accumbens; Piperidines; Receptors, Opioid, kappa; Tetrahydroisoquinolines

Adiponectin can participate in the regulation of glucose and lipid metabolism, energy regulation, immune response, resistance to inflammation, oxidative stress, and apoptosis. Studies in rodents demonstrated that the small molecule compound adiponectin receptor agonist AdipoRon could activate the adiponectin receptor and played the same biological role as adiponectin. To explore the influence and regulation of AdipoRon on lipid metabolism disorder in Huoyan goose liver, in this study, goslings were fed a high-fat diet and then administered different dosages of AdipoRon. Subsequently, goose body weight, liver index, liver histopathological changes, blood glucose, blood and liver lipid, biochemical indexes related to liver function and oxidative stress, and the expression levels of genes related to lipid metabolism, inflammation, apoptosis, and autophagy, adiponectin and its receptors, key molecules of adiponectin involved signal pathway, and transcription factors in the liver, were detected using H&E and Oil red O staining, ELISA, and qRT-PCR methods. The results indicated that AdipoRon could alter the expression of lipid metabolism-related genes, inflammatory factors, apoptosis and autophagy genes, and adiponectin and its receptor genes in liver tissues through signaling pathways such as AMPK and p38 MAPK, as well as the involvement of transcription factors such as PPARα, PPARγ, SIRT1, and FOXO1, reduce the lipid content in blood and liver tissues of geese fed high-fat diets, improve liver antioxidant capacity, regulate apoptosis and autophagy of hepatocytes, and reduce liver inflammatory injury. Our study suggests that AdipoRon has a protective effect on fatty liver injury in goslings fed a high-fat diet.

Topics: Adiponectin; Animals; Chickens; Diet, High-Fat; Geese; Inflammation; Lipids; Liver; Piperidines; Receptors, Adiponectin; Transcription Factors

Fatty acid composition in the Western diet has shifted from saturated to polyunsaturated fatty acids (PUFAs), and specifically to linoleic acid (LA, 18:2), which has gradually increased in the diet over the past 50 y to become the most abundant dietary fatty acid in human adipose tissue. PUFA-derived oxylipins regulate a variety of biological functions. The cytochrome P450 (CYP450)–formed epoxy fatty acid metabolites of LA (EpOMEs) are hydrolyzed by the soluble epoxide hydrolase enzyme (sEH) to dihydroxyoctadecenoic acids (DiHOMEs). DiHOMEs are considered cardioprotective at low concentrations but at higher levels have been implicated as vascular permeability and cytotoxic agents and are associated with acute respiratory distress syndrome in severe COVID-19 patients. High EpOME levels have also correlated with sepsis-related fatalities; however, those studies failed to monitor DiHOME levels. Considering the overlap of burn pathophysiology with these pathologies, the role of DiHOMEs in the immune response to burn injury was investigated. 12,13-DiHOME was found to facilitate the maturation and activation of stimulated neutrophils, while impeding monocyte and macrophage functionality and cytokine generation. In addition, DiHOME serum concentrations were significantly elevated in burn-injured mice and these increases were ablated by administration of 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), a sEH inhibitor. TPPU also reduced necrosis of innate and adaptive immune cells in burned mice, in a dose-dependent manner. The findings suggest DiHOMEs are a key driver of immune cell dysfunction in severe burn injury through hyperinflammatory neutrophilic and impaired monocytic actions, and inhibition of sEH might be a promising therapeutic strategy to mitigate deleterious outcomes in burn patients.

Topics: Animals; Burns; Epoxide Hydrolases; Humans; Immunity, Innate; Inflammation; Linoleic Acid; Mice; Mice, Inbred C57BL; Phenylurea Compounds; Piperidines; Sepsis

Alveolar epithelial cell death, inflammation, and oxidative stress are typical features of acute lung injury (ALI). Aloperine (Alo), an alkaloid isolated from Sophora alopecuroides, has been reported to display various biological effects, such as anti-inflammatory, immunoregulatory, and anti-oxidant properties. In this study, we investigated the effects and mechanisms of Alo in treating a lipopolysaccharide (LPS)-induced ALI in a murine model.. The effects of Alo in LPS-induced ALI were investigated in C57BL/6 mice. The RIPK1 inhibitor (Nec-1) and the RIPK3 inhibitor (GSK'872) were used to evaluate the relationship of necroptosis, NF-κB activation, and PDC subunits in LPS-treated mouse alveolar epithelial cells (MLE-12). Then the effects of Alo on necroptosis, inflammation, and oxidative stress of LPS-stimulated MLE-12 cells were evaluated.. Alo significantly attenuated histopathological lung injuries and reduced lung wet/dry ratio in LPS-induced ALI mice. Alo also remarkedly reduced total protein and neutrophils recruitment in bronchoalveolar lavage fluid of ALI mice. Meanwhile, Alo ameliorated the LPS-induced necroptosis in the lungs of ALI mice. The RIPK3 inhibitor GSK'872, but not the RIPK1 inhibitor Nec-1, reversed LPS-induced p65 phosphorylation and translocation to the nucleus in MLE-12 cells. GSK'872 also reversed the LPS-induced increase in ROS and binding of RIPK3 and PDC subunits in MLE-12 cells. Moreover, Alo down-regulated the levels of p-RIPK1, p-RIPK3, p-MLKL, p-p65, the translocation of p65 to the nucleus, and reduced the expression of IL-6 and IL-8 in LPS-stimulated MLE-12 cells. Alo also inhibited the binding of RIPK3 and PDC-E1α, PDC-E1β, PDC-E2, and PDC-E3 and the ROS production in LPS-treated MLE-12 cells.. The present study validated the beneficial effects of Alo on LPS-induced ALI , suggesting Alo may be a new drug candidate against ALI.

Topics: Acute Lung Injury; Animals; Disease Models, Animal; Inflammation; Lipopolysaccharides; Lung; Mice; Mice, Inbred C57BL; Necroptosis; NF-kappa B; Oxidative Stress; Piperidines; Quinolizidines; Reactive Oxygen Species

Rheumatoid arthritis (RA) is a systemic autoimmune disease, which has been reported closely associated with the dysfunction of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. This study aims to explore the potential therapeutic effect of Tofacitinib, a putative JAK/STAT inhibitor, in RA. Tofacitinib suppressed proliferation and accelerated apoptosis of rheumatoid arthritis synovial fibroblasts (RA-FLS) as confirmed by CCK-8, EdU and Western blot assays. Tofacitinib significantly inhibited expression of pro-inflammatory factors including tumor necrosis factor-α (TNF-α), vascular endothelial growth factor A, matrix metalloproteinase 1, matrix metalloproteinase 3, interleukin-6 and interferon gamma in RA-FLS cells. mechanistically, tofacitinib decreased signal transducer and activator of transcription 6 (STAT6), which transcriptionally activates miR-425-5p, and thus increased insulin like growth factor 1 (IGF1) expression, a target of miR-425-5p in RA-FLS. Overexpression of STAT6 restored the expression of pro-inflammatory factors and proliferation inhibited by Tofacitinib in RA-FLS. Overall, Tofacitinib exerted inhibitory effect on proliferation and inflammation of RA-FLS through modulating STAT6/miR-425-5p/IGF1 signal axis. These findings shed light on the novel strategies for improving RA.

Topics: Arthritis, Rheumatoid; Cell Proliferation; Cells, Cultured; Fibroblasts; Humans; Inflammation; Insulin-Like Growth Factor I; Interferon-gamma; Interleukin-6; Janus Kinases; Matrix Metalloproteinase 1; MicroRNAs; Piperidines; Pyrimidines; Sincalide; STAT6 Transcription Factor; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

This study aimed to investigate the differential effects of remifentanil and sufentanil anesthesia on post-operative pain and recovery of cognitive functions following surgical resection of human colon cancer orthotopically transplanted in rats. Human colon cancer cells HT-29 were used to establish a rat model of orthotopically transplanted colon cancer on to the cecal wall of rats. The transplanted tumors were then surgically removed after 5 weeks, using different doses of remifentanil and sufentanil anesthesia. At 24 h after the surgery, von Frey test, hot plate test and voluntary wheel running test were used to evaluated post-operative pain in the rats. Morris water maze test and fear conditioning test were employed to assess cognitive functions. Serum and colon tissues of the rats were also subjected to ELISA to measure levels of stress response factors, while colon tissues were analyzed by RT-PCR and Western blot to measure expression of inflammation response factors and NF-κB pathway-related factors. Sufentanil showed better effect in reducing post-operative pain, while remifentanil showed better recovery of cognitive functions after surgery. In addition, remifentanil resulted in less stress and inflammation response, caused milder activation of NF-κB pathway-related factors after surgery. Remifentanil and sufentanil exhibited differential effects on post-operative pain and recovery of cognitive function. Specifically, remifentanil caused lower stress and inflammation response, associated with dampened activation of the NF-κB pathway. Our results could provide theoretical basis for adopting appropriate analgesic strategy and agents according to the characteristics of individual patients.

Topics: Analgesics, Opioid; Anesthesia; Animals; Cognition; Colonic Neoplasms; Humans; Inflammation; Motor Activity; NF-kappa B; Pain, Postoperative; Piperidines; Rats; Remifentanil; Sufentanil

Rapid joint clearance of small molecule drugs is the major limitation of current clinical approaches to osteoarthritis and its subtypes, including post-traumatic osteoarthritis (PTOA). Particulate systems such as nano/microtechnology could provide a potential avenue for improved joint retention of small molecule drugs. One drug of interest for PTOA treatment is flavopiridol, which inhibits cyclin-dependent kinase 9 (CDK9). Herein, polylactide-co-glycolide microparticles encapsulating flavopiridol were formulated, characterized, and evaluated as a strategy to mitigate PTOA-associated inflammation through the inhibition of CDK9. Characterization of the microparticles, including the drug loading, hydrodynamic diameter, stability, and release profile was performed. The mean hydrodynamic diameter of flavopiridol particles was ∼15 µm, indicating good syringeability and low potential for phagocytosis. The microparticles showed no cytotoxicity in-vitro, and drug activity was maintained after encapsulation, even after prolonged exposure to high temperatures (60 °C). Flavopiridol-loaded microparticles or blank (unloaded) microparticles were administered by intraarticular injection in a rat knee injury model of PTOA. We observed significant joint retention of flavopiridol microparticles compared to the soluble flavopiridol, confirming the sustained release behavior of the particles. Matrix metalloprotease (MMP) activity, an indicator of joint inflammation, was significantly reduced by flavopiridol microparticles 3 days post-injury. Histopathological analysis showed that flavopiridol microparticles reduced PTOA severity 28 days post-injury. Taken altogether, this work demonstrates a promising biomaterial platform for sustained small molecule drug delivery to the joint space as a therapeutic measure for post-traumatic osteoarthritis. STATEMENT OF SIGNIFICANCE: Post-traumatic osteoarthritis (PTOA) begins with the deterioration of subchondral bone and cartilage after acute injuries. In spite of the prevalence of PTOA and its associated financial and psychological burdens, therapeutic measures remain elusive. A number of small molecule drugs are now under investigation to replace FDA-approved palliative measures, including cyclin-dependent kinase 9 (CDK9) inhibitors which work by targeting early inflammatory programming after injury. However, the short half-life of these drugs is a major hurdle to their success. Here, we show that biomaterial encapsulation of Flavopirido

Topics: Animals; Biocompatible Materials; Cartilage, Articular; Cyclin-Dependent Kinase 9; Flavonoids; Inflammation; Injections, Intra-Articular; Osteoarthritis; Piperidines; Rats

Topics: Alkaloids; Anti-Inflammatory Agents; Antioxidants; Benzodioxoles; Cyclophosphamide; Cytokines; Humans; Inflammation; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Reactive Oxygen Species; Ubiquinone

Systemic inflammation is the main factor underlying secondary osteoporosis in patients with rheumatoid arthritis (RA). Janus kinase inhibitors (JAKi), such as tofacitinib (Tofa), can control systemic inflammation and may have beneficial effects on bone in various models. This might be due to direct effects on the bone microenvironment and not exclusively based on their anti-inflammatory function. Bone marrow adipocytes (BMAds) are abundant in the bone microenvironment. The effect of JAKi on BMAds is unknown, but evidence suggests that there is competition between human bone marrow-derived stromal cell (hBMSC) differentiation routes towards BMAds and osteoblasts (Ob) in osteoporosis.. The aims of the study are to determine whether Tofa influences BMAds and Ob derived from hBMSCs and to investigate the potential effects of Tofa on bone marrow adiposity in RA patients.. To determine the effect of Tofa on cellular commitment, hBMSCs were differentiated to BMAds or OBs for 3 days together with Tofa at 200, 400, or 800 nM and TNFα. This study was also conducted using differentiated BMAds. The impact of Tofa was determined by gene and protein expression analysis and cell density monitoring. In parallel, in a pilot study of 9 RA patients treated with Tofa 5 mg twice a day (NCT04175886), the proton density fat fraction (PDFF) was measured using MRI at the lumbar spine at baseline and at 6 months.. In non-inflammatory conditions, the gene expression of Runx2 and Dlx5 decreased in Ob treated with Tofa (p <0.05). The gene expression of PPARγ2, C/EBPα, and Perilipin 1 were increased compared to controls (p <0.05) in BMAds treated with Tofa. Under inflammatory conditions, Tofa did not change the expression profiles of Ob compared to TNFα controls. In contrast, Tofa limited the negative effect of TNFα on BMAd differentiation (p <0.05). An increase in the density of differentiated BMAds treated with Tofa under TNFα was noted (p <0.001). These findings were consolidated by an increase in PDFF at 6 months of treatment with Tofa in RA patients (46.3 ± 7.0% versus 53.2 ± 9.2% p <0.01).. Together, these results suggest a stimulatory effect of Tofa on BMAd commitment and differentiation, which does not support a positive effect of Tofa on bone.

Topics: Adipocytes; Arthritis, Rheumatoid; Bone Marrow; Clinical Studies as Topic; Humans; Inflammation; Osteoporosis; Pilot Projects; Piperidines; Pyrimidines

It has been reported that oxidative stress and chronic inflammation may be involved in the pathogenesis of polycystic ovary syndrome (PCOS). 8-oxoguanine DNA glycosylase (OGG1) is the main glycosylase that catalyzes the excision of DNA oxidation products. In this study, we investigated the role and potential mechanisms of OGG1 in the development of PCOS. We first analyzed OGG1 levels in serum and follicular fluid (FF) of PCOS patients, and significantly elevated OGG1 levels were noted in PCOS patients. We similarly observed a significant upregulation of OGG1 expression levels in ovarian tissue of the dehydroepiandrosterone (DHEA)-induced PCOS rat model. In addition, increased apoptosis and increased production of reactive oxygen species (ROS) were observed after the addition of OGG1-specific inhibitor (TH5487) in human granulosa-like tumor cell line (KGN) cells following a concentration gradient, along with a significant decrease in mRNA levels of inflammatory factors such as CXCL2, IL-6, MCP1, IL-1β, and IL-18. Significant decreases in protein phosphorylation levels of P65 and IκBα were also observed in cells. In addition, we found a significant positive correlation between OGG1 and IL-6 expression levels in human and DHEA-induced PCOS rat models. In conclusion, our results suggest that OGG1 might be involved in the pathogenesis of PCOS by regulating the secretion of IL-6 through NF-κB signaling pathway, and there might be a balance between the inhibition of oxidative stress and the promotion of chronic inflammation by OGG1 on KGN cells.

Topics: Animals; Benzimidazoles; Dehydroepiandrosterone; DNA Glycosylases; Female; Guanine; Humans; Inflammation; Interleukin-6; NF-kappa B; Piperidines; Polycystic Ovary Syndrome; Rats; Signal Transduction

Opioid agonists are powerful drugs for managing pain. However, their central side effects are limiting their use and drugs with similar potency, but a lower risk profile are needed. (±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenylpropionamide (NFEPP) is a novel opioid agonist that preferentially activates opioid receptors at acidic extracellular pH. NFEPP was designed to activate peripheral opioid receptors in injured tissue, therefore precluding side effects elicited at normal pH in brain or intestinal wall. Considering the common combination of opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) in multimodal analgesia, we investigated the interaction between NFEPP and a widely prescribed prototypical NSAID, diclofenac (DCF), in a rat model of unilateral hindpaw inflammation induced by complete Freund's adjuvant. We evaluated the effects of systemically applied DCF on the paw tissue pH, on the expression of inflammatory mediators in immune cells from inflamed paws and on the expression of opioid receptors in dorsal root ganglia. Additionally, we investigated the antinociceptive efficacy of NFEPP injected into the inflamed paws after DCF treatment. We found that DCF reduced inflammation-induced nociceptive responses and tissue acidosis, but did not change the mRNA expression of IL-1β, TNF-α, IL-6, IL-4, NGF, or of mu-, delta-, or kappa-opioid receptors. The treatment with DCF moderately reduced the antinociceptive efficacy of NFEPP, suggesting a correlation between an increase in local tissue pH and the decreased antinociceptive effect of this pH-sensitive opioid agonist.

Topics: Acidosis; Analgesics; Analgesics, Opioid; Animals; Hydrogen-Ion Concentration; Inflammation; Piperidines; Rats; Receptors, Opioid

Fatty acid synthase (FASN) is an attractive therapeutic target in non-alcoholic steatohepatitis (NASH) because it drives de novo lipogenesis and mediates pro-inflammatory and fibrogenic signaling. We therefore tested pharmacological inhibition of FASN in human cell culture and in three diet induced mouse models of NASH. Three related FASN inhibitors were used; TVB-3664, TVB-3166 and clinical stage TVB-2640 (denifanstat). In human primary liver microtissues, FASN inhibiton (FASNi) decreased triglyceride (TG) content, consistent with direct anti-steatotic activity. In human hepatic stellate cells, FASNi reduced markers of fibrosis including collagen1α (COL1α1) and α-smooth muscle actin (αSMA). In CD4+ T cells exposed to NASH-related cytokines, FASNi decreased production of Th17 cells, and reduced IL-1β release in LPS-stimulated PBMCs. In mice with diet induced NASH l, FASNi prevented development of hepatic steatosis and fibrosis, and reduced circulating IL-1β. In mice with established diet-induced NASH, FASNi reduced NAFLD activity score, fibrosis score, ALT and TG levels. In the CCl4-induced FAT-NASH mouse model, FASN inhibition decreased hepatic fibrosis and fibrosis markers, and development of hepatocellular carcinoma (HCC) tumors by 85%. These results demonstrate that FASN inhibition attenuates inflammatory and fibrotic drivers of NASH by direct inhibition of immune and stellate cells, beyond decreasing fat accumulation in hepatocytes. FASN inhibition therefore provides an opportunity to target three key hallmarks of NASH.

Topics: Actins; Animals; Carcinoma, Hepatocellular; Cytokines; Disease Models, Animal; Fatty Acid Synthase, Type I; Fatty Acid Synthases; Humans; Inflammation; Lipopolysaccharides; Liver Cirrhosis; Liver Neoplasms; Mice; Nitriles; Non-alcoholic Fatty Liver Disease; Piperidines; Triazoles; Triglycerides

Nonalcoholic steatohepatitis (NASH) is a rising public health burden, and there is a lack of effective therapeutic drugs in clinical practice. Sustained hepatic inflammation is considered as the key histopathological feature and dangerous fact for NASH. Different causes vary from one NASH patient to another, while sustained hepatic inflammation affects all NASH patients. AdipoRon is the first small-molecule AdipoR agonist, exerting antidiabetic and anti-inflammatory effect. In order to find novel AdipoRon analogues with more potent anti-inflammatory activity, we designed, synthesized and biologically evaluated 32 analogues. Among them, Q7 exerted potent anti-inflammatory activity and less cytotoxicity. Q7 could dose-dependently stimulate the increasing of AMPK phosphorylation, the widely recognized downstream effector of AdipoR1 activation. In NASH model mice, Q7 showed significant anti-inflammatory, anti-fibrotic and lipid-lowering effect in mice liver, and was superior to AdipoRon. Together, Q7 holds promise for developing anti-inflammatory and anti-NASH agents.

Topics: Animals; Anti-Inflammatory Agents; Inflammation; Liver; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Piperidines

Cyclophosphamide (CP) is widely used as a chemotherapy against various types of cancers. However, CP is accompanied with multiple organ toxicity due to production of reactive oxygen species (ROS), induction of inflammation and consequently apoptosis. Alogliptin (Alo) is a dipeptidyl peptidase 4 (DPP-IV) inhibitor, which is booming as an antidiabetic agent. Interestingly, gliptins are currently studied for their counter-regulatory effects against oxidative stress and inflammation via multiple pathways, among which is the mitogen-activated protein kinase (MAPK)/c-Jun N-terminal kinase (JNK) pathway. This cascade can reduce inflammation via mitigating the activity of mothers against decapentaplegic homolog 3 (SMAD3) and c-Jun. However, Alo effect against CP-induced kidney injury has not been previously elucidated. This tempted us to investigate the possible beneficial effect of Alo against CP-induced kidney injury via modulating the MAP3K/JNK/SMAD3 signaling cascade. Thirty-two male Wistar rats were randomly allocated into four groups. CP-treated group received a single dose of CP (200 mg/kg; i.p.). Alo-treated group received Alo (20 mg/kg/day; p.o.) for 7 days with single CP injection on day 2. Marked decrease in renal injury was observed upon Alo treatment, as evidenced through declined serum kidney function markers, oxidative stress and apoptosis markers, MAP3K expression, phospho (p)-SMAD3, p-JNK, and p-c-Jun levels. These cellular effects were reflected in reduced transforming growth factor beta (TGF-β) and tumor necrosis factor alpha (TNF-α) fibrotic and inflammatory mediators, coinciding with improved histopathological portrait. In conclusion, the current study provides novel application of Alo as a therapeutic modality against CP-induced nephrotoxicity.

Topics: Animals; Cyclophosphamide; Inflammation; Male; Oxidative Stress; Piperidines; Rats; Rats, Wistar; Signal Transduction; Uracil

Ibrutinib is a small-molecule drug approved for the treatment of haematological disorders and is known to be associated with visual disturbances, but uveitis has not yet been reported as an adverse effect of this medication. We present two cases of ibrutinib-associated severe uveitis in patients with chronic lymphocytic leukaemia.. Our first case is a 65-year-old woman who presented with acute onset of bilateral fibrinous anterior uveitis 1 day after starting ibrutinib. Her vision was hand movements in the right eye and 20/120 in the left with hyperaemic discs and subretinal fluid. Ibrutinib was stopped and she experienced a significant improvement under local and oral steroid treatment. The second case is a 64-year-old male with subacute onset of bilateral hypertensive anterior uveitis with pupillary seclusion and right eye hyphaema. He was on ibrutinib for the past 9 months. His vision at presentation was 20/80 and 20/60 for the right and left eye, respectively. He responded poorly to local steroid treatment until ibrutinib was stopped due to cardiac side-effects, after which his uveitis resolved and treatment was stopped.. The temporal association between changes in ibrutinib treatment and our patients' ocular inflammation suggests a causative link. Ibrutinib increases Th1-based immune responses which is proposed as a mechanism for drug-induced uveitis. Its antiplatelet effect may explain the fibrinous nature of the inflammation and hyphaema.

Topics: Adenine; Aged; Female; Humans; Hyphema; Inflammation; Male; Middle Aged; Piperidines; Uveitis; Uveitis, Anterior; Vision Disorders

Mevalonate Kinase Deficiency (MKD) is a rare inborn disease belonging to the family of periodic fever syndromes. The MKD phenotype is characterized by systemic inflammation involving multiple organs, including the nervous system. Current anti-inflammatory approaches to MKD are only partially effective and do not act specifically on neural inflammation. According to the new emerging pharmacology trends, the repositioning of drugs from the indication for which they were originally intended to another one can make mechanistic-based medications easily available to treat rare diseases. According to this perspective, the squalene synthase inhibitor Lapaquistat (TAK-475), originally developed as a cholesterol-lowering drug, might find a new indication in MKD, by modulating the mevalonate cholesterol pathway, increasing the availability of anti-inflammatory isoprenoid intermediates. Using an in vitro model for MKD, we mimicked the blockade of the cholesterol pathway and evaluated the potential anti-inflammatory effect of Lapaquistat. The results obtained showed anti-inflammatory effects of Lapaquistat in association with a low blockade of the metabolic pathway, while this effect did not remain with a tighter blockade. On these bases, Lapaquistat could be configured as an effective treatment for MKD's mild forms, in which the residual enzymatic activity is only reduced and not almost completely absent as in the severe forms.

Topics: Alendronate; Animals; Anti-Inflammatory Agents; Apoptosis; Autophagy; Biosynthetic Pathways; Cell Death; Cell Shape; Farnesyl-Diphosphate Farnesyltransferase; Inflammation; Interleukin-6; Lipopolysaccharides; Macrophages; Mevalonate Kinase Deficiency; Mevalonic Acid; Mice; Mitochondria; Oxazepines; Piperidines; RAW 264.7 Cells; Tumor Necrosis Factor-alpha

Skin is susceptible to senescence-associated secretory phenotype (SASP) and inflamm-ageing partly owing to the degeneration of mitochondria. AdipoRon (AR) has protective effects on mitochondria in metabolic diseases such as diabetes. We explored the role of AR on mitochondria damage induced by skin inflamm-ageing and its underlying mechanism.. Western blot, immunofluorescence and TUNEL staining were used to detect inflammatory factors and apoptosis during skin ageing. Transmission electron microscopy, ATP determination kit, CellLight Mitochondria GFP (Mito-GFP), mitochondrial stress test, MitoSOX and JC-1 staining were used to detect mitochondrial changes. Western blot was applied to explore the underlying mechanism. Flow cytometry, scratch test, Sulforhodamine B assay and wound healing test were used to detect the effects of AR on cell apoptosis, migration and proliferation.. AR attenuated inflammatory factors and apoptosis that increased in aged skin, and improved mitochondrial morphology and function. This process at least partly depended on the suppression of dynamin-related protein 1 (Drp1)-mediated excessive mitochondrial division. More specifically, AR up-regulated the phosphorylation of Drp1 at Serine 637 by activating AMP-activated protein kinase (AMPK), thereby inhibiting the mitochondrial translocation of Drp1. Moreover, AR reduced mitochondrial fragmentation and the production of superoxide, preserved the membrane potential and permeability of mitochondria and accelerated wound healing in aged skin.. AR rescues the mitochondria in aged skin by suppressing its excessive division mediated by Drp1.

Topics: Animals; Inflammation; Male; Mice; Mitochondria; Mitochondrial Dynamics; Piperidines; Receptors, Adiponectin; Skin Aging

Topics: Arthritis, Rheumatoid; Humans; Inflammation; Piperidines; Positron Emission Tomography Computed Tomography; Prospective Studies; Pyrimidines

The present study has explored the hypothesis that neurokinin1 receptors (NK1Rs) in medial septum (MS) modulate nociception evoked on hind paw injection of formalin. Indeed, the NK1Rs in MS are localized on cholinergic neurons which have been implicated in nociception. In anaesthetized rat, microinjection of L-733,060, an antagonist at NK1Rs, into MS antagonized the suppression of CA1 population spike (PS) evoked on peripheral injection of formalin or on intraseptal microinjection of substance P (SP), an agonist at NK1Rs. The CA1 PS reflects the synaptic excitability of pyramidal cells in the region. Furthermore, microinjection of L-733,060 into MS, but not LS, attenuated formalin-induced theta activation in both anaesthetized and awake rat, where theta reflects an oscillatory information processing by hippocampal neurons. The effects of L-733,060 on microinjection into MS were nociceptive selective as the antagonist did not block septo-hippocampal response to direct MS stimulation by the cholinergic receptor agonist, carbachol, in anaesthetized animal or on exploration in awake animal. Interestingly, microinjection of L-733,060 into both MS and LS attenuated formalin-induced nociceptive flinches. Collectively, the foregoing novel findings highlight that transmission at NK1R provide an affective valence to septo-hippocampal information processing and that peptidergic transmission in the septum modulates nociceptive behaviours.

Topics: Animals; Disinfectants; Formaldehyde; Hippocampus; Inflammation; Male; Nociception; Pain; Piperidines; Prosencephalon; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-1; Septal Nuclei

Patients with ulcerative colitis (UC) are at elevated risk of cardiovascular disease vs the general population, despite a lower prevalence of traditional risk factors, including hyperlipidemia. Mechanistic studies in patients with rheumatoid arthritis and psoriasis suggest that tofacitinib restores serum lipids to preinflammation levels by reversing inflammation-induced cholesterol metabolism changes. We reviewed data on lipid levels and cardiovascular events, alongside recommendations for managing lipid levels during tofacitinib treatment in patients with UC, based on up-to-date expert guidelines.. Data were identified from a phase 3/open-label, long-term extension (OLE) tofacitinib UC clinical program (cutoff May 27, 2019). Literature was identified from PubMed (search terms "lipid," "cholesterol," "lipoprotein," "cardiovascular," "inflammation," "atherosclerosis," "tofacitinib," "rheumatoid arthritis," "psoriasis," "inflammatory bowel disease," "ulcerative colitis," "hyperlipidemia," and "guidelines") and author knowledge. Data were available from 4 phase 3 clinical trials of 1124 patients with moderately to severely active UC who received ≥1 dose of tofacitinib 5 or 10 mg twice daily in induction (two identical trials), maintenance, and OLE studies (treatment duration ≤6.8 years; 2576.4 patient-years of drug exposure).. In the OLE study, tofacitinib treatment was not associated with major changes from baseline in total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, total cholesterol/high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol/high-density lipoprotein cholesterol, with lipid levels and ratios generally remaining stable over time. The major adverse cardiovascular events incidence rate was 0.26/100 patient-years (95% confidence interval, 0.11-0.54).. Lipid levels and ratios remained generally unchanged from baseline in the OLE study after tofacitinib treatment, and major adverse cardiovascular events were infrequent. Long-term studies are ongoing.. NCT01465763, NCT01458951, NCT01458574, NCT01470612.

Topics: Arthritis, Rheumatoid; Cardiovascular Diseases; Cholesterol; Clinical Trials, Phase III as Topic; Colitis, Ulcerative; Heart Disease Risk Factors; Humans; Inflammation; Lipids; Lipoproteins, HDL; Lipoproteins, LDL; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Risk Factors; Treatment Outcome

The Nicotinamide phosphoribosyltransferase (Nampt)-NAD-Sirt1 pathway modulates processes involved in the pathogenesis of multiple diseases by influencing inflammation. This study aimed to explore the effect of Nampt in osteogenic differentiation and inflammatory response of osteoblastic MC3T3-E1 cells. We developed an

Topics: Acrylamides; Animals; Carbazoles; Cell Differentiation; Cell Line; Cytokines; Gene Knockdown Techniques; Inflammation; Interleukin-6; Lipopolysaccharides; MAP Kinase Kinase Kinases; Mice; Nicotinamide Phosphoribosyltransferase; Osteoblasts; Osteogenesis; Piperidines; Signal Transduction; Sirtuin 1; Transcription Factor RelA

Eosinophils are terminally differentiated cells derived from hematopoietic stem cells (HSCs) in the bone marrow. Several studies have confirmed the effective roles of eosinophils in asthmatic airway pathogenesis. However, their regulatory functions have not been well elucidated. Here, increased C-C chemokine ligand 6 (CCL6) in asthmatic mice and the human orthologs CCL15 and CCL23 that are highly expressed in asthma patients are described, which are mainly derived from eosinophils. Using Ccl6 knockout mice, further studies revealed CCL6-dependent allergic airway inflammation and committed eosinophilia in the bone marrow following ovalbumin (OVA) challenge and identified a CCL6-CCR1 regulatory axis in hematopoietic stem cells (HSCs). Eosinophil differentiation and airway inflammation were remarkably decreased by the specific CCR1 antagonist BX471. Thus, the study identifies that the CCL6-CCR1 axis is involved in the crosstalk between eosinophils and HSCs during the development of allergic airway inflammation, which also reveals a potential therapeutic strategy for targeting G protein-coupled receptors (GPCRs) for future clinical treatment of asthma.

Topics: Adolescent; Adult; Aged; Animals; Asthma; Bone Marrow; Cell Differentiation; Chemokines, CC; Eosinophils; Female; Healthy Volunteers; Hematopoietic Stem Cells; Humans; Hypersensitivity; Inflammation; Lung; Macrophage Inflammatory Proteins; Male; Mice; Mice, Knockout; Middle Aged; Ovalbumin; Phenylurea Compounds; Piperidines; Receptors, CCR1; Signal Transduction; Young Adult

Piperine, the major pharmacological ingredient of pepper, can delay the procession of "obesity to diabetes". However, the underlying mechanism remains unclear. This study aims to investigate whether piperine protects against β-cell dysfunction by inhibiting macrophage accumulation and M. Pre-diabetic model was induced by feeding 60% high-fat diet (HFD) in C57BL/6C mice, piperine (15 or 30 mg/kg/day) and rosiglitazone (4 mg/kg/day) were given orally for 8 weeks. Oral glucose tolerance test (OGTT), insulin tolerance test (ITT), fasting blood glucose (FBG), total cholesterol (TC) and triglyceride (TG) were used to assay the disorder of glycolipid metabolism. Serum levels of cytokines and insulin were measured by Elisa. Hyperglycemic clamp assay was carried out to evaluate β-cell function. RT-PCR, immunofluorescence and western blot were used to detect the expression of biomarkers associated with macrophage polarization and β-cell dedifferentiation.. Piperine markedly ameliorates the dedifferentiation and dysfunction of β-cell by inhibiting the accumulation and M

Topics: Adipose Tissue; Alkaloids; Animals; Benzodioxoles; Cytochrome P-450 Enzyme Inhibitors; Inflammation; Insulin-Secreting Cells; Macrophage Activation; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Piperidines; Polyunsaturated Alkamides

We previously demonstrated that ibrutinib modulates LPS-induced neuroinflammation in vitro and in vivo, but its effects on the pathology of Alzheimer's disease (AD) and cognitive function have not been investigated. Here, we investigated the effects of ibrutinib in two mouse models of AD. In 5xFAD mice, ibrutinib injection significantly reduced Aβ plaque levels by promoting the non-amyloidogenic pathway of APP cleavage, decreased Aβ-induced neuroinflammatory responses, and significantly downregulated phosphorylation of tau by reducing levels of phosphorylated cyclin-dependent kinase-5 (p-CDK5). Importantly, tau-mediated neuroinflammation and tau phosphorylation were also alleviated by ibrutinib injection in PS19 mice. In 5xFAD mice, ibrutinib improved long-term memory and dendritic spine number, whereas in PS19 mice, ibrutinib did not alter short- and long-term memory but promoted dendritic spinogenesis. Interestingly, the induction of dendritic spinogenesis by ibrutinib was dependent on the phosphorylation of phosphoinositide 3-kinase (PI3K). Overall, our results suggest that ibrutinib modulates AD-associated pathology and cognitive function and may be a potential therapy for AD.

Topics: Adenine; Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Cognition; Cyclin-Dependent Kinase 5; Cytokines; Dendritic Spines; Disease Models, Animal; Down-Regulation; Gliosis; Inflammation; Inflammation Mediators; Memory, Long-Term; Mice, Transgenic; Neurogenesis; Neuroglia; Phosphorylation; Piperidines; Plaque, Amyloid; tau Proteins

Alleviating microglia-mediated neuroinflammation bears great promise to reduce neurodegeneration. Nicotinamide phosphoribosyltransferase (NAMPT) may exert cytokine-like effect in the brain. However, it remains unclear about role of NAMPT in microglial inflammation. Also, it remains unknown about effect of NAMPT inhibition on microglial inflammation. In the present study, we observed that FK866 (a specific noncompetitive NAMPT inhibitor) dose-dependently inhibited lipopolysaccharide (LPS)-induced proinflammatory mediator (interleukin (IL)-6, IL-1β, inducible nitric oxide synthase, nitric oxide and reactive species) level increase in BV2 microglia cultures. FK866 also significantly inhibited LPS-induced polarization change in microglia. Furthermore, LPS significantly increased NAMPT expression and nuclear factor kappa B (NF-κB) phosphorylation in microglia. FK866 significantly decreased NAMPT expression and NF-κB phosphorylation in LPS-treated microglia. Finally, conditioned medium from microglia cultures co-treated with FK866 and LPS significantly increased SH-SY5Y and PC12 cell viability compared with conditioned medium from microglia cultures treated with LPS alone. Our study strongly indicates that NAMPT may be a promising target for microglia modulation and NAMPT inhibition may attenuate microglial inflammation.

Topics: Acrylamides; Animals; Anti-Inflammatory Agents; Cell Line, Tumor; Cell Survival; Cytokines; Enzyme Inhibitors; Humans; Inflammation; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; Microglia; Neuroprotective Agents; NF-kappa B p50 Subunit; Nicotinamide Phosphoribosyltransferase; Nitric Oxide Synthase Type II; Phosphorylation; Piperidines; Rats

Leptomeningeal inflammation in multiple sclerosis is associated with worse clinical outcomes and greater cortical pathology. Despite progress in identifying this process in multiple sclerosis patients using post-contrast fluid-attenuated inversion recovery imaging, early trials attempting to target meningeal inflammation have been unsuccessful. There is a lack of appropriate model systems to screen potential therapeutic agents targeting meningeal inflammation. We utilized ultra-high field (11.7 T) MRI to perform post-contrast imaging in SJL/J mice with experimental autoimmune encephalomyelitis induced via immunization with proteolipid protein peptide (PLP139-151) and complete Freund's adjuvant. Imaging was performed in both a cross-sectional and longitudinal fashion at time points ranging from 2 to 14 weeks post-immunization. Following imaging, we euthanized animals and collected tissue for pathological evaluation, which revealed dense cellular infiltrates corresponding to areas of contrast enhancement involving the leptomeninges. These areas of meningeal inflammation contained B cells (B220+), T cells (CD3+) and myeloid cells (Mac2+). We also noted features consistent with tertiary lymphoid tissue within these areas, namely the presence of peripheral node addressin-positive structures, C-X-C motif chemokine ligand-13 (CXCL13)-producing cells and FDC-M1+ follicular dendritic cells. In the cortex adjacent to areas of meningeal inflammation we identified astrocytosis, microgliosis, demyelination and evidence of axonal stress/damage. Since areas of meningeal contrast enhancement persisted over several weeks in longitudinal experiments, we utilized this model to test the effects of a therapeutic intervention on established meningeal inflammation. We randomized mice with evidence of meningeal contrast enhancement on MRI scans performed at 6 weeks post-immunization, to treatment with either vehicle or evobrutinib [a Bruton tyrosine kinase (BTK) inhibitor] for a period of 4 weeks. These mice underwent serial imaging; we examined the effect of treatment on the areas of meningeal contrast enhancement and noted a significant reduction in the evobrutinib group compared to vehicle (30% reduction versus 5% increase; P = 0.003). We used ultra-high field MRI to identify areas of meningeal inflammation and to track them over time in SJL/J mice with experimental autoimmune encephalomyelitis, and then used this model to identify BTK inhibition as a novel therapeutic approa

Topics: Agammaglobulinaemia Tyrosine Kinase; Animals; Brain; Encephalomyelitis, Autoimmune, Experimental; Female; Inflammation; Meninges; Mice; Piperidines; Pyrimidines

Coumarins (2H-1-benzopyran-2-one), derivatives that can be isolated from several plants, have been reported for their anticoagulant, antimicrobial, anti-inflammatory, or anticancer activity. Some of these structures are currently approved for the treatment of cardiovascular diseases, as antibiotics or as an anticancer drug. Given the great potential of this structure and the limited number of studies that focus on molecules derived from carbon 8 of the benzopyranone heterocycle, we synthesized in this project 38 coumarin derivatives by substituting carbon 8 of the benzopyran ring with some aromatic and aliphatically substituted piperidines and piperazines. As a few of these structures were already shown to exhibit some carbonic anhydrase (CA) inhibition and as CA enzymes are reported to be closely related to inflammation, the synthesized derivatives were evaluated for their anti-inflammatory activity in vitro. The results indicated that compounds 20 and 31 revealed promising anti-inflammatory activity, as they demonstrated better activity than the reference drugs.

Topics: Animals; Anti-Inflammatory Agents; Coumarins; Inflammation; Mice; Piperazines; Piperidines; RAW 264.7 Cells; Structure-Activity Relationship

Topics: Acute Pain; Analgesics; Animals; Behavior, Animal; CHO Cells; Cricetinae; Cricetulus; Cycloheptanes; Humans; Hyperalgesia; In Vitro Techniques; Inflammation; Male; Mice; Models, Molecular; Molecular Docking Simulation; Morphine; Movement; Naloxone; Naltrexone; Nociceptin; Oligopeptides; Opioid Peptides; Pain Management; Piperidines; Receptors, Opioid, mu

Adiponectin is an important immunomodulatory mediator in inflammatory conditions. While we previously showed that adiponectin receptor 1 (AdipoR1) is expressed in murine regulatory T cells (Tregs), its expression in human Tregs remain unknown. Here, we examined the expression of AdipoR1 in human Tregs and whether its ligand, globular adiponectin (gAd) affects the Treg ability to secrete IL-10 and the role of Type 2 (T2) inflammation in such process.. Human Tregs from peripheral blood were analyzed by flow cytometry for AdipoR1, Helios and IL-10 expression. CD4. We found that a subset of human Tregs expressed AdipoR1. Importantly, more Helios. Collectively, our findings suggest that adiponectin/AdipoR1 axis promotes IL-10 release by Tregs, mainly in Helios

Topics: Adiponectin; Blood Donors; Cells, Cultured; Forkhead Transcription Factors; Humans; Ikaros Transcription Factor; Inflammation; Interleukin-10; Ligands; p38 Mitogen-Activated Protein Kinases; Piperidines; Receptors, Adiponectin; Signal Transduction; T-Lymphocytes, Regulatory

Although the etiology of sciatica remains uncertain, there is increasing evidence that the disease process of sciatica is associated with the levels of inflammatory factors. Piperine, an alkaloid isolated from Piper nigrum, has previously been demonstrated to inhibit inflammation and analgesic effects. The purpose of this study is to verify the regulatory relationship between miR-520a and p65 and to explore how miR-520a/P65 affects the level of cytokines under the action of piperine, so as to play a therapeutic role in sciatica. Through ELISA experiment, we confirmed that four inflammatory factors (IL-1β, TNF-α, IL-10, TGF-β1) can be used as evaluation indexes of sciatica. The differentially expressed miRNA was screened as miR-520a, by microarray technology, and the downstream target of miR-520a was P65 by bioinformatics. Real-time fluorescence quantitative PCR confirmed that the expression of miR-520a was negatively correlated with pro-inflammatory cytokines, positively correlated with anti-inflammatory cytokines and negatively correlated with p65 expression at mRNA level. The expression of p65 was positively correlated with pro-inflammatory cytokines and negatively correlated with anti-inflammatory cytokines at the protein level verified by ELISA and Western blot. HE staining analysis showed that the nerve fibers were repaired by piprine, the vacuoles were significantly reduced, and the degree of nerve fiber damage was also improved. Immunohistochemical analysis showed that the expression of p65 decreased after administration of piperine. Dual-luciferase reporter gene assay confirmed that the luciferase signal decreased significantly after cotransfection of miR-520a mimics and p65 3'UTR recombinant plasmid. To sum up, in the rat model of non-compressed lumbar disc herniation, piperine plays a significant role in analgesia. MiR-520a can specifically and directly target P65, and piperine can promote the expression of miR-520a, then inhibit the expression of p65, down-regulate the pro-inflammatory factors IL-1β and TNF-α, and up-regulate the effects of anti-inflammatory factors IL-10 and TGF-β1, so as to treat sciatica.

Topics: Alkaloids; Animals; Benzodioxoles; Inflammation; MicroRNAs; Piperidines; Polyunsaturated Alkamides; Rats; Sciatica

Excess mitochondrial reactive oxygen species (mROS) in sepsis is associated with organ failure, in part by generating inflammation through the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. We determined the impact of a mitochondrial-targeted antioxidant (MitoTEMPO) on mitochondrial dysfunction in renal proximal tubular epithelial cells, peritoneal immune cell function ex vivo, and organ dysfunction in a rat model of sepsis.. The effects of MitoTEMPO were assessed ex vivo using adenosine triphosphate and lipopolysaccharide-stimulated rat peritoneal immune cells and fresh rat kidney slices exposed to serum from septic rats. We assessed mROS production and phagocytotic capacity (flow cytometry), mitochondrial functionality (multiphoton imaging, respirometry), and NLRP3 inflammasome activation in cell culture. The effect of MitoTEMPO on organ dysfunction was evaluated in a rat model of faecal peritonitis.. MitoTEMPO decreased septic serum-induced mROS (P<0.001) and maintained normal reduced nicotinamide adenine dinucleotide redox state (P=0.02) and mitochondrial membrane potential (P<0.001) in renal proximal tubular epithelial cells ex vivo. In lipopolysaccharide-stimulated peritoneal immune cells, MitoTEMPO abrogated the increase in mROS (P=0.006) and interleukin-1β (IL-1β) (P=0.03) without affecting non-mitochondrial oxygen consumption or the phagocytotic-induced respiratory burst (P>0.05). In vivo, compared with untreated septic animals, MitoTEMPO reduced systemic IL-1β (P=0.01), reduced renal oxidative stress as determined by urine isoprostane levels (P=0.04), and ameliorated renal dysfunction (reduced serum urea (P<0.001) and creatinine (P=0.05).. Reduction of mROS by a mitochondria-targeted antioxidant reduced IL-1β, and protected mitochondrial, cellular, and organ functionality after septic insults.

Topics: Animals; Antioxidants; Disease Models, Animal; Inflammasomes; Inflammation; Interleukin-1beta; Kidney Diseases; Male; Membrane Potential, Mitochondrial; Mitochondria; Organophosphorus Compounds; Oxidative Stress; Peritonitis; Piperidines; Rats; Rats, Wistar; Reactive Oxygen Species; Sepsis

Migraine is a common neurovascular disease which has been classified as the sixth most disabling disorder. Current migraine therapy was triptans, however, riptans can cause contraction of blood vessels. Therefore, novel drugs without cardiovascular effects emerged, such as CGRP and selective 5-HT

Topics: Animals; Body Weight; Dose-Response Relationship, Drug; Drug Design; Eating; Female; Haplorhini; HEK293 Cells; Humans; Inflammation; Male; Migraine Disorders; Molecular Structure; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptor, Serotonin, 5-HT1F; Receptors, Serotonin; Structure-Activity Relationship

Increasing evidence suggests that systemic inflammation triggers a neuroinflammatory response that involves sustained microglia activation. This response has deleterious consequences on memory and learning capability in experimental animal models and in patients. However, the mechanisms connecting systemic inflammation and microglia activation remain poorly understood. Here, we identify the autotaxin (ATX)/lysophosphatidic acid (LPA)/LPA-receptor axis as a potential pharmacological target to modulate the LPS-mediated neuroinflammatory response in vitro (the murine BV-2 microglia cell line) and in vivo (C57BL/6J mice receiving a single i.p. LPS injection). In LPS-stimulated (20 ng/mL) BV-2 cells, we observed increased phosphorylation of transcription factors (STAT1, p65, and c-Jun) that are known to induce a proinflammatory microglia phenotype. LPS upregulated ATX, TLR4, and COX2 expression, amplified NO production, increased neurotoxicity of microglia conditioned medium, and augmented cyto-/chemokine concentrations in the cellular supernatants. PF8380 (a type I ATX inhibitor, used at 10 and 1 µM) and AS2717638 (an LPA5 antagonist, used at 1 and 0.1 µM) attenuated these proinflammatory responses, at non-toxic concentrations, in BV-2 cells. In vivo, we demonstrate accumulation of PF8380 in the mouse brain and an accompanying decrease in LPA concentrations. In vivo, co-injection of LPS (5 mg/kg body weight) and PF8380 (30 mg/kg body weight), or LPS/AS2717638 (10 mg/kg body weight), significantly attenuated LPS-induced iNOS, TNFα, IL-1β, IL-6, and CXCL2 mRNA expression in the mouse brain. On the protein level, PF8380 and AS2717638 significantly reduced TLR4, Iba1, GFAP and COX2 expression, as compared to LPS-only injected animals. In terms of the communication between systemic inflammation and neuroinflammation, both inhibitors significantly attenuated LPS-mediated systemic TNFα and IL-6 synthesis, while IL-1β was only reduced by PF8380. Inhibition of ATX and LPA5 may thus provide an opportunity to protect the brain from the toxic effects that are provoked by systemic endotoxemia.

Topics: Animals; Benzoxazoles; Brain; Cell Line; Disease Models, Animal; Endotoxemia; Inflammation; Isoquinolines; Lipopolysaccharides; Mice; Microglia; Phosphoric Diester Hydrolases; Piperazines; Piperidines; Receptors, Lysophosphatidic Acid

Transient receptor potential (TRP) channels are widely expressed in the mammals. However, the functions of canonical TRP (TRPC) in inflammatory responses are largely unknown. The present study was focused on the effect of canonical TRP5 (TRPC5) channel on the polarization of macrophage to an M1 phenotype.. Polarization of macrophages was studied in TRPC5 knockout (TRPC5-/-) mice and in Raw264.7, a mouse macrophage cell line. Indicators of M1 type polarized macrophage were measured in the aorta of mice. Inhibition of TRPC5 in macrophages was achieved by the administration of ML204 (a non-selective TRPC5 antagonist) or the silencing of the TRPC5 gene with short hairpin RNA. Lipopolysaccharide (LPS) was used to stimulate Raw264.7 cells to an M1 type polarization. Proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 were measured in mice or cells, and protein expressions of Akt, phosphorylated (p)-Akt, IκBα, p-IκBα, and NF-κB were analyzed in Raw264.7 cells.. In TRPC5-/- mice the number of M1 type polarization of macrophages infiltrating into the aortic walls were significantly increased. The serum levels of inflammatory cytokines, TNF-α and IL-6 were also increased. Furthermore, after treated with ML204 or silenced the gene of TRPC5, the releases of TNF-α, IL-1β and IL-6 from lipopolysaccharide-stimulated RAW264.7 cells were significantly increased. Meanwhile, phosphorylations of Akt and IκBα were upregulated, and the shift of NF-κB from the cytoplasm to nucleus was markedly enhanced.. The activation of TRPC5 may inhibit the polarization of macrophage to an M1 phenotype by regulating Akt/IκB/NF-κB signaling pathways.

Topics: Animals; Cytokines; Gene Silencing; Indoles; Inflammation; Lipopolysaccharides; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B; NF-KappaB Inhibitor alpha; Piperidines; Proto-Oncogene Proteins c-akt; RAW 264.7 Cells; RNA, Small Interfering; TRPC Cation Channels

STING-associated vasculopathy with onset in infancy (SAVI) is a new rare auto-inflammatory disease. The purpose of this study is to report new cases and summarize the manifestations and outcome of SAVI.. We made a retrospective analysis of three pediatric patients diagnosed with SAVI between March 2016 and July 2018 in Beijing Children's Hospital.. Three patients comprised one boy and two girls. The median age of onset was 4 months. All patients had the same de novo heterozygous mutation (c.463G>A, p. V155M) of TMEM173. All patients presented with interstitial lung disease and one coexisted with diffuse alveolar hemorrhage. Rashes were presented in two patients. Other clinical manifestations include febrile attacks, failure to thrive, arthritis, myositis, cerebrovascular involvement, ureteral calculus, gastroesophageal reflux, and malnutrition. Ground-glass opacities were the most common features of chest computed tomography, followed with cysts and reticular opacities. Transbronchial lung biopsy was performed in one patient revealing pulmonary vasculitis. Skin biopsy was performed in one patient with changes of vasculitis. All patients were treated with corticosteroids and two patients received combined treatment of tofacitinib. The therapeutic effects of tofacitinib were limited on interstitial lung disease in both patients and were poor on rashes in one patient. One patient under the treatment of tofacitinib died.. New clinical aspect of diffuse alveolar hemorrhage is first reported to be associated with SAVI. Unsatisfactory therapeutic effects of tofacitinib are observed in this study and further evaluations are needed.

Topics: Child, Preschool; Female; Hemorrhage; Humans; Infant; Inflammation; Lung; Lung Diseases, Interstitial; Male; Membrane Proteins; Mutation; Piperidines; Pyrimidines; Retrospective Studies; Skin; Vascular Diseases

Aging-related cholinergic dysfunction, extensive neuroinflammation and oxidative stress in brain are predominant pathogenic factors for dementia. In the present study, we aimed to evaluate the protective effects of piperine, an alkaloid nutrient component of Piper nigrum, against cognitive impairment in a senescent mouse model induced by D-galactose (D-Gal) and to explore the underlying mechanisms. Senescent mouse model was established by repeated subcutaneous injection of D-Gal (150 mg/kg, once daily for 42 days). Fourteen days after the first D-Gal exposure, piperine (2.5, 5, 10 mg/kg) or vehicle was intraperitoneally administered once daily for 28 days. The cognitive function of mice was evaluated by Morris water maze test (MWM). Twenty-four hours after behavioral test, the cholinergic function and oxidative stress level in mouse hippocampus were measured by spectrophotometric assays. In addition, the hippocampal levels of proinflammatory cytokines, including tumor necrosis factor-α, interleukin-1β and interleukin-6, were quantified using enzyme-linked immunosorbent assay. Expressions of glycogen synthase kinase-3β (GSK-3β) and its upstream or downstream molecules including phosphatidylinositol 3-kinase (PI3K)，protein kinase B (AKT), protein kinase C (PKC), NF-E2-related factor 2, nuclear factor-κB and microtubule-associated protein tau in hippocampus were determined by western blotting, immunohistochemical or immunofluorescent staining. Our data revealed that chronic D-Gal exposure in mice led to cognitive impairment in MWM, along with cholinergic malfunction, extensive oxidative stress and neuroinflammation, as well as hyperphosphorylation of tau protein in hippocampus. All these neurochemical, neuroinflammatory and cognitive alterations could be ameliorated by 4-week repeated piperine administration. Moreover, piperine also reversed D-Gal-induced GSK-3β activation through modulating PKC and PI3K/AKT pathways in senescent mouse hippocampus, suggesting GSK-3β-related signaling might be involved in the benefits of piperine against D-Gal-induced cognitive decline in mice.

Topics: Aging; Alkaloids; Animals; Behavior, Animal; Benzodioxoles; Cellular Senescence; Cognition; Cognition Disorders; Cytokines; Galactose; Glutathione; Glycogen Synthase Kinase 3 beta; Hippocampus; Inflammation; Lipid Peroxidation; Male; Maze Learning; Mice; Models, Animal; Neurons; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Protein Kinase C; Reactive Oxygen Species; Signal Transduction

Clindamycin, a bacteriostatic semisynthetic lincosamide, is useful in the management of infections caused by aerobic and anaerobic Gram-positive cocci, including bacteremic pneumonia, streptococcal toxic shock syndrome and sepsis. It has been recently demonstrated that clindamycin inhibits in vitro and in vivo inflammatory cytokine production. In the present study, we investigated the effects of clindamycin in acute and chronic models of pain and inflammation in mice and the underlying mechanisms. Intraperitoneal (i.p.) administration of clindamycin (400 mg/kg) increased the animal's latency to exhibit the nociceptive behavior induced by noxious heat (hot plate model). Intrathecal injection of clindamycin (2, 10 and 50 µg) also increased the animals' latency to exhibit the nociceptive behavior. Tactile hypersensitivity and paw edema induced by intraplantar (i.pl.) injection of carrageenan were attenuated by previous administration of clindamycin (200 and 400 mg/kg, i.p.). Clindamycin (100, 200 and 400 mg/kg, i.p.) also attenuated ongoing tactile hypersensitivity and paw edema induced by i.pl. injection of complete Freund's adjuvant (CFA). The antinociceptive activity of clindamycin (400 mg/kg, i.p.) in the hot plate model was attenuated by previous administration of naltrexone (5 and 10 mg/kg, i.p.), but not glibenclamide or AM251. CFA-induced production of TNF-α and CXCL-1 was reduced by clindamycin (400 mg/kg, i.p.). Concluding, clindamycin exhibits activities in acute and chronic models of pain and inflammation. These effects are associated with reduced production of TNF-α and CXCL-1 and activation of opioidergic mechanisms. Altogether, these results indicate that the clindamycin's immunomodulatory effects may contribute to a pharmacological potential beyond its antibiotic property.

Topics: Analgesics; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Behavior, Animal; Carrageenan; Chemokine CXCL1; Clindamycin; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Inflammation; Male; Mice; Pain; Piperidines; Pyrazoles; Tumor Necrosis Factor-alpha

Topics: Acetic Acid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dose-Response Relationship, Drug; Formaldehyde; Humans; Hyperalgesia; Inflammation; Molecular Docking Simulation; Molecular Structure; Piperidines; Rats; Rats, Wistar; Structure-Activity Relationship; Triazines; Tryptophan

Endocannabinoids are showing great promise as effective mediators for controlling joint inflammation and pain. One strategy that could be harnessed to promote endogenous cannabinoid function is to inhibit the enzymatic break down of endocannabinoids locally in the joint. KML29 is an inhibitor of monoacylglycerol lipase (MAGL) activity which has been shown to promote increased 2-arachodonylglycerol (2-AG) levels in the circulation and in peripheral tissues. It is also known that 2-AG can be metabolised via the cyclo-oxygenase-2 (COX-2) pathway leading to the production of pro-inflammatory prostaglandins, which may counteract the effects of 2-AG. Therefore, this study examined the effect of KML29 alone as well as in combination with low-dose celecoxib (CXB) on joint pain and inflammation in the monoiodoacetate (MIA) model of osteoarthritis (OA) pain.. Injection of MIA (3 mg) into the knee joints of male Wistar rats was used to model OA pain, inflammation, and nerve damage. Pain behaviour was assessed by von Frey hair algesiometry, and inflammation was evaluated using intravital microscopy to measure leukocyte trafficking in the synovial microvasculature.. Intra-articular injection of MIA produced mechanical hypersensitivity as measured by von Frey hair algesiometry. Local injection of KML29 (700 μg) reduced joint pain at day 14 post-MIA induction, and this analgesic effect was blocked by the cannabinoid receptor antagonists AM281 and AM630 (P < 0.0001; n = 6). During the acute inflammatory phase of the MIA model (day 1), a significant reduction in withdrawal threshold (P < 0.0001; n = 6-8) and leukocyte trafficking was seen after treatment with KML29 + CXB (P < 0.0001; n = 6-8). Early treatment of MIA-injected knees (days 1-3) with KML29 + CXB ameliorated the development of mechanical secondary allodynia (P < 0.0001; n = 8) in the later stages of the MIA model.. Combination therapy of KML29 plus CXB reduced joint pain and inflammation. Thus, dual inhibition of MAGL and cyclooxygenase-2 pathways could be a useful approach to alleviate joint inflammation and pain in OA joints.

Topics: Animals; Anti-Inflammatory Agents; Arthralgia; Benzodioxoles; Celecoxib; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Drug Therapy, Combination; Enzyme Inhibitors; Inflammation; Knee Joint; Male; Monoacylglycerol Lipases; Osteoarthritis, Knee; Piperidines; Rats; Rats, Wistar

Macrophages, which develop by changing their functions according to various environmental conditions and stimuli, defend against the pathogens and play roles in homoeostasis and disease states. Bicarbonate (HCO3-) is important in the maintenance of intracellular and extracellular pH in the body. However, the effects of bicarbonate on macrophage function have not been examined. In this study, we investigated the effects of bicarbonate on macrophage activation in lipopolysaccharide (LPS) and interferon (IFN)-γ (LPS + IFN-γ)-stimulated murine macrophage-like RAW264.7 cells. The expression of the interleukin (IL)-6, inducible nitric oxide (NO) synthase and cyclooxygenase-2 genes was enhanced by sodium bicarbonate (NaHCO3) in a concentration-dependent manner in LPS + IFN-γ-stimulated RAW264.7 cells. The production of IL-6, NO2- and prostaglandin E2 was also increased by treatment with NaHCO3 in these cells. Moreover, NaHCO3-mediated elevation of inflammatory gene expression was abrogated by solute carrier (SLC) transporter inhibitors. Furthermore, its NaHCO3-mediated activation was negated by a JAK inhibitor , tofacitinib. NaHCO3-enhanced phosphorylation of STAT1, and its enhancement was abrogated by pre-treating with SLC transporter inhibitors in LPS + IFN-γ-stimulated RAW264.7 cells. In addition, similar results were obtained in murine bone marrow-derived macrophages. These results indicate that bicarbonate enhanced the inflammatory response through the JAK/STAT signalling in LPS + IFN-γ-stimulated macrophages.

Topics: Animals; Cyclooxygenase 2; Gene Expression; Inflammation; Interferon-gamma; Interleukin-6; Janus Kinase Inhibitors; Janus Kinases; Lipopolysaccharides; Macrophage Activation; Macrophages; Male; Mice; Mice, Inbred C57BL; Nitric Oxide; Piperidines; Pyrimidines; RAW 264.7 Cells; Recombinant Proteins; Signal Transduction; Sodium Bicarbonate; STAT1 Transcription Factor

Acute lung injury (ALI) is characterized by neutrophilic infiltration, uncontrolled oxidative stress and inflammatory processes. Despite various therapeutic regimes having been performed, there remains no effective pharmacotherapy available to treat ALI. Halofuginone (HF), a ketone isolated from Dichroa febrifuga, exhibits significant anti‑inflammatory and antifibrotic effects. Dexamethasone (DEX), a synthetic glucocorticoid, has been routinely used as an adjuvant therapy in treating inflammatory diseases, including ALI. The present study aimed to investigate the effects of the combination of HF and DEX in the treatment of ALI. The present results suggested that the simultaneous administration of HF and DEX markedly decreased the level of pro‑inflammatory cytokines and increased the level of anti‑inflammatory cytokines, as assessed by western blot analysis. In addition, HF and DEX effectively decreased nuclear factor‑κB activity via suppressing the phosphorylation of P65 in lipopolysaccharide (LPS)‑induced human pulmonary alveolar epithelial cells (HPAEpiC) and lung tissues extracted from ALI rats, as determined by immunofluorescence. Furthermore, in vivo experiments demonstrated that the combination of HF and DEX in LPS‑induced ALI rats defended against lung fibrosis, perivascular inflammation, congestion and edema of pulmonary alveoli, as assessed by histopathological analysis, TUNEL staining and immunohistochemistry assay. Taken together, the present study indicated the synergistic effect of HF and DEX on LPS‑induced ALI in HPAEpiC cells and a rat model. These results offer a novel therapeutic approach for the treatment of ALI.

Topics: Acute Lung Injury; Alveolar Epithelial Cells; Animals; Cell Survival; Dexamethasone; Disease Models, Animal; Drug Synergism; Humans; Inflammation; Lipopolysaccharides; NF-kappa B; Phosphorylation; Piperidines; Quinazolinones; Rats, Sprague-Dawley; Signal Transduction

Kelch-like ECH-associated protein (Keap1)-nuclear factor erythroid-2-related factor 2 (Nrf2) protein-protein interaction has become an important drug target for the treatment of Alzheimer's disease. In this study, we found a novel piperine derivative (HJ22) synthesized by our group with great ability to bind to Keap-1 and activate Keap1-Nrf2-ARE signaling pathway in vitro, driving us to investigate the beneficial effects of HJ22 on ibotenic acid (IBO)-induced neurological disorders in rats and underlying mechanisms. Interestingly, HJ22 significantly ameliorated IBO-induced cognitive impairment in Morris water maze, Y-maze and passive avoidance tests. Moreover, HJ22 significantly attenuated cholinergic dysfunction and neuronal morphological changes via inhibiting apoptotic cell death induced by IBO. Notably, HJ22 inhibited the interaction between Keap1 and Nrf2, and subsequently up-regulated nuclear Nrf2 expression, thereby inhibiting oxidative stress and Thioredoxin-interacting protein (TXNIP)-mediated Nod-like receptor protein 3 (NLRP3) inflammasome activation. These findings demonstrated that HJ22 exhibited potent therapeutic effects against IBO-induced cognitive impairment by alleviating cholinergic damage, oxidative stress, apoptosis and neuroinflammation, which might be partly attributed to its inhibitory activity on Keap1-Nrf2 protein-protein interaction.

Topics: Alkaloids; Animals; Apoptosis; Benzodioxoles; Cells, Cultured; Cognitive Dysfunction; Disease Models, Animal; Humans; Ibotenic Acid; Inflammasomes; Inflammation; Kelch-Like ECH-Associated Protein 1; Neurons; NF-E2-Related Factor 2; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Protein Binding; Protein Interaction Domains and Motifs; Rats; Rats, Sprague-Dawley

Neural inflammation is linked to coagulation. Low levels of thrombin have a neuroprotective effect, mediated by activated protein C (APC). We describe a sensitive novel method for the measurement of APC activity at the low concentrations found in neural tissue.. APC activity was measured using a fluorogenic substrate, Pyr-Pro-Arg-AMC, cleaved preferentially by APC. Selectivity was assessed using specific inhibitors and activators. APC levels were measured in human plasma, in glia cell lines, in mice brain slices following mild traumatic brain injury (mTBI) and systemic lipopolysaccharide (LPS) injection, and in cerebrospinal fluid (CSF) taken from viral meningoencephalitis patients and controls.. Selectivity required apixaban and alpha-naphthylsulphonylglycyl-4-amidinophenylalanine piperidine (NAPAP). APC levels were easily measurable in plasma and were significantly increased by Protac and CaCl. This method is selective and sensitive for the measurement of APC activity that significantly changes during inflammation in cell lines, animal models and human CSF.

Topics: Animals; Brain; Brain Concussion; Cell Line; Cerebrospinal Fluid; Dipeptides; Endothelial Protein C Receptor; Humans; Inflammation; Lipopolysaccharides; Male; Mice; Mice, Inbred ICR; Models, Animal; Neuroglia; Piperidines; Protein C; Pyrazoles; Pyridones; Receptor, PAR-1; Thrombin

To analyze how monocyte and macrophage exposure to CXCL4 induces inflammatory and fibrotic processes observed in Systemic sclerosis (SSc) patients.. In six independent experiments, monocytes of healthy controls (HC) and SSc patients were stimulated with CXCL4, TLR-ligands, IFNɑ or TGFβ and the secretion of cytokines in the supernatant was assessed by multiplex immunoassays. PDGF-BB production by monocyte-derived macrophages was quantified using immunoassays. The number of monocytes and PDGF-BB in circulation was quantified in HC and SSc patients with the Sysmex XT-1800i haematology counter and immunoassays. Intracellular PDGF-BB was quantified in monocytes by Western blot. PDGF-receptor inhibition was achieved using siRNA-mediated knockdown or treatment with Crenolanib. The production of inflammatory mediators and extracellular matrix (ECM) components by dermal fibroblasts was analyzed by qPCR, ELISA and ECM deposition assays.. SSc and HC monocytes released PDGF-BB upon stimulation with CXCL4. Conversely, TLR ligands, IFNɑ or TGFβ did not induce PDGF-bb release. PDGF-BB plasma levels were significantly (P = 0.009) higher in diffuse SSc patients (n = 19), compared with HC (n = 21). In healthy dermal fibroblasts, PDGF-BB enhanced TNFɑ-induced expression of inflammatory cytokines and increased ECM production. Comparable results were observed in fibroblasts cultured in supernatant taken from macrophages stimulated with CXCL4. This effect was almost completely abrogated by inhibition of the PDGF-receptor using Crenolanib.. Our findings demonstrate that CXCL4 can drive fibroblast activation indirectly via PDGF-BB production by myeloid cells. Hence, targeting PDGF-BB or CXCL4-induced PDGF-BB release could be clinically beneficial for patients with SSc.

Topics: Adult; Aged; Becaplermin; Benzimidazoles; Cells, Cultured; Cytokines; Female; Fibroblasts; Humans; Inflammation; Macrophages; Male; Middle Aged; Monocytes; Piperidines; Platelet Factor 4; Receptors, Platelet-Derived Growth Factor; Scleroderma, Systemic

FK866 is an inhibitor of nicotinamide phosphoribosyltransferase (NAMPT), which exhibits neuroprotective effects in ischemic brain injury. However, in traumatic brain injury (TBI), the role and mechanism of FK866 remain unclear. The present research was aimed to investigate whether FK866 could attenuate TBI and clarified the underlying mechanisms.. A controlled cortical impact model was established, and FK866 at a dose of 5 mg/kg was administered intraperitoneally at 1 h and 6 h, then twice per day post-TBI until sacrifice. Brain water content, Evans blue dye extravasation, modified neurological severity scores (mNSS), Morris water maze test, enzyme-linked immunosorbent assay (ELISA), immunofluorescence staining, and western blot were performed.. The results demonstrated that FK866 significantly mitigated the brain edema, blood-brain barrier (BBB) disruption, and ameliorated the neurological function post-TBI. Moreover, FK866 decreased the number of Iba-1-positive cells, GFAP-positive astrocytes, and AQP4-positive cells. FK866 reduced the protein levels of proinflammatory cytokines and inhibited NF-κB from translocation to the nucleus. FK866 upregulated the expression of Bcl-2, diminished the expression of Bax and caspase 3, and the number of apoptotic cells. Moreover, p38 MAPK and ERK activation were significantly inhibited by FK866.. FK866 attenuated TBI-induced neuroinflammation and apoptosis, at least in part, through p38/ERK MAPKs signaling pathway.

Topics: Acrylamides; Animals; Apoptosis; Behavior, Animal; Blood-Brain Barrier; Brain Edema; Brain Injuries, Traumatic; Cytokines; Disease Models, Animal; Female; Inflammation; Male; MAP Kinase Signaling System; Maze Learning; Neuroprotective Agents; NF-kappaB-Inducing Kinase; Piperidines; Protein Serine-Threonine Kinases; Rats; Rats, Sprague-Dawley

Animal models of inflammatory diseases support the idea that nuclear factor κB (NF-κB) activation plays a pathophysiological role and is widely implicated in multiple organ dysfunction (MOD). Indeed, the inhibition of the IκB kinase (IKK) complex, involved in the NF-κB pathway, can represent a promising approach to prevent MOD. The present work employed a rat model of systemic inflammation to investigate the preventive effects of Inhibitor of IKK complex (IKK16). In male Wistar rats, systemic inflammation was induced by a tail vein injection of lipopolysaccharides (LPS challenge; 12 mg/kg). Treatment with IKK16 (1 mg/kg body weight) was administered, by tail vein, 15 min post-LPS. Age- and sex-matched healthy rats and LPS rats without treatment were used as controls. At 24 h post-IKK16 treatment, serum enzyme levels indicative of liver, kidney, pancreas and muscle function were evaluated by biochemical analysis, and RT-PCR technique was used to analyze gene expression of pro-inflammatory cytokines. Hemodynamic parameters were also considered to assess the LPS-induced inflammation. IKK16 treatment yielded a strong therapeutic effect in preventing LPS-induced elevation of serological enzyme levels, attenuating hepatic, renal, pancreatic and muscular dysfunction after LPS challenge. Moreover, as expected, LPS promoted a significantly overexpression of TNF-α, IL-6 and IL-1β in the heart, kidney, and liver; which was diminished by IKK16 treatment. The present study provides convincing evidence that selective inhibition of the IκB kinase complex through the action of IKK16, plays a protective role against LPS-induced multiple organ dysfunction by reducing the acute inflammatory response induced by endotoxin exposure.

Topics: Animals; Anti-Inflammatory Agents; Baroreflex; Blood Pressure; Cytokines; Heart Rate; I-kappa B Kinase; Inflammation; Kidney; Lipopolysaccharides; Liver; Male; Myocardium; Piperidines; Protein Kinase Inhibitors; Pyrrolidines; Rats, Wistar

As the SARS-CoV-2 (COVID-19) pandemic spreads and the number of Bruton's tyrosine kinase inhibitor (BTKi)-treated COVID-19-affected patients grows, we must consider the pros and cons of BTKi discontinuation for our patients. In favor of BTKi continuation, BTK plays an active role in macrophage polarization. By modulating key transcription factors, BTK may regulate macrophage polarization downstream of classic M1 and M2 polarizing stimuli and mitigate the hyperinflammatory state associated with COVID-19. In favor of BTKi discontinuation, we note a potentially increased risk of secondary infections and impaired humoral immunity. We hypothesize that the potential benefit of blunting a hyperinflammatory response to SARS-CoV-2 through attenuation of M1 polarization outweighs the potential risk of impaired humoral immunity, not to mention the risk of rapid progression of B-cell malignancy following BTKi interruption. On the basis of this, we suggest continuing BTKi in patients with COVID-19.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Anti-Inflammatory Agents; Antineoplastic Agents; Benzamides; Betacoronavirus; Coronavirus Infections; COVID-19; Humans; Inflammation; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Macrophages; Pandemics; Piperidines; Pneumonia, Viral; Protein Kinase Inhibitors; Pyrazines; Pyrazoles; Pyrimidines; SARS-CoV-2

Epoxyeicosatrienoic acids (EET) and related epoxy fatty acids (EpFA) are endogenous anti-inflammatory compounds, which are converted by the soluble epoxide hydrolase (sEH) to dihydroxylethersatrienoic acids (DHETs) with lessened biological effects. Inhibition of sEH is used as a strategy to increase EET levels leading to lower inflammation. Rheumatoid arthritis is a chronic autoimmune disease that leads to destruction of joint tissues. This pathogenesis involves a complex interplay between the immune system, and environmental factors. Here, we investigate the effects of inhibiting sEH with 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) on a collagen-induced arthritis model. The treatment with TPPU ameliorates hyperalgesia, edema, and decreases the expression of important pro-inflammatory cytokines of Th1 and Th17 profiles, while increasing Treg cells. Considering the challenges to control RA, this study provides robust data supporting that inhibition of the sEH is a promising target to treat arthritis.

Topics: Animals; Arthritis, Experimental; Collagen; Epoxide Hydrolases; Inflammation; Male; Mice; Mice, Inbred DBA; Phenylurea Compounds; Piperidines; T-Lymphocytes, Regulatory

To assess the efficacy of biologic drugs, beyond tumor necrosis factor- (TNF-). Fourteen patients (19 eyes) were enrolled in the study. Scleritis inflammatory grading significantly improved from baseline to 3 months (. Our results, though limited to a low number of patients, highlight the effectiveness of different biologic therapies in the treatment of noninfectious refractory scleritis, showing to control scleral inflammation and allowing a significant reduction in the number of relapses.

Topics: Abatacept; Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Female; Humans; Immune System; Inflammation; Interleukin 1 Receptor Antagonist Protein; Male; Middle Aged; Ophthalmology; Piperidines; Pyrimidines; Recurrence; Retrospective Studies; Rituximab; Scleritis; Treatment Outcome

Systemic lupus erythematosus is a multisystem autoimmune disease. Apart from usual treatments, approximately 50% of lupus patients use complementary medicine. Resveratrol is a phytoalexin with various pharmacological properties. We hypothesised that prophylactic treatment with resveratrol may abrogate manifestations in pristane-induced murine model of lupus-like disease and piperine; a bio-enhancer of resveratrol may enhance these properties. The prophylactic effect of resveratrol (25 mg/kg body weight: P-Res) alone and in combination with piperine (2.5 mg/kg body weight: P-RP) were assessed. P-Res and P-RP were equally efficient in mitigating oxidative stress (enzyme activity of catalase, superoxide dismutase, glutathione peroxidase and level of reduced glutathione, lipid peroxidation, and reactive oxygen species). Inflammation is associated with an increase in inflammatory cytokines. IL-6 was decreased by 71.60% with P-Res, and TNF-α was reduced by 59.70% with P-Res and 62.66% with P-RP (p < 0.05). Prevention of renal pathologies was evident by reduction in creatinine level by P-RP (p < 0.05) and abrogation of proteinuria (P-Res and P-RP). P-RP was efficient in restoring histopathology of liver and lungs and decreased immune complexes in lungs. P-Res proved more beneficial by extenuating lipogranulomas, histopathological manifestations in kidney, liver, and lungs, and eliminating immune complexes in liver and lungs. None of the treatments could regulate auto-antibody formation. Resveratrol decreases the susceptibility of developing pathogenesis in murine model of lupus-like disease. The results also conclude that addressing the bioavailability of resveratrol using it in combination with piperine does not prove more efficacious in preventing lupus-associated pathologies than resveratrol alone.

Topics: Alkaloids; Animals; Antioxidants; Benzodioxoles; Cytokines; Disease Models, Animal; Female; Inflammation; Kidney; Lipid Peroxidation; Liver; Lung; Lupus Erythematosus, Systemic; Mice; Mice, Inbred BALB C; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Resveratrol; Terpenes

Cannabinoids and the endocannabinoid system significantly contributes to the airway inflammation. Fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) are two main enzymes responsible for the metabolism of the endocannabinoids anandamide (AEA) and 2-arachydonoyl glycerol (2-AG), respectively. In the present study, we aimed to investigate the effects of local and systemic FAAH and MAGL inhibitor treatments in experimental airway inflammation and tracheal hyperreactivity in mice. Airway inflammation was induced by intranasal (i.n.) lipopolysaccharide (LPS) application (60 μl; 0,1 mg/ml in PBS) to mice and the control group received PBS. Systemic (intraperitoneal (i.p.)) or local (i.n.) FAAH inhibitor URB597 and MAGL inhibitor JZL184 treatments were administered 1h before LPS/PBS application. Fourty 8 h after LPS/PBS application, tracheas were removed to assess airway reactivity, and the lungs and bronchoalveolar lavage (BAL) fluids were isolated for histopathological evaluation, cytokine and endocannabinoid measurements. LPS application lead to an increase in 5-hydroxytryptamine (5-HT) contractions in isolated tracheal rings while carbachol contractions remained unchanged. The increased 5-HT contractions were prevented by both systemic and local URB597 and JZL184 treatments. Systemic treatment with URB597 and JZL184, and local treatment with JZL184 reduced peribronchial and paranchymal inflammation in the LPS group while i.n. application of URB597 worsened the inflammation in the lungs. Systemic URB597 treatment increased lung AEA level whereas it had no effect on 2-AG level. However, JZL184 treatment increased 2-AG level by either systemic or local application, and also elevated AEA level. Inflammation-induced increase in neutrophil numbers was only prevented by systemic URB597 treatment. However, both URB597 and JZL184 treatments abolished the increased TNF-α level either they are administered systemically or locally. These results indicate that FAAH and MAGL inhibition may have a protective effect in airway inflammation and airway hyperreactivity, and therefore their therapeutic potential for airway diseases should be further investigated.

Topics: Amidohydrolases; Animals; Arachidonic Acids; Benzamides; Benzodioxoles; Carbamates; Cytokines; Endocannabinoids; Glycerides; Inflammation; Lipopolysaccharides; Lung; Male; Mice; Monoacylglycerol Lipases; Piperidines; Pneumonia; Polyunsaturated Alkamides; Respiratory Hypersensitivity

NF-kB translocation is the key point in the upstream neuroinflammatory pathways. It plays an import role in the pro-inflammatory chemokine, cytokine, and various enzyme expressions, consequently leading to the inflammatory response of the innate immune system. The NF-kB complex consists of structural homolog subunits, including c-Rel, RelB, p52, p65, and p50. Among the p65 subunit has a vital function of NF-kB translocation and DNA binding. NF-kB translocation may occur due to acetylation and phosphorylation LYS 310 and SER311 amino acids in chain A of the p65 subunit in response to IKK-α/β activity. Therefore, there are two ways to inhibit the NF-kB translocation, either directly blocking the active sites of IKK-α/β enzymes or protecting the LYS 310 and SER311 of p65 subunit from acetylation and phosphorylation. NF-kB translocation inhibitors can maintain the NF-kB complex in the inactive form inside the cytosol. In this study, we have designed and developed an NF-kB translocation inhibitor, D4. We have performed various in silico, in vitro and in situ studies on the anti-neuroinflammatory function of D4. It showed the ability to inhibit IKK-α/β in both genome and proteome levels and protect LYS310 of the p65 subunit of NF-kB from the acetylation process. Therefore, we can suggest D4 as the promising anti-neuroinflammatory agent with a function on the upstream process of inflammatory pathways.

Topics: Anti-Inflammatory Agents; Cells, Cultured; Computer Simulation; Humans; Inflammation; NF-kappa B; Piperidines; Transcription Factor RelA

Due to the highly complex biological formation procedure, tumor is still difficult to be treated efficiently and always associated with proliferation, migration and inflammation during treatment. Herein, a novel strategy of boosted photocatalytic activity induced NAMPT-regulating therapy is used for tumors inhibition based on FK866 loaded bismuth-humic acids heterojunction (Bi-HA/FK866). With the reduction function of HA, Bi (Ⅲ) can be reduced to elemental Bi, which can be excited by NIR laser to form electron-hole pair due to the narrow bandgap. Moreover, the coated HA and Bi could form a heterojunction structure, which could decrease the electron-hole recombination, and further boost the photocatalytic activity, leading to highly efficient ROS generation and GSH depletion. The resulted ROS could induce DNA damage of the tumor cells, thus enhancing the sensitivity to the inhibitor of NAMPT (FK866) to downregulate NAD/ERK/NF-κB signal pathways, and eventually simultaneously prevent cancer progression. Moreover, the decreased NAD could downregulate NADPH and further suppress the innate antioxidant defense system by inhibiting reduction of GSSG. The boosted photocatalytic activity induced NAMPT-regulating therapy offers a promising way to address the important issue of penetration depth limitation induced cancer relapse and migration, providing more possibilities toward successful clinical application.

Topics: Acrylamides; Bismuth; Cell Proliferation; Cytokines; Humans; Humic Substances; Inflammation; Neoplasms; Piperidines

Abdominal aortic aneurysm (AAA) formation is characterized by inflammation, leukocyte infiltration, and vascular remodeling. This study investigates the role of TRPV4 channels, which are transmembrane calcium channels that can regulate vascular tone, in modulating AAA formation. The elastase-treatment model of AAA in C57BL6 (WT) mice and Angiotensin II treatment model in ApoE

Topics: Animals; Aortic Aneurysm, Abdominal; Inflammation; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout, ApoE; Pancreatic Elastase; Piperidines; Quinolines; TRPV Cation Channels

Alcohol use disorders affect millions of people worldwide, and there is growing evidence that excessive alcohol intake causes severe damage to the brain of both humans and animals. Numerous studies on chronic alcohol exposure in animal models have identified that many functional impairments are associated with the hippocampus, which is a structure exhibiting substantial vulnerability to alcohol exposure. However, the precise mechanisms that lead to structural and functional impairments of the hippocampus are poorly understood. Herein, we report a novel cell death type, namely pyroptosis, which accounts for alcohol neurotoxicity in mice.. For this study, we used an in vivo model to induce alcohol-related neurotoxicity in the hippocampus. Adult male C57BL/6 mice were treated with 95% alcohol vapor either alone or in combination with selective cannabinoid receptor antagonists or agonists, and VX765 (Belnacasan), which is a selective caspase-1 inhibitor.. Alcohol-induced in vivo pyroptosis occurs because of an increase in the levels of pyroptotic proteins such as nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3), caspase-1, gasdermin D (GSDMD), and amplified inflammatory response. Our results indicated that VX765 suppressed the expression of caspase-1 and inhibited the maturation of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18. Additionally, chronic alcohol intake created an imbalance in the endocannabinoid system and regulated 2 cannabinoid receptors (CB1R and CB2R) in the hippocampus. Specific antagonists of CB1R (AM251 and AM281) significantly ameliorated alcohol-induced pyroptosis signaling and inactivated the inflammatory response.. Alcohol induces hippocampal pyroptosis, which leads to neurotoxicity, thereby indicating that pyroptosis may be an essential pathway involved in chronic alcohol-induced hippocampal neurotoxicity. Furthermore, cannabinoid receptors are regulated during this process, which suggests promising therapeutic strategies against alcohol-induced neurotoxicity through pharmacologic inhibition of CB1R.

Topics: Alcohol-Induced Disorders, Nervous System; Animals; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Caspase 1; Caspase Inhibitors; Central Nervous System Depressants; Dipeptides; Ethanol; Hippocampus; Inflammation; Interleukin-18; Interleukin-1beta; Intracellular Signaling Peptides and Proteins; Mice; Morpholines; Neuroprotective Agents; Neurotoxicity Syndromes; NLR Family, Pyrin Domain-Containing 3 Protein; para-Aminobenzoates; Phosphate-Binding Proteins; Piperidines; Pyrazoles; Pyroptosis; Receptor, Cannabinoid, CB1

The C-X-C chemokine receptor type 4 (CXCR4) is a potential therapeutic target for HIV infection, metastatic cancer, and inflammatory autoimmune diseases. In this study, we screened the ZINC chemical database for novel CXCR4 modulators through a series of in silico guided processes. After evaluating the screened compounds for their binding affinities to CXCR4 and inhibitory activities against the chemoattractant CXCL12, we identified a hit compound (ZINC 72372983) showing 100 nM affinity and 69% chemotaxis inhibition at the same concentration (100 nM). To increase the potency of our hit compound, we explored the protein-ligand interactions at an atomic level using molecular dynamics simulation which enabled us to design and synthesize a novel compound (Z7R) with nanomolar affinity (IC

Topics: Animals; Anti-Inflammatory Agents; Cell Line, Tumor; Drug Design; Humans; Inflammation; Mice; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Structure; Piperidines; Protein Binding; Receptors, CXCR4; Structure-Activity Relationship

The biology of harlequin ichthyosis (HI), a devastating skin disorder caused by loss-of-function mutations in the gene ABCA12, is poorly understood, and to date, no satisfactory treatment has been developed. We sought to investigate pathomechanisms of HI that could lead to the identification of new treatments for improving patients' quality of life. In this study, RNA-Seq and functional assays were performed to define the effects of loss of ABCA12 using HI patient skin samples and an engineered CRISPR/Cas9 ABCA12 KO cell line. The HI living skin equivalent (3D model) recapitulated the HI skin phenotype. The cytokines IL-36α and IL-36γ were upregulated in HI skin, whereas the innate immune inhibitor IL-37 was strongly downregulated. We also identified STAT1 and its downstream target inducible nitric oxide synthase (NOS2) as being upregulated in the in vitro HI 3D model and HI patient skin samples. Inhibition of NOS2 using the inhibitor 1400W or the JAK inhibitor tofacitinib dramatically improved the in vitro HI phenotype by restoring the lipid barrier in the HI 3D model. Our study has identified dysregulated pathways in HI skin that are feasible therapeutic targets.

Topics: Amidines; ATP-Binding Cassette Transporters; Benzylamines; Cell Culture Techniques; Cells, Cultured; Drug Delivery Systems; Gene Knockdown Techniques; Humans; Ichthyosis, Lamellar; Inflammation; Interleukin-1; Loss of Function Mutation; Models, Biological; Nitric Oxide Synthase Type II; Piperidines; Pyrimidines; STAT1 Transcription Factor

Topics: Animals; Antioxidants; Apoptosis; Biphenyl Compounds; Brain-Derived Neurotrophic Factor; Cell Line; Computational Biology; Cyclic AMP Response Element-Binding Protein; Cytokines; Databases, Chemical; Extracellular Signal-Regulated MAP Kinases; Heme Oxygenase-1; Humans; Hydrogen Peroxide; Inflammation; Lipopolysaccharides; Malondialdehyde; Membrane Glycoproteins; Membrane Potential, Mitochondrial; Membrane Proteins; Mice; Microglia; NF-E2-Related Factor 2; Oxidative Stress; Piperidines; Receptor, trkB; Signal Transduction

Contrast-induced nephropathy (CIN), a complication caused by using contrast medium during diagnostic and interventional procedures, occurs frequently and lacks effective treatment. AdipoRon, the agonist of adiponectin receptors, has been shown to benefit many organs including the kidney. This study aimed to investigate the role of AdipoRon in treating CIN.. CIN model was established via infusing iopromide (1.8 g/kg) in Sprague-Dawley (SD) rats; NRK52E cells were treated with iopromide (5-50 μM). Renal function, renal histopathology, levels of lactate dehydrogenase (LDH) release, cell vitality, oxidative stress and inflammatory markers were measured to evaluate the protective effects of AdipoRon. The level of pAMPK/AMPK was determined by western blot.. AdipoRon (50 mg/kg) significantly reversed serum creatinine, blood urea nitrogen, creatinine clearance and urinary kidney injury molecule-1 levels induced by iopromide in SD rats. Besides, it decreased the renal injury score and apoptosis of renal cells. AdipoRon also reversed the changes of antioxidant markers, pro-oxidant and inflammatory markers induced by iopromide. Moreover, the in vitro studies showed that AdipoRon decreased LDH release and increased cell vitality in NRK52E cells treated with iopromide. Then, we demonstrated that the protection of AdipoRon was accompanied by augmented AMPK phosphorylation. Both in vivo and in vitro studies demonstrated that compound c, an AMPK inhibitor, reversed the AdipoRon-mediated improvement in the CIN model.. Our data indicate that AdipoRon protects against the CIN by suppressing oxidative stress and inflammation via activating the AMPK pathway, showing that AdipoRon might be a potential candidate for the prevention and therapy of CIN.

Topics: AMP-Activated Protein Kinases; Animals; Apoptosis; Blood Urea Nitrogen; Cell Adhesion Molecules; Cell Line; Contrast Media; Creatinine; Disease Models, Animal; Inflammation; Iohexol; Kidney Diseases; Lactate Dehydrogenases; Male; Oxidative Stress; Phosphorylation; Piperidines; Protein Kinase Inhibitors; Rats; Rats, Sprague-Dawley; Receptors, Adiponectin; Signal Transduction

After confirmation of the presence of adiponectin (ADPN) receptors and intra-cellular binding proteins in coronary artery smooth muscle cells (VSMC), we tested the hypotheses that, in acute insulin resistance: (i) the activation/inactivation of metabolic and mitogenic insulin signaling pathways are inversely affected by ADPN and, (ii) changes in VSMC migration/proliferation rates correlate with signal activity/inactivity. In primary cultures of VSMC exposed to high glucose and palmitate plus insulin, the expression of PI-3 kinase (Akt and m-TOR), MAP-Kinase (Erk and p-38) molecules, and inflammatory markers (TLR-4 and IkB-α) were assessed with Western blot, in the absence/presence of AdipoRon (AR). Migration and proliferation rates were measured in similar experimental conditions. There were decreases of ~ 25% (p-Akt) and 40-60% (p-mTOR) expressions with high glucose/palmitate, which reversed when AR was added were. Elevations in p-Erk and p-p38 expressions were obliterated by AR. Although, no changes were detected with high glucose and palmitate, when AR was added, a decline in inflammatory activity was substantiated by a ~ 50% decrease in TLR-4 and 40-60% increase in IkBα expression. Functional assays showed 10-20% rise in VSMC proliferation with high glucose and palmitate, but addition of AR lead to 15-25% decline. The degree of VSMC migration was reduced with AR addition by ~ 15%, ~ 35% and 55%, in VSMC exposed to 5 mM, 25 mM glucose and 25 mM + 200 µM palmitate, respectively. Changes in intracellular molecular messaging in experiments mimicking acute insulin resistance suggest that anti-inflammatory and anti-atherogenic actions of ADPN in VSMC are mediated via insulin signaling pathways.

Topics: Adiponectin; Cell Line; Cell Movement; Cell Proliferation; Cell Survival; Glucose; Humans; I-kappa B Proteins; Inflammation; Insulin; MAP Kinase Signaling System; Muscle, Smooth, Vascular; p38 Mitogen-Activated Protein Kinases; Palmitates; Phosphorylation; Piperidines; Proto-Oncogene Proteins c-akt; Receptors, Adiponectin; Toll-Like Receptor 4; TOR Serine-Threonine Kinases

MitoTEMPO, a mitochondrial antioxidant, has protective effects on liver-related diseases. However, the role of MitoTEMPO on nonalcoholic fatty liver disease (NAFLD) and its possible mechanisms are largely unknown. Here, we investigated the effects of MitoTEMPO on NAFLD using high fat diet- (HFD-) induced obese mice as animal models. MitoTEMPO was intraperitoneally injected into HFD mice. Liver morphological changes were observed by H&E and Oil Red O staining, and the frequency of MDSCs in peripheral blood was analyzed by flow cytometry. Moreover, real-time quantitative PCR, western blot, and immunohistochemistry were conducted to detect the mRNA and protein expressions in the liver tissues. The results showed that the hepatic steatosis in liver tissues of HFD mice injected with MitoTEMPO was significantly ameliorated. Additionally, MitoTEMPO reduced the frequency of CD11b

Topics: Animals; Gene Expression Regulation; Inflammation; Liver; Male; Mice; Myeloid-Derived Suppressor Cells; Non-alcoholic Fatty Liver Disease; Organophosphorus Compounds; Piperidines

Myocardial infarction (MI) eventually exacerbates inflammatory response due to the release of inflammatory and pro-inflammatory factors. The aim of this study is to explore the protective efficacy of piperine supplementation against the inflammatory response in isoproterenol (ISO)-induced MI. Masson Trichome staining was executed to determine myocardial tissue architecture. Immunohistochemistry was performed for IL-6, TNF-α. RT-PCR studies were performed to ascertain the gene expression of IL-6, TNF-α, iNOS, eNOS, MMP-2, MMP-9, and collagen-III. Western blotting was performed to determine expression of HIF-1α, VEGF, Nrf-2, NF-ƙB, Cox-2, p-38, phospho-p38, ERK-1/2, phospho-ERK-1/2, and collagen-I. HIF-1α, VEGF, and iNOS expression were significantly upregulated with concomitant decline in eNOS expression in the heart myocardial tissue of rats received ISO alone whereas piperine pretreatment prevented these changes in ISO administered rats. Current results revealed ROS-mediated activation of MAPKs, namely, p-p38, p-ERK1/2 in the heart tissue of ISO administered group. Piperine pretreatment significantly prevented these changes in ISO treated group. NF-κB is involved in the modulation of gene expressions responsible for tissue repair. ISO-induced NF-κB-p65 expression was significantly reduced in the group pretreated with piperine and mitigated extent of myocardial inflammation. A significant increase in cardiac fibrosis upon ISO treatment was reported due to the increased hydroxyproline content, MMP-2 & 9 and upregulation of collagen-I protein compared to control group. All these cardiac hypertrophy markers were decreased in 'piperine pretreated ISO administered group' compared to group received ISO injection. Current findings concluded that piperine as a nutritional intervention could prevent inflammation of myocardium in ISO-induced MI.

Topics: Adrenergic beta-Agonists; Alkaloids; Animals; Benzodioxoles; Cardiomegaly; Cytokines; Endothelium; Fibrosis; Inflammation; Isoproterenol; Male; Myocardial Infarction; Myocardium; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Signal Transduction; Transcription Factor RelA

Metabolic inflammation is an essential event in obesity-induced diabetes and insulin resistance. In obesity, an increasing number of macrophages recruited into visceral adipose tissues undergo significant M. Newborn mice were subcutaneously (s.c.) injected with monosodium glutamate (MSG) to establish a diabetes model. After 24 weeks, the MSG obese mice were divided into three groups and treated with piperine (40 mg/kg/day), metformin (150 mg/kg/day) and vehicle for 10 successive weeks, respectively.. The obesity model was successfully established, as the body weight, insulin resistance, fasting blood glucose (FBG) and dyslipidemia were significantly increased. The 10-week administration of piperine to the obese mice not only significantly decreased the elevated FBG (Model: 6.45 ± 0.41 mM; Piperine: 4.72 ± 0.44 mM, p < 0.01), serum TC (Model: 5.66 ± 0.66 mM; Piperine: 3.55 ± 0.30 mM, p < 0.01) and TG (Model: 1.41 ± 0.08 mM; Piperine: 0.94 ± 0.05 mM, p < 0.001), but also enhanced the glucose infusion rate in the hyperglycemic clamp experiment. Meanwhile, piperine improved glucose intolerance and insulin resistance in MSG obese mice. Piperine markedly decreased the total and differential white blood cell (WBC) count, the serum levels of lipopolysaccharide (LPS) and pro-inflammatory cytokines such as galectin-3 (Gal-3) and interleukin-1β (IL-1β). Furthermore, piperine clearly down-regulated the mRNA levels of pro-inflammatory cytokines and the protein levels of M. Piperine served as an immunomodulator for the treatment of obesity-related diabetes through its anti-inflammatory effects, which might be achieved by inhibiting macrophages M

Topics: Adipose Tissue; Alkaloids; Animals; Benzodioxoles; Body Weight; Cytochrome P-450 Enzyme Inhibitors; Cytokines; Female; Flavoring Agents; Glucose Intolerance; Inflammation; Insulin Resistance; Macrophages; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Piperidines; Polyunsaturated Alkamides; Sodium Glutamate

Metabolic Syndrome (MetS) is increasing worldwide regardless of culture, genetic, gender, and geographic differences. While multiple individual risk factors, such as obesity, hypertension, diabetes, and hyperlipidemia, can cause cardiovascular disease (CVD), it is the intercurrence of these risk factors that defines MetS as a cluster that creates an environment for atherosclerosis and other manifestations of CVD. Despite the advances in the knowledge and management of each of the components of MetS, there are two molecular biology processes, chronic inflammation and oxidative stress, which are still underdiagnosed and undertreated. In order to assess the effect of a dietary supplement on chronic inflammation in MetS, we conducted a clinical trial with volunteers receiving a formula composed of resveratrol, piperine and alpha tocopherol (FRAMINTROL

Topics: Aged; Alkaloids; alpha-Tocopherol; Benzodioxoles; Biomarkers; C-Reactive Protein; Chronic Disease; Dietary Supplements; Female; Ferritins; Humans; Inflammation; Luminescent Measurements; Male; Metabolic Syndrome; Middle Aged; Neutrophils; Oxidative Stress; Oxygen Consumption; Piperidines; Polyunsaturated Alkamides; Resveratrol; Time Factors

The increase in intracellular reactive oxygen and nitrogen species plays a key role in ultraviolet B (UV-B)-induced inflammatory responses in the human skin. Piperine exhibits many pharmacological benefits. In the present study, the photoprotective effects and the possible underlying mechanisms of the anti-inflammatory effects of piperine on UV-B-irradiated keratinocytes were investigated. Piperine exerted strong, direct scavenging effects on DPPH radicals and exhibited free radical scavenging capabilities as demonstrated by the DCFH-DA and Griess assays. Consistent with these results, 10, 20, and 40 μM piperine pretreatments attenuated UV-B irradiation-induced keratinocyte cytotoxicity as reported by the resazurin assay. The highest concentration of piperine inhibited UV-B irradiation-induced cell apoptosis, as revealed by Hoechst 33342 staining. Moreover, we demonstrated the anti-inflammatory effects of piperine using western blot analysis, real-time PCR, and ELISA. Pretreatment with piperine suppressed the activation of phosphorylated p38, JNK, and AP-1 as well as the levels of COX-2/PGE

Topics: Alkaloids; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Benzodioxoles; Celecoxib; Cell Line; Dose-Response Relationship, Drug; Humans; Inflammation; Keratinocytes; Piperidines; Polyunsaturated Alkamides; Skin; Ultraviolet Rays

Acute and chronic inflammation in the central nervous system plays a critical role in the development of neurodegenerative disorders. Various pro-inflammatory cytokines, chemokines, and enzymes such as TNF-α, IL1-β, IL-6, COX-1, COX-2, iNOS, IKK, and inducible nitric oxide are expressed in several signalling pathways, and mediate the neuroinflammatory process. ROS and NF-kB nuclear translocation are the two fundamental pathways involved in neuroinflammatory pathogenesis in neuronal and glial cells. In recent years several compoundswere designed to affect the neuroinflammation and suppress neurodegenerative process. Derivatives of natural products (NPs) attract the most attention of drug developers and industries due to their safety and lesser side effects in comparison with generic drugs. One of the most well-known NP is piperine, which is a yellow crystalline alkaloid extracted from black and white pepper. Recently, we developed a novel piperine derivative (((2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-N-(4-(hydroxymethyl)phenyl)penta-2,4-dienamide, D4) to enhance the specificity and efficacy of the base molecule. Next, we evaluated the potential anti-inflammatory properities of D4 in CHME3 and SVG cell-lines corresponding to human microglia and astrocytes, respectively. Our results indicated that D4 inhibited NF-kB translocation pathway, and significantly reduced transcript and protein levels of pro-inflammatory cytokines in comparison with Aspirin, as a well-known non-selective NSAID. Furthermore, in silico study showed excellent D4 bioavailability in oral administration. The results of the present study suggest a novel molecule with high anti-neuroinflammatory potency for further pre-clinical tests and pharmacological drug investigation.

Topics: Anti-Inflammatory Agents; Astrocytes; Brain; Cell Line; Cytokines; Down-Regulation; Humans; Inflammation; Microglia; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Piperidines; PPAR gamma; Protein Transport

Atrial fibrillation (AF) commonly occurs after surgery and is associated with atrial remodeling. TRPV4 is functionally expressed in the heart, and its activation affects cardiac structure and functions. We hypothesized that TRPV4 blockade alleviates atrial remodeling and reduces AF induction in sterile pericarditis (SP) rats. TRPV4 antagonist GSK2193874 or vehicle was orally administered 1 day before pericardiotomy. AF susceptibility and atrial function were assessed using in vivo electrophysiology, ex vivo optical mapping, patch clamp, and molecular biology on day 3 after surgery. TRPV4 expression increased in the atria of SP rats and patients with AF. GSK2193874 significantly reduced AF vulnerability in vivo and the frequency of atrial ectopy and AF with a reentrant pattern ex vivo. Mechanistically, GSK2193874 reversed the abnormal action potential duration (APD) prolongation in atrial myocytes through the regulation of voltage-gated K+ currents (IK); reduced the activation of atrial fibroblasts by inhibiting P38, AKT, and STAT3 pathways; and alleviated the infiltration of immune cells. Our results reveal that TRPV4 blockade prevented abnormal changes in atrial myocyte electrophysiology and ameliorated atrial fibrosis and inflammation in SP rats; therefore, it might be a promising strategy to treat AF, particularly postoperative AF.

Topics: Action Potentials; Aged; Animals; Atrial Fibrillation; Atrial Remodeling; Female; Fibrosis; Heart Atria; Heart Rate; Humans; Inflammation; Male; Middle Aged; Myocytes, Cardiac; Pericarditis; Piperidines; Quinolines; Rats; Rats, Sprague-Dawley; TRPV Cation Channels

The NLR family pyrin domain containing 3 (NLRP3) inflammasome is a widely studied inflammasome that plays a critical role in inflammatory responses. Many triggers, including microbial pathogens (ie, bacteria and viruses) and other signals (ie, reactive oxygen species, adenosine triphosphate, urate, silicon, and asbestos), can stimulate the NLRP3 inflammasome. Liver ischemia/reperfusion (I/R) injury is a common pathologic process during liver surgery and shock and can induce severe liver damage. Although its pathogenesis is still unclear, oxidative stress and overproduction of the inflammatory response are likely to contribute to I/R injury. The NLRP3 inflammasome is activated during the I/R process, resulting in further recruitment and activation of caspase-1. Activated caspase-1 cleaves the pro-forms of interleukin-1β and interleukin-18 and results in their maturation, triggering a proinflammatory cytokine cascade and causing liver damage. Bruton's tyrosine kinase is a critical molecule involved in diverse cellular pathways, such as proliferation, apoptosis, inflammation, and angiogenesis. Intrahepatic Bruton's tyrosine kinase is mainly expressed on Kupffer cells and sinusoidal endothelial cells, and the inflammasome is activated in Kupffer cells. Our study found that inhibition of Bruton's tyrosine kinase effectively attenuated liver I/R injury by suppressing activation of the NLRP3 inflammasome in Kupffer cells.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Inflammasomes; Inflammation; Liver; Male; Mice; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein; Oxidative Stress; Piperidines; Reactive Oxygen Species; Reperfusion Injury

Sepsis is a life-threatening organ dysfunction initiated by a dysregulated response to infection, with imbalanced inflammation and immune homeostasis. Macrophages play a pivotal role in sepsis. N-[1-(1-oxopropyl)-4-piperidinyl]-N'-[4-(trifluoromethoxy)phenyl)-urea (TPPU) is an inhibitor of soluble epoxide hydrolase (sEH), which can rapidly hydrolyze epoxyeicosatrienoic acids (EETs) to the bio-inactive dihydroxyeicosatrienoic acids. TPPU was linked with the regulation of macrophages and inflammation. Here, we hypothesized that sEH inhibitor TPPU ameliorates cecal ligation and puncture (CLP)-induced sepsis by regulating macrophage functions.. A polymicrobial sepsis model induced by CLP was used in our study. C57BL/6 mice were divided into four groups: sham+ phosphate buffer saline (PBS), sham+TPPU, CLP+PBS, CLP+TPPU. Mice were observed 48 h after surgery to assess the survival rate. For other histological examinations, mice were sacrificed 6 h after surgery. Macrophage cell line RAW264.7 was used for in vitro studies.. TPPU treatment, accompanied with increased EETs levels, markedly improved the survival of septic mice induced by CLP surgery, which was associated with alleviated organ damage and dysfunction triggered by systemic inflammatory response. Moreover, TPPU treatment significantly inhibited systemic inflammatory response via EETs-induced inactivation of mitogen-activated protein kinase signaling due to enhanced macrophage phagocytic ability and subsequently reduced bacterial proliferation and dissemination, and decreased inflammatory factors release.. sEH inhibitor TPPU ameliorates cecal ligation and puncture-induced sepsis by regulating macrophage functions, including improved phagocytosis and reduced inflammatory response. Our data indicate that sEH inhibition has potential therapeutic effects on polymicrobial-induced sepsis.

Topics: Animals; Cecum; Disease Models, Animal; Enzyme Inhibitors; Epoxide Hydrolases; Flow Cytometry; Inflammation; Ligation; Macrophages; Male; Mice; Mice, Inbred C57BL; Phagocytosis; Phenylurea Compounds; Piperidines; Sepsis

Asthma is a chronic allergic inflammatory airway disease caused by aberrant immune responses to inhaled allergens, which leads to airway hyperresponsiveness (AHR) to contractile stimuli and airway obstruction. Blocking T helper 2 (T

Topics: Animals; Asthma; Bronchoconstriction; Cell Differentiation; Diacylglycerol Kinase; Enzyme Inhibitors; Humans; Inflammation; MAP Kinase Signaling System; Mice, Knockout; Myocytes, Smooth Muscle; Piperidines; Quinazolinones; Respiratory Hypersensitivity; Signal Transduction; Th2 Cells

C57BL6/J (B6) mice lacking Se-dependent GSH peroxidase 1 and 2 (GPx1/2-DKO) develop mild to moderate ileocolitis around weaning. These DKO mice have a disease resembling human very-early-onset inflammatory bowel disease (VEOIBD), which is associated with mutations in NADPH oxidase genes. Drugs including dexamethasone (Dex), Tofacitinib (Tofa; a Janus kinase/JAK inhibitor) and anti-TNF antibody are effective to treat adult, but not pediatric IBD.. To test the efficacy of hydrophobic Dex and hydrophilic Dex phosphate (Dex phos), Tofa, anti-Tnf Ab, Noxa1ds-TAT and gp91ds-TAT peptides (inhibiting NOX1 and NOX2 assembly respectively), antioxidant MJ33 and ML090, and pifithrin-α (p53 inhibitor) on alleviation of gut inflammation in DKO weanlings.. All treatments began on 22-day-old GPx1/2-DKO mice. The mouse intestine pathology was compared between the drug- and vehicle-treated groups after six or thirteen days of treatment.. Among all drugs tested, Dex, Dex phos and Tofa were the strongest to suppress ileocolitis in the DKO weanlings. Dex, Dex phos and Tofa inhibited crypt apoptosis and increased crypt density. Dex or Dex phos alone also inhibited cell proliferation, exfoliation and crypt abscess in the ileum. Dex, but not Tofa, retarded mouse growth. Both Dex and Tofa inhibited ileum Nox1, Nox4 and Duox2, but not Nox2 gene expression. Noxa1ds-TAT and gp91ds-TAT peptides as well as MJ33 had subtle effect on suppressing pathology, while others had negligible effect.. These findings suggest that NADPH oxidases can be novel drug targets for pediatric IBD therapy, and Tofa may be considered for treating VEOIBD.

Topics: Animals; Apoptosis; Crohn Disease; Dexamethasone; Glutathione Peroxidase; Glutathione Peroxidase GPX1; Ileum; Inflammation; Inflammatory Bowel Diseases; Mice; Mice, Inbred C57BL; NADPH Oxidase 1; NADPH Oxidases; Oxidation-Reduction; Peroxidases; Piperidines; Pyrimidines; Pyrroles

LiTCTP is a toxin from the Translationally Controlled Tumor Protein (TCTP) family identified in

Topics: Animals; Biomarkers, Tumor; Cimetidine; Cromolyn Sodium; Dose-Response Relationship, Drug; Hypersensitivity; Inflammation; Injections, Intraperitoneal; Injections, Intravenous; Mast Cells; Mice; Phosphoric Diester Hydrolases; Piperidines; Promethazine; Rabbits; Rats; Skin Diseases; Spider Venoms; Tumor Cells, Cultured; Tumor Protein, Translationally-Controlled 1

Myelin-laden macrophages (mye-MΦ), resulting primarily from internalization of myelin debris by infiltrating bone marrow-derived macrophages in spinal cord injury (SCI), trigger inflammatory responses that largely contribute to secondary injury. Adiponectin, which is secreted from adipose tissue, is an important hormone that modulates macrophage inflammation. In the present study, we examined the role of adiponectin on macrophage-mediated neuroinflammation after SCI. We found that in vitro activation of adiponectin receptors (AdipoRs) by their agonist AdipoRon suppressed myelin lipid accumulation in mye-MΦ through APPL1/PPARγ/LXRα/ABCA1-mediated lipid efflux, subsequently inhibiting inflammation and restoring normal function to mye-MΦ. In vivo data further confirmed that intravenous administration of AdipoRon after SCI dampened recruitment of macrophages and reduced myelin lipid accumulation. Accordingly, AdipoRon treatment ameliorated post-SCI tissue damage and astrogliosis, resulting in improved motor function. Although there was no significant pathological exacerbation in adiponectin-null mice subjected to SCI, our work reveals a functional link between adiponectin and hematogenous macrophages in the context of SCI, suggesting that activation of adiponectin signaling is a promising therapeutic approach to mitigate mye-MΦ-mediated neuroinflammation in neurological disorders involving demyelination.

Topics: Adiponectin; Animals; Inflammation; Lipids; Macrophage Activation; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Myelin Sheath; Piperidines; Receptors, Adiponectin; Signal Transduction; Spinal Cord Injuries

Paclitaxel induces microglial activation and production of proinflammatory mediators in the dorsal horn, which contribute to the development and maintenance of central sensitization and pain behavior. MDA7, 1-([3-benzyl-3-methyl-2,3-dihydro-1-benzofuran-6-yl]carbonyl) piperidine, is a novel highly selective cannabinoid type 2 (CB2) agonist. We tested the hypothesis that activation of CB2 receptor by MDA7 modulates microglial dysregulation, suppresses the overexpression of brain-derived neurotrophic factor (BDNF) in microglia in the dorsal horn, and attenuates the central sensitization and pain behavior induced by paclitaxel. For 4 consecutice days, groups of rats randomly received saline or 1.0 mg/kg of paclitaxel daily intraperitoneally for a total cumulative dose of 4 mg/kg. MDA7 15 mg/kg intraperitoneally or vehicle were administered 15 min before administering paclitaxel for 4 days and then continued for another 10 days. Behavioral and molecular studies were performed. Paclitaxel induced the expression of CB2 receptors and production of interleukin (IL)-6 in microglia in the dorsal horn. MDA7 attenuated the expression of IL-6 and promoted the expression of IL-10. Paclitaxel induced epigenetic upregulation of IRF8 and P2X purinoceptor 4 (P2X4) in microglia and subsequently increased the expression of alpha isoform of calcium/calmodulin-dependent protein kinase II (CaMKIIα), transcriptional factors p-CREB and ΔFosB, leading to the overproduction of BDNF in microglia. Paclitaxel also upregulated the expression of glutamate receptor subunits GluR1 and NR2B, decreased the expression of K

Topics: Animals; Benzofurans; Brain-Derived Neurotrophic Factor; Cannabinoid Receptor Agonists; Central Nervous System Sensitization; Epigenesis, Genetic; Hyperalgesia; Inflammation; Male; Microglia; Neuralgia; Paclitaxel; Piperidines; Random Allocation; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB2; Spinal Cord Dorsal Horn

Disruption of epithelial cell-cell junctions is essential for the initiation and perpetuation of airway inflammation in asthma. We've previously reported compromised epithelial barrier integrity in a toluene diisocyanate (TDI)-induced occupational asthma model. This study is aimed to explore the role of transient receptor potential vanilloid 4 (TRPV4) and transient receptor potential ankyrin 1 (TRPA1) in the dysfunction of adherens junctions in TDI-induced asthma. Mice were sensitized and challenged with TDI for a chemical-induced asthma model. Selective blockers of TRPV4 glycogen synthase kinase (GSK)2193874, 5 and 10 mg/kg) and TRPA1 (HC030031, 10 and 20 mg/kg) were intraperitoneally given to the mice. Immunohistochemistry revealed different expression pattern of TRPV4 and TRPA1 in lung. TDI exposure increased TRPV4 expression in the airway, which can be suppressed by GSK2193874, while treatment with neither TDI alone nor TDI together with HC030031 led to changes of TRPA1 expression in the lung. Blocking either TRPV4 or TRPA1 blunted TDI-induced airway hyperreactivity, airway neutrophilia and eosinophilia, as well as Th2 responses in a dose-dependent manner. At the same time, membrane levels of E-cadherin and β-catenin were significantly decreased after TDI inhalation, which were inhibited by GSK2193874 or HC030031. Moreover, GSK2193874 and HC030031 also suppressed serine phosphorylation of glycogen synthase kinase 3β, tyrosine phosphorylation of β-catenin, as well as activation and nuclear transport of β-catenin in mice sensitized and challenged with TDI. Our study suggested that both TRPV4 and TRPA1 contribute critically to E-cadherin and β-catenin dysfunction in TDI-induced asthma, proposing novel therapeutic targets for asthma.

Topics: Acetanilides; Adherens Junctions; Animals; Asthma; beta Catenin; Bronchoalveolar Lavage Fluid; Cadherins; Cytokines; Epithelial Cells; Inflammation; Lung; Mice; Mice, Inbred C57BL; Phosphorylation; Piperidines; Purines; Quinolines; Toluene 2,4-Diisocyanate; Transient Receptor Potential Channels; TRPA1 Cation Channel; TRPV Cation Channels

Rohitukine (referred to as RHK) is a bioactive chromone alkaloid isolated from the leaves of plant Dysoxylum binectariferum, which has been reported to possess diverse pharmacological properties for the treatment of inflammatory bowel disease (IBD), diarrhoea and anti-lipidemic. However, the underlying mechanism by which RHK exerts its anti-inflammatory activity has not yet demonstrated. This study aimed to elucidate the anti-inflammatory mechanism of RHK using lipopolysaccharide (LPS) - stimulated J774A.1 macrophage cells and in-vivo inflammatory models. Results demonstrated that RHK treatment could significantly decrease the LPS-induced production of nitric oxide, prostaglandin E2 (PGE2), interleukins (ILs) and tumour necrosis factor (TNF)-α in J774A.1 cells. Molecular studies revealed that RHK inhibited the activation of upstream mediator nuclear factor-κB by suppressing the phosphorylation of IκBα and p65. In in-vivo experiments showed prominent anti-inflammatory activity of RHK. Thus, RHK could be considered as a promising candidate for the treatment of inflammatory diseases.

Topics: Animals; Anti-Inflammatory Agents; Cell Line; Chromones; Dinoprostone; Humans; Inflammation; Interleukins; Lipopolysaccharides; Macrophages; Male; Meliaceae; Mice; Mice, Inbred BALB C; NF-kappa B; Nitric Oxide; Piperidines; Rats; Rats, Wistar; Signal Transduction; Tumor Necrosis Factor-alpha

Among the molecular signals underlying cutaneous inflammation is the transcription complex NF-κB, its upstream modulators, and cytokines and chemokines that are the downstream proinflammatory effectors. Central to NF-κB activation is IκB kinase (IKK), which phosphorylates IκBα, releasing NF-κB to the nucleus. In a screening of a kinase inhibitor library, we identified two IKK inhibitors that were high-affinity substrates for p-glycoprotein (ABCB1), the multidrug resistance protein known to facilitate transdermal drug delivery. ACHP (2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(4-piperidinyl)-3-pyridinecarbonitrile) and IKK 16 prevented both nuclear translocation of NF-κB and activation of a NF-κB reporter and reduced the induction of cytokine and chemokine transcripts in human or mouse keratinocytes by IL-1α, tumor necrosis factor-α, and phorbol myristate acetate. ACHP, but not IKK 16, was nontoxic to mouse or human keratinocytes at any dose tested. In mice, topical ACHP prevented the cutaneous inflammation induced by topical phorbol myristate acetate or imiquimod, reduced the inflammation from erythema doses of artificial sunlight, and lowered the tumor incidence of mice treated with 7,12-dimethyl benzanthracene when applied before phorbol myristate acetate. Topical ACHP also reduced the NF-κB and IL-17 inflammatory signature after multiple doses of imiquimod. Thus, ACHP and IKK 16 hit their NF-κB target in mouse and human keratinocytes, and ACHP is an effective topical nonsteroidal anti-inflammatory in mice.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Administration, Topical; Animals; Anti-Inflammatory Agents, Non-Steroidal; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cytokines; Disease Models, Animal; Drug Therapy, Combination; Humans; Imiquimod; Inflammation; Keratinocytes; Mice; NF-kappa B; Nicotinic Acids; Nitriles; Piperidines; Pyrrolidines; Skin; Skin Neoplasms

The adoption of Warburg metabolism is critical for the activation of macrophages in response to lipopolysaccharide. Macrophages stimulated with lipopolysaccharide increase their expression of nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in NAD

Topics: Acrylamides; Animals; Cells, Cultured; Cytokines; DNA Damage; Electron Transport Complex III; HEK293 Cells; Humans; Inflammation; Macrophage Activation; Macrophages; Mice; Mice, Inbred C57BL; Mitochondria; NAD; Nicotinamide Phosphoribosyltransferase; Piperidines; Reactive Oxygen Species

Tofacitinib (Tofa) has been approved for moderately to severely active ulcerative colitis (UC). To improve its therapeutic efficacy and limit dose-dependent toxicity, we developed a macromolecular prodrug of Tofa (P-Tofa). If the prodrug design improves the potency and duration of Tofa therapy, it would widen its therapeutic window, potentially leading to improved safety and better clinical management of UC.. P-Tofa was synthesized by conjugating Tofa to N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer via a cleavable carbamate linker. DSS-induced UC mouse model were treated with Tofa (daily oral gavage, from day 8), P-Tofa (single intravenous administration on day 8, dose equivalent to Tofa treatment) and saline. Healthy mice were used as a positive control. The therapeutic efficacy was evaluated using disease activity index (DAI), endoscopic score and end-point histology. The optical imaging, immunohistochemistry and flow cytometry were used to understand P-Tofa's working mechanism.. DAI results suggested that a single dose P-Tofa treatment was more efficacious than dose equivalent daily Tofa treatment. Endoscopic evaluation and histology analyses confirmed that while both P-Tofa and Tofa protected the colon, P-Tofa treated group was observed with better colon integrity with less tissue damage. Optical imaging, flow cytometry and immunohistochemistry results showed that P-Tofa passively targeted the inflamed colon and being retained via cellular sequestration.. Single intravenous administration of P-Tofa was more effective than dose equivalent daily oral Tofa gavage in ameliorating DSS-induced colitis. This observed superior therapeutic efficacy may be attributed to P-Tofa's passive targeting to and retention by the inflamed colon.

Topics: Animals; Colitis, Ulcerative; Colon; Dextran Sulfate; Disease Models, Animal; Inflammation; Janus Kinases; Male; Methacrylates; Mice; Piperidines; Polymers; Prodrugs; Pyrimidines; Pyrroles

Inflammatory bowel disease (IBD) is characterized by chronic, recurring inflammation of the digestive tract. Current therapeutic approaches are limited and include biologics and steroids such as anti-TNFα monoclonal antibodies and corticosteroids, respectively. Significant adverse drug effects can occur for chronic usage and include increased risk of infection in some patients. GPR4, a pH-sensing G protein-coupled receptor, has recently emerged as a potential therapeutic target for intestinal inflammation. We have assessed the effects of a GPR4 antagonist, 2-(4-((2-Ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)phenyl)-5-(piperidin-4-yl)-1,3,4-oxadiazole (GPR4 antagonist 13, also known as NE-52-QQ57) in the dextran sulfate sodium (DSS)-induced acute colitis mouse model. The GPR4 antagonist 13 inhibited intestinal inflammation. The clinical parameters such as body weight loss and fecal score were reduced in the GPR4 antagonist 13 treatment group compared to vehicle control. Macroscopic disease indicators such as colon shortening, splenic expansion, and mesenteric lymph node enlargement were all reduced in severity in the GPR4 antagonist 13 treated mice. Histopathological features of active colitis were alleviated in GPR4 antagonist 13 treatment groups compared to vehicle control. Finally, inflammatory gene expression in the colon tissues and vascular adhesion molecule expression in the intestinal endothelia were attenuated by GPR4 antagonist 13. Our results indicate that GPR4 antagonist 13 provides a protective effect in the DSS-induced acute colitis mouse model, and inhibition of GPR4 can be explored as a novel anti-inflammatory approach.

Topics: Animals; Colitis; Disease Models, Animal; E-Selectin; Female; Gene Expression Regulation; Inflammation; Intestinal Mucosa; Male; Mice; Mice, Inbred C57BL; Oxadiazoles; Piperidines; Pyrazoles; Receptors, G-Protein-Coupled; Vascular Cell Adhesion Molecule-1

The Janus-activated kinase (JAK) family together with signal transducer and activator of transcription (STAT) signaling pathway has a key role in regulating the expression and function of many inflammatory cytokines. This has led to the discovery of JAK inhibitors for the treatment of inflammatory diseases, some of them already in the market. Considering the adverse effects associated with JAK inhibition by oral route, we wanted to explore whether JAK inhibition by inhaled route is enough to inhibit airway inflammation. The aim of this study was to characterize the enzymatic and cellular potency and the selectivity of LAS194046, a novel JAK inhibitor, compared with the reference compounds ruxolitinib and tofacitinib. The efficacy of this new JAK inhibitor is described in a model of ovalbumin (OVA)-induced airway inflammation in Brown Norway rats by inhaled administration. As potential markers of target engagement, we assessed the effect of LAS194046 on the STAT activation state. LAS194046 is a selective inhaled pan-JAK inhibitor that reduces allergen-induced airway inflammation, late asthmatic response, and phosphor-STAT activation in the rat OVA model. Our results show that topical inhibition of JAK in the lung, without relevant systemic exposure, is sufficient to reduce lung inflammation and improve lung function in a rat asthma model. In summary, JAK-STAT pathway inhibition by inhaled route constitutes a promising therapeutic option for lung inflammatory diseases.

Topics: Administration, Inhalation; Allergens; Animals; Asthma; Inflammation; Isoenzymes; Janus Kinase Inhibitors; Janus Kinases; Male; Nitriles; Phosphoproteins; Piperidines; Pyrimidines; Rats; Rats, Sprague-Dawley; Signal Transduction; STAT Transcription Factors; Time Factors

Fatty acid amide hydrolase (FAAH) has been recognized as a therapeutic target for several neurological diseases because its inhibition can exert neuroprotective and anti-inflammatory effects by boosting the endogenous levels of

Topics: Amidohydrolases; Animals; Anti-Inflammatory Agents; Benzamides; Carbamates; Cell Line; Cyclooxygenase 2; Cytokines; Dinoprostone; Gene Knockdown Techniques; Inflammation; Microglia; Piperidines; Pyridines

The epoxyeicosatrienoic acids (EETs) are products of cytochrome P450 epoxygenases and have recently been found to have an anti-inflammatory activity. However, the role of EETs in non-alcoholic steatohepatitis has not been fully understood. In this study, we investigated the protective role of EETs in methionine-choline-deficient (MCD) diet-induced non-alcoholic steatohepatitis (NASH) in mice and the potential mechanisms. We used 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea(TPPU), a soluble epoxide hydrolase inhibitor, to increase the endogenous EET level in mice. Upon TPPU treatment, the liver steatosis and inflammatory damage were significantly ameliorated in mice with steatohepatitis, paralleled by the downregulation of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) as well as chemokines (CXCL1, MCP-1). Compared with untreated NASH mice, mRNA levels of sterol regulatory element binding protein 1c (SREBP1c) and inflammation relevant adhesion molecules (ICAM-1, VCAM-1) were downregulated, whereas mRNA level of peroxisome proliferator-activated receptor α(PPAR-α) was elevated in TPPU-treated mice. In vitro, 11,12-EET treatment remarkably attenuated free fatty acid (FFA)-induced inflammation in HepG2 and THP-1 cells. Further, 11,12-EET inhibited the activation of NF-κB signalling pathway in macrophages from mice with steatohepatitis. Collectively, these results suggest that EETs play a protective role and alleviate the MCD diet-induced steatohepatitis in mice mainly by downregulating activation of NF-κB pathway in macrophages.

Topics: Animals; Cell Line; Cell Line, Tumor; Chemokines; Choline; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme System; Cytokines; Diet; Down-Regulation; Hep G2 Cells; Humans; Inflammation; Intercellular Adhesion Molecule-1; Liver; Macrophages; Methionine; Mice; NF-kappa B; Non-alcoholic Fatty Liver Disease; Phenylurea Compounds; Piperidines; PPAR alpha; RNA, Messenger; Signal Transduction; Sterol Regulatory Element Binding Protein 1; THP-1 Cells; Vascular Cell Adhesion Molecule-1

Obesity is characterized by chronic low-grade inflammation that contributes to development of cardiometabolic disorders. Cannabinoid receptor 1 (CB1) antagonists attenuate diet-induced obesity (DIO) and related inflammation, although the precise anti-inflammatory mechanisms involved have not been fully explored. In the current study we used a mouse model of DIO intervention to determine the microRNA (miRNA, miR)-mediated anti-obesity and anti-inflammatory effects of the CB1 antagonist, AM251. DIO mice that were fed high-fat diet (HFD) for 12 weeks were treated with AM251 (10 mg/kg) for an additional 4 weeks. HFD + AM251 mice experienced rapid and prolonged weight loss and reduced inflammatory M1 adipose tissue macrophage (ATM) infiltration. To investigate miRNA-mediated regulation of ATMs, F4/80+ cells from stromal vascular fractions (SVF) of epididymal fat were subjected to miR microarray analysis. Several miRs were differentially expressed in AM251-treated mice that were independent of calorie restriction. Prominently, miR-30e-5p was upregulated in ATMs from HFD + AM251 mice while the miR-30e-5p target, DLL4, was downregulated. Consistent with a decrease in DLL4-Notch signaling, fat storage and pro-inflammatory cytokine/chemokine expression was reduced following AM251 treatment. Furthermore, we found that AM251-treated macrophages can suppress DLL4-mediated Th1 polarization in CD4+ T cells. Together these data demonstrate that blocking CB1 receptors leads to upregulation of miR-30e-5p and down regulation of DLL4 in ATMs, which in turn suppress DLL4-Notch signaling-induced polarization of inflammatory Th1 cells and adipocyte energy storage. This combined effect of ATMs and T cells leads to an anti-inflammatory state and attenuation of DIO. These data support therapeutic potential of miR-30 in the treatment of cardiometabolic disorders.

Topics: Adaptor Proteins, Signal Transducing; Adipose Tissue; Animals; Calcium-Binding Proteins; Diet, High-Fat; Inflammation; Macrophages; Mice; Mice, Inbred C57BL; Mice, Obese; MicroRNAs; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Th1 Cells

Piperine, the major alkaloid constituent of black pepper, has been reported to possess a wide range of pharmacological effects on the central nervous system, including antidepressant, anticonvulsant and anti-ischemic activities. In the present study, we aimed to investigate the therapeutic potential and neuroprotective mechanisms of piperine in an experimental mouse model of sporadic Alzheimer's disease (sAD) induced by intracerebroventricular (ICV) infusion of streptozotocin (STZ). STZ was infused bilaterally at a dose of 1.5 mg/kg/day on day 1 and day 3. From day 8, piperine (2.5-10 mg/kg body weight) was administered intraperitoneally once daily for 15 consecutive days. The locomotor activity and cognitive performance of mice were evaluated using open field test and Morris water maze test, respectively. On day 23, all animals were sacrificed, and the hippocampus was used for biochemical, neurochemical and neuroinflammatory determinations. Our data revealed that the ICV-STZ-infused sAD mouse showed an increased oxidative-nitrosative stress, an altered neurotransmission and an elevated neuroinflammation in hippocampus, as well as significant cognitive deficits. All these alterations can be ameliorated by piperine in a dose-dependent manner. In summary, our findings predict a therapeutic potential of piperine against cognitive deficits in sAD mouse. This effect might be due to its abilities to ameliorate oxidative-nitrosative stress, restore neurotransmission and reduce neuroinflammation.

Topics: Alkaloids; Alzheimer Disease; Animals; Benzodioxoles; Cognition Disorders; Disease Models, Animal; Hippocampus; Inflammation; Infusions, Intraventricular; Male; Maze Learning; Memory Disorders; Mice; Neuroprotective Agents; Nitrogen; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Streptozocin

To observe the effects of AdipoRon orally on the functions of spleen and pancreas in type 2 diabetic mice, in order to present data for clinical application.. Forty C57/BL6 male mice were randomly divided into 2 groups: normal control group (n=10) and model group (n=30), the former group was fed normally, while the later group was fed with high fat and sugar for 4 weeks.After that, type 2 diabetes model was established in DM group induced by intraperitoneal injection of streptozotocin (STZ, 40 mg/kg).As type 2 diabetes model established successfully, the model mice were randomly divided into three groups (n=10): diabetes mellitus (DM) group, high dose of AdipoRon group (DM + H) and low dose of adiponRon group (DM + L).All the four groups were treated with saline, saline, AdipoRon at the doses of 20 mg/kg and 50 mg/kg by gavages respectively, once a day for 10 days.And then put them to death for collecting blood, pancreas and spleen.Pathological changes of pancreas were observed with a light microscope after HE staining.Protein contents of insulin receptor (INSR), insulin receptor substrate 1( IRS-1) and tumor necrosis factor-α(TNF-α) in pancreatic and spleen tissues were detected by ELISA.The protein level of phosphorylation insulin receptor substrate 1(p-IRS-1) in pancreas was determined by Western blot, and the expression of insulin mRNA in pancreas was tested by RT-PCR.. Under the light microscope, it was visible that the pancreatic tissue in NC group was full and closely packed, and the islet was big.Pancreatic tissue of DM mice was incompact and the islet of DM mice was smaller than that of normal mice.As for the mice treated with AdipoRon orally, the pancreatic tissue was full and closely arranged, and the islet was slightly smaller.Compared with NC group, the levels of TNF-α in pancreas and spleen of DM group were increased markedly, the levels of INSR and IRS-1 were decreased, the spleen coefficient, p-IR-1 protein level and insulin mRNA expression in pancreas were decreased, all were significant statistically (P＜0.05).Compared with DM group, the levels of TNF-α in pancreas and spleen of AdipoRon groups were decreased, the levels of INSR and IRS-1 in pancreas and spleen of AdipoRon groups were increased, while the spleen coefficient was increased (P＜0.05).The p-IRS-1 protein level and insulin mRNA expression in pancreas in DM+H group were increased (P＜0.05).Compared with DM + L group, the level of TNF-α was decreased, and the levels of INSR and IRS-1 were significantly increased (P＜0.05) in DM + H group (P＜0.05).. Oral administration of AdipoRon can protect the spleen and pancreas of diabetic mice by decreasing the inflammatory response, up-regulating the expression of INSR, and increasing p-IRS-1 level in diabetic mice.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Inflammation; Insulin; Insulin Receptor Substrate Proteins; Male; Mice; Pancreas; Piperidines; Random Allocation; Receptor, Insulin; Spleen

Rheumatoid arthritis (RA) is an autoimmune disease characterized by persistent synovial inflammation. The major drivers of synovial inflammation are cytokines and chemokines. Among these molecules, TNF activates fibroblast-like synoviocytes (FLSs), which leads to the production of inflammatory mediators. Here, we show that TNF regulates the expression of the transcription factor interferon regulatory factor 1 (IRF1) in human FLSs as well as in a TNF transgenic arthritis mouse model. Transcriptomic analyses of IRF1-deficient, TNF-stimulated FLSs define the interferon (IFN) pathway as a major target of IRF1. IRF1 expression is associated with the expression of IFNβ, which leads to the activation of the JAK-STAT pathway. Blocking the JAK-STAT pathway with the Janus kinase inhibitor (JAKinib) baricitinib or tofacitinib reduces the expression of IFN-regulated genes (IRGs) in TNF-activated FLSs. Therefore, we conclude that TNF induces a distinct inflammatory cascade, in which IRGs are key elements, in FLSs. The IFN-signature might be a promising biomarker for the efficient and personalized use of new treatment strategies for RA, such as JAKinibs.

Topics: Animals; Arthritis, Rheumatoid; Azetidines; Biomarkers; Female; Gene Expression; Humans; Inflammation; Interferon Regulatory Factor-1; Interferons; Janus Kinase Inhibitors; Mice; Mice, Inbred C57BL; Mice, Transgenic; Piperidines; Purines; Pyrazoles; Pyrimidines; Pyrroles; Signal Transduction; Sulfonamides; Synovial Membrane; Synoviocytes; Tumor Necrosis Factor-alpha

The intestinal epithelium serves as an essential barrier to the outside world and is maintained by functionally distinct populations of rapidly cycling intestinal stem cells (CBC ISCs) and slowly cycling, reserve ISCs (r-ISCs). Because disruptions in the epithelial barrier can result from pathological activation of the immune system, we sought to investigate the impact of inflammation on ISC behavior during the regenerative response. In a murine model of αCD3 antibody-induced small-intestinal inflammation, r-ISCs proved highly resistant to injury, while CBC ISCs underwent apoptosis. Moreover, r-ISCs were induced to proliferate and functionally contribute to intestinal regeneration. Further analysis revealed that the inflammatory cytokines interferon gamma and tumor necrosis factor alpha led to r-ISC activation in enteroid culture, which could be blocked by the JAK/STAT inhibitor, tofacitinib. These results highlight an important role for r-ISCs in response to acute intestinal inflammation and show that JAK/STAT-1 signaling is required for the r-ISC regenerative response.

Topics: Acute Disease; Animals; Apoptosis; Cytokines; Enteritis; Inflammation; Intestinal Mucosa; Intestine, Small; Janus Kinases; Mice; Mice, Transgenic; Piperidines; Pyrimidines; Pyrroles; Regeneration; Signal Transduction; STAT1 Transcription Factor; Stem Cells

Clinical and preclinical studies firmly support the involvement of the inflammation in the pathogenesis of Alzheimer's disease (AD). Despite acetylcholinesterase inhibitors (AChEI) being widely used in AD patients, there is no conclusive evidence about their impact on the inflammatory response.. This study investigates peripheral proinflammatory cytokines (interferon gamma [IFN-γ], tumor necrosis factor alpha [TNF-α], and interleukins 1β [IL-1β] and 6 [IL-6]) by firstly comparing peripheral blood mononuclear cell (PBMC)-derived secretion in drug-naïve and AChEI-treated AD patients versus healthy controls. A subset of those drug-naïve AD patients, who were prescribed the AChEI donepezil, was followed-up for 6 months to investigate if donepezil suppresses proinflammatory cell-derived cytokine secretion.. Patients with AD showed higher levels of PBMC-derived proinflammatory cytokines (IFN-γ, TNF-α, IL-1β, and IL-6) in comparison with healthy controls. On reexamination, previously drug-naïve AD patients who received donepezil treatment for 6 months displayed a decrease in cell-derived IFN-γ, TNF-α, IL-1β, and IL-6.. Proinflammatory PBMC-derived cytokines were increased in patients with AD in comparison with healthy controls and donepezil-reduced proinflammatory cytokines when examining drug-naïve AD patients before and after AChEI treatment.

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Cytokines; Donepezil; Female; Follow-Up Studies; Humans; Indans; Inflammation; Male; Middle Aged; Piperidines

Ischemia/reperfusion (I/R) is a critical risk factor for acute kidney injury (AKI). Recent studies provided evidence that tubular epithelial cells (TEC)-associated inflammation aggravates kidney injury and impairs tissue repair after I/R injury. Here we demonstrated that the Nod-like receptor protein 3 (NLRP3) inflammasome is activated by mitochondrial reactive oxygen species (mROS) during I/R injury via direct interactions between the inflammasome and thioredoxin-interacting protein (TXNIP). Firstly, we found that NLRP3 inflammasome activation was induced by I/R injury, peaking at day 3 after reperfusion. Consistent with this observation, NLRP3 deletion significantly attenuated I/R-induced kidney damage and markers of inflammasome activation. Then, we observed mitochondrial dysfunction, characterized by ultrastructural changes and cytochrome C (Cyt c) redistribution. Mitochondria-targeted antioxidant MitoTEMPO prevented mROS overproduction and the decline in mitochondrial membrane potential (MMP) in vitro. MitoTEMPO treatment also inhibited NLRP3 inflammasome activation and co-localization of NLRP3 and TXNIP after simulated ischemia/reperfusion (SI/R) injury. Finally, we transfected HK-2 cells with TXNIP siRNA to explore the role of TXNIP in mROS-induced NLRP3 inflammasome activation. We found that TXNIP siRNA significantly inhibited NLRP3 inflammasome activation. These results demonstrate that NLRP3 inflammasome is activated through the mROS-TXNIP-NLRP3 pathway and provide a potential therapeutic target in ischemic AKI.

Topics: Acute Kidney Injury; Animals; Antioxidants; Carrier Proteins; Cell Proliferation; Cells, Cultured; Inflammasomes; Inflammation; Interleukin-1beta; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; NLR Family, Pyrin Domain-Containing 3 Protein; Organophosphorus Compounds; Piperidines; Reactive Oxygen Species; Reperfusion Injury; Thioredoxins

Investigators are searching to find new therapeutic strategies to reduce stroke secondary injury. JZL-184 (JZL) is an inhibitory factor for production of arachidonic acid (AA). Thus, it suppresses production of AA metabolites which are the cause of inflammation and tissue edema. Therefore, JZL may be considered for suppression of stroke secondary injury in mice middle cerebral artery occlusion (MCAO) model. Additionally, Aspirin is a known anti-inflammatory factor which is used to reduce pro-inflammatory secondary injury. The aim of this study was to determine the effects of JZL on the reduction of stroke secondary injury and to compare them with Aspirin effects.. MCAO model has been induced and accordingly 83 male MCAO induced mice have been introduced to the study. The animals were divided to seven groups including intact, controls, vehicle, Aspirin, JZL 4, 8 and 16 mg/kg administrated groups. Brain edema and infarction, behavioral functions and brain levels of IL-10, TNF-α and matrix metaloperoteinase-9 (MMP9) have been examined in the evaluated groups.. The results revealed that JZL reduced brain edema, infarction, brain levels of TNF-α and MMP9 and also increased brain levels of IL-10 as well as improved behavioral functions in all three concentrations. The therapeutic effects of JZL were observed as well as Aspirin.. Based on the results, it seems that JZL can be considered as a good candidate for inhibition of stroke secondary injury in the case of delayed treatment.

Topics: Animals; Aspirin; Behavior, Animal; Benzodioxoles; Brain; Brain Edema; Brain Ischemia; Disease Models, Animal; Edema; Infarction, Middle Cerebral Artery; Inflammation; Interleukin-10; Male; Matrix Metalloproteinase 9; Mice; Monoacylglycerol Lipases; Neuroprotective Agents; Piperidines; Stroke; Tumor Necrosis Factor-alpha

Topical Janus kinase (JAK) inhibition is a promising therapeutic target for several inflammatory skin diseases of humans.. To evaluate the anti-inflammatory effect of tofacitinib, a JAK 1/3 inhibitor, on immediate and late-phase skin reactions in dogs.. Five healthy laboratory beagle dogs.. Topical tofacitinib (total daily dosage: 0.5 mg/cm. The tofacitinib gel was well-tolerated; one dog developed mild erythema at Day 5 that resolved by the next application. Treatment with tofacitinib reduced histamine and anticanine-IgE global wheal scores (one-way ANOVA, P ≤ 0.005 for both) compared to baseline; there was no significant difference for the vehicle placebo (histamine; P = 0.163; IgE, P = 0.223). Late-phase reactions (LPRs) were markedly, but not significantly reduced after tofacitinib treatment (P = 0.071). A blinded histological evaluation of 6 h-anti-IgE-associated LPRs revealed a significant reduction in the total leucocyte superficial dermal cellularity (P = 0.022), as well as eosinophil (P = 0.022) and mast cell (P = 0.022) counts at tofacitinib-treated sides compared with pretreatment values. Post-treatment complete blood counts and serum chemistry profiles did not show relevant tofacitinib-induced changes.. Our observations suggest that topical tofacitinib exerts an inhibitory effect on activated canine skin-emigrating immune cells; this drug should be investigated further as a topical immunosuppressive drug in dogs.

Topics: Animals; Anti-Inflammatory Agents; Dermatitis, Atopic; Dog Diseases; Dogs; Hypersensitivity, Delayed; Hypersensitivity, Immediate; Inflammation; Pilot Projects; Piperidines; Pyrimidines; Pyrroles

Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible lung disease with high mortality rate. The etiology is unknown and treatment choices are limited. Thus, there is great interest to investigate novel agents for IPF therapy. Ibrutinib, BTK, and ITK irreversible inhibitor is a FDA-approved small molecule for the clinical therapy of B cell lymphoma. Its role in pulmonary fibrosis remains unknown. In this study, we investigated the anti-fibrotic activity of ibrutinib. Strikingly, ibrutinib did not inhibit but exacerbated bleomycin-induced pulmonary fibrosis by increased epithelial cell apoptosis, and inflammation in the lung. The upregulated TGF-β and EMT transformation also contributes to enhanced myofibroblast differentiation and ECM deposition. Our findings reveal the detrimental effects of ibrutinib against bleomycin-mediated fibrosis and added to the understanding of IPF pathogenesis.

Topics: Adenine; Animals; Apoptosis; Bleomycin; Disease Models, Animal; Epithelial Cells; Humans; Idiopathic Pulmonary Fibrosis; Inflammation; Mice; Piperidines; Pulmonary Fibrosis; Pyrazoles; Pyrimidines

Epoxyeicosatrienoic acids (EETs) are produced by cytochrome P450 epoxygenases from arachidonic acid, and their rapid metabolism is mainly through soluble epoxide hydrolase (sEH). EETs exert vasodilatory, anti-inflammatory, anti-apoptotic, and pro-angiogenic effects. Administration of sEH inhibitors before or at the onset of stroke is protective, but the effects of post-treatment at reperfusion, when inflammation is augmented, has not been as well studied. We tested the hypothesis that 1-Trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea (TPPU), a potent and highly selective sEH inhibitor, suppresses inflammation and protects the brain when administered at reperfusion. Vehicle or 1 mg/kg TPPU was administered at reperfusion after 90 minutes of focal ischemia and again 24 hours later. Protein expression and activity of sEH increased after reperfusion and activity was decreased by TPPU administration. TPPU decreased infarct volume by 50%, reduced neurologic deficits and improved performance on sensorimotor tasks. Furthermore, TPPU significantly lowered the mRNA expression of interleukin-1beta by 3.5-fold and tumor necrosis factor-alpha by 2.2-fold, increased transforming growth factor-beta mRNA by 1.8-fold, and augmented immunostaining of vascular endothelial growth factor in peri-infarct cortex. Thus, inhibition of sEH at reperfusion significantly reduces infarction and improves sensorimotor function, possibly by suppressing early proinflammatory cytokines and promoting reparative cytokines and growth factors.

Topics: Animals; Brain; Brain Ischemia; Cerebral Infarction; Enzyme Inhibitors; Epoxide Hydrolases; Inflammation; Phenylurea Compounds; Piperidines; Rats; Rats, Sprague-Dawley; Reperfusion Injury

Topics: Administration, Oral; Analgesics; Animals; Epoxide Hydrolases; HEK293 Cells; Humans; Inflammation; Lipopolysaccharides; Male; Molecular Structure; Pain; Phosphodiesterase 4 Inhibitors; Piperidines; Rats, Sprague-Dawley

Eicosanoids play a crucial role in inflammatory pain. However, there is very little knowledge about the contribution of oxidized linoleic acid metabolites in inflammatory pain and peripheral sensitization. Here, we identify 12,13-dihydroxy-9Z-octadecenoic acid (12,13-DiHOME), a cytochrome P450-derived linoleic acid metabolite, as crucial mediator of thermal hyperalgesia during inflammatory pain. We found 12,13-DiHOME in increased concentrations in peripheral nervous tissue during acute zymosan- and complete Freund's Adjuvant-induced inflammatory pain. 12,13-DiHOME causes calcium transients in sensory neurons and sensitizes the transient receptor potential vanilloid 1 (TRPV1)-mediated intracellular calcium increases via protein kinase C, subsequently leading to enhanced TRPV1-dependent CGRP-release from sensory neurons. Peripheral injection of 12,13-DiHOME in vivo causes TRPV1-dependent thermal pain hypersensitivity. Finally, application of the soluble epoxide hydrolase (sEH)-inhibitor TPPU reduces 12,13-DiHOME concentrations in nervous tissue and reduces zymosan- and CFA-induced thermal hyperalgesia in vivo. In conclusion, we identify a novel role for the lipid mediator 12,13-DiHOME in mediating thermal hyperalgesia during inflammatory pain and propose a novel mechanism that may explain the antihyperalgesic effects of sEH inhibitors in vivo.

Topics: Analgesics; Animals; Behavior, Animal; Disease Models, Animal; Enzyme Inhibitors; Epoxide Hydrolases; Female; Freund's Adjuvant; Hot Temperature; Humans; Hyperalgesia; Inflammation; Linoleic Acid; Male; Mice; Oleic Acids; Oxidation-Reduction; Pain; Phenylurea Compounds; Piperidines; Protein Kinase C; Sensory Receptor Cells; TRPV Cation Channels; Zymosan

The purpose of the study was to explore the therapeutic potential of Betulinic acid (BA) in streptozotocin (STZ) induced memory damage in experimental rats.. STZ (3mg/kg bilaterally) as intracerebroventrical (icv) route was administered on day 1 and 3 in rats. Donepezil (5mg/kg/day po), used as standard, and BA (5, 10 and 15mg/kg/day po) were administered after 1h of 1st STZ infusion up to 21days. Object recognition task (ORT) for non-spatial, Morris water maze (MWM) for spatial and locomotor activity were performed to evaluate behavioral changes in rats. On 22nd day, animals were decapitated and hippocampus was separated to perform biochemical (AChE, LPO, GSH, nitrite), neuroinflammatory (TNF-α, IL-1β, and IL-6), neurotransmitters (NTs) (dopamine, norepinephrine and serotonin) analysis.. STZ infusion significantly impaired memory as observed in MWM and ORT, increased oxidative stress, pro-inflammatory cytokine's level and altered NTs level. Moreover, BA demonstrated a neuroprotective effect in a dose-dependent manner. BA dose dependently (5, 10 and 15mg/kg) significantly restore STZ induced memory changes and pathological abnormalities in rat brain.. The findings of the current study suggests that BA protect rat brain from STZ induced neuronal damage via acting through multiple mechanisms and would be used to curb cognitive decline associated with neurodegenerative disorders especially AD.

Topics: Acetylcholinesterase; Animals; Betulinic Acid; Cognitive Dysfunction; Disease Models, Animal; Donepezil; Glutathione; Hippocampus; Indans; Inflammation; Injections, Intraventricular; Male; Maze Learning; Memory; Memory Disorders; Neuroprotective Agents; Neurotransmitter Agents; Oxidative Stress; Pentacyclic Triterpenes; Piperidines; Rats; Rats, Wistar; Streptozocin; Triterpenes

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.\ \ Given the comments of Dr Elisabeth Bik regarding this article “… the Western blot bands in all 400+ papers are all very regularly spaced and have a smooth appearance in the shape of a dumbbell or tadpole, without any of the usual smudges or stains. All bands are placed on similar looking backgrounds, suggesting they were copy/pasted from other sources, or computer generated”, the journal requested the authors to provide the raw data. However, the authors were not able to fulfil this request and therefore the Editor-in-Chief decided to retract the article.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents; Apoptosis; Benzodioxoles; Cell Line; Cell Survival; Chondrocytes; Cytokines; Dose-Response Relationship, Drug; Down-Regulation; Inflammation; Lipopolysaccharides; Mice; MicroRNAs; Myeloid Differentiation Factor 88; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Piperidines; Polyunsaturated Alkamides; Signal Transduction; Up-Regulation

Stroke is a prevalent disorder which is associated with several complications including inflammation. JZL-184 (JZL) inhibits arachidonic acid (AA) production and consequently results in two-arachidonoylglycerol (2-AG) accumulation. Both reduced production of AA metabolic products and increased 2-AG, the agonist of type 1 cannabinoid receptor (CB1), can result in reduced inflammation. In this study, we investigated the mechanisms of JZL in the improvement of stroke complications in mouse permanent cerebral ischemia (PPMCAO) model using AM251, the antagonist of CB1.. PMCAO mice were divided into six groups including intact, controls, vehicle, JZL, AM251 and JZL plus AM251 administrated groups. Brain infarction and edema, brain levels of matrix metalloperoteinase-9 (MMP9), interleukin (IL)-10 and tumor necrosis factor-α (TNF-α) and behavioral functions have been examined in all groups.. The results showed that JZL lowered brain infarction, neurological disorders, TNF-α and MMP9 more effectively than JZL plus AM251. JZL and JZL plus AM251 reduced brain edema and increased brain IL-10. JZL, AM251 and JZL plus AM251 improve behavioral functions.. JZL reduces brain infarction and brain pro-inflammatory molecules in CB1 pathway dependent manner. JZL also reduces brain edema and increased IL-10 in CB1 pathways or decreased AA metabolites. Further, AM251 improves behavioral functions via unknown mechanisms.

Topics: Animals; Benzodioxoles; Brain Edema; Brain Infarction; Cannabinoids; Down-Regulation; Enzyme Inhibitors; Inflammation; Interleukin-10; Male; Matrix Metalloproteinase 9; Mice; Monoacylglycerol Lipases; Piperidines; Pyrazoles; Signal Transduction; Tumor Necrosis Factor-alpha

Clinical trials have shown combinations of anti-tumor necrosis factor biologicals plus methotrexate (MTX) are more effective treatments for rheumatoid arthritis than biological monotherapies, based, in part, on the assumption that MTX reduces the immunogenicity of biologicals. However, co-treatment with the anti-interleukin-6 receptor-alpha antibody tocilizumab (TCZ) and MTX does not demonstrate the same level of incremental benefit over TCZ monotherapy. Using the human primary cell based BioMAP phenotypic profiling platform, we investigated the impact of TCZ, adalimumab (ADA), and the small molecule drug tofacitinib (TOF), alone and in combination with MTX, on translational biomarkers that could indicate unique pharmacodynamic interactions outside those of reduced immunogenicity.. TCZ, ADA, and TOF, alone and in combination with MTX, were profiled in BioMAP systems at concentrations close to clinical exposure levels: TCZ, 200 μg/ml; TOF1, 1.1 μM; TOF2, 0.12 µM; MTX, 10 μM. Changes in biomarkers were evaluated by statistical methods to determine whether combinations differed from the individual agents.. Although the BioMAP activity profile for TCZ + MTX was not significantly different from that for TCZ alone, profiles for ADA + MTX and TOF1 + MTX or TOF2 + MTX had a greater number of statistically significant different activities (P < 0.01) than did agents profiled individually.. These data support the comparable efficacy of TCZ as monotherapy and as combination therapy and suggest that TOF, like ADA, may be more beneficial in combination with MTX. Taking an orthogonal approach to directly compare monotherapy and combination therapies indicates that MTX contributes to the efficacy of some, but not all, RA therapies and can be affected by factors additional to reduced immunogenicity.

Topics: Adalimumab; Antibodies, Monoclonal, Humanized; Arthritis, Rheumatoid; Drug Therapy, Combination; Humans; Inflammation; Methotrexate; Phenotype; Piperidines; Pyrimidines; Pyrroles; Receptors, Interleukin-6; Signal Transduction

Allergic asthma is an inflammatory condition accompanied by inflammation as well as oxidative stress. Supplementation of an anti-inflammatory agent having antioxidant properties may have therapeutic effects against this disease. Over the recent decades, the interest in combination therapy as new alternative medication has increased and it offers numerous benefits along with noticeable lack of toxicity as well as side effects. In this study, protective effects of curcumin alone and in combination with piperine were evaluated in mouse model of allergic asthma. Balb/c mice were sensitized on days 0, 7, and 14 and challenged from days 16-30 on alternate days with ovalbumin (OVA). Mice were pretreated with curcumin (Cur; 10 and 20 mg/kg) and piperine (Pip; 5 mg/kg) alone and in combination via the intraperitoneal route on days 16-30 and compared with intranasal curcumin (5 mg/kg) treatment. Blood, bronchoalveolar lavage fluid (BALF), and lungs were collected after mice were sacrificed on day 31st. Mice immunized with OVA have shown significant increase in airway inflammation and oxidative stress as determined by oxidative stress markers. A significant suppression was observed with all the treatments, but intranasal curcumin treatment group has shown maximum suppression. So, among all the treatment strategies utilized, intranasal curcumin administration was most appropriate in reducing inflammation and oxidative stress and possesses therapeutic potential against allergic asthma. Present study may prove the possibility of development of curcumin nasal drops towards treatment of allergic asthma.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents; Asthma; Benzodioxoles; Bronchoalveolar Lavage Fluid; Curcumin; Drug Administration Routes; Drug Therapy, Combination; Inflammation; Lung; Mice; Mice, Inbred BALB C; Ovalbumin; Oxidative Stress; Piperidines; Polyunsaturated Alkamides

There is clear evidence that neuroinflammation plays a crucial role in the pathogenesis of Alzheimer's disease. Consequently, modulating the inflammatory environment in brain has become a powerful and attractive strategy to deal with Alzheimer's disease physiopathology. In spite of the neuroprotective capacity shown by ASS234, a multitarget propargylamine targeted for Alzheimer's disease, its regulation of inflammation in the brain still remains unexplored. Therefore, we aimed to characterize possible anti-inflammatory effects of ASS234, counteracting induced inflammatory effects in RAW 264.7 cells and evaluating seven neuroinflammation related genes expression profiling (IL-6, IL-10, IL1β, NF-κB, TNF-α, TNFR1, and TGF-β), after ASS234 (5 μM) treatment in SH-SY5Y cells. The analysis of the obtained fold changes lead us to conclude that ASS234 may play an important role facing the neuroinflammatory environment in Alzheimer's disease pathology.

Topics: Alzheimer Disease; Animals; Cell Line, Tumor; Cytokines; Gene Expression; Humans; Indoles; Inflammation; Interleukin-10; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; Mice; Neurons; NF-kappa B; Piperidines; RAW 264.7 Cells; Receptors, Tumor Necrosis Factor, Type I; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

The hallmarks of systemic sclerosis (SSc) are autoimmunity, microangiopathy and fibrosis. Skin fibrosis is accompanied by attrition of the dermal white adipose tissue layer, and alterations in the levels and function of adiponectin. Since these findings potentially implicate adiponectin in the pathogenesis of SSc, we employed a novel pharmacological approach to augment adiponectin signaling using AdipoRon, an orally active adiponectin receptor agonist. Chronic treatment with AdipoRon significantly ameliorated bleomycin-induced dermal fibrosis in mice. AdipoRon attenuated fibroblast activation, adipocyte-to-myofibroblast transdifferentiation, Th2/Th17-skewed polarization of the immune response, vascular injury and endothelial-to-mesenchymal transition within the lesional skin. In vitro, AdipoRon abrogated profibrotic responses elicited by TGF-β in normal fibroblasts, and reversed the inherently-activated profibrotic phenotype of SSc fibroblasts. In view of these broadly beneficial effects on all three cardinal pathomechanisms underlying the clinical manifestations of SSc, pharmacological augmentation of adiponectin signaling might represent a novel strategy for the treatment of SSc.

Topics: Administration, Oral; Animals; Bleomycin; Disease Models, Animal; Female; Fibrosis; Humans; Inflammation; Mice, Inbred C57BL; Piperidines; Receptors, Adiponectin; Scleroderma, Systemic; Signal Transduction; Skin; Vascular System Injuries

α/β-Hydrolase domain-containing 6 (ABHD6) contributes to the hydrolysis of the major endocannabinoid 2-arachidonoylglycerol (2-AG) in the central nervous system (CNS) and in the periphery. ABHD6 blockade has been proposed as novel strategy to treat multiple sclerosis (MS), based on the observation that the inhibitor WWL70 exerts protective anti-inflammatory effects in experimental autoimmune encephalomyelitis (EAE). According to recent data, WWL70 exhibits off-target anti-inflammatory activity in microglial cells and the potential of ABHD6 as drug target in MS remains controversial. Here we further investigated the role of ABHD6 during autoimmune demyelination by comparing the efficacy of two novel inhibitors with different CNS permeability in vivo. Preventive treatment with the systemically active inhibitor KT182 ameliorated the neurological signs of EAE during the time-course of disease. By contrast, administration of the peripherally restricted compound KT203 was ineffective in attenuating EAE symptomatology. Both inhibitors failed to improve corticospinal tract conduction latency and to attenuate inflammation at EAE recovery phase, despite being equally active at targeting brain ABHD6. Chronic administration of KT182 was associated to a partial loss of brain CB

Topics: Animals; Benzoates; Biphenyl Compounds; Brain; Calcium; Carbamates; Cells, Cultured; Encephalomyelitis, Autoimmune, Experimental; Female; Inflammation; Mice; Mitochondria; Molecular Targeted Therapy; Monoacylglycerol Lipases; N-Methylaspartate; Neural Conduction; Piperidines; Pyramidal Tracts; Receptor, Cannabinoid, CB1; Triazoles

P300/CBP-associated factor (PCAF) and general control nonderepressible 5 (GCN5) are closely related epigenetic proteins, each containing an acetyltransferase domain and a bromodomain. Consistent with reported roles for these proteins in immune function, we find that PCAF-deficient macrophages exhibit a markedly reduced ability to produce cytokines upon stimulation with lipopolysaccharide (LPS). Investigating the potential to target this pathway pharmacologically, we show that chemical inhibition of the PCAF/GCN5 bromodomains is insufficient to recapitulate the diminished inflammatory response of PCAF-deficient immune cells. However, by generating the first PCAF/GCN5 proteolysis targeting chimera (PROTAC), we identify small molecules able to degrade PCAF/GCN5 and to potently modulate the expression of multiple inflammatory mediators in LPS-stimulated macrophages and dendritic cells. Our data illustrate the power of the PROTAC approach in the context of multidomain proteins, revealing a novel anti-inflammatory therapeutic opportunity for targeting PCAF/GCN5.

Topics: Adaptor Proteins, Signal Transducing; Animals; Benzoates; Cell Differentiation; Cytokines; Dendritic Cells; Humans; Inflammation; Lipopolysaccharides; Macrophages; Mice; Monocytes; p300-CBP Transcription Factors; Peptide Hydrolases; Piperidines; Protein Domains; Proteolysis; Pyridazines; Stereoisomerism; Ubiquitin-Protein Ligases

The FDA-approved small-molecule drug ibrutinib is an effective targeted therapy for patients with chronic lymphocytic leukemia (CLL). Ibrutinib inhibits Bruton's tyrosine kinase (BTK), a kinase involved in B cell receptor signaling. However, the potential regulation of neuroinflammatory responses in the brain by ibrutinib has not been comprehensively examined.. BV2 microglial cells were treated with ibrutinib (1 μM) or vehicle (1% DMSO), followed by lipopolysaccharide (LPS; 1 μg/ml) or PBS. RT-PCR, immunocytochemistry, and subcellular fractionation were performed to examine the effects of ibrutinib on neuroinflammatory responses. In addition, wild-type mice were sequentially injected with ibrutinib (10 mg/kg, i.p.) or vehicle (10% DMSO, i.p.), followed by LPS (10 mg/kg, i.p.) or PBS, and microglial and astrocyte activations were assessed using immunohistochemistry.. Ibrutinib significantly reduced LPS-induced increases in proinflammatory cytokine levels in BV2 microglial and primary microglial cells but not in primary astrocytes. Ibrutinib regulated TLR4 signaling to alter LPS-induced proinflammatory cytokine levels. In addition, ibrutinib significantly decreased LPS-induced increases in p-AKT and p-STAT3 levels, suggesting that ibrutinib attenuates LPS-induced neuroinflammatory responses by inhibiting AKT/STAT3 signaling pathways. Interestingly, ibrutinib also reduced LPS-induced BV2 microglial cell migration by inhibiting AKT signaling. Moreover, ibrutinib-injected wild-type mice exhibited significantly reduced microglial/astrocyte activation and COX-2 and IL-1β proinflammatory cytokine levels.. Our data provide insights on the mechanisms of a potential therapeutic strategy for neuroinflammation-related diseases.

Topics: Adenine; Animals; Animals, Newborn; Anti-Inflammatory Agents; Cell Line, Transformed; Cells, Cultured; Culture Media, Serum-Free; Cyclooxygenase 2; Cytokines; Disease Models, Animal; Heterocyclic Compounds, 3-Ring; Inflammation; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Microglia; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Rats; Signal Transduction; Wound Healing

Accumulation of alpha-synuclein (ASYN) in neurons and other CNS cell types may contribute to the underlying pathology of synucleinopathies including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and Multiple Systems Atrophy (MSA). In support of this hypothesis for PD, ASYN immunopositive aggregates are a prominent pathological feature of PD, and mutations and gene multiplications of human wild type (WT) ASYN cause rare familial autosomal-dominant forms of PD. Targeted therapeutics that reduce the accumulation of ASYN could prevent or slow the neurodegenerative processes in PD and other synucleinopathies. NPT200-11 is a novel small molecule inhibitor of ASYN misfolding and aggregation. The effects of NPT200-11 on ASYN neuropathology were evaluated in animal models over expressing human alpha synuclein. Longitudinal studies using retinal imaging in mice expressing a hASYN::GFP fusion protein revealed that 2 months of once daily administration of NPT200-11 (5 mg/kg IP) resulted in a time-dependent and progressive reduction in retinal ASYN pathology. The effects of NPT200-11 on ASYN pathology in cerebral cortex and on other disease-relevant endpoints was evaluated in the Line 61 transgenic mouse model overexpressing human wild type ASYN. Results from these studies demonstrated that NPT200-11 reduced alpha-synuclein pathology in cortex, reduced associated neuroinflammation (astrogliosis), normalized striatal levels of the dopamine transporter (DAT) and improved motor function. To gain insight into the relationship between dose, exposure, and therapeutic benefit pharmacokinetic studies were also conducted in mice. These studies demonstrated that NPT200-11 is orally bioavailable and brain penetrating and established target plasma and brain exposures for future studies of potential therapeutic benefit.

Topics: alpha-Synuclein; Animals; Cerebral Cortex; Disease Models, Animal; Gene Expression Regulation; Humans; Inflammation; Lewy Body Disease; Mice; Mice, Transgenic; Multiple System Atrophy; Neurons; Parkinson Disease; Piperidines; Protein Aggregation, Pathological; Protein Folding; Pyrazines; Pyrimidines; Retina

To explore the effects of aloperine (ALO) on allergic airway inflammation, we investigated whether its mechanism is related with NF-κB, MAPK, and Nrf2/HO-1 signaling pathways. Histochemical staining and inflammatory cell count were used to observe lung histopathological changes in mice. ELISA was used to detect the content of inflammatory cytokines and IgE in the mouse bronchoalveolar lavage fluid (BALF). Airway hyperresponsiveness (AHR) to inhale methacholine was measured by the plethysmography in conscious mice. Immunohistochemical method was used to detect the expression levels of Nrf2 and HO-1 in lung tissues. The key proteins of MAPK, NF-κB, and Nrf2/HO-1 in lung tissues were quantitatively analyzed by Western blot. Finally, the in vitro effect of ALO on the production of pro-inflammatory mediators and cytokines by lipopolysaccharide-stimulated RAW 264.7 cells was also evaluated. In the ovalbumin (OVA)-induced asthma mouse model, ALO reduced the exudation and infiltration of inflammatory cells and suppressed goblet cell hyperplasia. ALO-treated asthmatic mice also decreased the protein levels of interleukin (IL)-4, IL-5, IL-13, IFN-γ, and IgE in BALF and attenuated AHR. Furthermore, ALO inhibited the expression of key proteins of MAPK and NF-κB pathways, and increased the expression of Nrf2/HO-1 in OVA-challenged mice. Additional in vitro study has shown that ALO abrogates the macrophage production of inducible nitric oxide synthase, cyclooxygenase-2, tumor necrosis factor-α, IL-6, and IL-1β. Taken together, ALO attenuated allergic airway inflammation through regulating NF-κB, MAPK, and Nrf2/HO-1 signaling pathways. The results suggest the utility of ALO as an anti-inflammatory agent for the treatment of asthma.

Topics: Animals; Anti-Inflammatory Agents; Cells, Cultured; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Female; Heme Oxygenase-1; Humans; Hypersensitivity; Inflammation; Mice; Mice, Inbred BALB C; NF-E2-Related Factor 2; NF-kappa B; Piperidines; Quinolizidines; Respiratory System; Signal Transduction

The onset of inflammation is associated with reactive oxygen species and oxidative damage to macromolecules like 7,8-dihydro-8-oxoguanine (8-oxoG) in DNA. Because 8-oxoguanine DNA glycosylase 1 (OGG1) binds 8-oxoG and because

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzimidazoles; DNA Glycosylases; DNA Repair; Enzyme Inhibitors; Gene Expression; Gene Knockout Techniques; Guanine; HEK293 Cells; Humans; Inflammation; Jurkat Cells; Mice; Mice, Mutant Strains; NF-kappa B; Piperidines; Promoter Regions, Genetic; Tumor Necrosis Factor-alpha

Inflammation is a risk factor for cancer development. Individuals with preleukemic TET2 mutations manifest clonal hematopoiesis and are at a higher risk of developing leukemia. How inflammatory signals influence the survival of preleukemic hematopoietic stem and progenitor cells (HSPCs) is unclear. We show a rapid increase in the frequency and absolute number of Tet2-KO mature myeloid cells and HSPCs in response to inflammatory stress, which results in enhanced production of inflammatory cytokines, including interleukin-6 (IL-6), and resistance to apoptosis. IL-6 induces hyperactivation of the Shp2-Stat3 signaling axis, resulting in increased expression of a novel anti-apoptotic long non-coding RNA (lncRNAs), Morrbid, in Tet2-KO myeloid cells and HSPCs. Expression of activated Shp2 in HSPCs phenocopies Tet2 loss with regard to hyperactivation of Stat3 and Morrbid. In vivo, pharmacologic inhibition of Shp2 or Stat3 or genetic loss of Morrbid in Tet2 mutant mice rescues inflammatory-stress-induced abnormalities in HSPCs and mature myeloid cells, including clonal hematopoiesis.

Topics: Animals; Benzoquinones; Dioxygenases; DNA-Binding Proteins; Female; Hematopoiesis; Hematopoietic Stem Cells; Inflammation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation; Myeloid Cells; Oxidative Stress; Piperidines; Propionates; Proto-Oncogene Proteins; Pyrimidines; RNA, Long Noncoding; Signal Transduction

Topics: Alveolar Bone Loss; Animals; Apoptosis; Endoplasmic Reticulum Stress; Epoxide Hydrolases; Inflammation; Inflammation Mediators; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Periodontitis; Phenylurea Compounds; Piperidines; Receptor Activator of Nuclear Factor-kappa B; Signal Transduction

The endocannabinoid system has previously been shown to play a role in the permeability and inflammatory response of the human gut. The goal of our study was to determine the effects of endogenous anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) on the permeability and inflammatory response of intestinal epithelium under normal, inflammatory, and hypoxic conditions. Human intestinal mucosa was modeled using Caco-2 cells. Human tissue was collected from planned colorectal resections. Accumulation of AEA and 2-AG was achieved by inhibiting their metabolizing enzymes URB597 (a fatty acid amide hydrolase inhibitor) and JZL184 (a monoacylglycerol lipase inhibitor). Inflammation and ischemia were simulated with TNF-α and IFN-γ and oxygen deprivation. Permeability changes were measured by transepithelial electrical resistance. The role of the CB

Topics: Amidohydrolases; Arachidonic Acids; Benzamides; Benzodioxoles; Caco-2 Cells; Carbamates; Colorectal Neoplasms; Cytokines; Electric Impedance; Endocannabinoids; Gene Expression Regulation; Glycerides; Humans; Inflammation; Intestinal Mucosa; Intestines; Monoacylglycerol Lipases; Oxygen Consumption; Permeability; Piperidines; Polyunsaturated Alkamides; Receptor, Cannabinoid, CB1; Tissue Culture Techniques

Donepezil is a potent and selective acetylcholinesterase inhibitor developed for the treatment of Alzheimer's disease. In the present study, we investigated the responses of astrocytes to bradykinin, an inflammatory mediator, and the effect of donepezil on these responses using cultured cortical astrocytes. Bradykinin induced a transient increase of intracellular calcium concentration ([Ca

Topics: Acetylcholinesterase; Animals; Astrocytes; Bradykinin; Calcium; Cells, Cultured; Cerebral Cortex; Cholinesterase Inhibitors; Donepezil; Indans; Inflammation; Mecamylamine; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Reactive Oxygen Species; Thapsigargin

Patients with active rheumatoid arthritis (RA) have increased cardiovascular mortality, paradoxically associated with reduced circulating lipid levels. The JAK inhibitor tofacitinib ameliorates systemic and joint inflammation in RA with a concomitant increase in serum lipids. We analysed the effect of tofacitinib on the lipid profile of hyperlipidaemic rabbits with chronic arthritis (CA) and on the changes in reverse cholesterol transport (RCT) during chronic inflammation.. CA was induced in previously immunized rabbits, fed a high-fat diet, by administering four intra-articular injections of ovalbumin. A group of rabbits received tofacitinib (10 mg·kg. Tofacitinib decreased systemic and synovial inflammation and increased circulating lipid levels. Although it did not modify synovial macrophage density, it reduced the lipid content within synovial macrophages. In foam macrophages in culture, IFNγ further stimulated intracellular lipid accumulation, while the JAK/STAT inhibition provoked by tofacitinib induced lipid release by increasing the levels of cellular liver X receptor α and ATP-binding cassette transporter (ABCA1) synthesis.. Active inflammation could be associated with lipid accumulation within macrophages of CA rabbits. JAK inhibition induced lipid release through RCT activation, providing a plausible explanation for the effect of tofacitinib on the lipid profile of RA patients.

Topics: Animals; Arthritis, Rheumatoid; Cholesterol; Diet, High-Fat; Dose-Response Relationship, Drug; Inflammation; Lipids; Macrophages; Male; Piperidines; Pyrimidines; Pyrroles; Rabbits; Structure-Activity Relationship

Lysophosphatidic acid (LPA) is a bioactive lipid that acts via at least six G protein-coupled receptors, LPA receptors 1-6 (LPA1-6), for various physiological functions. We examined (1) whether LPA5 is involved in pain signaling in the spinal cord; and (2) the pharmacological effects of a novel LPA5 antagonist on intrathecal prostaglandin (PG)- and (S)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-induced allodynia, and neuropathic and inflammatory pain in rodents. Intrathecal injection of a selective LPA5 agonist, geranylgeranyl diphosphate, and a non-selective agonist, LPA, induced allodynia in wild type, but not in LPA5 knockout mice. These novel results suggest that LPA5 is important for pain signal transmission in the spinal cord. AS2717638 (6,7-dimethoxy-2-(5-methyl-1,2-benzoxazol-3-yl)-4-(piperidin-1-ylcarbonyl)isoquinolin-1(2H)-one) bound to the LPA-binding site on LPA5 and selectively inhibited LPA-induced cyclic adenosine monophosphate accumulation in human LPA5-but not LPA1-, 2-, or 3-expressing cells. Further, oral administration of AS2717638 inhibited LPA5 agonist-induced allodynia in mice. AS2717638 also significantly improved PGE

Topics: Analgesics; Animals; Benzoxazoles; Cells, Cultured; Cyclic AMP; Female; Hyperalgesia; Inflammation; Injections, Spinal; Isoquinolines; Lysophospholipids; Male; Mice, Inbred C57BL; Mice, Knockout; Neuralgia; Pain; Pain Threshold; Piperidines; Polyisoprenyl Phosphates; Rats, Inbred Lew; Rats, Sprague-Dawley; Receptors, Lysophosphatidic Acid

Influenza viruses, the main cause of respiratory tract diseases, cause high morbidity and mortality in humans. Excessive inflammation in the lungs is proposed to be a hallmark for the severe influenza virus infection, especially influenza A virus infection. Strategies against inflammation induced by influenza A virus infection could be a potential anti-influenza therapy. Here, lethal dose of mouse-adapted H1N1 strain PR8A/PR/8/34 was inoculated C57BL/6 mice to detect the anti-influenza activity of andrographolide, the active component of traditional Chinese medicinal herb Andrographis paniculata, with or without influenza virus entry inhibitor CL-385319. Treatment was initiated on 4 days after infection. The survival rate, body weight, lung pathology, viral loads, cytokine expression were monitored in 14 days post inoculation. The combination group had the highest survival rate. Andrographolide treatment could increase the survival rate, diminish lung pathology, decrease the virus loads and the inflammatory cytokines expression induced by infection. Mechanism studies showed the NF-κB and JAK-STAT signaling pathway were involved in the activity of andrographolide. In conclusion, combination of virus entry inhibitor with immunomodulator might be a promising therapeutic approach for influenza.

Topics: A549 Cells; Andrographis; Animals; Benzamides; Cell Line; Cytokines; Disease Models, Animal; Diterpenes; Dogs; Drug Therapy, Combination; Female; Humans; Inflammation; Influenza A Virus, H1N1 Subtype; Janus Kinases; Madin Darby Canine Kidney Cells; Mice; Mice, Inbred C57BL; NF-kappa B; Orthomyxoviridae Infections; Piperidines; STAT1 Transcription Factor; STAT2 Transcription Factor; Virus Internalization

Estrogen was reported to protect against obesity, however the mechanism remains unclear. We aimed to investigate the impact of 17β-estradiol (17β-E2) on triglyceride metabolism in adipocytes with or without lipopolysacchride (LPS) stimulating, providing novel potential mechanism for estrogen action.. 3T3-L1 adipocytes were cultured and differentiated into mature adipocytes in vitro. The differentiated 3T3-L1 cells were divided into six groups: (i) control group, treated with 0.1% DMSO alone; (ii) 17β-E2 group, treated with 1, 0.1, or 0.001 μM 17β-E2 for 48 h; (iii) 17β-E2 plus MPP group, pre-treated with 10 μM MPP (a selective ERα receptor inhibitor) for 1 h, then incubated with 1 μM 17β-E2 for 48 h; (iv) 17β-E2 plus PHTPP group, pre-treated with 10 μM PHTPP (a selective ERβ receptor inhibitor), then incubated with 1 μM 17β-E2 for 48 h; (v) LPS group, pre-treated with 100 ng/mL LPS for 24 h, then cells were washed by PBS for 3 times and incubated with 0.1% DMSO alone for 48 h; (vi) 17β-E2 plus LPS group, pre-treated with 100 ng/mL LPS for 24 h, then cells were washed by PBS for 3 times and incubated with 1 μM 17β-E2 for 48 h. The levels of triglyceride and adipose triglyceride lipase (ATGL) in differentiated 3T3-L1 cells and the concentrations of interleukin-6 (IL-6) in culture medium were measured.. Comparing with control group, 1 μM and 0.1 μM 17β-E2 decreased the intracellular TG levels by about 20% and 10% respectively (all P < 0.05). The triglyceride-lowing effect of 17β-E2 in differentiated 3T3-L1 cells was abolished by ERα antagonist MPP but not ERβ antagonist PHTPP. Comparing with control group, the IL-6 levels were significantly higher in the culture medium of the cultured differentiated 3T3-L1 cells in LPS group and 17β-E2 + LPS group (all P < 0.05). And, the IL-6 levels were similar in LPS group and 17β-E2 + LPS group (P > 0.05). There was no significant difference in the triglyceride contents of differentiated 3T3-L1 cells among control group, LPS group and 17β-E2 + LPS group (all P > 0.05). ATGL expression in 17β-E2 group was significantly higher than control group (P < 0.05), which was abolished by ERα antagonist MPP or LPS.. 17β-E2 increased ATGL expression and lowered triglycerides in adipocytes but not in LPS stimulated adipocytes via estrogen ERα.

Topics: 3T3-L1 Cells; Adipocytes; Animals; Cell Differentiation; Estradiol; Estrogen Antagonists; Estrogen Receptor alpha; Estrogen Receptor beta; Gene Expression Regulation; Inflammation; Interleukin-6; Lipase; Lipid Metabolism; Lipopolysaccharides; Mice; Piperidines; Pyrazoles; Pyrimidines; Triglycerides

Surgery and anesthesia have been linked to postoperative cognitive disturbance and increased risk of Alzheimer's disease. It is not clear by which mechanisms this increased risk for cognitive disease is mediated. Further, amyloid β production has been suggested to depend on the sleep-wake cycle and neuronal activity. The aim of the present study was to examine if cerebrospinal fluid (CSF) concentrations of a number of biomarkers for Alzheimer's disease-related processes, including amyloid β, neuronal injury, and inflammation, changed over time during intravenous anesthesia in surgical patients.. We included patients scheduled for hysterectomy via laparotomy during general anesthesia with intravenous propofol and remifentanil. CSF samples were obtained before, during, and after surgery (5 h after induction) and tested for 27 biomarkers. Changes over time were tested with linear mixed effects models.. A total of 22 patients, all females, were included. The mean age was 50 years (± 9 SD). The mean duration of the anesthesia was 145 min (± 40 SD). Interleukin (IL)-6, IL-8, monocyte chemoattractant protein 1, and vascular endothelial growth factor A increased over time. IL-15 and IL-7 decreased slightly over time. Macrophage inflammatory protein 1β and placental growth factor also changed significantly. There were no significant effects on amyloid β (Aβ) or tau biomarkers.. Surgery and general anesthesia with intravenous propofol and remifentanil induce, during and in the short term after the procedure, a neuroinflammatory response which is dominated by monocyte attractants, without biomarker signs of the effects on Alzheimer's disease pathology or neuronal injury.

Topics: Adult; Alzheimer Disease; Amyloid beta-Peptides; Anesthesia, Intravenous; Biomarkers; Cohort Studies; Cytokines; Female; Humans; Inflammation; Middle Aged; Peptide Fragments; Piperidines; Propofol; Remifentanil; tau Proteins; Vascular Endothelial Growth Factor A

Inflammatory myofibroblastic tumor (IMT) is a neoplasm characterized by the proliferaton of myofibroblasts with the infiltration of inflammatory cells. There is no standard treatment for patients with recurrent or metastatic IMT. We describe here a patient with hyper-progressive IMT with an anaplastic lymphoma kinase (ALK) fusion gene that dramatically responded to alectinib without adverse events. His dramatic and enduring response supports the observation that alectinib may be considered a good treatment option for rare aggressive ALK-positive tumors.

Topics: Adult; Anaplastic Lymphoma Kinase; Carbazoles; Granuloma, Plasma Cell; Humans; Inflammation; Male; Oncogene Proteins, Fusion; Piperidines; Receptor Protein-Tyrosine Kinases

Psychological stress, depression and anxiety lead to multiple organ dysfunctions wherein stress-related mucosal disease (SRMD) is common to people experiencing stress and also occur as a side effect in patients admitted to intensive care units; however the underlying molecular aetiology is still obscure. We report that in rat-SRMD model, cold restraint-stress severely damaged gut mitochondrial functions to generate superoxide anion (O

Topics: Adenosine Triphosphate; Animals; Antipsychotic Agents; bcl-2-Associated X Protein; Cold Temperature; Corticosterone; Electron Transport Complex I; Gastric Mucosa; Gene Expression Regulation; Immobilization; Inflammation; Membrane Transport Proteins; Mifepristone; Mitochondria; Mitochondrial Dynamics; Mitochondrial Precursor Protein Import Complex Proteins; Mitochondrial Proteins; Mitophagy; NF-kappa B; Organophosphorus Compounds; Oxidative Stress; Piperidines; Protein Kinases; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, Cytoplasmic and Nuclear; Receptors, Glucocorticoid; Stomach; Stress, Psychological; Superoxides; Ubiquitin-Protein Ligases

The hepatitis B virus (HBV) has caused acute and chronic liver diseases in ~350 million infected people worldwide. Halofuginone (HF) is a plant alkaloid which has been demonstrated to play a crucial role in immune regulation. Our present study explored the function of HF in the immune response of HBV-infected Sprague Dawley (SD) rats. Plasmid containing pCDNA3.1-HBV1.3 was injected in SD rats for the construction of an acute HBV-infected animal model. Our data showed that HF reduced the high concentrations of serum hepatitis B e-antigen, hepatitis B surface antigen, and HBV DNA induced by HBV infection. HF also reduced the number of T helper (Th)17 cells and the expression of interleukin (IL)-17 compared with the pCDNA3.1-HBV1.3 group. Moreover, pro-inflammatory cytokine levels (IL-17, IL-23, interferon-γ, and IL-2) were downregulated and anti-inflammatory cytokine levels (IL-4 and IL-13) were upregulated by HF. Through further research we found that the expression of AMP-activated protein kinase (AMPK) and IKBA which suppressed NF-κB activation was increased while the expression of p-NF-κB P65 was decreased in pCDNA3.1-HBV1.3+HF group compared with pCDNA3.1-HBV1.3 group, indicating that HF may work through the activation of AMPK. Finally, our conjecture was further verified by using the AMPK inhibitor compound C, which counteracted the anti-inflammation effect of HF, resulting in the decreased expression of AMPK, IKBA and increased expression of p-NF-κB P65 and reduced number of Th17 cells. In our present study, HF was considered as an anti-inflammatory factor in acute HBV-infected SD rats and worked through AMPK-mediated NF-κB p65 inactivation. This study implicated HF as a potential therapeutic strategy for hepatitis B.

Topics: Acute Disease; AMP-Activated Protein Kinases; Animals; Anti-Inflammatory Agents; Cytokines; Disease Models, Animal; DNA, Viral; Female; Hepatitis B; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Inflammation; Piperidines; Quinazolinones; Rats; Rats, Sprague-Dawley; Severity of Illness Index; Transcription Factor RelA

Topics: Animals; Anthracenes; Antigens, CD; Carcinogenesis; Gene Expression Regulation; Inflammation; Keratinocytes; Macrophage Migration-Inhibitory Factors; Mice; Mice, Inbred BALB C; Mice, Knockout; Mice, Transgenic; Piperidines; Pyridines; Receptors, CXCR; Skin; Skin Neoplasms

Topics: Adenine; Adenosine Diphosphate; Animals; Blood Platelets; Collagen; Crotalid Venoms; Gene Expression Regulation; Hemorrhage; Hemostasis; Inflammation; Lectins, C-Type; Lipopolysaccharides; Lung; Membrane Glycoproteins; Mice; Oligopeptides; Piperidines; Platelet Aggregation; Platelet Membrane Glycoproteins; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Receptors, Purinergic P2Y12; Skin

N-acylethanolamines (NAEs) such as N-palmitoylethanolamine and anandamide are endogenous bioactive lipids having numerous functions, including the control of inflammation. Their levels and therefore actions can be controlled by modulating the activity of two hydrolytic enzymes, N-acylethanolamine-hydrolyzing acid amidase (NAAA) and fatty acid amide hydrolase (FAAH). As macrophages are key to inflammatory processes, we used lipopolysaccharide-activated J774 macrophages, as well as primary mouse alveolar macrophages, to study the effect of FAAH and NAAA inhibition, using PF-3845 and AM9053 respectively, on macrophage activation and NAE levels measured by HPLC-MS. Markers of macrophage activation were measured by qRT-PCR and ELISA. Activation of macrophages decreased NAAA expression and NAE hydrolytic activity. FAAH and NAAA inhibition increased the levels of the different NAEs, although with different magnitudes, whether in control condition or following LPS-induced macrophage activation. Both inhibitors reduced several markers of macrophage activation, such as mRNA expression of inflammatory mediators, as well as cytokine and prostaglandin production, with however some differences between FAAH and NAAA inhibition. Most of the NAEs tested - including N-docosatetraenoylethanolamine and N-docosahexaenoylethanolamine - also reduced LPS-induced mRNA expression of inflammatory mediators, again with differences depending on the marker and the NAE, thus offering a potential explanation for the differential effect of the inhibitors on macrophage activation markers. In conclusion, we show different and complementary effects of NAE on lipopolysaccharide-induced macrophage activation. Our results support an important role for inhibition of NAE hydrolysis and NAAA inhibition in particular in controlling macrophage activation, and thus inflammation.

Topics: Amides; Amidohydrolases; Animals; Arachidonic Acids; Endocannabinoids; Ethanolamines; Gene Expression Regulation, Enzymologic; Humans; Inflammation; Lipopolysaccharides; Macrophage Activation; Macrophages, Alveolar; Mice; Palmitic Acids; Piperidines; Polyunsaturated Alkamides; Pyridines

The Janus Kinase (JAK) family mediates the cytokine receptor-induced signalling pathways involved in inflammatory processes. The activation of the signal transducers and activators of transcription (STATs) by JAK kinases is a key point in these pathways. Four JAK proteins, JAK1, JAK2, JAK3 and tyrosine kinase 2 (Tyk2) associate with the intracellular domains of surface cytokine receptors are phosphorylating STATs and modulating gene expression. The aim of this study was to explore the role of JAK inhibition in an acute model of inhaled lipopolysaccharide (LPS)-induced airway inflammation in rats through evaluating the effects of tofacitinib, a marketed pan-JAK inhibitor. Specifically, some pulmonary inflammation parameters were studied and the lung STAT3 phosphorylation was assessed as a target engagement marker of JAK inhibition in the model.. Rats were exposed to an aerosol of LPS (0.1 mg/ml) or phosphate-buffered saline (PBS) during 40 min. Bronchoalveolar lavage fluid (BALF) and lung samples were collected 4 h after PBS or LPS exposure. Neutrophils in BALF were counted and a panel of cytokines were measured in BALF. Phosphorylation of STAT3 was studied in lung homogenates by ELISA and localization of phospho-STAT3 (pSTAT3) in lung tissue was also evaluated by immunohistochemistry. In order to assess the effect of JAK inhibition, tofacitinib was administered 1 h before challenge at doses of 3, 10 and 30 mg/kg p.o.. Inhaled LPS challenge induced an augment of neutrophils and cytokines in the BALF as well as an increase in pSTAT3 expression in the lungs. Tofacitinib by oral route inhibited the LPS-induced airway neutrophilia, the levels of some cytokines in the BALF and the phosphorylation of STAT3 in the lung tissue.. In summary, this study shows that JAK inhibition ameliorates inhaled LPS-induced airway inflammation in rats, suggesting that at least JAK/STAT3 signalling is involved in the establishment of the pulmonary neutrophilia induced by LPS. JAKs inhibitors should be further investigated as a potential therapy for respiratory inflammatory diseases.

Topics: Animals; Bronchoalveolar Lavage Fluid; Cytokines; Disease Models, Animal; Inflammation; Janus Kinases; Lipopolysaccharides; Lung; Male; Neutrophils; Phosphorylation; Piperidines; Pneumonia; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Rats; Rats, Sprague-Dawley; Signal Transduction; STAT3 Transcription Factor

The study investigates the potential of Rolipram a phosphodiesterase-4 inhibitor in cognitive deficits induced by streptozotocin (STZ, 3mg/kg intracerebroventricularly) and natural ageing in mice. Morris water maze (MWM) test was employed to evaluate learning and memory of the animals. Extent of oxidative stress was measured by estimating the levels of brain glutathione (GSH) and thiobarbituric acid reactive species (TBARS). Brain acetylcholinestrase (AChE) activity was also estimated. The brain activity of myeloperoxidase (MPO) was measured as a marker of inflammation. STZ and ageing results in marked decline in MWM performance of the animals, reflecting impairment of learning and memory. STZ treated mice and aged mice exhibited a marked accentuation of AChE activity, TBARS and MPO activity along with fall in GSH level. Further the stained micrographs of STZ treated mice and aged mice indicate pathological changes, severe neutrophilic infiltration and amyloid deposition. Rolipram treatment significantly attenuated STZ induced and age related memory deficits, biochemical and histopathological alterations. The findings demonstrate the potential of Rolipram in memory dysfunctions which may probably be attributed to its anti-cholinesterase, anti-amyloid, anti-oxidative and anti-inflammatory effects. The study concludes that PDE-4 can be explored as a potential therapeutic target in dementia.

Topics: Acetylcholinesterase; Aging; Alzheimer Disease; Animals; Antioxidants; Brain; Cholinesterase Inhibitors; Donepezil; Female; Indans; Inflammation; Learning; Male; Maze Learning; Memory Disorders; Mice; Neutrophil Infiltration; Oxidative Stress; Phosphodiesterase 4 Inhibitors; Piperidines; Plaque, Amyloid; Rolipram; Streptozocin

Topics: Arthritis, Psoriatic; Humans; Inflammation; Interleukin-17; Interleukin-23; Janus Kinases; Piperidines; Pyrimidines; Pyrroles

Topics: Arthritis, Psoriatic; Humans; Inflammation; Interleukin-17; Interleukin-23; Janus Kinases; Piperidines; Pyrimidines; Pyrroles

Increased activity of the endocannabinoid system has emerged as a pathogenic factor in visceral obesity, which is a risk factor for type 2 diabetes mellitus (T2DM). The endocannabinoid system is composed of at least two Gprotein-coupled receptors (GPCRs), the cannabinoid receptor type 1 (CB1), and the cannabinoid receptor type 2 (CB2). Downregulation of CB1 activity in rodents and humans has proven efficacious to reduce food intake, abdominal adiposity, fasting glucose levels, and cardiometabolic risk factors. Unfortunately, downregulation of CB1 activity by universally active CB1 inverse agonists has been found to elicit psychiatric side effects, which led to the termination of using globally active CB1 inverse agonists to treat diet-induced obesity. Interestingly, preclinical studies have shown that downregulation of CB1 activity by CB1 neutral antagonists or peripherally restricted CB1 inverse agonists provided similar anorectic effects and metabolic benefits without psychiatric side effects seen in globally active CB1 inverse agonists. Furthermore, downregulation of CB1 activity may ease endoplasmic reticulum and mitochondrial stress which are contributors to obesity-induced insulin resistance and type 2 diabetes. This suggests new approaches for cannabinoid-based therapy in the management of obesity and obesity-related metabolic disorders including type 2 diabetes.

Topics: Animals; Cannabinoid Receptor Antagonists; Diabetes Mellitus, Type 2; Down-Regulation; Drug Inverse Agonism; Eating; Endocannabinoids; Endoplasmic Reticulum Stress; Humans; Inflammation; Insulin Resistance; Mitochondria; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Signal Transduction

Pro-inflammatory cytokines secreted by adipose tissue macrophages (ATMs) contribute to chronic low-grade inflammation and obesity-induced insulin resistance. Recent studies have shown that adipose tissue hypoxia promotes an inflammatory phenotype in ATMs. However, our understanding of how hypoxia modulates the response of ATMs to free fatty acids within obese adipose tissue is limited. We examined the effects of hypoxia (1% O2) on the pro-inflammatory responses of human monocyte-derived macrophages to the saturated fatty acid palmitate. Compared with normoxia, hypoxia significantly increased palmitate-induced mRNA expression and protein secretion of IL-6 and IL-1β. Although palmitate-induced endoplasmic reticulum stress and nuclear factor κB pathway activation were not enhanced by hypoxia, hypoxia increased the activation of JNK and p38 mitogen-activated protein kinase signaling in palmitate-treated cells. Inhibition of JNK blocked the hypoxic induction of pro-inflammatory cytokine expression, whereas knockdown of hypoxia-induced transcription factors HIF-1α and HIF-2α alone or in combination failed to reduce IL-6 and only modestly reduced IL-1β gene expression in palmitate-treated hypoxic macrophages. Enhanced pro-inflammatory cytokine production and JNK activity under hypoxia were prevented by inhibiting reactive oxygen species generation. In addition, silencing of dual-specificity phosphatase 16 increased normoxic levels of IL-6 and IL-1β and reduced the hypoxic potentiation in palmitate-treated macrophages. The secretome of hypoxic palmitate-treated macrophages promoted IL-6 and macrophage chemoattractant protein 1 expression in primary human adipocytes, which was sensitive to macrophage JNK inhibition. Our results reveal that the coexistence of hypoxia along with free fatty acids exacerbates macrophage-mediated inflammation.

Topics: Acetylcysteine; Adipocytes; Animals; Basic Helix-Loop-Helix Transcription Factors; Cell Hypoxia; Cells, Cultured; Culture Media, Conditioned; Cytokines; Dual-Specificity Phosphatases; Endoplasmic Reticulum Stress; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Inflammation Mediators; Macrophages; Mice, Inbred C57BL; Mitochondria; Mitogen-Activated Protein Kinase Phosphatases; Mitogen-Activated Protein Kinases; NF-kappa B; Organophosphorus Compounds; Oxygen; Palmitates; Phosphorylation; Piperidines; Reactive Oxygen Species; Signal Transduction

Atherosclerotic coronary artery disease (CAD) is one of the most prevalent diseases worldwide. Atherosclerosis was considered to be the single most important contributor to CAD. In this study, a distinct serum protein expression pattern in CAD patients was demonstrated by proteomic analysis with two-dimensional gel electrophoresis coupled with mass spectrometry. In particular, CDK9 was found to be highly elevated in serum, monocytes and artery plaque samples of CAD patients. Furthermore, there was high infiltration of CD14+ monocytes/macrophages within artery plaques correlated with the expression of CDK9. Moreover, Flavopiridol (CDK9 inhibitor) could inhibit THP-1 cell (monocytic acute leukemia cell line) proliferation by targeting CDK9. Altogether, These findings indicate that CDK9 represent an important role for inflammation in the pathogenesis of atherosclerosis. It may be a potential biomarker of atherosclerotic inflammation and offer insights into the pathophysiology and targeted therapy for atherosclerotic CAD.

Topics: Aged; Apoptosis; Atherosclerosis; Biomarkers; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cells, Cultured; Coronary Artery Disease; Cyclin-Dependent Kinase 9; Female; Flavonoids; Gene Expression; Humans; Immunohistochemistry; Inflammation; Male; Middle Aged; Monocytes; Piperidines; Protein Kinase Inhibitors; Proteomics; Reverse Transcriptase Polymerase Chain Reaction

Prostaglandin E2 (PGE2), one of the terminal products in the cyclooxygenase pathway, plays an important role in various inflammatory responses. To determine whether selective inhibition of PGE2 may relieve these inflammatory symptoms, we synthesized a selective PGE2 synthesis inhibitor, compound A [1-(6-fluoro-5,7-dimethyl-1,3-benzothiazol-2-yl)-N-[(1S,2R)-2-(hydroxymethyl)cyclohexyl]piperidine-4-carboxamide], then investigated the effects on pyrexia, arthritis and inflammatory pain in guinea pigs. In LPS-stimulated guinea pig macrophages, compound A selectively inhibited inducible PGE2 biosynthesis in a dose-dependent manner whereas enhanced the formation of thromboxane B2 (TXB2). Compound A suppressed yeast-evoked PGE2 production selectively and enhanced the production of TXB2 and 6-keto PGF1αin vivo. In addition, compound A relieved yeast-induced pyrexia and also suppressed paw swelling in an adjuvant-induced arthritis model. The effect on gastrointestinal (GI) ulcer formation was also evaluated and compound A showed a lower GI adverse effect than indomethacin. However, compound A failed to relieve yeast-induced thermal hyperalgesia. These results suggest that selective inhibition of PGE2 synthesis may have anti-pyretic and anti-inflammatory properties without GI side effect, but lack the analgesic efficacy.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Benzothiazoles; Depression, Chemical; Dinoprostone; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Fever; Guinea Pigs; Imidazoles; Indomethacin; Inflammation; Macrophages; Pain; Peptic Ulcer; Phenanthrenes; Piperidines; Stimulation, Chemical; Thromboxane B2

Prostaglandin E2 (PGE2) is a terminal prostaglandin in the cyclooxygenase (COX) pathway. Inhibition of PGE2 production may relieve inflammatory symptoms such as fever, arthritis, and inflammatory pain. We report here the profile of a novel selective PGE2 synthesis inhibitor, compound A [N-[(1S,3S)-3-carbamoylcyclohexyl]-1-(6-methyl-3-phenylquinolin-2-yl)piperidine-4-carboxamide], in animal models of pyrexia and inflammation. The compound selectively suppressed the synthesis of PGE2 in human alveolar adenocarcinoma cell line A549 cells and rat macrophages. In the lipopolysaccharide-induced pyrexia model, this compound selectively reduced PGE2 production in cerebrospinal fluid and showed an anti-pyretic effect. In the adjuvant-induced arthritis model, compound A therapeutically decreased foot swelling in the established arthritis. Our data demonstrates that selective suppression of PGE2 synthesis shows anti-pyretic and anti-inflammatory effects, suggesting that selective PGE2 synthesis inhibitors can be applied as an alternative treatment to nonsteroidal, anti-inflammatory drugs (NSAIDs) or COX-2-selective inhibitors.

Topics: A549 Cells; Animals; Anti-Inflammatory Agents; Antipyretics; Arthritis, Experimental; Cell Line, Tumor; Dinoprostone; Disease Models, Animal; Fever; Humans; Inflammation; Lipopolysaccharides; Macrophages, Peritoneal; Piperidines; Quinolines; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley

Depression is a severe and chronic psychiatric disease, affecting 350 million subjects worldwide. Although multiple antidepressants have been used in the treatment of depressive symptoms, their beneficial effects are limited. The soluble epoxide hydrolase (sEH) plays a key role in the inflammation that is involved in depression. Thus, we examined here the role of sEH in depression. In both inflammation and social defeat stress models of depression, a potent sEH inhibitor, TPPU, displayed rapid antidepressant effects. Expression of sEH protein in the brain from chronically stressed (susceptible) mice was higher than of control mice. Furthermore, expression of sEH protein in postmortem brain samples of patients with psychiatric diseases, including depression, bipolar disorder, and schizophrenia, was higher than controls. This finding suggests that increased sEH levels might be involved in the pathogenesis of certain psychiatric diseases. In support of this hypothesis, pretreatment with TPPU prevented the onset of depression-like behaviors after inflammation or repeated social defeat stress. Moreover, sEH KO mice did not show depression-like behavior after repeated social defeat stress, suggesting stress resilience. The sEH KO mice showed increased brain-derived neurotrophic factor (BDNF) and phosphorylation of its receptor TrkB in the prefrontal cortex, hippocampus, but not nucleus accumbens, suggesting that increased BDNF-TrkB signaling in the prefrontal cortex and hippocampus confer stress resilience. All of these findings suggest that sEH plays a key role in the pathophysiology of depression, and that epoxy fatty acids, their mimics, as well as sEH inhibitors could be potential therapeutic or prophylactic drugs for depression.

Topics: Animals; Antidepressive Agents; Brain; Brain-Derived Neurotrophic Factor; Depression; Disease Models, Animal; Enzyme Inhibitors; Epoxide Hydrolases; Humans; Inflammation; Male; Mice, Inbred C57BL; Mice, Knockout; Oxylipins; Phenylurea Compounds; Piperidines; Rats, Mutant Strains; Social Behavior; Stress, Psychological

Epilepsy is a chronic disorder characterized by spontaneous recurrent seizures. Brain inflammation is increasingly recognized as a critical factor for seizure precipitation, but the molecular mediators of such proconvulsant effects are only partly understood. The chemokine CCL2 is one of the most elevated inflammatory mediators in patients with pharmacoresistent epilepsy, but its contribution to seizure generation remains unexplored. Here, we show, for the first time, a crucial role for CCL2 and its receptor CCR2 in seizure control. We imposed a systemic inflammatory challenge via lipopolysaccharide (LPS) administration in mice with mesial temporal lobe epilepsy. We found that LPS dramatically increased seizure frequency and upregulated the expression of many inflammatory proteins, including CCL2. To test the proconvulsant role of CCL2, we administered systemically either a CCL2 transcription inhibitor (bindarit) or a selective antagonist of the CCR2 receptor (RS102895). We found that interference with CCL2 signaling potently suppressed LPS-induced seizures. Intracerebral administration of anti-CCL2 antibodies also abrogated LPS-mediated seizure enhancement in chronically epileptic animals. Our results reveal that CCL2 is a key mediator in the molecular pathways that link peripheral inflammation with neuronal hyperexcitability.. Substantial evidence points to a role for inflammation in epilepsy, but currently there is little insight as to how inflammatory pathways impact on seizure generation. Here, we examine the molecular mediators linking peripheral inflammation with seizure susceptibility in mice with mesial temporal lobe epilepsy. We show that a systemic inflammatory challenge via lipopolysaccharide administration potently enhances seizure frequency and upregulates the expression of the chemokine CCL2. Remarkably, selective pharmacological interference with CCL2 or its receptor CCR2 suppresses lipopolysaccharide-induced seizure enhancement. Thus, CCL2/CCR2 signaling plays a key role in linking systemic inflammation with seizure susceptibility.

Topics: Animals; Antibodies; Benzoxazines; Chemokine CCL2; Disease Models, Animal; Electroencephalography; Epilepsy, Temporal Lobe; Excitatory Amino Acid Agonists; Hippocampus; Indazoles; Inflammation; Kainic Acid; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Piperidines; Propionates; Receptors, CCR2; RNA, Messenger; Signal Transduction; Up-Regulation

The host innate immune response is the first line of defense against pathogens and is orchestrated by the concerted expression of genes induced by microbial stimuli. Deregulated expression of these genes is linked to the initiation and progression of diseases associated with exacerbated inflammation. We identified topoisomerase 1 (Top1) as a positive regulator of RNA polymerase II transcriptional activity at pathogen-induced genes. Depletion or chemical inhibition of Top1 suppresses the host response against influenza and Ebola viruses as well as bacterial products. Therapeutic pharmacological inhibition of Top1 protected mice from death in experimental models of lethal inflammation. Our results indicate that Top1 inhibition could be used as therapy against life-threatening infections characterized by an acutely exacerbated immune response.

Topics: Animals; Azepines; Camptothecin; DNA Topoisomerases, Type I; Ebolavirus; Flavonoids; Gene Expression Regulation; HEK293 Cells; Hemorrhagic Fever, Ebola; Host-Pathogen Interactions; Humans; Immunity, Innate; Inflammation; Influenza A virus; Interferon-beta; Mice; Mice, Inbred C57BL; Piperidines; Positive Transcriptional Elongation Factor B; RNA Polymerase II; Sendai virus; Staphylococcal Infections; Staphylococcus aureus; Topoisomerase I Inhibitors; Topotecan; Transcription, Genetic; Triazoles

Fatty-acid amide hydrolase (FAAH) is the major enzyme responsible for degradation of anandamide, an endocannabinoid. Pharmacological inhibition or genetic deletion of FAAH (FAAH KO) produces antinociception in preclinical pain models that is largely attributed to anandamide-induced activation of cannabinoid receptors. However, FAAH metabolizes a wide range of structurally related, biologically active lipid signaling molecules whose functions remain largely unknown. Some of these endogenous lipids, including anandamide itself, may exert pro-nociceptive effects under certain conditions. In our study, FAAH KO mice exhibited a characteristic analgesic phenotype in the tail flick test and in both formalin and carrageenan models of inflammatory nociception. Nonetheless, intradermal injection of the transient receptor potential channel V1 (TRPV1) agonist capsaicin increased nocifensive behavior as well as mechanical and heat hypersensitivity in FAAH KO relative to wild-type mice. This pro-nociceptive phenotype was accompanied by increases in capsaicin-evoked Fos-like immunoreactive (FLI) cells in spinal dorsal horn regions implicated in nociceptive processing and was attenuated by CB1 (AM251) and TRPV1 (AMG9810) antagonists. When central sensitization was established, FAAH KO mice displayed elevated levels of anandamide, other fatty-acid amides, and endogenous TRPV1 agonists in both paw skin and lumbar spinal cord relative to wild-type mice. Capsaicin decreased spinal cord 2-AG levels and increased arachidonic acid and prostaglandin E2 levels in both spinal cord and paw skin irrespective of genotype. Our studies identify a previously unrecognized pro-nociceptive phenotype in FAAH KO mice that was unmasked by capsaicin challenge. The heightened nociceptive response was mediated by CB1 and TRPV1 receptors and accompanied by enhanced spinal neuronal activation. Moreover, genetic deletion of FAAH has a profound impact on the peripheral and central lipidome. Thus, genetic deletion of FAAH may predispose animals to increased sensitivity to certain types of pain. More work is necessary to determine whether such changes could explain the lack of efficacy of FAAH inhibitors in clinical trials.

Topics: Acrylamides; Amidohydrolases; Analgesia; Animals; Arachidonic Acid; Bridged Bicyclo Compounds, Heterocyclic; Capsaicin; Carrageenan; Disease Models, Animal; Ethanolamines; Formaldehyde; Genotype; Hyperalgesia; Inflammation; Injections, Intraperitoneal; Ligands; Lumbar Vertebrae; Mice, Inbred C57BL; Mice, Knockout; Nociception; Pain; Pain Threshold; Phenotype; Piperidines; Proto-Oncogene Proteins c-fos; Pyrazoles; Receptor, Cannabinoid, CB1; Skin; Spinal Cord Dorsal Horn; TRPV Cation Channels

Lichen planus is a chronic inflammatory disease of the skin, mucous membranes and nails. Management of oral involvement, particularly atrophic and erosive lesions, is challenging. Noteworthy, there is a lack of published evidence for treatment. Cell-mediated cytotoxicity is actually regarded as a major mechanism of pathogenesis. The interferon-gamma induced chemokines CXCL10 and CXCL9 are strongly expressed in serum of patients as well as in both skin and mucosal lesions. Therefore the interferon gamma/CXCL10 axis is considered a key process for both progression and maintenance of chronic cytotoxic inflammation. According to these findings, the interferon gamma/CXCL10 axis could be considered a therapeutically attractive target to reverse inflammation. Since interferon gamma signal transduction occurs through JAK 1 and 2, JAK inhibitors could lead to blockade of interferon gamma signaling and downstream CXCL10 expression.

Topics: Chemokine CXCL10; Chemokine CXCL9; Enzyme Inhibitors; Humans; Inflammation; Interferon-gamma; Lichen Planus; Models, Theoretical; Piperidines; Promoter Regions, Genetic; Pyrimidines; Pyrroles; Signal Transduction; Skin; Treatment Outcome

Phototherapy with UV light is a standard treatment for psoriasis, yet the mechanisms underlying the therapeutic effects are not well understood. Studies in human and mouse keratinocytes and in the skin tissues from human patients and mice showed that UV treatment triggers ubiquitination and downregulation of the type I IFN receptor chain IFNAR1, leading to suppression of IFN signaling and an ensuing decrease in the expression of inflammatory cytokines and chemokines. The severity of imiquimod-induced psoriasiform inflammation was greatly exacerbated in skin of mice deficient in IFNAR1 ubiquitination (Ifnar1(SA)). Furthermore, these mice did not benefit from UV phototherapy. Pharmacologic induction of IFNAR1 ubiquitination and degradation by an antiprotozoal agent halofuginone also relieved psoriasiform inflammation in wild-type but not in Ifnar1(SA) mice. These data identify downregulation of IFNAR1 by UV as a major mechanism of the UV therapeutic effects against the psoriatic inflammation and provide a proof of principle for future development of agents capable of inducing IFNAR1 ubiquitination and downregulation for the treatment of psoriasis.

Topics: Animals; Cell Line; Chemokines; Cytokines; Disease Models, Animal; Down-Regulation; Humans; Inflammation; Keratinocytes; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Piperidines; Psoriasis; Quinazolinones; Receptor, Interferon alpha-beta; Signal Transduction; Skin; Ubiquitination; Ultraviolet Therapy

We have previously demonstrated that the pharmacotherapy with donepezil, an acetylcholinesterase inhibitor, suppresses cardiac remodeling in a mouse model of ischemic heart failure after myocardial infarction (MI). However, the precise mechanisms of the cardioprotective effect of donepezil have not been completely delineated. Because post-ischemic inflammation is a pathological key event in the cardiac remodeling process following MI, we investigated the hypothesis that donepezil acts as an inhibitor of inflammatory mediators. RAW 264.7 murine macrophage cells were pretreated with donepezil (100µM) prior to a pro-inflammatory stimulation by administration of lipopolysaccharide (LPS, 10ng/ml). Donepezil significantly reduced intra- and extracellular levels of various kinds of inflammatory mediators such as TNF-α, IL-1β, IL-2, IL-6 and IL-18 after the LPS stimulation, and attenuated LPS-induced nuclear translocation of nuclear factor-kappa B (NF-κB). These results indicate that donepezil possesses an anti-inflammatory property. However, the inhibitory effect of donepezil on the macrophage inflammatory responses was never reproduced by ACh, nor was disrupted by ACh receptor blockers. Moreover, other kinds of acetylcholinesterase inhibitors failed to inhibit the inflammatory responses in LPS-stimulated macrophage cells. These results suggest that a cholinergic anti-inflammatory pathway would not be involved in the anti-inflammatory effect of donepezil and that the specific characteristics of donepezil in suppressing the LPS-induced cytokine release and the NF-κB activation would be independent of its acetylcholinesterase inhibition. The present study showed that donepezil exerts an anti-inflammatory effect independently of acetylcholinesterase inhibitory action, thereby donepezil may contribute to cardioprotection during cardiac remodeling process in an ischemic heart failure after MI.

Topics: Acetylcholinesterase; Active Transport, Cell Nucleus; Animals; Anti-Inflammatory Agents; Cell Nucleus; Cell Survival; Cholinesterase Inhibitors; Cytokines; Donepezil; Gene Expression Regulation; Indans; Inflammation; Lipopolysaccharides; Macrophages; Mice; NF-kappa B; Piperidines; RAW 264.7 Cells

Stress evokes lipolytic release of free fatty acid (FFA) and low-grade inflammation in visceral adipose tissue, mediated by increased adipokine secretion, and contributes to glucose metabolism disorder and prothrombotic state. We tested the hypothesis that alogliptin, a dipeptidyl peptidase-4 inhibitor, can ameliorate the biological effects of chronic stress in mice.. C57BL/6J mice were subjected to 2-week intermittent restraint stress and orally treated with vehicle or alogliptin (dose: 15 or 45mg/kg/day). Plasma levels of lipids, proinflammatory cytokines (monocyte chemoattractant protein-1, tumor necrosis factor-α, and interleukin-6), and 8-hydroxydeoxyguanosine were measured with enzyme-linked immunosorbent assay. Monocyte/macrophage accumulation in inguinal white adipose tissue (WAT) was examined by CD11b-positive cell count and mRNA expression of CD68 and F4/80 was examined by immunohistochemistry and RT-PCR, respectively. The mRNA levels of the above-mentioned proinflammatory cytokines, NADPH oxidase 4, adiponectin, and coagulation factors (plasminogen activation inhibitor-1 and tissue factor) in WAT were also assessed with RT-PCR. Glucose metabolism was assessed by glucose and insulin tolerance tests, plasma levels of DPP-4 activity, glucagon-like peptide-1, expression of DPP-4, insulin receptor substrate-1 and glucose transporter 4 in WAT and skeletal muscle. Alogliptin administration suppressed stress-induced FFA release, oxidative stress, adipose tissue inflammation, DPP-4 activation, and prothrombotic state in a dose-dependent manner, and improved insulin sensitivity in stressed mice.. The results indicate that alogliptin improves stress-induced prothrombotic state and insulin resistance; suggesting that alogliptin could have beneficial therapeutic effects against cardiovascular complications in diabetic patients under stress.

Topics: Adipose Tissue; Animals; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Inflammation; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Piperidines; Stress, Psychological; Thrombophilia; Uracil

The bis (1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)-decandioate (IAC), is an innovative non- radical scavenger used with success in numerous disease models such as inflammation, neurological disorders, hepatitis and diabetes. The pharmacological treatments have been performed by the intraperitoneal route of administration, representing to date, the main limit for the drug use. The aim of this study was to develop a delivery system that allows the oral administration of IAC while maintaining its therapeutic efficacy. Solid Lipid Microparticles (SLMs) containing a theoretical 18% (w/w) of IAC have been produced by the spray congealing technology; three formulations have been tested (A, B and C) using different low melting point carriers (stearic acid, Compritol(®) HD5ATO and carnauba wax) alone or in combination. All IAC loaded SLMs exhibited a spherical shape, encapsulation efficiency higher than 94% and particle size suitable for the oral route. Administered per os at different dosages in an inflammation rat model, all SLMs demonstrated their efficacy in reducing oedema and alleviating pain, compared to the gold standards Indomethacin and Paracetamol. These results suggested that the SLMs are an efficacious delivery system for the oral administration of IAC, potentially useful for the treatment of others diseases related to an over production of free radicals.

Topics: Acetaminophen; Administration, Oral; Animals; Disease Models, Animal; Free Radical Scavengers; Glycerol; Indomethacin; Inflammation; Liposomes; Male; Particle Size; Piperidines; Polyethylene Glycols; Rats; Stearic Acids; Waxes

The present study was designed to investigate the potential therapeutic effect of trikatu, an herbal compound and its underlying molecular mechanism in rats with adjuvant-induced arthritis (AIA). Our results indicate that trikatu (1000 mg/kg/b.wt. oral) administration suppressed the production of pro-inflammatory cytokines (tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and monocyte chemoattractant protein (MCP)-1) and downregulated the mRNA expression levels of inflammatory mediators (TNF-α, IL-1β, IL-6, IL-17, MCP-1, receptor activator of nuclear factor kappa B ligand (RANKL), cyclooxygenase (COX)-2, and inducible nitric oxide synthase (iNOS)) and transcription factors (nuclear factor kappa B 65 (NFкB-p65) and activator protein-1 (AP-1)) in cultured AIA-fibroblast like synoviocytes and synovial tissue of AIA rats. Consistently, the protein expression of NFкB-p65, IL-17, TNF-α, COX-2, and RANKL was also dramatically reduced in cultured AIA-fibroblast like synoviocytes and synovial tissue of AIA rats by trikatu treatment. In addition, trikatu suppressed the expression and phosphorylation of NFкB-p65 similar to the Bay 11-7082 (NFкB inhibitor) in cultured AIA-fibroblast like synoviocytes. Furthermore, trikatu alleviated the histopathology of joint of arthritic rats. Overall, these data highlights that trikatu could be a promising alternative modality for the possible treatment of rheumatoid arthritis and other inflammatory diseases.

Topics: Alkenes; Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Blotting, Western; Cells, Cultured; Chromatography, High Pressure Liquid; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Fibroblasts; Fluorescent Antibody Technique; Gas Chromatography-Mass Spectrometry; Inflammation; Inflammation Mediators; Male; NF-kappa B; Phytotherapy; Piperidines; Rats, Wistar; Real-Time Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Synovial Membrane; Synoviocytes

Neutrophilic inflammation is tightly regulated and subsequently resolves to limit tissue damage and promote repair. When the timely resolution of inflammation is dysregulated, tissue damage and disease results. One key control mechanism is neutrophil apoptosis, followed by apoptotic cell clearance by phagocytes such as macrophages. Cyclin-dependent kinase (CDK) inhibitor drugs induce neutrophil apoptosis in vitro and promote resolution of inflammation in rodent models. Here we present the first in vivo evidence, using pharmacological and genetic approaches, that CDK9 is involved in the resolution of neutrophil-dependent inflammation. Using live cell imaging in zebrafish with labelled neutrophils and macrophages, we show that pharmacological inhibition, morpholino-mediated knockdown and CRISPR/cas9-mediated knockout of CDK9 enhances inflammation resolution by reducing neutrophil numbers via induction of apoptosis after tailfin injury. Importantly, knockdown of the negative regulator La-related protein 7 (LaRP7) increased neutrophilic inflammation. Our data show that CDK9 is a possible target for controlling resolution of inflammation.

Topics: Animals; Apoptosis; CRISPR-Cas Systems; Cyclin-Dependent Kinase 9; Disease Models, Animal; Flavonoids; Gene Knockdown Techniques; Inflammation; Macrophages; Neutrophils; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Ribonucleoproteins; Zebrafish; Zebrafish Proteins

Persistently active PKMζ has been implicated in maintaining spinal nociceptive sensitization that underlies pain hypersensitivity. However, evidence for PKMζ in the maintenance of pain hypersensitivity comes exclusively from short-term studies in males using pharmacological agents of questionable selectivity. The present study examines the contribution of PKMζ to long-lasting allodynia associated with neuropathic, inflammatory, or referred visceral and muscle pain in males and females using pharmacological inhibition or genetic ablation.. Pharmacological inhibition or genetic ablation of PKMζ reduced mild formalin pain and slowly developing contralateral allodynia in nerve-injured rats, but not moderate formalin pain or ipsilateral allodynia in models of neuropathic and inflammatory pain. Pharmacological inhibition or genetic ablation of PKMζ also effectively reduced referred visceral and muscle pain in male, but not in female mice and rats.. We show pharmacological inhibition and genetic ablation of PKMζ consistently attenuate long-lasting pain hypersensitivity. However, differential effects in models of referred versus inflammatory and neuropathic pain, and in males versus females, highlight the roles of afferent input-dependent masking and sex differences in the maintenance of pain hypersensitivity.

Topics: Animals; Capsaicin; Cell-Penetrating Peptides; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Freund's Adjuvant; Inflammation; Lipopeptides; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neuralgia; Pain Threshold; Piperidines; Protein Kinase C; Rats; Rats, Long-Evans; Sex Characteristics; Spinal Cord

Traumatic brain injury (TBI) is an increasingly frequent and poorly understood condition lacking effective therapeutic strategies. Inflammation and oxidative stress (OS) are critical components of injury, and targeted interventions to reduce their contribution to injury should improve neurobehavioral recovery and outcomes. Recent evidence reveals potential protective, yet short-lived, effects of the endocannabinoids (ECs), 2-arachidonoyl glycerol (2-AG) and N-arachidonoyl-ethanolamine (AEA), on neuroinflammatory and OS processes after TBI. The aim of this study was to determine whether EC degradation inhibition after TBI would improve neurobehavioral recovery by reducing inflammatory and oxidative damage. Adult male Sprague-Dawley rats underwent a 5-mm left lateral craniotomy, and TBI was induced by lateral fluid percussion. TBI produced apnea (17±5 sec) and a delayed righting reflex (479±21 sec). Thirty minutes post-TBI, rats were randomized to receive intraperitoneal injections of vehicle (alcohol, emulphor, and saline; 1:1:18) or a selective inhibitor of 2-AG (JZL184, 16 mg/kg) or AEA (URB597, 0.3 mg/kg) degradation. At 24 h post-TBI, animals showed significant neurological and -behavioral impairment as well as disruption of blood-brain barrier (BBB) integrity. Improved neurological and -behavioral function was observed in JZL184-treated animals. BBB integrity was protected in both JZL184- and URB597-treated animals. No significant differences in ipsilateral cortex messenger RNA expression of interleukin (IL)-1β, IL-6, chemokine (C-C motif) ligand 2, tumor necrosis factor alpha, cyclooxygenase 2 (COX2), or nicotinamide adenine dinucleotide phosphate oxidase (NOX2) and protein expression of COX2 or NOX2 were observed across experimental groups. Astrocyte and microglia activation was significantly increased post-TBI, and treatment with JZL184 or URB597 blocked activation of both cell types. These findings suggest that EC degradation inhibition post-TBI exerts neuroprotective effects. Whether repeated dosing would achieve greater protection remains to be examined.

Topics: Animals; Arachidonic Acids; Benzamides; Benzodioxoles; Blood-Brain Barrier; Blotting, Western; Brain Injuries; Carbamates; Disease Models, Animal; Endocannabinoids; Glycerides; Immunohistochemistry; Inflammation; Male; Neuroprotective Agents; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Recovery of Function

Increasing evidences suggest that, apart from activation of guanylyl cyclase, intracellular nitric oxide (NO) signaling is associated with an interaction between NO and reactive oxygen species (ROS) to modulate physiological or pathophysiological processes. The aim of this study was to understand the contribution of mitochondrial ROS (mtROS) to NO-mediated signaling in hepatocytes on inflammation.. In rats treated with lipopolysaccharide (LPS), mitochondria-targeted antioxidants (mtAOX) (mitoTEMPO and SkQ1) reduced inducible nitric oxide synthase (iNOS) gene expression in liver, NO levels in blood and plasma, and markers of organ damage (lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase). In cultured hepatocytes, treated with inflammatory mediators, generated ex vivo by incubation of white blood cells with LPS, we observed an increase in NO and mtROS levels. l-NG-monomethyl arginine citrate, a NOS inhibitor, decreased both NO and mtROS levels. mtAOX reduced mtROS, cytoplasmic ROS levels, and expression of iNOS and interleukin (IL)-6. These data suggest that NO, generated by iNOS, elevates mtROS, which, in turn, diffuse into the cytoplasm and upregulate iNOS and IL-6.. Here, for the first time, we show that intracellular signaling pathways mediated by NO and ROS are linked to each other via mtROS and form an iNOS-mtROS feed-forward loop which aggravates liver failure on acute inflammation.. Our results provide a mechanistic explanation of how NO and mtROS cooperate to conduct inflammatory intracellular signals. We anticipate our results to be the missing mechanistic link between acute systemic inflammation and liver failure.

Topics: Animals; Antioxidants; Biomarkers; Cell Line; Hepatocytes; Inflammation; Lipopolysaccharides; Liver; Male; Mitochondria; Nitric Oxide; Nitric Oxide Synthase Type II; Organophosphorus Compounds; Piperidines; Plastoquinone; Rats, Sprague-Dawley; Reactive Oxygen Species; Signal Transduction

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

Activation of microglia cells in the brain contributes to neurodegenerative processes promoted by many neurotoxic factors such as pro-inflammatory cytokines and nitric oxide (NO). Reactive oxygen species (ROS) actively affect microglia-associated neurodegenerative diseases through their role as pro-inflammatory molecules and modulators of pro-inflammatory processes. Although the ROS which involved in microglia activation are thought to be generated primarily by NADPH oxidase (NOX) and involved in the immune response, mitochondrial ROS have also been proposed as important regulators of the inflammatory response in the innate immune system. However, the role of mitochondrial ROS in microglial activation has yet to be fully elucidated. In this study, we demonstrate that inhibition of mitochondrial ROS by treatment with Mito-TEMPO effectively suppressed the level of mitochondrial and intracellular ROS. Mito-TEMPO treatment also significantly prevented LPS-induced increase in the TNF-α, IL-1β, IL-6, iNOS and Cox-2 in BV-2 and primary microglia cells. Furthermore, LPS-induced suppression of mitochondrial ROS generation not only affected LPS-stimulated activation of MAPKs, including ERK, JNK, and p38, but also regulated IκB activation and NF-κB nuclear localization. These results indicate that mitochondria constitute a major source of ROS generation in LPS-mediated activated microglia cells. Additionally, suppression of LPS-induced mitochondrial ROS plays a role in modulating the production of pro-inflammatory mediators by preventing MAPK and NF-κB activation in microglia cells. Our findings suggest that a potential strategy in the development of therapy for inflammation-associated degenerative neurological diseases involves targeting the regulation of mitochondrial ROS in microglial cells.

Topics: Animals; Cell Line; Extracellular Signal-Regulated MAP Kinases; Inflammation; Lipopolysaccharides; MAP Kinase Kinase 4; Mice; Microglia; Mitochondria; Mitogen-Activated Protein Kinases; NF-kappa B; Organophosphorus Compounds; p38 Mitogen-Activated Protein Kinases; Piperidines; Reactive Oxygen Species; Signal Transduction

The anti-inflammatory effect of piperine has been largely investigated in macrophages, but its activity on epithelial cells in inflammatory settings is unclear. The present study aimed to investigate the effect of piperine on the expression of inflammatory cytokines in lipopolysaccharide (LPS)-stimulated human epithelial-like SW480 and HT-29 cells. Our data showed that although piperine inhibited the proliferation of SW480 and HT-29 cells in a dose-dependent manner, it had low cytotoxicity on these cell lines with 50 % inhibiting concentration (IC50) values greater than 100 μM. As epithelial-like cells, SW480 and HT-29 cells secreted high levels of the chemokine CXCL8 upon LPS stimulation. Importantly, piperine dose-dependently suppressed LPS-induced secretion of CXCL8 and the expression of CXCL8 messenger RNA (mRNA). Although piperine failed to affect the critical inflammatory nuclear factor-κB pathway, it attenuated the c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) signaling. Consistent with previous reports, p38 signaling seemed to play a more pronounced role on the CXCL8 expression than JNK signaling since inhibition of p38, instead of JNK, greatly suppressed LPS-induced CXCL8 expression. Collectively, our results indicated that piperine could attenuate the inflammatory response in epithelial cells via downregulating the MAPK signaling and thus the expression of CXCL8, suggesting its potential application in anti-inflammation therapy.

Topics: Alkaloids; Anti-Inflammatory Agents; Benzodioxoles; Cell Line; Cell Proliferation; Cell Survival; Down-Regulation; Epithelial Cells; HT29 Cells; Humans; Inflammation; Inflammatory Bowel Diseases; Interleukin-8; JNK Mitogen-Activated Protein Kinases; Lipopolysaccharides; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Piperidines; Polyunsaturated Alkamides; RNA, Messenger

Monoacylglycerol lipase (MAGL) is part of the endocannabinoid and the prostaglandin signaling system. MAGL degrades the endocannabinoid 2-arachidonoylglycerol (2-AG) into glycerol and arachidonic acid. MAGL-induced arachidonic acid is the primary source for prostaglandin synthesis in the brain. 2-AG mainly induces neuroprotective and anti-inflammatory effects, whereas prostaglandins are related to pro-inflammatory effects inducing neurotoxicity. Therefore, inhibition of MAGL represents a promising target for neurological diseases characterized by inflammation. However, as 2-AG is an agonist for the cannabinoid receptor 1 (CB1), inhibition of MAGL might be associated with unwanted cannabimimetic effects. Here, we show that oral administration of KML29, a highly selective inhibitor of MAGL, induced large and dose-dependent changes in 2-AG levels in vivo in brain and spinal cord of mice. Of note, MAGL inhibition by KML29 induced a decrease in prostaglandin levels in brain and most peripheral tissues but not in the spinal cord. MAGL expression was highest in fat, liver and brain, whereas the cytosolic phospholipase A2 (cPLA2), a further enzyme responsible for arachidonic acid production, was highly expressed in spinal cord, muscle and spleen. In addition, high doses (10 mg/kg) of KML29 induced some cannabimimetic effects in vivo in the tetrad test, including hypothermia, analgesia and hypomotility without induction of cataleptic behavior. In summary, inhibition of MAGL by KML29 represents a promising strategy for targeting the cannabinoid and prostaglandin system of the brain with only a moderate induction of cannabimimetic effects.

Topics: Adipose Tissue, Brown; Analgesics; Animals; Arachidonic Acid; Arachidonic Acids; Benzodioxoles; Brain Chemistry; Endocannabinoids; Enzyme Inhibitors; Female; Glycerides; Inflammation; Liver; Male; Mice; Monoacylglycerol Lipases; Motor Activity; Nociception; Piperidines; Prostaglandins; Quadriceps Muscle; Spinal Cord; Spleen

2014 saw the emergence of a novel rheumatoid arthritis therapy to rival methotrexate, as well as advances in our understanding of mouse T.cell biology and of the cross-talk between the nervous system and the immune system. How will these advances affect the future of rheumatoid arthritis research and therapy?

Topics: Animals; Arthritis, Rheumatoid; Disease Models, Animal; Humans; Inflammation; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; T-Lymphocytes, Regulatory

The pharmacological inhibition of anandamide (AEA) hydrolysis by fatty acid amide hydrolase (FAAH) attenuates pain in animal models of osteoarthritis (OA) but has failed in clinical trials. This may have occurred because AEA also activates transient receptor potential vanilloid type 1 (TRPV1), which contributes to pain development. Therefore, we investigated the effectiveness of the dual FAAH-TRPV1 blocker OMDM-198 in an MIA-model of osteoarthritic pain. We first investigated the MIA-induced model of OA by (1) characterizing the pain phenotype and degenerative changes within the joint using X-ray microtomography and (2) evaluating nerve injury and inflammation marker (ATF-3 and IL-6) expression in the lumbar dorsal root ganglia of osteoarthritic rats and differences in gene and protein expression of the cannabinoid CB1 receptors FAAH and TRPV1. Furthermore, we compared OMDM-198 with compounds acting exclusively on FAAH or TRPV1. Osteoarthritis was accompanied by the fragmentation of bone microstructure and destroyed cartilage. An increase of the mRNA levels of ATF3 and IL-6 and an upregulation of AEA receptors and FAAH in the dorsal root ganglia were observed. OMDM-198 showed antihyperalgesic effects in the OA model, which were comparable with those of a selective TRPV1 antagonist, SB-366,791, and a selective FAAH inhibitor, URB-597. The effect of OMDM-198 was attenuated by the CB1 receptor antagonist, AM-251, and by the nonpungent TRPV1 agonist, olvanil, suggesting its action as an "indirect" CB1 agonist and TRPV1 antagonist. These results suggest an innovative strategy for the treatment of OA, which may yield more satisfactory results than those obtained so far with selective FAAH inhibitors in human OA.

Topics: Activating Transcription Factor 3; Amidohydrolases; Anilides; Animals; Arachidonic Acids; Benzamides; Capsaicin; Carbamates; Cinnamates; Disease Models, Animal; Endocannabinoids; Ganglia, Spinal; Gene Expression; Hyperalgesia; Inflammation; Interleukin-6; Lumbar Vertebrae; Male; Osteoarthritis; Pain; Pain Management; Pain Measurement; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; TRPV Cation Channels

Piperine exhibits anti-inflammatory activity, and has a long history of medicinal use. The objective of this study was to investigate the protective effects of piperine on inflammation, alveolar bone and collagen fibers in experimental periodontitis. We evaluated the related expression of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, matrix metalloproteinase (MMP)-8 and MMP-13 to enhance insight into these effects.. Thirty-two Wistar rats were divided into four groups of eight animals each: control group, periodontitis group, periodontitis plus 50 mg/kg piperine group and periodontitis plus 100 mg/kg piperine group. Histopathologic changes were detected by hematoxylin and eosin staining. Alveolar bone loss and trabecula microstructures were evaluated by micro-computed tomography. Changes in collagen fibers were assessed by picrosirius red staining. Western blot analysis was conducted to determine the levels of IL-1β, TNF-α, MMP-8 and MMP-13.. Piperine clearly inhibited alveolar bone loss and reformed trabecula microstructures in a dose-dependent manner. Histological staining showed that piperine significantly reduced the infiltration of inflammation in soft tissues. Both doses of piperine limited the fractions of degraded areas in collagen fibers. Piperine (100 mg/kg) significantly downregulated the expressions of IL-1β, MMP-8 and MMP-13 in periodontitis, but not that of TNF-α.. Piperine displays significantly protective effects on inflammation, alveolar bone loss, bone microstructures and collagen fiber degradation in experimental periodontitis. The effects may be ascribed to its inhibitory activity on the expressions of IL-1β, MMP-8 and MMP-13.

Topics: Alkaloids; Alveolar Bone Loss; Animals; Benzodioxoles; Blotting, Western; Collagen; Cytochrome P-450 Enzyme Inhibitors; Disease Models, Animal; Histocytochemistry; Inflammation; Interleukin-1beta; Male; Matrix Metalloproteinase 13; Matrix Metalloproteinase 8; Periodontitis; Piperidines; Polyunsaturated Alkamides; Proteolysis; Rats, Wistar; Treatment Outcome; Tumor Necrosis Factor-alpha; X-Ray Microtomography

It is hypothesized that chronic increase of availability of acetylcholine, resulting from the effect of antiacetylcholinesterases, may prevent autonomic imbalance and reduce inflammation yielding benefic effects for cardiovascular disorders in hypertension. The effect of long-term administration of antiacetylcholinesterase agents with central and/or peripheral action, i.e., donepezil and pyridostigmine, were investigated on arterial pressure (AP), sympathovagal balance, plasma cytokine levels, and cardiac remodeling in spontaneously hypertensive rats (SHR).. Chronic treatment with donepezil or pyridostigmine started before the onset of hypertension. AP was measured by plethysmography every 4 weeks. At the end of 16 weeks of treatment, methylatropine was used to evaluate the cardiac vagal tone; AP and pulse interval (PI) variability were also evaluated followed by plasma and heart collection for analysis.. Pyridostigmine, which does not cross the blood-brain barrier, increased cardiac vagal tone, and reduced cardiomyocyte diameter and collagen density, but did not affect the AP and plasma cytokine levels. Donepezil, which crosses the blood-brain barrier, attenuated the development of hypertension, increased cardiac vagal tone, and improved AP and PI variability. Likewise, donepezil reduced the plasma levels of tumor necrosis factor-α, interleukin 6, and interferon γ, besides reducing cardiomyocyte diameter and collagen density.. Donepezil attenuated the development of hypertension in SHR probably involving antiinflammatory effects, indicating that acetylcholinesterase inhibition yields benefic effects for antihypertensive therapy.

Topics: Animals; Blood Pressure; Cholinesterase Inhibitors; Cytokines; Donepezil; Drug Evaluation, Preclinical; Heart; Heart Rate; Hypertension; Indans; Inflammation; Male; Piperidines; Pyridostigmine Bromide; Rats, Inbred SHR; Rats, Inbred WKY; Ventricular Remodeling

Hepatic steatosis is the accumulation of excess fat in the liver. Recently, hepatic steatosis has become more important because it occurs in the patients with obesity, type 2 diabetes, and hyperlipidemia and is associated with endoplasmic reticulum (ER) stress and insulin resistance. C-C chemokine receptor 2 (CCR2) inhibitor has been reported to improve inflammation and glucose intolerance in diabetes, but its mechanisms remained unknown in hepatic steatosis. We examined whether CCR2 inhibitor improves ER stress-induced hepatic steatosis in type 2 diabetic mice. In this study, db/db and db/m (n = 9) mice were fed CCR2 inhibitor (2 mg/kg/day) for 9 weeks. In diabetic mice, CCR2 inhibitor decreased plasma and hepatic triglycerides levels and improved insulin sensitivity. Moreover, CCR2 inhibitor treatment decreased ER stress markers (e.g., BiP, ATF4, CHOP, and XBP-1) and inflammatory cytokines (e.g., TNFα, IL-6, and MCP-1) while increasing markers of mitochondrial biogenesis (e.g., PGC-1α, Tfam, and COX1) in the liver. We suggest that CCR2 inhibitor may ameliorate hepatic steatosis by reducing ER stress and inflammation in type 2 diabetes mellitus.

Topics: Animals; Benzoxazines; Blotting, Western; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Endoplasmic Reticulum Stress; Fatty Liver; Glucose Tolerance Test; Humans; Immunoenzyme Techniques; Inflammation; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Obesity; Piperidines; Real-Time Polymerase Chain Reaction; Receptors, CCR2; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Recent studies showed that the pharmacological inhibition of endocannabinoid degrading enzymes such as fatty acid amide hydrolase (FAAH) and monoacyl glycerol lipase (MAGL) elicit promising analgesic effects in a variety of nociceptive models without serious side effects. However, the full spectrum of activities is not observed upon inhibition of either FAAH or MAGL enzymes alone and thus dual FAAH and MAGL inhibitors have been described. Visceral pain is strongly associated with inflammation and distension of the gut. Thus, we explored the comparable effects of FAAH, MAGL, and dual FAAH/MAGL inhibitors on inflammatory and mechanically evoked visceral pain models.. Visceral inflammatory and distension-induced pain were assessed with the 0.6% acetic acid writhing test in mice and colorectal distension (CRD) test in rats, respectively. The selective FAAH inhibitor PF 3845, MAGL inhibitor JZL 184, dual inhibitor JZL 195, and the cannabis analog CP 55,940 were given systemically 30 min prior to nociceptive testing.. PF 3845 (5, 10, and 20 mg/kg), JZL 184 (5, 10, and 20 mg/kg), and JZL 195 (5, 10, and 20 mg/kg) elicit dose-dependent antinociceptive in the acetic acid writhing test. In the CRD model, while JZL 195 (5, 10, or 20 mg/kg) and PF3845 (10, 20, and 40 mg/kg) produced dose-dependent antinociceptive effects comparable to those of CP 55,940 (0.1, 0.3, or 1 mg/kg), JZL 184 (10, 20, and 40 mg/kg) alone did not alter the visceromotor response (VMR).. The selective FAAH inhibitor and dual FAAH/MAGL inhibitors were effective in both inflammatory and mechanically evoked visceral pain, while the MAGL inhibitor elicited an analgesic effect in inflammatory, but not in distension-induced, visceral pain.

Topics: Amidohydrolases; Animals; Benzodioxoles; Carbamates; Colon; Cyclohexanols; Inflammation; Male; Mice; Mice, Inbred BALB C; Monoacylglycerol Lipases; Pain Measurement; Piperazines; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Visceral Pain

Currently little is known as to how nutritionally derived compounds may affect dendritic cell (DC) maturation and potentially prevent inappropriate inflammatory responses that are characteristic of chronic inflammatory syndromes. Previous observations have demonstrated that two polyphenols quercetin and piperine delivered through reconstituted oil bodies (ROBs-QP) can influence DC maturation in response to LPS leading to a modulated inflammatory response. In the present study, we examined the molecular effects of ROBs-QP exposure on DC differentiation in mice and identified a unique molecular signature in response to LPS administration that potentially modulates DC maturation and activity in inflammatory conditions. Following LPS administration, ROBs-QP-exposed DCs expressed an altered molecular profile as compared with control DCs, including cytokine and chemokine production, chemokine receptor repertoire, and antigen presentation ability. In vivo ROBs-QP administration suppresses antigen-specific T-cell division in the draining lymph nodes resulting from a reduced ability to create stable immunological synapse. Our data demonstrate that polyphenols exposure can drive DCs toward a new anti-inflammatory molecular profile capable of dampening the inflammatory response, highlighting their potential as complementary nutritional approaches in the treatment of chronic inflammatory syndromes.

Topics: Alkaloids; Animals; Antigen Presentation; Benzodioxoles; Cell Differentiation; Cell Proliferation; Cytokines; Dendritic Cells; Gene Expression; Inflammation; Lipopolysaccharides; Lymphocyte Activation; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Piperidines; Polyphenols; Polyunsaturated Alkamides; Primary Cell Culture; Quercetin; Receptors, Chemokine; T-Lymphocytes

The Rho-kinase (ROCK) inhibitor Fasudil has proven beneficial in experimental autoimmune encephalomyelitis (EAE). Given the small safety window of Fasudil, we are looking for novel ROCK inhibitors, which have similar or stronger effect on EAE with greater safety. In this study, we report that WAR-5, a Y-27632 derivative, alleviates the clinical symptoms, attenuates myelin damage and reduces CNS inflammatory responses in EAE C57BL/6 mice at an extent similar to Fasudil, while exhibits less vasodilator and adverse reaction in vivo. WAR-5 inhibits ROCK activity, and selectively suppresses the expression of ROCK II in spleen, brain and spinal cord of EAE mice, especially in spinal cord, accompanied by decreased expression of Nogo. WAR-5 also regulates the imbalance of Th1/Th17 T cells and regulatory T cells, inhibits inflammatory microenvironment induced with NF-κB-IL-1β pathway. Importantly, WAR-5 converts M1 toward M2 microglia/macrophages that are positively correlated with BDNF and NT-3 production. Taken together, WAR-5 exhibits therapeutic potential in EAE by more selectively inhibits ROCK II, with a greater safety than Fasudil, and is worthy of further clinical study to clarify its clinical value.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Amides; Aminopyridines; Animals; Cytokines; Encephalomyelitis, Autoimmune, Experimental; Enzyme-Linked Immunosorbent Assay; Female; Immunoblotting; Immunoenzyme Techniques; Inflammation; Macrophages; Mice; Mice, Inbred C57BL; Microglia; Nerve Growth Factors; Piperidines; Protein Kinase Inhibitors; Pyridines; rho-Associated Kinases; T-Lymphocytes, Regulatory

The prevalence of allergic skin disorders has increased rapidly, and development of therapeutic agents to alleviate the symptoms are still needed. In this study, we orally or topically administered the Janus kinase (JAK) inhibitors, tofacitinib and oclacitinib, in a mouse model of dermatitis, and compared the efficacy to reduce the itch and inflammatory response. In vitro effects of JAK inhibitors on bone marrow-derived dendritic cells (BMDCs) were analyzed. For the allergic dermatitis model, female BALB/c mice were sensitized and challenged with toluene-2,4-diisocyanate (TDI). Each JAK inhibitor was orally or topically applied 30 minutes before and 4 hours after TDI challenge. After scratching bouts and ear thickness were measured, cytokines were determined in challenged skin and the cells of the draining lymph node were analyzed by means of flow cytometry. In vitro, both JAK inhibitors significantly inhibited cytokine production, migration, and maturation of BMDCs. Mice treated orally with JAK inhibitors showed a significant decrease in scratching behavior; however, ear thickness was not significantly reduced. In contrast, both scratching behavior and ear thickness in the topical treatment group were significantly reduced compared with the vehicle treatment group. However, cytokine production was differentially regulated by the JAK inhibitors, with some cytokines being significantly decreased and some being significantly increased. In conclusion, oral treatment with JAK inhibitors reduced itch behavior dramatically but had only little effect on the inflammatory response, whereas topical treatment improved both itch and inflammatory response. Although the JAK-inhibitory profile differs between both JAK inhibitors in vitro as well as in vivo, the effects have been comparable.

Topics: Administration, Oral; Administration, Topical; Animals; Anti-Inflammatory Agents; Antipruritics; Cytokines; Dermatitis, Allergic Contact; Disease Models, Animal; Female; Inflammation; Janus Kinases; Lymph Nodes; Mice; Mice, Inbred BALB C; Piperidines; Pruritus; Pyrimidines; Pyrroles; Skin; Sulfonamides

Efficient apoptotic cell clearance and induction of immunologic tolerance is a critical mechanism preventing autoimmunity and associated pathology. Our laboratory has reported that apoptotic cells induce tolerance by a mechanism dependent on the tryptophan catabolizing enzyme indoleamine 2,3 dioxygenase 1 (IDO1) in splenic macrophages (MΦ). The metabolic-stress sensing protein kinase GCN2 is a primary downstream effector of IDO1; thus, we tested its role in apoptotic cell-driven immune suppression. In vitro, expression of IDO1 in MΦs significantly enhanced apoptotic cell-driven IL-10 and suppressed IL-12 production in a GCN2-dependent mechanism. Suppression of IL-12 protein production was due to attenuation of IL-12 mRNA association with polyribosomes inhibiting translation while IL-10 mRNA association with polyribosomes was not affected. In vivo, apoptotic cell challenge drove a rapid, GCN2-dependent stress response in splenic MΦs with increased IL-10 and TGF-β production, whereas myeloid-specific deletion of GCN2 abrogated regulatory cytokine production with provocation of inflammatory T-cell responses to apoptotic cell antigens and failure of long-tolerance induction. Consistent with a role in prevention of apoptotic cell driven autoreactivity, myeloid deletion of GCN2 in lupus-prone mice resulted in increased immune cell activation, humoral autoimmunity, renal pathology, and mortality. In contrast, activation of GCN2 with an agonist significantly reduced anti-DNA autoantibodies and protected mice from disease. Thus, this study implicates a key role for GCN2 signals in regulating the tolerogenic response to apoptotic cells and limiting autoimmunity.

Topics: Amino Acids; Animals; Apoptosis; Autoimmunity; Cells, Cultured; Cytokines; Disease Models, Animal; Gene Expression Regulation; Immune Tolerance; Indoleamine-Pyrrole 2,3,-Dioxygenase; Inflammation; Lupus Erythematosus, Systemic; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid Cells; Piperidines; Protein Serine-Threonine Kinases; Quinazolinones; Signal Transduction

Alzheimer's disease (AD) is one of the most patient devastating central nervous system diseases with no curative therapy. An effective oral therapy with brain-targeting potential is required that is hampered by blood-brain barrier. Piperine (PIP) is a natural alkaloid with memory enhancing potentials. Oral PIP delivery suffers from its hydrophobicity and first-pass metabolism. In this study, novel Tween-modified monoolein cubosomes (T-cubs) were elaborated as bioactive nanocarriers for brain-targeted oral delivery of PIP. Seven liquid crystalline nanoparticles (cubosomes) were prepared testing different bioactive surfactants (Tween 80, poloxamer, and Cremophor). Full in vitro characterization was carried out based on particle size, zeta potential, polydispersity index, entrapment efficiency, and in vitro release. Morphological examination and structure elucidation were performed using transmission and polarizing microscopes. Sporadic dementia of Alzheimer's type was induced in 42 male Wistar rats on which full behavioral and biochemical testing was conducted. Brain toxicity was assessed based on Caspase-3 assay for apoptosis and tumor necrosis factor-α for inflammation. Liver and kidney toxicity studies were conducted as well. Among others, T-cubs exhibited optimum particle size (167.00±10.49 nm), polydispersity index (0.18±0.01), and zeta potential (-34.60±0.47 mv) with high entrapment efficiency (86.67%±0.62%). Cubs could significantly sustain PIP in vitro release. In vivo studies revealed T-cubs potential to significantly enhance PIP cognitive effect and even restore cognitive function to the normal level. Superiority of T-cubs over others suggested brain-targeting effect of Tween. Toxicological studies contended safety of cubs on kidney, liver, and even brain. T-cubs exhibited potential anti-inflammatory and anti-apoptotic activity of loaded PIP, indicating potential to stop AD progression that was first suggested in this article. Novel oral nanoparticles elaborated possess promising in vitro and in vivo characteristics with high safety for effective chronic treatment of AD.

Topics: Administration, Oral; Alkaloids; Alzheimer Disease; Animals; Benzodioxoles; Blood-Brain Barrier; Brain; Caspase 3; Disease Models, Animal; Drug Delivery Systems; Glycerides; Humans; Inflammation; Kidney; Liquid Crystals; Liver; Male; Nanomedicine; Nanoparticles; Oxidative Stress; Particle Size; Piperidines; Poloxamer; Polyethylene Glycols; Polysorbates; Polyunsaturated Alkamides; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

Obesity, a worldwide epidemic, is a major risk factor for the development of metabolic syndrome (MetS) including diabetes and associated health complications. Recent studies indicate that chronic low-grade inflammation (CLGI) plays a key role in metabolic deterioration in the obese population. Previously, we reported that Jak3 was essential for mucosal differentiation and enhanced colonic barrier functions and its loss in mice resulted in basal CLGI and predisposition to DSS induced colitis. Since CLGI is associated with diabetes, obesity, and metabolic syndrome, present studies determined the role of Jak3 in development of such conditions. Our data show that loss of Jak3 resulted in increased body weight, basal systemic CLGI, compromised glycemic homeostasis, hyperinsulinemia, and early symptoms of liver steatosis. Lack of Jak3 also resulted in exaggerated symptoms of metabolic syndrome by western high-fat diet. Mechanistically, Jak3 was essential for reduced expression and activation of Toll-like receptors (TLRs) in murine intestinal mucosa and human intestinal epithelial cells where Jak3 interacted with and activated p85, the regulatory subunit of the PI3K, through tyrosine phosphorylation of adapter protein insulin receptor substrate (IRS1). These interactions resulted in activation of PI3K-Akt axis, which was essential for reduced TLR expression and TLR associated NFκB activation. Collectively, these results demonstrate the essential role of Jak3 in promoting mucosal tolerance through suppressed expression and limiting activation of TLRs thereby preventing intestinal and systemic CLGI and associated obesity and MetS.

Topics: Animals; Body Weight; Caco-2 Cells; Cytokines; Diet, High-Fat; Disease Models, Animal; Genetic Predisposition to Disease; Glucose Tolerance Test; Humans; Immunity, Innate; Inflammation; Insulin; Janus Kinase 3; Liver; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Fluorescence; Obesity; Organ Size; Piperidines; Pyrimidines; Pyrroles; Risk Factors; Signal Transduction; Toll-Like Receptors

Gout is an inflammatory joint disorder characterized by hyperuricaemia and precipitation of monosodium urate crystals in the joints. In the present study, we aimed to investigate the anti-inflammatory effect of trikatu, a herbal compound in monosodium urate crystal-induced inflammation in rats, an experimental model for acute gouty arthritis. Paw volume and levels/activities of lysosomal enzymes, lipid peroxidation, anti-oxidant status and histopathological examination of ankle joints were determined in control and monosodium urate crystal-induced rats. In addition, analgesic (acetic acid-induced writhing response), anti-pyretic (yeast-induced pyrexia) and gastric ulceration effects were tested. The levels of lysosomal enzymes, lipid peroxidation and paw volume were significantly increased, and anti-oxidant status was found to be reduced in monosodium urate crystal-induced rats, whereas the biochemical changes were reverted to near normal levels upon trikatu (1000 mg/kg b.wt) administration. The trikatu has also been found to exhibit significant analgesic and anti-pyretic effects with the absence of gastric damage. In conclusion, the present results clearly indicated that trikatu exert a potent anti-inflammatory effect against monosodium urate crystal-induced inflammation in rats in association with analgesic and anti-pyretic effects in the absence of gastrointestinal damage.

Topics: Acute Disease; Alkenes; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Gouty; Female; Fruit; Gout Suppressants; Indomethacin; Inflammation; Lipid Peroxidation; Male; Piper; Piperidines; Rats; Rats, Wistar; Uric Acid; Zingiber officinale

The NLRP3 (NALP3, cryopyrin) inflammasome, a key component of the innate immune system, facilitates caspase-1 and interleukin (IL)-1β processing, which amplifies the inflammatory response. Here, we investigated whether NLRP3 knockdown decreases neutrophil infiltration, reduces brain edema, and improves neurological function in an intracerebral hemorrhage (ICH) mouse model. We also determined whether mitochondrial reactive oxygen species (ROS) governed by mitochondrial permeability transition pores (mPTPs) would trigger NLRP3 inflammasome activation following ICH.. ICH was induced by injecting autologous arterial blood (30μl) into a mouse brain. NLRP3 small interfering RNAs were administered 24 hours before ICH. A mPTP inhibitor (TRO-19622) or a specific mitochondria ROS scavenger (Mito-TEMPO) was coinjected with the blood. In naive animals, rotenone, which is a respiration chain complex I inhibitor, was applied to induce mitochondrial ROS production, and followed by TRO-19622 or Mito-TEMPO treatment. Neurological deficits, brain edema, enzyme-linked immunosorbent assay, Western blot, in vivo chemical cross-linking, ROS assay, and immunofluorescence were evaluated.. ICH activated the NLRP3 inflammasome. NLRP3 knockdown reduced brain edema and decreased myeloperoxidase (MPO) levels at 24 hours, and improved neurological functions from 24 to 72 hours following ICH. TRO-19622 or Mito-TEMPO reduced ROS, NLRP3 inflammasome components, and MPO levels following ICH. In naive animals, rotenone administration induced mPTP formation, ROS generation, and NLRP3 inflammasome activation, which were then reduced by TRO-19622 or Mito-TEMPO.. The NLRP3 inflammasome amplified the inflammatory response by releasing IL-1β and promoting neutrophil infiltration following ICH. Mitochondria ROS may be a major trigger of NLRP3 inflammasome activation. The results of our study suggest that the inhibition of the NLRP3 inflammasome may effectively reduce the inflammatory response following ICH.ANN NEUROL 2014;75:209-219.

Topics: Animals; Antioxidants; Brain Edema; Carrier Proteins; Cerebral Hemorrhage; Cholestenones; Disease Models, Animal; Enzyme Inhibitors; Gene Expression Regulation; Hematoma; Inflammation; Injections, Intraventricular; Male; Mice; Neutrophil Infiltration; NLR Family, Pyrin Domain-Containing 3 Protein; Organophosphorus Compounds; Piperidines; RNA, Small Interfering

The sigma 1 (σ1) receptor, which is widely distributed in the CNS in areas that are known to be important for pain control, may play a role in persistent pain characterized by the hypersensitivity of nociceptive transmission. Here, we investigated the effect of σ1 blockade in an inflammatory pain model.. An intraplantar injection of carrageenan (2 %) was used to induce paw inflammation. The effects of the σ1 antagonist (+)-MR200, given subcutaneously at a dose of 0.1, 0.25, 0.5,1, 1.5, and 2 mg/kg prior to injection of carrageenan, on inflammatory pain and inflammation were assessed. Mechanical allodynia with von Frey filaments, thermal hyperalgesia with the plantar test and edema evaluation with a plethysmometer were measured. Intergroup comparisons were assessed by one- or two-way analysis of variance when appropriate, followed by post-hoc tests (Dunnett's test for one-way or Bonferroni for two-way ANOVA).. (+)-MR200 dose-dependently prevented allodynia and hyperalgesia induced by carrageenan. Furthermore, it reduced paw edema with a significant inhibition percentage of 37.82 % at 3 h after carrageenan treatment.. The blockade of the σ1 receptor with the selective antagonist (+)-MR200 may contribute to the suppression of the typical symptoms of inflammatory pain.

Topics: Animals; Carrageenan; Chronic Pain; Cyclopropanes; Dose-Response Relationship, Drug; Edema; Foot; Hot Temperature; Hyperalgesia; Inflammation; Male; Physical Stimulation; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, sigma; Sigma-1 Receptor

Cyclin-dependent kinase 9 (CDK-9) controls the activation of primary inflammatory response genes. The purpose of this study was to determine whether CDK-9 inhibition protects cartilage from the catabolic effects of proinflammatory cytokines.. Human chondrocytes were challenged with different proinflammatory stimuli (interleukin-1β [IL-1β], lipopolysaccharides, and tumor necrosis factor α) in the presence or absence of either the CDK-9 inhibitor flavopiridol or small interfering RNA (siRNA). The expression of messenger RNA (mRNA) for inflammatory mediator genes, catabolic genes, and anabolic genes were determined by real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis. Cartilage explants were incubated for 6 days with IL-1β in the presence or absence of flavopiridol. Cartilage matrix degradation was assessed by the release of glycosaminoglycan (GAG) and cleaved type II collagen (COL2A) peptides.. CDK-9 inhibition by flavopiridol or knockdown by siRNA effectively suppressed the induction of mRNA for inducible nitric oxide synthase by all 3 proinflammatory stimuli. Results from NF-κB-targeted PCR array analysis showed that flavopiridol suppressed IL-1β induction of a broad range of inflammatory mediator genes (59 of 67 tested). CDK-9 inhibition also suppressed the induction of catabolic genes (matrix metalloproteinase 1 [MMP-1], MMP-3, MMP-9, MMP-13, ADAMTS-4, and ADAMTS-5), but did not affect the basal expression of anabolic genes (COL2A, aggrecan, and cartilage oligomeric matrix protein) and housekeeping genes. Flavopiridol had no apparent short-term cytotoxicity, as assessed by G6PDH activity. Finally, in IL-1β-treated cartilage explants, flavopiridol reduced the release of the matrix degradation product GAG and cleaved COL2A peptides, but did not affect long-term chondrocyte viability.. CDK-9 activity is required for the primary inflammatory response in chondrocytes. Flavopiridol suppresses the induction of inflammatory mediator genes and catabolic genes to protect cartilage from the deleterious effects of proinflammatory cytokines, without affecting cell viability and functions.

Topics: ADAM Proteins; ADAMTS4 Protein; ADAMTS5 Protein; Adult; Aged; Aged, 80 and over; Cartilage, Articular; Cells, Cultured; Chondrocytes; Collagen Type II; Cyclin-Dependent Kinase 9; Cytokines; Flavonoids; Glycosaminoglycans; Humans; In Vitro Techniques; Inflammation; Interleukin-1beta; Lipopolysaccharides; Matrix Metalloproteinases; Middle Aged; Piperidines; Procollagen N-Endopeptidase; Protein Kinase Inhibitors; RNA, Small Interfering; Tumor Necrosis Factor-alpha

The IL-23 pathway is genetically linked to autoimmune disease in humans and is required for pathogenic Th17 cell function in mice. However, because IL-23R-expressing mature Th17 cells are rare and poorly defined in mice at steady-state, little is known about IL-23 signaling. In this study, we show that the endogenous CCR6(+) memory T cell compartment present in peripheral lymphoid organs of unmanipulated mice expresses Il23r ex vivo, displays marked proinflammatory responses to IL-23 stimulation in vitro, and is capable of transferring experimental autoimmune encephalomyelitis. The prolyl-tRNA synthetase inhibitor halofuginone blocks IL-23-induced Stat3 phosphorylation and IL-23-dependent proinflammatory cytokine expression in endogenous CCR6(+) Th17 cells via activation of the amino acid starvation response (AAR) pathway. In vivo, halofuginone shows therapeutic efficacy in experimental autoimmune encephalomyelitis, reducing both established disease progression and local Th17 cell effector function within the CNS. Mechanistically, AAR activation impairs Stat3 responses downstream of multiple cytokine receptors via selective, posttranscriptional suppression of Stat3 protein levels. Thus, our study reveals latent pathogenic functions of endogenous Th17 cells that are regulated by both IL-23 and AAR pathways and identifies a novel regulatory pathway targeting Stat3 that may underlie selective immune regulation by the AAR.

Topics: Amino Acids; Animals; Encephalomyelitis, Autoimmune, Experimental; Inflammation; Interleukin-23; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Mice, Knockout; Phosphorylation; Piperidines; Quinazolinones; Receptors, CCR6; Receptors, Interleukin; STAT3 Transcription Factor; Th17 Cells

Polyphenols are natural compounds capable of interfering with the inflammatory pathways of several in vitro model systems. In this study, we developed a stable and effective strategy to administer polyphenols to treat in vivo models of acute intestinal inflammation. The in vitro suppressive properties of several polyphenols were first tested and compared for dendritic cells (DCs) production of inflammatory cytokines. A combination of the polyphenols, quercetin and piperine, were then encapsulated into reconstituted oil bodies (OBs) in order to increase their stability. Our results showed that administration of low dose reconstituted polyphenol OBs inhibited LPS-mediated inflammatory cytokine secretion, including IL-6, IL-23, and IL-12, while increasing IL-10 and IL-1Rα production. Mice treated with the polyphenol-containing reconstituted OBs (ROBs) were partially protected from dextran sodium sulfate (DSS)-induced colitis and associated weight loss, while mortality and inflammatory scores revealed an overall anti-inflammatory effect that was likely mediated by impaired DC immune responses. Our study indicates that the administration of reconstituted quercetin and piperine-containing OBs may represent an effective and potent anti-inflammatory strategy to treat acute intestinal inflammation.

Topics: Acute Disease; Alkaloids; Animals; Benzodioxoles; Capsules; Colitis; Dendritic Cells; Dextran Sulfate; Dose-Response Relationship, Drug; Drug Stability; Inflammation; Interleukin-6; Intestinal Diseases; Lipopolysaccharides; Liposomes; Mice; Peptidoglycan; Piperidines; Polyphenols; Polyunsaturated Alkamides; Quercetin; Tumor Necrosis Factor-alpha

In the last 15 years, the therapeutical options for the treatment of chronic inflammatory diseases in rheumatology have increased a lot. Nevertheless, some patients do not respond or respond partially to the current therapies--including to the biologics therapy. Tofacitinib (Xeljanz) is now on the Swiss market. It inhibits the JAK pathway. Tofacitinib--as monotherapy or with methotrexate--improves the control of rheumatoid arthritis (RA). In a comparative study, tofacitinib was as effective as adalimumab. Further, tofacitinib reduced structural damages in RA and is considered as an alternative, in case of non-response, to anti-TNF and probably to other biologics therapy. The side effects are upper respiratory tract and opportunist infections and tuberculosis. Blood count, lipids, kidney function, liver tests, CK and blood pressure have to be monitored.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Chronic Disease; Drug Approval; Humans; Inflammation; Janus Kinases; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Rheumatic Diseases; Switzerland

Neuropathic pain is characterized by spontaneous pain, hyperalgesia, and allodynia. The aim of this study was to investigate whether KMUP-1 (7-[2-[4-(2-chlorobenzene)piperazinyl]ethyl]-1,3-dimethylxanthine) could improve pain hypersensitivity and reduce inflammatory mediators, and also explore possible mechanisms in the rat sciatic nerve using bilateral chronic constriction injury (CCI) to induce neuropathic pain. Sprague-Dawley rats were randomly divided into four groups: Sham, Sham+KMUP-1, CCI, and CCI+KMUP-1. KMUP-1 (5 mg/kg/day) was injected intraperitoneally starting at day 1 after surgery. Mechanical and thermal responses were assessed before surgery and at days 3, 7, and 14 after CCI. Sciatic nerves around the injury site were isolated for Western blots and enzyme-linked immunosorbent assay to analyze protein and cytokine levels. The results show that thermal hyperalgesia and mechanical allodynia were reduced in the KMUP-1 treated group as compared to that in the CCI group. Inflammatory proteins (COX2, iNOS, and nNOS) and proinflammatory cytokines (TNF-α and IL-1β) induced by CCI were decreased in the KMUP-1 treated group at day 7 after surgery. KMUP-1 also inhibited neuropathic pain-related mechanisms, including p38 and ERK activation, but not JNK. Furthermore, KMUP-1 blocked IκB phosphorylation (p-IκB) and phospho-nuclear factor κB (p-NF-κB) translocation to nuclei. Double immunofluorescent staining further demonstrated that p-IκB (an indicator of activated NFκB) and p-NFκB proteins were almost abolished by KMUP-1 in peripheral macrophages and spinal microglia cells at day 7 after surgery. On the basis of these findings, we concluded that KMUP-1 has antiinflammatory and antihyperalgesia properties in CCI-induced neuropathic pain via decreases in MAPKs and NF-κB activation.

Topics: Animals; Blotting, Western; Hyperalgesia; Immunohistochemistry; Inflammation; Male; Mitogen-Activated Protein Kinases; Neuralgia; NF-kappa B; Piperidines; Rats; Rats, Sprague-Dawley; Xanthine; Xanthines

Piperine has been shown to have anti-inflammatory properties. The molecular mechanisms by which it mediates anti-inflammatory activities remain elusive. Type II phosphatidylinositol 4-kinase(s) are key components in FcεRI receptor-mediated signaling leading to inflammatory mediators release in RBL-2H3 cells. The effects of piperine on IgE-mediated signaling and mast cell degranulation were investigated. Pretreatment of RBL-2H3 cells with piperine inhibited IgE-induced activation of type II PtdIns 4-kinase(s). In vitro lipid kinase assays showed piperine-inhibited type II PtdIns 4-kinase activity in a dose-dependent fashion with no effect on PtdIns 3-kinase activity. Concomitantly, pretreatment of RBL-2H3 cells with piperine also inhibited IgE-induced β-hexosaminidase release in RBL-2H3 cells. These results suggest that type II PtdIns 4-kinases are part of piperine-mediated anti-inflammatory signaling mechanisms.

Topics: Alkaloids; Benzodioxoles; Cell Line; Humans; Immunoglobulin E; Inflammation; Mast Cells; Minor Histocompatibility Antigens; Phosphatidylinositols; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor); Piperidines; Polyunsaturated Alkamides; Receptors, IgE; Signal Transduction

After spinal cord injury (SCI), the disruption of blood-spinal cord barrier by activation of the endothelin (ET) system is a critical event leading to leukocyte infiltration, inflammatory response and oxidative stress, contributing to neurological disability. In the present study, we showed that blockade of ET receptor A (ETAR) and/or ET receptor B (ETBR) prevented early inflammatory responses directly via the inhibition of neutrophil and monocyte diapedesis and inflammatory mediator production following traumatic SCI in mice. Long-term neurological improvement, based on a series of tests of locomotor performance, occurred only in the spinal cord‑injured mice following blockade of ETAR and ETBR. We also examined the post‑traumatic changes of the micro-environment within the injured spinal cord of mice following blockade of ET receptors. Oxidative stress reflects an imbalance between malondialdehyde and superoxide dismutase in spinal cord‑injured mice treated with vehicle, whereas blockade of ETAR and ETBR reversed the oxidation state imbalance. In addition, hemeoxygenase-1, a protective protease involved in early SCI, was increased in spinal cord‑injured mice following the blockade of ETAR and ETBR, or only ETBR. Matrix metalloproteinase-9, a tissue-destructive protease involved in early damage, was decreased in the injured spinal cord of mice following blockade of ETAR, ETBR or a combination thereof. The findings of the present study therefore suggested an association between ETAR and ETBR in regulating early pathogenesis of SCI and determining the outcomes of long‑term neurological recovery.

Topics: Animals; Cell Movement; Endothelin Receptor Antagonists; Female; Gene Expression Regulation; Heme Oxygenase-1; Inflammation; Malondialdehyde; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Monocytes; Motor Activity; Neutrophils; Oligopeptides; Peptides, Cyclic; Piperidines; Receptor, Endothelin A; Receptor, Endothelin B; Recovery of Function; Signal Transduction; Spinal Cord; Spinal Cord Injuries; Superoxide Dismutase

Idiopathic pulmonary fibrosis is thought to involve lung injury caused by reactive oxygen species (ROS), which in turn is followed by abnormal fibrosis. A transforming growth factor (TGF)-β1-induced increase in myofibroblast number plays an important role in this abnormal fibrosis. We recently found that mepenzolate bromide (mepenzolate), which has been used clinically to treat gastrointestinal disorders, has ROS-reducing properties. In the present study, we examined the effect of mepenzolate on bleomycin-induced pulmonary fibrosis and lung dysfunction in mice. The severity of pulmonary fibrosis was assessed by histopathologic evaluation and determination of hydroxyproline levels. Lung mechanics (elastance) and respiratory function [forced vital capacity (FVC)] were assessed using a computer-controlled ventilator. Respiratory function was also evaluated by monitoring percutaneous arterial oxygen saturation (SpO2). Intratracheal administration of mepenzolate prior to bleomycin treatment reduced the extent of pulmonary fibrosis and changes in lung mechanics and led to a significant recovery of both FVC and SpO2 compared with control. Furthermore, mepenzolate produced a therapeutic effect even when it was administered after the development of fibrosis. Administration of mepenzolate also prevented bleomycin-induced pulmonary cell death and inflammatory responses and increased myofibroblast number. Mepenzolate also decreased NADPH oxidase activity and active TGF-β1 level or increased glutathione S-transferase (GST) activity in the presence of bleomycin treatment. These results show that the intratracheal administration of mepenzolate reduced bleomycin-induced pulmonary fibrosis and lung dysfunction in mice. These effects may be due to this drug's inhibitory effect on NADPH oxidase and TGF-β1 activities and its stimulatory effect on GST.

Topics: Animals; Benzilates; Bleomycin; Bronchoalveolar Lavage Fluid; Cell Count; Cell Death; Glutathione Transferase; Hydroxyproline; Inflammation; Lung; Lung Compliance; Male; Mice; Myofibroblasts; NADPH Oxidases; Oxygen; Piperidines; Pulmonary Fibrosis; Transforming Growth Factor beta1; Vital Capacity

The cell-cycle inhibitor flavopiridol has been shown to improve recovery from spinal cord injury in animal models. However, the systemic dose of flavopiridol has side-effects and the mechanism of action is not clear. This study aimed to develop a strategy for the local delivery of flavopiridol and investigate its mechanisms of action. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) were used for the sustained delivery of flavopiridol. The spinal cord was right-hemisectioned and NPs were delivered into the injury site. Transparent spinal cord technology was used for the three-dimensional observation of anterograde tracing. The results showed that flavopiridol NPs had a sustained release of up to 3 days in vitro. Flavopiridol NPs significantly decreased inflammatory factor synthesis by astrocytes, including TNF-α, IL-1β, and IL-6, while the IL-10 expression was elevated. In vivo study demonstrated that flavopiridol NPs decreased cell-cycle activation, inflammatory expression and glial scarring, and facilitated neuronal survival and regeneration. The cavitation volume was decreased by ~90%. Administration of flavopiridol NPs also improved the motor recovery of injured animals. These findings demonstrated that local delivery of flavopiridol in PLGA NPs improves recovery from spinal cord injury by inhibiting astrocyte growth and inflammatory factor synthesis.

Topics: Animals; Astrocytes; Behavior, Animal; Cell Cycle Proteins; Cell Proliferation; Cells, Cultured; Drug Delivery Systems; Female; Flavonoids; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Inflammation; Inflammation Mediators; Lactic Acid; Microtubule-Associated Proteins; Nanoparticles; Neurons; Piperidines; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Rats, Sprague-Dawley; Recovery of Function; Spinal Cord Injuries; Wound Healing

Palmitoylethanolamide (PEA), a naturally occurring acylethanolamide chemically related to the endocannabinoid anandamide, interacts with targets that have been identified in peripheral nerves controlling gastrointestinal motility, such as cannabinoid CB1 and CB2 receptors, TRPV1 channels and PPARα. Here, we investigated the effect of PEA in a mouse model of functional accelerated transit which persists after the resolution of colonic inflammation (post-inflammatory irritable bowel syndrome).. Intestinal inflammation was induced by intracolonic administration of oil of mustard (OM). Mice were tested for motility and biochemical and molecular biology changes 4 weeks later. PEA, oleoylethanolamide and endocannabinoid levels were measured by liquid chromatography-mass spectrometry and receptor and enzyme mRNA expression by qRT-PCR.. OM induced transient colitis and a functional post-inflammatory increase in upper gastrointestinal transit, associated with increased intestinal anandamide (but not 2-arachidonoylglycerol, PEA or oleoylethanolamide) levels and down-regulation of mRNA for TRPV1 channels. Exogenous PEA inhibited the OM-induced increase in transit and tended to increase anandamide levels. Palmitic acid had a weaker effect on transit. Inhibition of transit by PEA was blocked by rimonabant (CB1 receptor antagonist), further increased by 5'-iodoresiniferatoxin (TRPV1 antagonist) and not significantly modified by the PPARα antagonist GW6471.. Intestinal endocannabinoids and TRPV1 channel were dysregulated in a functional model of accelerated transit exhibiting aspects of post-inflammatory irritable bowel syndrome. PEA counteracted the accelerated transit, the effect being mediated by CB1 receptors (possibly via increased anandamide levels) and modulated by TRPV1 channels.

Topics: Amides; Animals; Colitis; Disease Models, Animal; Ethanolamines; Gastrointestinal Motility; Inflammation; Injections, Intraperitoneal; Irritable Bowel Syndrome; Male; Mice; Mice, Inbred ICR; Mustard Plant; Palmitic Acids; Piperidines; Plant Oils; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; RNA, Messenger; TRPV Cation Channels

Cyclooxygenase (COX) possesses substrate affinity for the endocannabinoids (EC) anandamide (AEA) and 2-arachidonylglycerol (2-AG). We hypothesized that selective antagonism/activation of the cannabinoid receptors will increase COX activity and the availability of EC as substrates will lead to higher COX activity. Since the relationship between EC signaling of the endocannabinoid system (ECS) and the COX pathway in muscle has not been investigated, we examined agonist, antagonists and polyunsaturated fatty acid effects on ECS genes in myoblasts. At 50% confluency, C2C12 myoblasts were pretreated with 5 μM of the cannabinoid receptor (CB)2 inverse agonist AM630 for 2 h and one with both AM630 and 1 μM of the CB1 antagonist NESS0327. Cell cultures pretreated with AM630 were then administered with 25 μM of either arachidonic acid (20:4n6), eicosapentaenoate (EPA) (20:5n3), docosahexaenoate (DHA) (22:6n3), AEA or bovine serum albumin (vehicle control) for 24 h. Quantitative polymerase chain reaction analyses were performed looking at ECS and prostaglandin genes. Total COX activity and COX-1 protein were greater in the AM630+AEA-treated cells compared to all other cell cultures. The mRNA for the AEA synthesis enzyme N-acyl phosphatidylethanolamine phospholipase D and the 2-AG synthesis enzymes diacylglycerol lipase (DAGL)α and DAGLβ were higher in AM630+EPA-treated cells compared to the other groups. The mRNA levels of CB1 and CB2 were both highest in the AM630+EPA group. The mRNA for interleukin-6 and tumor necrosis factor-α was higher with AEA but lower with DHA and docosahexaenoyl ethanolamide (DHEA), supporting previous findings that the EC AEA supports activation of the COX system. These findings suggest that COX activity and protein levels are influenced by the ECS, specifically by the ligand AEA for CB1 and by inverse agonism of CB2.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Cannabinoid Receptor Antagonists; Endocannabinoids; Fatty Acids, Unsaturated; Gene Expression Regulation; Glycerides; Indoles; Inflammation; Interleukin-6; Lipoprotein Lipase; Mice; Myoblasts; Piperidines; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Tumor Necrosis Factor-alpha

Monoacylglycerol lipase (MGL) is the main enzyme responsible for degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG). Selective inhibitors of MGL have antinociceptive effects upon acute administration and, therefore, hold promise as analgesics. To gain insight into the possible consequences of their prolonged administration, genetically modified mice with the knocked-out MGL gene were tested in several models of acute (phasic, tonic) and chronic (inflammatory, neuropathic) pain. MGL knockout mice showed normal acute phasic pain perception (pain thresholds) and no alleviation of pain perception in models of inflammatory and neuropathic pain. However, compared with wild-type controls, they showed significantly augmented nociceptive behavior in models of acute somatic and visceral tonic pain (formalin and acetic acid tests). The observed proalgesic changes in perception of tonic pain in MGL knockouts could have resulted from desensitization of cannabinoid receptors (known to occur after genetic inactivation of MGL). Supporting this notion, chronic pretreatment with the selective CB1 receptor antagonist AM 251 (employed to re-sensitize cannabinoid receptors in MGL knockouts) resulted in normalization of their tonic pain-related behaviors. Similar augmentation of tonic pain-related behaviors was replicated in C57BL/6N mice pretreated chronically with the selective MGL inhibitor JZL 184 (employed to pharmacologically desensitize CB1 receptors). These findings imply that prolonged use of MGL inhibitors, at doses causing close to complete inhibition of MGL enzymatic activity, not only have no beneficial analgesic effects, they may lead to exacerbation of some types of pain (particularly those with a tonic component).

Topics: Animals; Arachidonic Acids; Benzodioxoles; Cannabinoid Receptor Modulators; Endocannabinoids; Glycerides; Inflammation; Male; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Knockout; Neuralgia; Pain; Pain Threshold; Phosphotransferases (Alcohol Group Acceptor); Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1

It has been recently recognized that the descending serotonin (5-HT) system from the rostral ventromedial medulla (RVM) in the brainstem and the 5-HT3 receptor subtype in the spinal dorsal horn are involved in enhanced descending pain facilitation after tissue and nerve injury. However, the mechanisms underlying the activation of the 5-HT3 receptor and its contribution to facilitation of pain remain unclear.. In the present study, activation of spinal 5-HT3 receptors by intrathecal injection of a selective 5-HT3 receptor agonist SR 57227 induced spinal glial hyperactivity, neuronal hyperexcitability and pain hypersensitivity in rats. We found that there was neuron-to-microglia signaling via the chemokine fractalkine, microglia to astrocyte signaling via cytokine IL-18, astrocyte to neuronal signaling by IL-1β, and enhanced activation of NMDA receptors in the spinal dorsal horn. Glial hyperactivation in spinal dorsal horn after hindpaw inflammation was also attenuated by molecular depletion of the descending 5-HT system by intra-RVM Tph-2 shRNA interference.. These findings offer new insights into the cellular and molecular mechanisms at the spinal level responsible for descending 5-HT-mediated pain facilitation during the development of persistent pain after tissue and nerve injury. New pain therapies should focus on prime targets of descending facilitation-induced glial involvement, and in particular the blocking of intercellular signaling transduction between neurons and glia.

Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Hyperalgesia; Inflammation; Male; Neuralgia; Neuroglia; Neurons; Pain Perception; Piperidines; Rats; Rats, Sprague-Dawley; Serotonin Antagonists; Serotonin Receptor Agonists; Signal Transduction; Spinal Cord; Spinal Nerves

Topics: Cartilage, Articular; Chondrocytes; Cyclin-Dependent Kinase 9; Cytokines; Flavonoids; Humans; Inflammation; Piperidines; Protein Kinase Inhibitors

Topics: Cartilage, Articular; Chondrocytes; Cyclin-Dependent Kinase 9; Cytokines; Flavonoids; Humans; Inflammation; Piperidines; Protein Kinase Inhibitors

During the progression of rheumatoid arthritis (RA), there are frequent but intermittent flares in which the joint becomes acutely inflamed and painful. Although a number of drug therapies are currently used to treat RA, their effectiveness is variable and side effects are common. Endocannabinoids have the potential to ameliorate joint pain and inflammation, but these beneficial effects are limited by their rapid degradation. One enzyme responsible for endocannabinoid breakdown is fatty acid amide hydrolase (FAAH). The present study examined whether URB597, a potent and selective FAAH inhibitor, could alter inflammation and pain in a mouse model of acute synovitis.. Acute joint inflammation was induced in male C57BL/6 mice by intra-articular injection of 2% kaolin/2% carrageenan. After 24 hr, articular leukocyte kinetics and blood flow were used as measures of inflammation, while hindlimb weight bearing and von Frey hair algesiometry were used as measures of joint pain. The effects of local URB597 administration were then determined in the presence or absence of either the cannabinoid (CB)1 receptor antagonist AM251, or the CB2 receptor antagonist AM630.. URB597 decreased leukocyte rolling and adhesion, as well as inflammation-induced hyperaemia. However, these effects were only apparent at low doses and the effects of URB597 were absent at higher doses. In addition to the anti-inflammatory effects of URB597, fatty acid amide hydrolase (FAAH) inhibition improved both hindlimb weight bearing and von Frey hair withdrawal thresholds. The anti-inflammatory effects of URB597 on leukocyte rolling and vascular perfusion were blocked by both CB1 and CB2 antagonism, while the effect on leukocyte adherence was independent of cannabinoid receptor activation. The analgesic effects of URB597 were CB1 mediated.. These results suggest that the endocannabinoid system of the joint can be harnessed to decrease acute inflammatory reactions and the concomitant pain associated with these episodes.

Topics: Acute Disease; Amidohydrolases; Animals; Arthralgia; Benzamides; Carbamates; Carrageenan; Endocannabinoids; Hindlimb; Hyperalgesia; Indoles; Inflammation; Kaolin; Knee Joint; Male; Mice, Inbred C57BL; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Synovitis; Weight-Bearing

Novel analgesics that do not suppress the respiratory drive are urgently needed. Glutamate signaling through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors plays important roles in central pain circuits. AMPAkines augment AMPA receptor function and have been shown to stimulate the respiratory drive to oppose opioid-induced hypoventilation. However, their role in chronic pain states remains unknown.. The authors studied AMPAkines (CX546 and CX516) in rat spared nerve injury (SNI) model of neuropathic pain and Complete Freund's Adjuvant (CFA) model of inflammatory pain. They measured the effect of AMPAkines on mechanical and cold allodynia. They also evaluated their effect on depressive symptoms of pain using the forced swim test, as time of immobility on this test has been used as a measure for behavioral despair, a feature of depression.. The authors found that CX546, compared with dimethyl sulfoxide (DMSO) control, reduced both mechanical and sensory allodynia in SNI (DMSO group, n = 9; CX546 group, n = 11) and CFA models (both DMSO and CX546 groups, n = 9). They found that CX546, compared with control, also reduced depressive symptoms of pain by decreasing immobility on the forced swim test in both SNI (both DMSO and CX546 groups, n = 8) and CFA models (both DMSO and CX546 groups, n = 10). Finally, they found that CX516, compared with control, also reduced mechanical and cold allodynia in the SNI model (both DMSO and CX516 groups, n = 10).. AMPAkines alleviate pain hypersensitivity as well as depression-like behavior associated with long-lasting nerve injury and inflammatory insult.

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antidepressive Agents; Behavior, Animal; Dioxoles; Inflammation; Male; Motor Activity; Neuralgia; Pain Measurement; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Swimming

Considerable evidence indicates a link between systemic inflammation and central 5-HT function. This study used pharmacological magnetic resonance imaging (phMRI) to study the effects of systemic inflammatory events on central 5-HT function. Changes in blood oxygenation level dependent (BOLD) contrast were detected in selected brain regions of anaesthetised rats in response to intravenous administration of the 5-HT-releasing agent, fenfluramine (10 mg/kg). Further groups of rats were pre-treated with the bacterial lipopolysaccharide (LPS; 0.5 mg/kg), to induce systemic inflammation, or the selective 5-HT2A receptor antagonist MDL100907 prior to fenfluramine. The resultant phMRI data were investigated further through measurements of cortical 5-HT release (microdialysis), and vascular responsivity, as well as a more thorough investigation of the role of the 5-HT2A receptor in sickness behaviour. Fenfluramine evoked a positive BOLD response in the motor cortex (+15.9±2%) and a negative BOLD response in the dorsal raphe nucleus (-9.9±4.2%) and nucleus accumbens (-7.7±5.3%). In all regions, BOLD responses to fenfluramine were significantly attenuated by pre-treatment with LPS (p<0.0001), but neurovascular coupling remained intact, and fenfluramine-evoked 5-HT release was not affected. However, increased expression of the 5-HT2A receptor mRNA and decreased 5-HT2A-dependent behaviour (wet-dog shakes) was a feature of the LPS treatment and may underpin the altered phMRI signal. MDL100907 (0.5 mg/kg), 5-HT2A antagonist, significantly reduced the BOLD responses to fenfluramine in all three regions (p<0.0001) in a similar manner to LPS. Together these results suggest that systemic inflammation decreases brain 5-HT activity as assessed by phMRI. However, these effects do not appear to be mediated by changes in 5-HT release, but are associated with changes in 5-HT2A-receptor-mediated downstream signalling pathways.

Topics: Animals; Autoradiography; Brain; Brain Chemistry; Chromatography, High Pressure Liquid; Fenfluramine; Fluorobenzenes; Image Processing, Computer-Assisted; Inflammation; Laser-Doppler Flowmetry; Magnetic Resonance Imaging; Male; Microdialysis; Piperidines; Rats; Rats, Sprague-Dawley; Selective Serotonin Reuptake Inhibitors; Serotonin; Serotonin Antagonists

The purpose of the present study was to investigate the effect of various opioids including remifentanil, sufentanil, alfentanil and fentanyl on human neutrophil activation induced by lipopolysaccharide (LPS) and to reveal the correlation involving the activation of cytokines and mitogen-activated protein kinases (MAPKs). Neutrophils from human blood were incubated with various concentrations of opioids with LPS. We measured protein levels for tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6 and IL-8 after 4 h incubation period. To clarify the intracellular signaling pathway, we measured the levels of phosphorylation of p38, extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) and c-Jun N-terminal kinase. We also measured the levels for cytokines and MAPKs to reveal the effects of several opioid receptor subtype antagonists on remifentanil with LPS. In the present experiment, only remifentanil could attenuate activation of human neutrophils exposed to LPS. In particular, remifentanil decreased activation of intracellular signaling pathways, including p38 and ERK1/2, and expression of pro-inflammatory cytokines, including TNF-α, IL-6 and IL-8. Especially the decreased activation of cytokines and MAPKs was significantly reverted by a kappa-opioid receptor antagonist on remifentanil with LPS. These results demonstrate that remifentanil can attenuate human neutrophils activations induced by LPS and a kappa-opioid receptor be probably involved in these anti-inflammatory effects mediated by remifentanil.

Topics: Adult; Analgesics, Opioid; Cells, Cultured; Drug Interactions; Female; Humans; Inflammation; Interleukin-6; Interleukin-8; JNK Mitogen-Activated Protein Kinases; Lipopolysaccharides; Male; MAP Kinase Signaling System; Middle Aged; Mitogen-Activated Protein Kinases; Neutrophil Activation; Neutrophils; p38 Mitogen-Activated Protein Kinases; Piperidines; Remifentanil; Signal Transduction; Tumor Necrosis Factor-alpha; Young Adult

The molecular mechanisms involved in the development of obesity and related complications remain unclear. Here, we report that obese mice and human subjects have increased activity of neutrophil elastase (NE) and decreased serum levels of the NE inhibitor α1-antitrypsin (A1AT, SerpinA1). NE null (Ela2(-/-)) mice and A1AT transgenic mice were resistant to high-fat diet (HFD)-induced body weight gain, insulin resistance, inflammation, and fatty liver. NE inhibitor GW311616A reversed insulin resistance and body weight gain in HFD-fed mice. Ela2(-/-) mice also augmented circulating high molecular weight (HMW) adiponectin levels, phosphorylation of AMP-activated protein kinase (AMPK), and fatty acid oxidation (FAO) in the liver and brown adipose tissue (BAT) and uncoupling protein (UCP1) levels in the BAT. These data suggest that the A1AT-NE system regulates AMPK signaling, FAO, and energy expenditure. The imbalance between A1AT and NE contributes to the development of obesity and related inflammation, insulin resistance, and liver steatosis.

Topics: Adiponectin; Adipose Tissue, Brown; alpha 1-Antitrypsin; AMP-Activated Protein Kinase Kinases; Animals; Diet, High-Fat; Energy Metabolism; Fatty Acids; Fatty Liver; Hep G2 Cells; Humans; Inflammation; Insulin Resistance; Ion Channels; Leptin; Leukocyte Elastase; Liver; Metabolome; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Mice, Transgenic; Mitochondrial Proteins; Obesity; Oxidation-Reduction; Phosphorylation; Piperidines; Protein Kinases; Uncoupling Protein 1; Weight Gain

Bilateral destruction of the olfactory bulbs is known to cause behavioral changes analogous to symptoms of depression. Curcumin, a traditional Indian spice is currently being investigated in different psychiatric problems including depression. Dietary phytochemicals are currently used as an adjuvant therapy to accelerate their therapeutic efficacy. Therefore, the present study is an attempt to elucidate the neuroprotective mechanism of curcumin and its co-administration with piperine against olfactory bulbectomy induced depression in rats.. Rats undergone olfactory bulbs ablations were analyzed after post-surgical rehabilitation period of 2 weeks. Animals were then treated with different doses of curcumin (100, 200 and 400 mg/kg; p.o.), piperine (20 mg/kg; p.o.) and their combination daily for another 2 weeks. Imipramine (10 mg/kg; i.p.) served as a standard control. Various behavioral tests like forced swim test (FST), open field behaviour and sucrose preference test (SPT) were performed, followed by estimation of biochemical, mitochondrial, molecular and histopathological parameters in rat brain.. Ablation of olfactory bulbs caused depression-like symptoms as evidenced by increased immobility time in FST, hyperactivity in open field arena, and anhedonic like response in SPT along with alterations in mitochondrial enzyme complexes, increased serum corticosterone levels and oxidative damage. These deficits were integrated with increased inflammatory cytokines (TNF-α) and apoptotic factor (caspase-3) levels along with a marked reduction in neurogenesis factor (BDNF) in the brain of olfactory bulbectomized (OBX) rats. Curcumin treatment significantly and dose-dependently restored all these behavioral, biochemical, mitochondrial, molecular and histopathological alterations associated with OBX induced depression. Further, co-administration of piperine with curcumin significantly potentiated their neuroprotective effects as compared to their effects alone.. The present study highlights that curcumin along with piperine exhibits neuroprotection against olfactory bulbectomy induced depression possibly by modulating oxidative-nitrosative stress induced neuroinflammation and apoptosis.

Topics: Alkaloids; Animals; Apoptosis; Benzodioxoles; Brain; Brain-Derived Neurotrophic Factor; Caspase 3; Corticosterone; Curcumin; Depression; Disease Models, Animal; Drug Therapy, Combination; Electron Transport Chain Complex Proteins; Food Preferences; Immobilization; Inflammation; Lipid Peroxidation; Male; Mitochondria; Olfactory Bulb; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Signal Transduction; Sucrose; Tumor Necrosis Factor-alpha

The aim of this study was to investigate the factors that could participate on salivary glands hypofunction during inflammation and the participation of endocannabinoids in hyposalivation induced by the presence of inflammogens in the submandibular gland (SMG) or in the brain.. Salivary secretion was assessed in the presence of inflammogens and/or the cannabinoid receptor antagonist AM251 in the SMG or in the brain of rats. At the end of the experiments, some systemic and glandular inflammatory markers were measured and histopathological analysis was performed.. The inhibitory effect observed 1h after lipopolysaccharide (LPS, 50μg/50μl) injection into the SMG (ig) was completely prevented by the injection of AM251 (5μg/50μl) by the same route (P<0.05). The LPS (ig)-induced increase in PGE2 content was not altered by AM251 (ig), while the glandular production of TNFα induced by the endotoxin (P<0.001) was partially blocked by it. Also, LPS injection produced no significant changes in the wet weight of the SMG neither damage to lipid membranes of its cells, nor significant microscopic changes in them, after hispopathological analysis, compared to controls. Finally, TNFα (100ng/5μl) injected intracerebro-ventricularly (icv) inhibited methacholine-induced salivary secretion evaluated 30min after (P<0.01), but the previous injection of AM251 (500ng/5μl, icv) prevented completely that effect.. We conclude that endocannabinoids mediate the hyposialia induced by inflammogens in the SMG and in the brain. The hypofunction would be due to changes on signalling pathway produced by inflammatory compounds since anatomical changes were not observed.

Topics: Analysis of Variance; Animals; Cannabinoid Receptor Agonists; Dinoprostone; Endocannabinoids; Hypothalamus; Inflammation; Lipopolysaccharides; Male; Piperidines; Pyrazoles; Radioimmunoassay; Rats; Rats, Wistar; Submandibular Gland; Thiobarbituric Acid Reactive Substances; Tumor Necrosis Factor-alpha; Xerostomia

Bacterial infections induce exacerbations in chronic lung diseases, e.g., chronic obstructive pulmonary disease (COPD), by enhancing airway inflammation. Exacerbations are frequently associated with right heart decompensation and accelerate disease progression. Endothelin receptor antagonists (ERAs) might have therapeutic potential as pulmonary vasodilators and anti-inflammatory agents, but utility in exacerbations of chronic lung diseases is unknown. We hypothesized that cytokine releases induced by lipopolysaccharide (LPS), the major bacterial trigger of inflammation, are reduced by ERAs in pulmonary vascular smooth muscle cells (PVSMCs). Ex vivo cultivated human PVSMCs were preincubated with the endothelin-A-receptor selective inhibitor ambrisentan, with the endothelin-B-receptor selective inhibitor BQ788 [sodium (2R)-2-{[(2S)-2-({[(2R,6S)-2,6-dimethyl-1-piperidinyl]carbonyl}amino)-4,4-dimethylpentanoyl][1-(methoxycarbonyl)-d-tryptophyl]amino}hexanoate], or with the dual blocker bosentan before stimulation with smooth LPS (S-LPS), rough LPS (Re-LPS), or a mixture of long and short forms (M-LPS). Expression of cytokines and LPS receptors (TLR4, CD14) were analyzed via enzyme-linked immunosorbent assay (ELISA) and/or quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). All LPS forms induced interleukin (IL)-6-, IL-8-, and granulocyte macrophage-colony stimulating factor (GM-CSF) release. Bosentan and BQ788 inhibited M-LPS-induced release of all cytokines and soluble CD14 (sCD14) but not TLR4 expression. Ambrisentan blocked M-LPS-induced IL-6 release but not IL-8, GM-CSF, or LPS receptors. IL-8 release induced by S-LPS, which requires CD14 to activate TLR4, was blocked by bosentan and BQ788. IL-8 release induced by Re-LPS, which does not require CD14 to activate TLR4, was insensitive to both bosentan and BQ788. In conclusion, PVSMCs contribute to inflammation in bacteria-induced exacerbations of chronic lung diseases. Inhibition of the endothelin-B receptor suppresses cytokine release induced by long/smooth LPS attributable to sCD14 downregulation. ERAs, particularly when targeting the endothelin-B receptor, might have therapeutic utility in exacerbations of chronic lung diseases.

Topics: Anti-Inflammatory Agents; Bosentan; Cells, Cultured; Cytokines; Endothelin B Receptor Antagonists; Endothelin Receptor Antagonists; Humans; Inflammation; Interleukin-8; Lipopolysaccharide Receptors; Lipopolysaccharides; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Oligopeptides; Phenylpropionates; Piperidines; Pulmonary Artery; Pyridazines; RNA, Messenger; Salmonella; Sulfonamides

A single intrathecal dose of adenosine 2A receptor (A2AR) agonist was previously reported to produce a multi-week reversal of allodynia in a chronic constriction injury (CCI) model of neuropathic pain. We aimed to determine if this long-term reversal was induced by A2AR agonism versus more generalized across adenosine receptor subtypes, and begin to explore the intracellular signaling cascades involved. In addition, we sought to identify whether the enduring effect could be extended to other models of neuropathic pain. We tested an A1R and A2BR agonist in CCI and found the same long duration effect with A2BR but not A1R agonism. An A2AR agonist (ATL313) produced a significant long-duration reversal of mechanical allodynia induced by long established CCI (administered 6 weeks after surgery), spinal nerve ligation and sciatic inflammatory neuropathy. To determine if ATL313 had a direct effect on glia, ATL313 was coadministered with lipopolysaccharide to neonatal microglia and astrocytes in vitro. ATL313 significantly attenuated TNFα production in both microglia and astrocytes but had no effect on LPS induced IL-10. Protein kinase C significantly reversed the ATL313 effects on TNFα in vitro in microglia and astrocytes, while a protein kinase A inhibitor only effected microglia. Both intrathecal PKA and PKC inhibitors significantly reversed the effect of the A2AR agonist on neuropathic allodynia. Therefore, A2AR agonists administered IT remain an exciting novel target for the treatment of neuropathic pain.

Topics: Adenosine A2 Receptor Agonists; Animals; Cells, Cultured; Chronic Disease; Constriction, Pathologic; Cyclic AMP-Dependent Protein Kinases; Hyperalgesia; Inflammation; Injections, Spinal; Ligation; Male; Piperidines; Protein Kinase C; Random Allocation; Rats; Rats, Sprague-Dawley; Sciatic Neuropathy; Signal Transduction

Topics: Analgesics; Animals; Brain; Inflammation; Male; Pain; Piperidines; Receptors, Metabotropic Glutamate; Receptors, Opioid, delta; Receptors, Opioid, mu

Despite common pathophysiological mechanisms, inflammatory and neuropathic pain do not respond equally to the analgesic effect of antidepressants, except for selective serotonin reuptake inhibitors (SSRIs), which show a limited efficacy in both conditions. We previously demonstrated that an interfering peptide (TAT-2ASCV) disrupting the interaction between 5-HT2A receptors and its associated PDZ proteins (e.g. PSD-95) reveals a 5-HT2A receptor-mediated anti-hyperalgesic effect and enhances the efficacy of fluoxetine (a SSRI) in diabetic neuropathic pain conditions in rats. Here, we have examined whether the same strategy would be useful to treat inflammatory pain. Sub-chronic inflammatory pain was induced by injecting λ-carrageenan (100 µl, 2%) into the left hind paw of the rat. Mechanical hyperalgesia was assessed after acute treatment with TAT-2ASCV or/and fluoxetine (SSRI) 2.5 h after λ-carrageenan injection. Possible changes in the level of 5-HT2A receptors and its associated PDZ protein PSD-95 upon inflammation induction were quantified by Western blotting in dorsal horn spinal cord. Administration of TAT-2ASCV peptide (100 ng/rat, intrathecally) but not fluoxetine (10 mg/kg, intraperitoneally) relieves mechanical hyperalgesia (paw pressure test) in inflamed rats. This anti-hyperalgesic effect involves spinal 5-HT2A receptors and GABAergic interneurons as it is abolished by a 5-HT2A antagonist (M100907, 150 ng/rat, intrathecally) and a GABAA antagonist, (bicuculline, 3 µg/rat, intrathecally). We also found a decreased expression of 5-HT2A receptors in the dorsal spinal cord of inflamed animals which could not be rescued by TAT-2ASCV injection, while the amount of PSD-95 was not affected by inflammatory pain. Finally, the coadministration of fluoxetine does not further enhance the anti-hyperalgesic effect of TAT-2ASCV peptide. This study reveals a role of the interactions between 5-HT2A receptors and PDZ proteins in the pathophysiological pathways of inflammatory pain and opens new perspectives in its control thanks to molecules disrupting 5-HT2A receptor/PDZ protein interactions.

Topics: Animals; Bicuculline; Carrageenan; Disks Large Homolog 4 Protein; Fluorobenzenes; Fluoxetine; Hyperalgesia; Inflammation; Injections; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Pain; Peptides; Piperidines; Posterior Horn Cells; Protein Binding; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Serotonin 5-HT2 Receptor Antagonists

Reactive oxygen species (ROS) scavengers have not been widely used for treatment of local inflammatory reactions such as arthritis and periodontal disease because they are rapidly eliminated from the inflamed site, which results in a low therapeutic effect. Therefore, to enhance the local retention time of ROS scavengers, we developed a redox-active injectable gel (RIG) system by using poly[4-(2,2,6,6-tetramethylpiperidine-N-oxyl)aminomethylstyrene]-b-poly(ethylene glycol)-b-poly[4-(2,2,6,6-tetramethylpiperidine-N-oxyl)aminomethylstyrene] (PMNT-PEG-PMNT) triblock copolymer, which possesses ROS scavenging nitroxide radicals as side chains of the PMNT segment. Cationic PMNT segment in PMNT-PEG-PMNT forms polyion complexes with anionic poly(acrylic acid) (PAAc) to form a flower-like micelle (ca. 79 nm), which exhibits in situ thermo-irreversible gelation under physiological conditions. We confirmed the prolonged site-specific retention time of RIG by performing in vivo noninvasive electron spin resonance imaging and quantitative evaluation. In contrast to low-molecular-weight nitroxide radical compounds that disappeared from injection sites in less than 1h after subcutaneous injection, 40% of the RIG remained even at 3 days. We also found that RIG inhibits neutrophil infiltration and cytokine production, which leads to suppression of hyperalgesia. These findings indicate the potential of RIG as an innovative approach for treatment of local inflammation.

Topics: Acrylic Resins; Animals; Antioxidants; Arthritis; Delayed-Action Preparations; Gels; Inflammation; Injections; Ions; Male; Mice; Micelles; Nitrogen Oxides; Oxidation-Reduction; Phase Transition; Piperidines; Polyethylene Glycols; Styrene; Temperature

Adiponectin secreted from adipocytes binds to adiponectin receptors AdipoR1 and AdipoR2, and exerts antidiabetic effects via activation of AMPK and PPAR-α pathways, respectively. Levels of adiponectin in plasma are reduced in obesity, which causes insulin resistance and type 2 diabetes. Thus, orally active small molecules that bind to and activate AdipoR1 and AdipoR2 could ameliorate obesity-related diseases such as type 2 diabetes. Here we report the identification of orally active synthetic small-molecule AdipoR agonists. One of these compounds, AdipoR agonist (AdipoRon), bound to both AdipoR1 and AdipoR2 in vitro. AdipoRon showed very similar effects to adiponectin in muscle and liver, such as activation of AMPK and PPAR-α pathways, and ameliorated insulin resistance and glucose intolerance in mice fed a high-fat diet, which was completely obliterated in AdipoR1 and AdipoR2 double-knockout mice. Moreover, AdipoRon ameliorated diabetes of genetically obese rodent model db/db mice, and prolonged the shortened lifespan of db/db mice on a high-fat diet. Thus, orally active AdipoR agonists such as AdipoRon are a promising therapeutic approach for the treatment of obesity-related diseases such as type 2 diabetes.

Topics: Adenylate Kinase; Adiponectin; Adipose Tissue, White; Administration, Oral; Animals; Diabetes Mellitus, Type 2; Diet, High-Fat; Drug Evaluation, Preclinical; Dyslipidemias; Enzyme Activation; Glucose Intolerance; Inflammation; Insulin Resistance; Liver; Longevity; Mice; Mitochondria; Muscle Fibers, Skeletal; Muscles; Obesity; Oxidative Stress; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Piperidines; PPAR alpha; Receptors, Adiponectin; Signal Transduction; Small Molecule Libraries; Transcription Factors; Triglycerides

The clinical treatment of chronic obstructive pulmonary disease (COPD) requires not only an improvement of airflow by bronchodilation but also the suppression of emphysema by controlling inflammation. Here we screen a compound library consisting of clinically used drugs for their ability to prevent elastase-induced airspace enlargement in mice. We show that intratracheal administration or inhalation of mepenzolate bromide, a muscarinic antagonist used to treat gastrointestinal disorders, decreases the severity of elastase-induced airspace enlargement and respiratory dysfunction. Although mepenzolate bromide shows bronchodilatory activity, most other muscarinic antagonists do not improve elastase-induced pulmonary disorders. Apart from suppressing elastase-induced pulmonary inflammatory responses and the production of superoxide anions, mepenzolate bromide reduces the level of cigarette smoke-induced airspace enlargement and respiratory dysfunction. Based on these results, we propose that mepenzolate bromide may be an effective therapeutic for the treatment of COPD due to its anti-inflammatory and bronchodilatory activities.

Topics: Administration, Inhalation; Animals; Anions; Anti-Inflammatory Agents; Benzilates; Bronchoalveolar Lavage; Bronchodilator Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Inflammation; Infusions, Parenteral; Lung; Male; Mice; Mice, Inbred DBA; Mice, Inbred ICR; NADPH Oxidases; NF-kappa B; Pancreatic Elastase; Piperidines; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Superoxides; Swine; Time Factors

Endocannabinoid signaling is terminated by enzymatic hydrolysis, a process that, for 2-Arachidonoylglycerol (2-AG), is mediated by monoacylglycerol lipase (MAGL). The piperidine carbamate, 4-nitrophenyl- 4-(dibenzo[d] [1,3]dioxol-5-yl (hydroxy) methyl) piperidine- 1-carboxylate (JZL184), is a drug that inhibits MAGL and presents high potency and selectivity. Thus, JZL184 increases the levels of 2-AG, an endocannabinoid that acts on the CB1 and CB2 cannabinoid receptors. Here, we investigated the effects of MAGL inhibition, with a single dose (16 mg/kg, intraperitoneally (i.p.)) of JZL184, in a murine model of lipopolysaccharide (LPS) -induced acute lung injury (ALI) 6, 24 and 48 hours after the inflammatory insult. Treatment with JZL184 decreased the leukocyte migration into the lungs as well as the vascular permeability measured through the bronchoalveolar lavage fluid (BAL) and histological analysis. JZL184 also reduced the cytokine and chemokine levels in the BAL and adhesion molecule expression in the blood and BAL. The CB1 and CB2 receptors were considered involved in the anti-inflammatory effects of JZL184 because the AM281 selective CB1 receptor antagonist (1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide) and the AM630 selective CB2 receptor antagonist ([6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl)-methanone) blocked the anti-inflammatory effects previously described for JZL184. It was concluded that MAGL inhibition, and consequently the increase in 2-AG levels, produced anti-inflammatory effects in a murine model of LPS-induced ALI, a finding that was considered a consequence of the activation of the CB1 and CB2 receptors.

Topics: Acute Lung Injury; Animals; Arachidonic Acids; Benzodioxoles; Bronchoalveolar Lavage Fluid; Capillary Permeability; Cell Adhesion Molecules; Endocannabinoids; Glycerides; Indoles; Inflammation; Leukocytes; Male; Mice; Mice, Inbred C57BL; Monoacylglycerol Lipases; Piperidines; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2

The NMDAR glutamate receptor subtype mediates various vital physiological neuronal functions. However, its excessive activation contributes to neuronal damage in a large variety of acute and chronic neurological disorders. NMDAR antagonists thus represent promising therapeutic tools that can counteract NMDARs' overactivation. Channel blockers are of special interest since they are use-dependent, thus being more potent at continuously activated NMDARs, as may be the case in pathological conditions. Nevertheless, it has been established that NMDAR antagonists, such as MK801, also have unacceptable neurotoxic effects. Presently only Memantine is considered a safe NMDAR antagonist and is used clinically. It has recently been speculated that antagonists that preferentially target extrasynaptic NMDARs would be less toxic. We previously demonstrated that the phencyclidine derivative GK11 preferentially inhibits extrasynaptic NMDARs. We thus anticipated that this compound would be safer than other known NMDAR antagonists. In this study we used whole-genome profiling of the rat cingulate cortex, a brain area that is particularly sensitive to NMDAR antagonists, to compare the potential adverse effects of GK11 and MK801. Our results showed that in contrast to GK11, the transcriptional profile of MK801 is characterized by a significant upregulation of inflammatory and stress-response genes, consistent with its high neurotoxicity. In addition, behavioural and immunohistochemical analyses confirmed marked inflammatory reactions (including astrogliosis and microglial activation) in MK801-treated, but not GK11-treated rats. Interestingly, we also showed that GK11 elicited less inflammation and neuronal damage, even when compared to Memantine, which like GK11, preferentially inhibits extrasynaptic NMDAR. As a whole, our study suggests that GK11 may be a more attractive therapeutic alternative in the treatment of CNS disorders characterized by the overactivation of glutamate receptors.

Topics: Animals; Astrocytes; Cyclohexenes; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Gyrus Cinguli; Inflammation; Injections, Intraperitoneal; Memantine; Microglia; Neurons; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

Acute lung injury (ALI) is characterized by overwhelming lung inflammation and anti-inflammation treatment is proposed to be a therapeutic strategy for ALI. Poly (ADP-ribose) polymerase-1 has been demonstrated to be involved in tissue inflammation and one of its inhibitors, 3, 4-Dihydro-5[4-(1-piperindinyl)butoxy]-1(2H)-isoquinoline (DPQ), exerts anti-inflammatory effect. However, it is still unclear whether the DPQ possesses the protective effect on ALI and what mechanisms are involved. In this study, we tested the effect of DPQ on the lung inflammation induced by lipopolysaccharide (LPS) challenge in mice. We found that 6 h-LPS challenge induced significant lung inflammation and vascular leakage in mice. Treatment with DPQ at the dose of 10 μg/kg markedly reduced the neutrophil infiltration, myeloperoxidase activity and up-regulation of pro-inflammatory mediators and cytokines. LPS-elevated vascular permeability was decreased by DPQ treatment, accompanied by the inhibition of apoptotic cell death in mice lungs. In addition, we isolated mice peritoneal macrophages and showed pretreatment with DPQ at 10 μM inhibited the production of cytokines in the macrophages following LPS stimulation. DPQ treatment also inhibited the phosphorylation and degradation of IκB-α, subsequently blocked the activation of nuclear factor (NF)-κB induced by LPS in vivo and in vitro. Taken together, our results show that DPQ treatment inhibits NF-κB signaling in macrophages and protects mice against ALI induced by LPS, suggesting inhibition of Poly (ADP-ribose) polymerase-1 may be a potential and effective approach to resolve inflammation for the treatment of ALI.

Topics: Acute Lung Injury; Animals; Apoptosis; Blotting, Western; Cells, Cultured; Inflammation; Isoquinolines; Lipopolysaccharides; Macrophages; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Peroxidase; Piperidines; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Real-Time Polymerase Chain Reaction; Sepsis

The present study tested whether the selective monoacylglycerol lipase (MAGL) inhibitor JZL184 would reduce allodynia and paw edema in the carrageenan test.. The anti-edematous and anti-allodynic effects of JZL184 were compared to those of PF-3845, an inhibitor of fatty acid amide hydrolase (FAAH), and diclofenac, a non-selective cyclooxygenase inhibitor. Cannabinoid receptor involvement in the anti-edematous and anti-allodynic effects of JZL184 was evaluated by administration of the respective CB1 and CB2 receptor antagonists rimonabant and SR144528 as well as with CB1(-/-) and CB2(-/-) mice. JZL184 (1.6, 4, 16, or 40mg/kg) was administered for six days to assess tolerance.. JZL184 administered before or after carrageenan significantly attenuated carrageenan-induced paw edema and mechanical allodynia. Complementary genetic and pharmacological approaches revealed that the anti-allodynic effects of JZL184 required both CB1 and CB2 receptors, but only CB2 receptors mediated its anti-edematous actions. Importantly, both the anti-edematous and anti-allodynic effects underwent tolerance following repeated injections of high dose JZL184 (16 or 40mg/kg), but repeated administration of low dose JZL184 (4mg/kg) retained efficacy.. These results suggest that the MAGL inhibitor JZL184 reduces inflammatory nociception through the activation of both CB1 and CB2 receptors, with no evidence of tolerance following repeated administration of low doses.

Topics: Amidohydrolases; Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzodioxoles; Carrageenan; Diclofenac; Edema; Hyperalgesia; Inflammation; Mice; Mice, Inbred C57BL; Mice, Knockout; Monoacylglycerol Lipases; Pain; Pain Measurement; Physical Stimulation; Piperidines; Pyridines; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2

Inflammatory pain presents a problem of clinical relevance and often elicits allodynia, a condition in which non-noxious stimuli are perceived as painful. One potential target to treat inflammatory pain is the endogenous cannabinoid (endocannabinoid) system, which is comprised of CB1 and CB2 cannabinoid receptors and several endogenous ligands, including anandamide (AEA). Blockade of the catabolic enzyme fatty acid amide hydrolase (FAAH) elevates AEA levels and elicits antinociceptive effects, without the psychomimetic side effects associated with Δ(9) -tetrahydrocannabinol (THC).. Allodynia was induced by intraplantar injection of LPS. Complementary genetic and pharmacological approaches were used to determine the strategy of blocking FAAH to reverse LPS-induced allodynia. Endocannabinoid levels were quantified using mass spectroscopy analyses.. FAAH (-/-) mice or wild-type mice treated with FAAH inhibitors (URB597, OL-135 and PF-3845) displayed an anti-allodynic phenotype. Furthermore, i.p. PF-3845 increased AEA levels in the brain and spinal cord. Additionally, intraplantar PF-3845 produced a partial reduction in allodynia. However, the anti-allodynic phenotype was absent in mice expressing FAAH exclusively in the nervous system under a neural specific enolase promoter, implicating the involvement of neuronal fatty acid amides (FAAs). The anti-allodynic effects of FAAH-compromised mice required activation of both CB1 and CB2 receptors, but other potential targets of FAA substrates (i.e. µ-opioid, TRPV1 and PPARα receptors) had no apparent role.. AEA is the primary FAAH substrate reducing LPS-induced tactile allodynia. Blockade of neuronal FAAH reverses allodynia through the activation of both cannabinoid receptors and represents a promising target to treat inflammatory pain.. This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7.

Topics: Amidohydrolases; Animals; Arachidonic Acids; Brain; Endocannabinoids; Enzyme Inhibitors; Female; Glycerides; Hyperalgesia; Inflammation; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Peripheral Nervous System; Piperidines; Polyunsaturated Alkamides; Pyridines; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Spinal Cord

Activation of cannabinoid receptors decreases emesis, inflammation, gastric acid secretion and intestinal motility. The ability to modulate intestinal permeability in inflammation may be important in therapy aimed at maintaining epithelial barrier integrity. The aim of the present study was to determine whether cannabinoids modulate the increased permeability associated with inflammation in vitro.. Confluent Caco-2 cell monolayers were treated for 24 h with IFNγ and TNFα (10 ng·mL(-1) ). Monolayer permeability was measured using transepithelial electrical resistance and flux measurements. Cannabinoids were applied either apically or basolaterally after inflammation was established. Potential mechanisms of action were investigated using antagonists for CB(1) , CB(2) , TRPV1, PPARγ and PPARα. A role for the endocannabinoid system was established using inhibitors of the synthesis and degradation of endocannabinoids.. Δ(9) -Tetrahydrocannabinol (THC) and cannabidiol accelerated the recovery from cytokine-induced increased permeability; an effect sensitive to CB(1) receptor antagonism. Anandamide and 2-arachidonylglycerol further increased permeability in the presence of cytokines; this effect was also sensitive to CB(1) antagonism. No role for the CB(2) receptor was identified in these studies. Co-application of THC, cannabidiol or a CB(1) antagonist with the cytokines ameliorated their effect on permeability. Inhibiting the breakdown of endocannabinoids worsened, whereas inhibiting the synthesis of endocannabinoids attenuated, the increased permeability associated with inflammation.. These findings suggest that locally produced endocannabinoids, acting via CB(1) receptors play a role in mediating changes in permeability with inflammation, and that phytocannabinoids have therapeutic potential for reversing the disordered intestinal permeability associated with inflammation.. This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7.

Topics: Amidohydrolases; Benzamides; Benzodioxoles; Caco-2 Cells; Cannabinoids; Carbamates; Cell Survival; Enzyme Inhibitors; Humans; Indoles; Inflammation; Interferon-gamma; Intestinal Mucosa; Monoacylglycerol Lipases; Permeability; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Tumor Necrosis Factor-alpha

Many cells express proteinase activated receptor 2 (PAR2) on their plasma membrane. PAR2 is activated by proteolytic enzymes, such as trypsin and tryptase that cleave the receptor N-terminus, inititating signalling to intracellular G proteins. Studies on PAR2 have relied heavily upon activating effects of proteases and peptide agonists that lack stability and bioavailability in vivo.. A novel small molecule agonist GB110 and an antagonist GB88 were characterized in vitro against trypsin, peptide agonists, PAR2 antibody, PAR1 agonists and flow cytometry,in seven cell lines using intracellular Ca(2+) mobilization and examined in vivo against PAR2- and PAR1-induced rat paw oedema.. GB110 is a potent non-peptidic agonist activating PAR2-mediated Ca(2+) release in HT29 cells (EC(50) ∼200 nM) and six other human cell lines, inducing PAR2 internalization. GB88 is a unique PAR2 antagonist, inhibiting PAR2 activated Ca(2+) release (IC(50) ∼2 µM) induced by native (trypsin) or synthetic peptide and non-peptide agonists. GB88 was a competitive and surmountable antagonist of agonist 2f-LIGRLO-NH(2), a competitive but insurmountable antagonist of agonist GB110, and a non-competitive insurmountable antagonist of trypsin. GB88 was orally active and anti-inflammatory in vivo, inhibiting acute rat paw oedema elicited by agonist GB110 and proteolytic or peptide agonists of PAR2 but not by corresponding agonists of PAR1 or PAR4.. The novel PAR2 agonist and antagonist modulate intracellular Ca(2+) and rat paw oedema, providing novel molecular tools for examining PAR2-mediated diseases.

Topics: Animals; Anti-Inflammatory Agents; Calcium; Cell Line; Dipeptides; Edema; HT29 Cells; Humans; Inflammation; Isoxazoles; Oligopeptides; Peptides; Piperidines; Rats; Receptor, PAR-1; Receptor, PAR-2; Spiro Compounds; Trypsin

Soluble epoxide hydrolase inhibitors (sEHIs) possess anti-inflammatory, antiatherosclerotic, antihypertensive and analgesic properties. The pharmacokinetics (PK) and pharmacodynamics in terms of inhibitory potency of sEHIs were assessed in non-human primates (NHPs). Development of a sEHI for use in NHPs will facilitate investigations on the role of sEH in numerous chronic inflammatory conditions.. PK parameters of 11 sEHIs in cynomolgus monkeys were determined after oral dosing with 0.3 mg·kg(-1). Their physical properties and inhibitory potency in hepatic cytosol of cynomolgus monkeys were examined. Dose-dependent effects of the two inhibitors 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) and the related acetyl piperidine derivative, 1-trifluoromethoxyphenyl-3-(1-acetylpiperidin-4-yl) urea (TPAU), on natural blood eicosanoids, were determined.. Among the inhibitors tested, TPPU and two 4-(cyclohexyloxy) benzoic acid urea sEHIs displayed high plasma concentrations (>10 × IC(50)), when dosed orally at 0.3 mg·kg(-1). Although the 4-(cyclohexyloxy) benzoic acid ureas were more potent against monkey sEH than piperidyl ureas (TPAU and TPPU), the latter compounds showed higher plasma concentrations and more drug-like properties. The C(max) increased with dose from 0.3 to 3 mg·kg(-1) for TPPU and from 0.1 to 3 mg·kg(-1) for TPAU, although it was not linear over this range of doses. As an indication of target engagement, ratios of linoleate epoxides to diols increased with TPPU administration.. Our data indicate that TPPU is suitable for investigating sEH biology and the role of epoxide-containing lipids in modulating inflammatory diseases in NHPs.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Antihypertensive Agents; Cytosol; Eicosanoids; Enzyme Inhibitors; Epoxide Hydrolases; Female; Inflammation; Liver; Macaca fascicularis; Phenylurea Compounds; Piperidines; Urea

Recent studies have identified enzymes that use NAD as a substrate, thus contributing to its net consumption. To maintain the intracellular pool, NAD is re-synthesized by a salvage pathway using nicotinamide, the by-product generated by the enzymatic cleavage of NAD. Enzymes involved in NAD re-synthesis include nicotinamide phosphoribosyltransferase (NAMPT) and nicotinamide mononucleotide adenylyltransferase. Our studies show, that NAMPT was substantially up-regulated by LPS in primary human monocytes, suggesting that it may be especially required during the process of monocyte activation. To evaluate the contribution of the NAD rescue pathway to LPS-induced biological responses in human monocytes, we used APO866, a well-characterized inhibitor of NAMPT. Concomitant with the inhibition of NAMPT, LPS-induced TNF-α protein synthesis declined, while TNF-α mRNA levels were minimally affected. Moreover, APO866 strongly decreased the production of reactive oxygen species (ROS), increased surface expression of the NAD-consuming enzyme CD38, and modified the production of selective eicosanoids. We further demonstrate that protein ADP-ribosylation was strongly reduced, indicating a possible link between this post-translational protein modification and human monocyte inflammatory responses. Despite a substantial reduction in intracellular NAD levels, activated monocytes were resistant to apoptosis, while resting monocytes were not. Taken together, our data suggest that activated monocytes strongly depend on the NAD salvage pathway to mount an appropriate inflammatory response. Their survival is not affected by NAD-depletion, probably as a result of LPS-mediated anti-apoptotic signals.

Topics: Acrylamides; ADP-ribosyl Cyclase 1; Apoptosis; Cells, Cultured; Eicosanoids; Humans; Inflammation; Inflammation Mediators; Lipopolysaccharides; Monocytes; NAD; Nicotinamide Phosphoribosyltransferase; Piperidines; Protein Processing, Post-Translational; Reactive Oxygen Species; Tumor Necrosis Factor-alpha; Up-Regulation

Natural products have been revealed as relevant sources of therapeutic agents including those for the management of pain states. In this study, the anti-nociceptive and anti-inflammatory effects of (-)-cassine, isolated from Senna spectabilis were evaluated using pharmacological, behavioural and biochemical approaches. Oral treatment with (-)-cassine (3-30 mg/kg) reduced carrageenan-induced mechanical and thermal nociception associated with the suppression of myeloperoxidase activity in the mouse paw. Moreover, (-)-cassine (1-10 μg/site) prevented mechanical hyperalgesia induced by carrageenan when given through the intraplantar (i.pl.), spinal and intracerebroventricular routes. Additionally, oral treatment with (-)-cassine (3-60 mg/kg) prevented the mechanical hyperalgesia elicited by intraplantar injection of prostaglandin E(2), complete Freund's adjuvant, interleukin-1β, interleukin-6 and keratinocyte-derived chemokine. Furthermore, (-)-cassine inhibited the mechanical nociceptive response induced by ligation of the sciatic nerve and also significantly reduced the levels of cytokines/chemokines in paw tissue following i.pl. injection of carrageenan. In addition, the anti-nociceptive and anti-inflammatory actions of (-)-cassine were associated with its ability to interact with both TRPV1 and TRPA1 receptors and by inhibiting the upregulation of cyclooxigenase-2 as well as inhibiting the phosphorylation of MAPK/ERK and the transcription factor NF-κB. It is important to highlight that oral treatment with (-)-cassine did not produce any effects related to temperature, locomotor activity or catalepsy. Altogether, the present data demonstrate that (-)-cassine has systemic, spinal and supraspinal anti-nociceptive properties when assessed in inflammatory and neuropathic pain models. These effects are associated with its ability to block several signalling pathways associated with inflammatory and nociceptive responses. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.

Topics: Animals; Behavior, Animal; Carrageenan; Freund's Adjuvant; Hyperalgesia; Inflammation; Ketones; Male; Mice; Neuralgia; Pain Measurement; Pain Threshold; Piperidines

The principal aim of the study was to determine the influence of influenza A virus infection on capsaicin-induced relaxation responses in mouse isolated tracheal segments and clarify the underlying mechanisms. Anesthetized mice were intranasally inoculated with influenza A/PR-8/34 virus (VIRUS) or vehicle (SHAM), and 4 days later tracheal segments were harvested for isometric tension recording and biochemical and histologic analyses. Capsaicin induced dose-dependent relaxation responses in carbachol-contracted SHAM trachea (e.g., 10 μM capsaicin produced 66 ± 4% relaxation; n = 11), which were significantly inhibited by capsazepine [transient receptor potential vanilloid type 1 (TRPV1) antagonist], (2S,3S)-3-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-2-phenylpiperidine hydrochloride (L-733,060) [neurokinin 1 (NK₁) receptor antagonist], indomethacin [cyclooxygenase (COX) inhibitor], and the combination of 6-isopropoxy-9-oxoxanthene-2-carboxylic acid (AH6809) and 7-[5α-([1S,1α(Z)-biphenyl]-4-ylmethoxy)-2β-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid, calcium salt, hydrate (AH23848) [E-prostanoid (EP)₂ and EP₄ receptor antagonists, respectively], indicating that capsaicin-induced relaxation involved the TRPV1-mediated release of substance P (SP), activation of epithelial NK₁ receptors, and production of COX products capable of activating relaxant EP₂/EP₄ receptors. Consistent with this postulate, capsaicin-induced relaxation was associated with the significant release of SP and prostaglandin E₂ (PGE₂) from mouse tracheal segments. As expected, influenza A virus infection was associated with widespread disruption of the tracheal epithelium. Tracheal segments from VIRUS mice responded weakly to capsaicin (7 ± 3% relaxation) and were 25-fold less responsive to SP than tracheas from SHAM mice. In contrast, relaxation responses to exogenous PGE₂ and the β-adrenoceptor agonist isoprenaline were not inhibited in VIRUS trachea. Virus infection was associated with impaired capsaicin-induced release of PGE₂, but the release of SP was not affected. In summary, influenza A virus infection profoundly inhibits capsaicin- and SP-induced relaxation responses, most likely by inhibiting the production of PGE₂.

Topics: Animals; Biphenyl Compounds; Bronchoalveolar Lavage Fluid; Capsaicin; Carbachol; Cyclooxygenase Inhibitors; Dinoprostone; Dose-Response Relationship, Drug; Indomethacin; Inflammation; Influenza A virus; Isoproterenol; Leukocytes; Male; Mice; Mice, Inbred BALB C; Models, Biological; Muscle Contraction; Muscle Relaxation; Muscle, Smooth; Orthomyxoviridae Infections; Piperidines; Prostaglandin Antagonists; Respiratory Mucosa; Specific Pathogen-Free Organisms; Substance P; Trachea; TRPV Cation Channels; Xanthones

Nocistatin (NST) and Nociceptin/Orphanin FQ (N/OFQ) are derived from the same precursor protein, pre-proN/OFQ, and exert opposite effects on the modulation of pain signals. However, the role of the peripheral N/OFQ and the NOP receptor, which is located at the endings of sensory nerves, in inflammatory pain was not ascertained. NST administered intrathecally (i.t.) prevented the nociceptive effects induced by i.t. N/OFQ and PGE₂. Moreover an up regulation of N/OFQ was shown in the rat in response to peripheral inflammation. Here, we investigated the effects of intraplantar (i.pl.) administration of functional N/OFQ and NOP receptor antagonists in a rat model of inflammatory pain. Our findings showed that i.pl. injection of (±)-J 113397, a selective antagonist of the NOP receptor, and NST, the functional N/OFQ antagonist, prior to carrageenan significantly reduced the paw allodynic and thermal hyperalgesic threshold induced by the inflammatory agent. The resulting antiallodynic and antihyperalgesic effects by co-administering NST and (±)-J 113397 prior to carrageenan were markedly enhanced, and the basal latencies were restored. Thus, it is likely that the peripheral N/OFQ/NOP receptor system contributes to the abnormal pain sensitivity in an inflammatory state.

Topics: Analgesics; Analgesics, Opioid; Animals; Behavior, Animal; Benzimidazoles; Disease Models, Animal; Drug Therapy, Combination; Hyperalgesia; Inflammation; Injections, Subcutaneous; Male; Metatarsus; Narcotic Antagonists; Nociceptin; Nociceptin Receptor; Nociceptive Pain; Opioid Peptides; Pain Threshold; Peripheral Nerves; Piperidines; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Signal Transduction

Spinal glial activation has been implicated in sustained morphine-mediated paradoxical pain sensitization. Since activation of glial CB2 cannabinoid receptors attenuates spinal glial activation in neuropathies, we hypothesized that CB2 agonists may also attenuate sustained morphine-mediated spinal glial activation and pain sensitization. Our data indicate that co-administration of a CB2-selective agonist (AM 1241) attenuates morphine (intraperitoneal; twice daily; 6 days)-mediated thermal hyperalgesia and tactile allodynia in rats. A CB2 (AM 630) but not a CB1 (AM 251) antagonist mitigated this effect. AM 1241 co-treatment also attenuated spinal astrocyte and microglial marker and pro-inflammatory mediator (IL-1β, TNFα) immunoreactivities in morphine-treated rats, suggesting that CB2 agonists may be useful to prevent the neuroinflammatory consequences of sustained morphine treatment.

Topics: Analgesics; Analgesics, Opioid; Animals; Cannabinoids; Hyperalgesia; Indoles; Inflammation; Interleukin-1beta; Male; Morphine; Neuroglia; Pain; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB2; Spinal Cord; Tumor Necrosis Factor-alpha

The most commonly used drugs against pain act by inhibiting the cyclooxygenases (COXs). Metamizol (dipyrone) inhibits the COXs and is widely used in Europe and Latin America as a non-opioid analgesic. One target of metamizol and other non-opioid analgesics is the periaqueductal grey matter (PAG), where they trigger descending inhibition of spinal nociceptive transmission. Also, cannabinoids exert an analgesic action at several structures in the peripheral and central nervous system, including the PAG. The present study investigates whether the antinociceptive action of metamizol in the lateral-ventrolateral (LVL) PAG during inflammation is related to endocannabinoids. In anaesthetized rats, unitary action potentials were recorded from spinal nociceptive neurons with receptive fields in the ipsilateral hind paw. Inflammation of the paw induced neuronal hyperexcitability, which was attenuated by intra-LVL-PAG microinjection of metamizol either at the beginning of inflammation or when hyperexcitability was fully established. In both cases, the antinociceptive effect of metamizol was reduced by a microinjection of AM251, an antagonist at the CB1 cannabinoid receptor, either into the LVL-PAG or into the rostral ventromedial medulla (RVM). The RVM is a downstream structure that funnels PAG-derived descending inhibition into the spinal cord. These results show that endocannabinoids and their CB1 receptor (1) contribute at the LVL-PAG to the antinociceptive effects of metamizol, and possibly other non-opioid analgesics; and (2) participate in the PAG-derived activation of RVM descending antinociceptive influences.

Topics: Action Potentials; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cannabinoid Receptor Modulators; Dipyrone; Endocannabinoids; Hyperalgesia; Inflammation; Male; Medulla Oblongata; Microinjections; Neurons; Nociceptors; Pain Measurement; Periaqueductal Gray; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1

Oviductal disease is a primary cause of infertility, a problem that largely stems from excessive inflammation of this key reproductive organ. Our poor understanding of the mechanisms regulating oviductal inflammation restricts our ability to diagnose, treat, and/or prevent oviductal disease. Using mice, our objective was to determine the spatial localization, regulatory mechanism, and functional attributes of a hypothesized regulator of oviductal inflammation, the hematopoietic form of prostaglandin D synthase (HPGDS). Immunohistochemistry revealed specific localization of HPGDS to the oviduct's epithelium. In the isthmus, expression of HPGDS was consistent. In the ampulla, expression of HPGDS appeared dependent upon stage of the estrous cycle. HPGDS was expressed in the epithelium of immature and cycling mice but not in the oviducts of estrogen receptor α knockouts. Two receptor subtypes bind PGD₂: PGD₂ receptor and G protein-coupled receptor 44. Expression of mRNA for Ptgdr was higher in the epithelial cells (EPI) than in the stroma (P < 0.05), whereas mRNA for Gpr44 was higher in the stroma than epithelium (P < 0.05). Treatment of human oviductal EPI with HQL-79, an inhibitor of HPGDS, decreased cell viability (P < 0.05). Treatment of mice with HQL-79 increased mRNA for chemokine (C-C motif) ligands 3, 4, and 19; chemokine (C-X-C motif) ligands 11 and 12; IL-13 and IL-17B; and TNF receptor superfamily, member 1b (P < 0.02 for each mRNA). Overall, these results suggest that HPGDS may play a role in the regulation of inflammation and EPI health within the oviduct.

Topics: Animals; Cell Survival; Epithelial Cells; Estrogen Receptor alpha; Estrous Cycle; Female; In Vitro Techniques; Inflammation; Intramolecular Oxidoreductases; Isomerases; Mice; Mice, Inbred Strains; Mice, Knockout; Mice, Transgenic; Oviducts; Piperidines; Receptors, Immunologic; Receptors, Prostaglandin; RNA, Messenger

The present study was undertaken to investigate the anti-inflammatory effect of piperine against adjuvant-induced arthritis in rats, an experimental model for rheumatoid arthritis and compared it with that of the non-steroidal anti-inflammatory drug indomethacin. Administration of heat-killed Mycobacterium tuberculosis (0. 1 ml) intradermally into the right hind paw of rats resulted in increased paw volume, lysosomal enzymes, glycoproteins and tissue marker enzymes and decreased body weight. However, these changes were reverted to near normal levels upon piperine (30 mg/kg body weight, i.p.) treatment. Histopathological analysis of joints also revealed that synovial hyperplasia and mononuclear infiltration observed in arthritic rats were alleviated by piperine. Thus, the present study clearly indicated that piperine possesses promising anti-inflammatory effect against adjuvant-induced arthritis by suppressing inflammation and cartilage destruction.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Benzodioxoles; Edema; Female; Glycoproteins; Indomethacin; Inflammation; Joints; Male; Mycobacterium tuberculosis; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar

Visfatin (also termed pre-B-cell colony-enhancing factor (PBEF) or nicotinamide phosphoribosyltransferase (Nampt)) is a pleiotropic mediator acting on many inflammatory processes including osteoarthritis. Visfatin exhibits both an intracellular enzymatic activity (nicotinamide phosphoribosyltransferase, Nampt) leading to NAD synthesis and a cytokine function via the binding to its hypothetical receptor. We recently reported the role of visfatin in prostaglandin E(2) (PGE(2)) synthesis in chondrocytes. Here, our aim was to characterize the signaling pathways involved in this response in exploring both the insulin receptor (IR) signaling pathway and Nampt activity. IR was expressed in human and murine chondrocytes, and visfatin triggered Akt phosphorylation in murine chondrocytes. Blocking IR expression with siRNA or activity using the hydroxy-2-naphthalenyl methyl phosphonic acid tris acetoxymethyl ester (HNMPA-(AM)(3)) inhibitor diminished visfatin-induced PGE(2) release in chondrocytes. Moreover, visfatin-induced IGF-1R(-/-) chondrocytes released higher concentration of PGE(2) than IGF-1R(+/+) cells, a finding confirmed with an antibody that blocked IGF-1R. Using RT-PCR, we found that visfatin did not regulate IR expression and that an increased insulin release was also unlikely to be involved because insulin was unable to increase PGE(2) release. Inhibition of Nampt activity using the APO866 inhibitor gradually decreased PGE(2) release, whereas the addition of exogenous nicotinamide increased it. We conclude that the proinflammatory actions of visfatin in chondrocytes involve regulation of IR signaling pathways, possibly through the control of Nampt enzymatic activity.

Topics: Acrylamides; Animals; Cells, Cultured; Chondrocytes; Cytokines; Dinoprostone; Gene Expression Regulation; Humans; Inflammation; Insulin; Mice; Mice, Knockout; Naphthalenes; Nicotinamide Phosphoribosyltransferase; Organophosphonates; Piperidines; Receptor, IGF Type 1; Receptor, Insulin; Signal Transduction

In this study we analyzed the mechanisms underlying celecoxib-induced analgesia in a model of inflammatory pain in rats, using the intracerebroventricular (i.c.v.) administration of selective opioid and cannabinoid antagonists.. Analgesic effects of celecoxib were prevented by selective μ-(β-funaltrexamine) and δ-(naltrindole), but not κ-(nor-binaltorphimine) opioid antagonists, given i.c.v. 30 min before celecoxib. Similar pretreatment with AM 251, but not SR 144528, cannabinoid CB(1) and CB(2) receptor antagonists, respectively, prevented celecoxib-induced analgesia. The fatty acid amide hydrolase inhibitor, URB 597, also prevented celecoxib-induced analgesia.. Our data provided further evidence for the involvement of endogenous opioids and revealed a new cannabinoid component of the mechanism(s) underlying celecoxib-induced analgesia.

Topics: Analgesics; Animals; Carrageenan; Celecoxib; Central Nervous System; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Inflammation; Male; Naltrexone; Pain; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptors, Opioid, delta; Receptors, Opioid, mu; Sulfonamides

Studies have shown that N-methyl-D-aspartate (NMDA) receptors play a critical role in pain processing at different levels of the central nervous system. In this study, we used female adult Wistar rats to examine the effects of antagonizing the NR2B subunit of the NMDA receptor in phasic and tonic pain processes. All the rats underwent stereotaxic surgery for cortical cannula implantation and after at least one week of recovery, rats performed behavioral tests. For evaluating the effects of drugs on motor coordination rats were tested in the rotarod apparatus. Moreover, rats were evaluated in the paw withdrawal latency (PWL) to a noxious thermal stimulus. Furthermore, rats were tested in the formalin-pain test. Rats that received the NR2B antagonist Ro 25-6981 before and after formalin injection showed significantly reduced pain responses in the formalin test, as compared with female control rats (p<0.05). In contrast, no differences among groups were found in the phasic pain test (Hargreaves) and the rotarod test. Taken together, these results suggest that cortical antagonism of the NR2B subunit of NMDA receptors is able to reduce inflammatory pain levels not only before, but after the formalin injection in females at different phases of the estrous cycle.

Topics: Animals; Drug Evaluation, Preclinical; Estrous Cycle; Excitatory Amino Acid Antagonists; Female; Formaldehyde; Gyrus Cinguli; Hot Temperature; Inflammation; Injections; Long-Term Potentiation; Pain; Pain Measurement; Phenols; Piperidines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Rotarod Performance Test

Piperine, one of the main components of Piper longum Linn. and P. nigrum Linn., is a plant alkaloid with a long history of medicinal use. Piperine has been shown to modulate the immune response, but the mechanism underlying this modulation remains unknown. Here, we examined the effects of piperine on lipopolysaccharide (LPS)-induced inflammatory responses in bone-marrow-derived dendritic cells (BMDCs). Piperine significantly inhibited the expression of major histocompatibility complex class II, CD40 and CD86 in BMDCs in a dose-dependent manner. Furthermore, piperine treatment led to an increase in fluorescein-isothiocyanate-dextran uptake in LPS-treated dendritic cells and inhibited the production of tumour necrosis factor alpha and interleukin (IL)-12, but not IL-6. The inhibitory effects of piperine were mediated via suppression of extracellular signal-regulated kinases and c-Jun N-terminal kinases activation, but not p38 or nuclear factor-κB activation. These findings provide insight into the immunopharmacological role of piperine.

Topics: Alkaloids; Animals; Benzodioxoles; Bone Marrow Cells; Cell Differentiation; Dendritic Cells; Inflammation; Interleukin-12; Interleukin-6; JNK Mitogen-Activated Protein Kinases; Lipopolysaccharides; MAP Kinase Signaling System; Mice; Phosphorylation; Piperidines; Polyunsaturated Alkamides; Tumor Necrosis Factor-alpha

The aim of the present study is to investigate the status of proinflammatory cytokine in the brain of intracerebroventricular (i.c.v.) okadaic acid (OKA) induced memory impaired rat.. OKA (200 ng) intracerebroventricular (i.c.v.) was administered in rats. Memory was assessed by Morris water maze test. Biochemical marker of neuroinflammation (TNF-α, IL-β), total nitrite, mRNA (RT PCR) and protein expression (WB) of iNOS and nNOS were estimated in rat brain areas.. OKA caused memory-impairment in rats with increased expression of proinflammatory cytokine TNF-α and IL-1β and total nitrite in brain regions hippocampus and cortex. The expression of mRNA and protein of iNOS was increased while; the expressions were decreased in case of nNOS. Pretreatment with antidementic drugs donepezil (5 mg/kg, p.o.) and memantine (10 mg/kg, p.o) for 13 days protected i.c.v. OKA induced memory impairment and changes in level of TNF-α, IL-β, total nitrite and expressions of iNOS and nNOS in OKA treated rat.. This study suggests that neuroinflammation may play a vital role in OKA induced memory impairment.

Topics: Animals; Behavior, Animal; Biomarkers; Blotting, Western; Donepezil; Excitatory Amino Acid Antagonists; Indans; Inflammation; Injections, Intraventricular; Interleukin-1beta; Male; Maze Learning; Memantine; Memory Disorders; Motor Activity; Nitrate Reductase; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Nitrites; Nootropic Agents; Okadaic Acid; Piperidines; Polymerase Chain Reaction; Rats; Rats, Sprague-Dawley; Reactive Nitrogen Species; RNA, Messenger; Tumor Necrosis Factor-alpha

Neuroinflammation and blood brain barrier (BBB) dysfunction have been implicated in the pathogenesis of Parkinson's disease (PD). The neuropeptide substance P (SP) is an important mediator of both neuroinflammation and BBB dysfunction through its NK1 receptor in a process known as neurogenic inflammation. Increased SP content has previously been reported following 6-OHDA treatment in vitro, with the levels of SP correlating with cell death. The present study used an in vivo 6-OHDA lesion model to determine if dopaminergic degeneration was associated with increased SP in the substantia nigra and whether this degeneration could be prevented by using a SP, NK1 receptor antagonist. Unilateral, intrastriatal 6-OHDA lesions were induced and SP (10 µg/2 µL) or the NK1 receptor antagonists, N-acetyl-L-tryptophan (2 µL at 50 nM) or L-333,060 (2 µL at 100 nM), administered immediately after the neurotoxin. Nigral SP content was then determined using immunohistochemical and ELISA methods, neuroinflammation and barrier integrity was assessed using Iba-1, ED-1, GFAP and albumin immunohistochemistry, while dopaminergic cell loss was assessed with tyrosine hydroxylase immunohistochemistry. Motor function in all animals was assessed using the rotarod task. Intrastriatal 6-OHDA lesioning produced an early and sustained increase in ipsilateral nigral SP content, along with a breakdown of the BBB and activation of microglia and astrocytes. Further exacerbation of SP levels accelerated disease progression, whereas NK1 receptor antagonist treatment protected dopaminergic neurons, preserved barrier integrity, reduced neuroinflammation and significantly improved motor function. We propose that neurogenic inflammation contributes to dopaminergic degeneration in early experimental PD and demonstrate that an NK1 receptor antagonist may represent a novel neuroprotective therapy.

Topics: Animals; Anti-Inflammatory Agents; Blood-Brain Barrier; Cells; Dopaminergic Neurons; Inflammation; Male; Motor Activity; Neurokinin-1 Receptor Antagonists; Neuroprotective Agents; Oxidopamine; Parkinson Disease, Secondary; Piperidines; Rats; Rats, Sprague-Dawley; Rotarod Performance Test; Substance P; Substantia Nigra; Tryptophan

Blockade of tyrosine kinase signaling by masitinib, a c-kit/PDGF receptor tyrosine kinase inhibitor, can modulate allergic airway inflammation, but effects on lung mechanics have not been well characterized. We hypothesized masitinib would decrease airway eosinophilia and consequently improve pulmonary mechanics in a feline allergic asthma model.. Asthma was induced in 12 cats using Bermuda grass allergen (BGA). Cats received 50 mg/day oral masitinib or placebo. Bronchoalveolar lavage fluid (BALF) was analyzed for eosinophils, total protein (TP) and BGA-specific IgE. Ventilator-acquired mechanics after methacholine (MCh) challenge determined MCh concentration needed to increase baseline airway resistance by 200% (EC(200)R(aw)), positive end expiratory occlusion pressure (PEEP) and end inspiratory breath hold pressure (P(plat)). An inverse correlate of respiratory system compliance P(plat)-PEEP was also calculated. Data were analyzed using the Wilcoxon test, with one-tailed significance set at p < 0.1.. After 4 weeks, percent eosinophils in BALF was lower in masitinib-treated cats (7 ± 9%) versus controls (30 ± 27%, p = 0.023). BALF TP significantly differed (p = 0.047) between groups, decreasing with masitinib and increasing with placebo. BALF BGA-specific IgE was unaffected by masitinib. Both groups showed an improvement in EC(200)R(aw) (masitinib, p = 0.015; control, p = 0.078) but no significant change in PEEP after 4 weeks. Masitinib-treated cats demonstrated decreased P(plat) (p = 0.033) and P(plat)-PEEP (p = 0.075) at week 4, suggesting an improvement in respiratory compliance.. Masitinib reduced BALF eosinophilia and TP, indicating improved airway inflammation and edema, and improved P(plat) and P(plat)-PEEP, suggesting benefit to respiratory compliance influenced by airway inflammation/edema. Masitinib deserves further study in humans with chronic allergic asthma.

Topics: Allergens; Animals; Anti-Asthmatic Agents; Asthma; Benzamides; Bronchoalveolar Lavage Fluid; Cats; Chronic Disease; Cynodon; Eosinophils; Immunoglobulin E; Inflammation; Lung; Male; Methacholine Chloride; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyridines; Thiazoles

The cannabinoid receptor-mediated analgesic effects of 2-arachidonoylglycerol (2-AG) are limited by monoacylglycerol lipase (MAGL). 4-nitrophenyl 4-[bis (1,3-benzodioxol-5-yl) (hydroxy) methyl] piperidine-1-carboxylate (JZL184) is a potent inhibitor of MAGL in the mouse, though potency is reportedly reduced in the rat. Here we have assessed the effects of spinal inhibition of MAGL with JZL184 on nociceptive processing in rats.. In vivo spinal electrophysiological assays in anaesthetized rats were used to determine the effects of spinal administration of JZL184 on spinal nociceptive processing in the presence and absence of hindpaw inflammation. Contributions of CB(1) receptors to these effects was assessed with AM251. Inhibition of 2-oleoylglycerol hydrolytic activity and alterations of 2-AG in the spinal cord after JZL 184 were also assessed.. Spinal JZL184 dose-dependently inhibited mechanically evoked responses of wide dynamic range (WDR) neurones in naïve anaesthetized rats, in part via the CB(1) receptor. A single spinal administration of JZL184 abolished inflammation-induced expansion of the receptive fields of spinal WDR neurones. However, neither spinal nor systemic JZL184 altered levels of 2-AG, or 2-oleoylglycerol hydrolytic activity in the spinal cord, although JZL184 displayed robust inhibition of MAGL when incubated with spinal cord tissue in vitro.. JZL184 exerted robust anti-nociceptive effects at the level of the spinal cord in vivo and inhibited rat spinal cord MAGL activity in vitro. The discordance between in vivo and in vitro assays suggests that localized sites of action of JZL184 produce these profound functional inhibitory effects.. This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.167.issue-8.

Topics: Amidohydrolases; Analgesics; Animals; Anti-Inflammatory Agents; Arachidonic Acids; Benzodioxoles; Carrageenan; Central Nervous System Sensitization; Drug Administration Routes; Endocannabinoids; Ethanolamines; Glycerides; Inflammation; Lipoprotein Lipase; Male; Mice; Mice, Inbred C57BL; Monoacylglycerol Lipases; Pain; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Species Specificity; Spinal Cord

JAK inhibitors have been developed as antiinflammatory and immunosuppressive agents and are currently undergoing testing in clinical trials. The JAK inhibitors CP-690,550 (tofacitinib) and INCB018424 (ruxolitinib) have demonstrated clinical efficacy in rheumatoid arthritis (RA). However, the mechanisms that mediate the beneficial actions of these compounds are not known. The purpose of this study was to examine the effects of both JAK inhibitors on inflammatory and tumor necrosis factor (TNF) responses in human macrophages.. In vitro studies were performed using peripheral blood macrophages derived from healthy donors and treated with TNF and using synovial fluid macrophages derived from patients with RA. Levels of activated STAT proteins and other transcription factors were detected by Western blotting, and gene expression was measured by real-time polymerase chain reaction analysis. The in vivo effects of JAK inhibitors were evaluated in the K/BxN serum-transfer model of arthritis.. JAK inhibitors suppressed the activation and expression of STAT-1 and downstream inflammatory target genes in TNF-stimulated and RA synovial macrophages. In addition, JAK inhibitors decreased nuclear localization of NF-κB subunits in TNF-stimulated and RA synovial macrophages. CP-690,550 significantly decreased the expression of interleukin-6 in synovial macrophages. JAK inhibitors augmented nuclear levels of NF-ATc1 and cJun, followed by increased formation of osteoclast-like cells. CP-690,550 strongly suppressed K/BxN serum-transfer arthritis, which is dependent on macrophages, but not lymphocytes.. Our findings demonstrate that JAK inhibitors suppress macrophage activation and attenuate TNF responses and further suggest that suppression of cytokine/chemokine production and innate immunity contribute to the therapeutic efficacy of JAK inhibitors.

Topics: Animals; Arthritis, Rheumatoid; Cells, Cultured; Disease Models, Animal; Enzyme Inhibitors; Humans; In Vitro Techniques; Inflammation; Interleukin-6; Janus Kinases; Macrophages; Mice; Mice, Inbred C57BL; NF-kappa B; NFATC Transcription Factors; Nitriles; Piperidines; Proto-Oncogene Proteins c-jun; Pyrazoles; Pyrimidines; Pyrroles; Signal Transduction; STAT1 Transcription Factor; Synovial Membrane; Tumor Necrosis Factor-alpha

The voltage-gated calcium channel Ca(v)2.2 (N-type calcium channel) is a critical regulator of synaptic transmission and has emerged as an attractive target for the treatment of chronic pain. We report here the discovery of sulfonamide-derived, state-dependent inhibitors of Ca(v)2.2. In particular, 19 is an inhibitor of Ca(v)2.2 that is selective over cardiac ion channels, with a good preclinical PK and biodistribution profile. This compound exhibits dose-dependent efficacy in preclinical models of inflammatory hyperalgesia and neuropathic allodynia and is devoid of ancillary cardiovascular or CNS pharmacology at the doses tested. Importantly, 19 exhibited no efficacy in Ca(v)2.2 gene-deleted mice. The discovery of metabolite 26 confounds further development of members of this aminopiperidine sulfonamide series. This discovery also suggests specific structural liabilities of this class of compounds that must be addressed.

Topics: Animals; Calcium Channel Blockers; Calcium Channels, N-Type; Cells, Cultured; Chronic Pain; Dogs; Humans; Hyperalgesia; Inflammation; Mice; Mice, Knockout; Microsomes, Liver; Neuralgia; Patch-Clamp Techniques; Piperidines; Rats; Rats, Sprague-Dawley; Sulfonamides; Tissue Distribution

The aim of this study was to determine whether peripheral N-methyl-d-aspartate (NMDA) receptors are involved in inflammation-induced mechanical hypersensitivity of the temporomandibular joint (TMJ) region. We developed a rat model of mechanical sensitivity to Complete Freund's Adjuvant (CFA; 2μl containing 1μg Mycobacterium tuberculosis)-induced inflammation of the TMJ and examined changes in sensitivity following injection of NMDA receptor antagonists (dl-2-amino-5-phosphonovaleric acid (AP5) or Ifenprodil) with CFA. CFA injected into the TMJ resulted in an increase in mechanical sensitivity relative to pre-injection that peaked at day 1 and lasted for up to 3days (n=8, P<0.05). There was no change in mechanical sensitivity in vehicle-injected rats at any time-point (n=9). At day 1, there was a significant increase in mechanical sensitivity in animals injected with CFA+vehicle (n=7) relative to those injected with vehicle alone (n=7, P<0.05), and co-injection of AP5 (n=6) or Ifenprodil (n=7) with CFA blocked this hypersensitivity. Subcutaneous injection of AP5 (n=7) and Ifenprodil (n=5) instead of into the TMJ had no significant effect on CFA-induced hypersensitivity of the TMJ region. Western blot analysis revealed constitutive expression of the NR1 and NR2B subunits in trigeminal ganglion lysates. Immunohistochemical studies showed that 99% and 28% of trigeminal ganglion neurons that innervated the TMJ contained the NR1 and NR2B subunits respectively. Our findings suggest a role for peripheral NMDA receptors in inflammation-induced pain of the TMJ region. Targeting peripheral NMDA receptors with peripheral application of NMDA receptor antagonists could provide therapeutic benefit and avoid side effects associated with blockade of NMDA receptors in the central nervous system.

Topics: Analysis of Variance; Animals; Blotting, Western; Excitatory Amino Acid Antagonists; Hyperalgesia; Immunohistochemistry; Inflammation; Male; Pain Measurement; Physical Stimulation; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Temporomandibular Joint

We studied whether cannabinoid receptor (CB1) blockade with rimonabant has an anti-inflammatory effect in obese mice, and whether this effect depends on weight loss and/or diet consumption. High-fat diet (HFD)-induced obese mice were treated orally with rimonabant (HFD-R) or vehicle (HFD-V) for 4 weeks. Paired-feeding was conducted in two additional groups of obese mice to achieve either the same body weight (HFD-BW) or the same HFD intake (HFD DI) as HFD-R. All these groups of mice were maintained on HFD throughout, with mice on normal diet (ND) throughout as lean controls. Rimonabant treatment of obese mice induced marked diet-intake reduction and weight loss during the first week, which was followed by maintenance of low body weight but not diet-intake reduction. Lower HFD intake was required to reach the same degree of weight loss in HFD-BW. HFD-DI had similar weight loss initially, but then started to gain weight, reaching a higher body weight than HFD-R. Despite the same degree of weight loss, HFD-R had less fat mass and lower adipogenic gene expression than HFD-BW. Compared to HFD-V or HFD-DI, HFD-R had reduced inflammation in adipose tissue (AT) and/or liver indicated primarily by lower monocyte chemoattractant protein-1 (MCP-1) levels. However, MCP-1 levels were not significantly different between HFD-R and HFD-BW. In vitro incubation of rimonabant with AT explants did not change MCP-1 levels. Thus, rimonabant induced weight loss in obese mice by diet-intake-dependent and -independent fashions. Rimonabant decreased inflammation in obese mice, possibly through a primary effect on weight reduction.

Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Chemokine CCL2; Diet; Dietary Fats; Disease Models, Animal; Energy Intake; Inflammation; Liver; Mice; Mice, Inbred C57BL; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Weight Gain; Weight Loss

Long-term treatment with haloperidol is associated with a number of extrapyramidal side effects, particularly the irregular movements of chorionic type. This limitation presents a marked therapeutic challenge. The present study investigates the molecular etiology of haloperidol neurotoxicity and the role of curcumin, a well-known anti-oxidant, in ameliorating these adverse effects. The redox status of haloperidol-treated brains along with NO, TNF-α, NF-kappaB p65 subunit, caspase-3, and monoamine neurotransmitters were measured in the striatum of rat brain. Chronic treatment with haloperidol (5 mg/kg, i.p., 21 days) produced orofacial dyskinetic movements which were coupled with marked increase in oxidative stress parameters, TNF-α, caspase-3 activity in cytoplasmic lysate and active p65 sub unit of NF-kappaB in nuclear lysates of the striatum. Neurochemically, chronic administration of haloperidol resulted in a significant decrease in the levels of norepinephrine, dopamine, and serotonin. The prototype atypical anti-psychotic, clozapine (10 mg/kg, i.p., 21 days) produced mild oxidative stress but did not alter any other parameters. Interestingly, co-administration of curcumin (25 and 50 mg/kg, i.p., 21 days) dose-dependently prevented all the behavioral, cellular, and neurochemical changes associated with the chronic administration of haloperidol. Curcumin per se (50 mg/kg) did not show any side effects. Co-administration of piperine significantly enhanced the effect of curcumin (25 mg/kg) but not of curcumin (50 mg/kg). Collectively, the data indicated the potential of curcumin as an adjunct to haloperidol treatment and provided initial clues to the underlying molecular mechanisms in haloperidol neurotoxicity. This study also provides a rationale for the combination of piperine and curcumin.

Topics: Alkaloids; Analysis of Variance; Animals; Apoptosis; Behavior, Animal; Benzodioxoles; Caspase 3; Colorimetry; Curcumin; Cytokines; Disease Models, Animal; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Haloperidol; Inflammation; Male; Neuroprotective Agents; Neurotoxicity Syndromes; Neurotransmitter Agents; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Statistics as Topic; Thiobarbituric Acid Reactive Substances

The cyclin-dependent kinase (CDK) inhibitor flavopiridol is currently being tested in clinical trials as anticancer drug. Beyond its cell death-inducing action, we hypothesized that flavopiridol affects inflammatory processes. Therefore, we elucidated the action of flavopiridol on leukocyte-endothelial cell interaction and endothelial activation in vivo and in vitro and studied the underlying molecular mechanisms.. Flavopiridol suppressed concanavalin A-induced hepatitis and neutrophil infiltration into liver tissue. Flavopiridol also inhibited tumor necrosis factor-α-induced leukocyte-endothelial cell interaction in the mouse cremaster muscle. Endothelial cells were found to be the major target of flavopiridol, which blocked the expression of endothelial cell adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin), as well as NF-κB-dependent transcription. Flavopiridol did not affect inhibitor of κB (IκB) kinase, the degradation and phosphorylation of IκBα, nuclear translocation of p65, or nuclear factor-κB (NF-κB) DNA-binding activity. By performing a cellular kinome array and a kinase activity panel, we found LIM domain kinase-1 (LIMK1), casein kinase 2, c-Jun N-terminal kinase (JNK), protein kinase C (PKC), CDK4, CDK6, CDK8, and CDK9 to be influenced by flavopiridol. Using specific inhibitors, as well as RNA interference (RNAi), we revealed that only CDK9 is responsible for the action of flavopiridol.. Our study highlights flavopiridol as a promising antiinflammatory compound and inhibition of CDK9 as a novel approach for the treatment of inflammation-associated diseases.

Topics: Animals; Cell Adhesion; Cell Communication; Cell Movement; Cells, Cultured; Chemical and Drug Induced Liver Injury; Concanavalin A; Cyclin-Dependent Kinase 9; Disease Models, Animal; E-Selectin; Endothelium, Vascular; Flavonoids; Humans; Inflammation; Intercellular Adhesion Molecule-1; Leukocytes; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Piperidines; Protein Kinase Inhibitors; Vascular Cell Adhesion Molecule-1

Topics: Butyrophenones; Cells, Cultured; Granulocyte-Macrophage Colony-Stimulating Factor; Histamine; Histamine H1 Antagonists; Humans; Inflammation; Inflammation Mediators; Interleukin-17; Interleukin-8; Keratinocytes; Piperidines; Receptors, Histamine H1; Tumor Necrosis Factor-alpha

Pathological changes identified in different tissues in hyperglycemic state are undoubtedly connected with increased oxidative/nitrosative stress and inflammation. In our study myeloperoxidase (MPO), nitrotyrosine and lipid peroxidation were enhanced in the heart and lung of alloxan-treated hyperglycemic animals. Additionally, pulmonary aconitase was inhibited. In the testis the changes occurred as an increase of MPO and lipid peroxidation, and as a decrease of aconitase. The effects of two different antidiabetics, the peroxisome proliferator activated receptor gamma (PPARγ) agonist, pioglitazone, and a short acting insulin secretagogue, repaglinide, on the mentioned parameters, were investigated and compared. The insulin deficient alloxan-induced hyperglycemic animals were used to differentiate a direct anti-oxidative effect of the drugs from secondary effects mediated via increased insulin sensitivity or secretion. Pioglitazone acted by normalization of pulmonary and testicular aconitase, normalization of pulmonary and cardiac nitrotyrosine, reduction of pulmonary and testicular MPO, and by reduction of lipid peroxidation in all tissues examined. Repaglinide prevented oxidative changes by normalization of aconitase activity in the lung and testis, and by reduction of lipid peroxidation and nitrotyrosine in the heart and lung. At the same time, no effect of this drug on MPO was observed. Finally, principal component analysis was performed to explore and visualize similarities and differences of the results obtained for the both drugs.

Topics: Aconitate Hydratase; Administration, Oral; Alloxan; Animals; Blood Glucose; Body Weight; Carbamates; Enzyme Activation; Hyperglycemia; Hypoglycemic Agents; Inflammation; Insulin; Lipid Peroxidation; Male; Oxidative Stress; Pioglitazone; Piperidines; Rabbits; Reactive Nitrogen Species; Thiazolidinediones

Fat Aussie mice (foz/foz) are morbidly obese, glucose intolerant and have liver steatosis that develops into steatohepatitis on a high-fat diet. The cannabinoid 1 receptor (CB1) antagonist SR141716 has been shown to improve obesity-associated metabolic complications in humans and rodent models. The aim of this study was to assess the effect of SR141716 in foz/foz mice.. Male wildtype (WT) and foz/foz mice were fed a chow or high-fat diet (45% saturated fat). Vehicle or SR141716 (10 mg kg(-1) per day) was administered in jelly once daily for 4 weeks from 4 months of age.. Foz/foz mice were obese but had less epididymal adipose tissue mass than fat-fed WT mice despite being significantly heavier. Liver weight was increased by twofold in foz/foz compared with WT mice and showed significant steatogenesis associated with impaired liver function. Foz/foz and fat-fed WT mice were glucose intolerant as determined by oral glucose tolerance test. In chow-fed foz/foz mice, SR141716 reduced body weight, liver weight, reversed hepatosteatosis and glucose intolerance. Subcutaneous white adipose tissue gene expression of the macrophage-specific marker Cd68 reflected the improvements in the metabolic status by SR141716 in these mice.. The results are consistent with the hypothesis that foz/foz mice have defective lipid metabolism, are unable to adequately store fat in adipose tissue but instead sequester fat ectopically in other metabolic tissues (liver) leading to insulin resistance and hepatic steatosis associated with inflammation. Our findings suggest that SR141716 can improve liver lipid metabolism in foz/foz mice in line with improved insulin sensitivity and adipose tissue inflammation.

Topics: Adipose Tissue; Animals; Diet, High-Fat; Disease Models, Animal; Fatty Liver; Glucose Intolerance; Glucose Tolerance Test; Inflammation; Insulin Resistance; Lipid Metabolism; Liver; Male; Mice; Obesity, Morbid; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

To assess the ability of pre-B cell colony-enhancing factor (PBEF) to regulate inflammation and degradative processes in inflammatory arthritis, using the small molecule inhibitor APO866 in human fibroblasts in vitro and in murine collagen-induced arthritis (CIA).. Enzyme-linked immunosorbent assays were used to examine regulation of expression of metalloproteinases and chemokines in human fibroblasts. The role of PBEF was further examined using APO866 in mice with CIA, with effects on disease activity assessed using radiography, histology, in vivo imaging, and quantitative polymerase chain reaction (qPCR).. In vitro activation of human fibroblasts with PBEF promoted expression of matrix metalloproteinase 3 (MMP-3), CCL2, and CXCL8, an effect inhibited by APO866. In mice with CIA, early intervention with APO866 inhibited synovial inflammation, including chemokine-directed leukocyte infiltration, and reduced a systemic marker of inflammation, serum hyaluronic acid. APO866 blockade led to reduced expression of MMP-3 and MMP-13 in joint extracts and to a reduction in a systemic marker of cartilage erosion, serum cartilage oligomeric matrix protein. Radiologic images revealed that APO866 protected against bone erosion, while qPCR demonstrated inhibition of RANKL expression. In mice with established disease, APO866 reduced synovial inflammation and cartilage destruction, and halted bone erosion. In addition, APO866 reduced the activity of MMP-3, CCL2, and RANKL in vivo, and inhibited production of CCL2 and RANKL in synovial explants from arthritic mice, a result that was reversed with nicotinamide mononucleotide.. These findings confirm PBEF to be an important regulator of inflammation, cartilage catabolism, and bone erosion, and highlight APO866 as a promising therapeutic agent for targeting PBEF activity in inflammatory arthritis.

Topics: Acrylamides; Animals; Arthritis, Experimental; Cartilage; Fibroblasts; Humans; Inflammation; Leukocytes; Mice; Nicotinamide Phosphoribosyltransferase; Piperidines

The inflammatory response plays an important role in the pathogenesis of many diseases in the central nervous system. Cannabinoids exhibit diverse pharmacological actions including anti-inflammatory activity. In this study, we tried to elucidate possible effects of cannabinoids on lipopolysaccharide (LPS)-induced expression of inflammatory cytokine mRNAs in rat cerebellar granule cells.. Inhibitory effects of cannabinoids on cytokine induction in cerebellar granule cells were determined by RT-PCR method.. In these cells, both mRNA and protein of cannabinoid receptor 1 (CB(1) ), but not CB(2) , were expressed. LPS (1 µg/ml) produced a marked increase in the induction of inflammatory cytokines, including interleukin-1β, interleukin-6 and tumour necrosis factor-α. CP55940, a synthetic cannabinoid analogue, concentration-dependently inhibited inflammatory cytokine expression induced by LPS. On the other hand, the endocannabinoids 2-arachidonoylglycerol and anandamide were not able to inhibit this inflammatory response. Notably, a CB(1) /CB(2) antagonist NESS0327 (3 µm) did not reverse the inhibition of cytokine mRNA expression induced by CP55940. GPR55, a putative novel cannabinoid receptor, mRNA was also expressed in cerebellar granule cells. Although it has been suggested that G(q) associates with GPR55, cannabinoids including CP55940 did not promote phosphoinositide hydrolysis and consequent elevation of intracellular Ca([2+]) concentration. Furthermore, a putative GPR55 antagonist, cannabidiol, also showed a similar inhibitory effect to that of CP55940.. These results suggest that the synthetic cannabinoid CP55940 negatively modulates cytokine mRNA expression in cerebellar granule cells by a CB and GPR55 receptor-independent mechanism.

Topics: Animals; Anti-Inflammatory Agents; Arachidonic Acids; Calcium; Cannabidiol; Cannabinoid Receptor Antagonists; Cannabinoid Receptor Modulators; Cannabinoids; Cerebellum; Cyclohexanols; Cytokines; Dose-Response Relationship, Drug; Endocannabinoids; Glycerides; Inflammation; Lipopolysaccharides; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptors, Cannabinoid; Receptors, G-Protein-Coupled; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Endocannabinoids have both anti-inflammatory and neuroprotective properties against harmful stimuli. We previously demonstrated that the endocannabinoid 2-arachidonoylglycerol (2-AG) protects hippocampal neurons by limiting the inflammatory response via a CB(1) receptor-dependent MAPK/NF-κB signalling pathway. The purpose of the present study was to determine whether PPARγ, an important nuclear receptor, mediates 2-AG-induced inhibition of NF-κB phosphorylation and COX-2 expression, and COX-2-enhanced miniature spontaneous excitatory postsynaptic currents (mEPSCs).. By using a whole-cell patch clamp electrophysiological recording technique and immunoblot analysis, we determined mEPSCs, expression of COX-2 and PPARγ, and phosphorylation of NF-kB in mouse hippocampal neurons in culture.. Exogenous and endogenous 2-AG-produced suppressions of NF-κB-p65 phosphorylation, COX-2 expression and excitatory synaptic transmission in response to pro-inflammatory interleukin-1β (IL-1β) and LPS were inhibited by GW9662, a selective PPARγ antagonist, in hippocampal neurons in culture. PPARγ agonists 15-deoxy-Δ(12,14) -prostaglandin J(2) (15d-PGJ(2)) and rosiglitazone mimicked the effects of 2-AG on NF-κB-p65 phosphorylation, COX-2 expression and mEPSCs, and these effects were eliminated by antagonism of PPARγ. Moreover, exogenous application of 2-AG or elevation of endogenous 2-AG by inhibiting its hydrolysis with URB602 or JZL184, selective inhibitors of monoacylglycerol lipase (MAGL), prevented the IL-1β- and LPS-induced reduction of PPARγ expression. The 2-AG restoration of the reduced PPARγ expression was blocked or attenuated by pharmacological or genetic inhibition of the CB(1) receptor.. Our results suggest that CB(1) receptor-dependent PPARγ expression is an important and novel signalling pathway in endocannabinoid 2-AG-produced resolution of neuroinflammation in response to pro-inflammatory insults.

Topics: Anilides; Animals; Arachidonic Acids; Benzodioxoles; Biphenyl Compounds; Cannabinoid Receptor Modulators; Cells, Cultured; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Endocannabinoids; Excitatory Postsynaptic Potentials; Glycerides; Hippocampus; Inflammation; Interleukin-1beta; Lipopolysaccharides; Mice; Monoacylglycerol Lipases; Neurons; NF-kappa B; Phosphorylation; Piperidines; PPAR gamma; Prostaglandin D2; Receptor, Cannabinoid, CB1; Rosiglitazone; Signal Transduction; Synaptic Transmission; Thiazolidinediones

The endogenous cannabinoid (endocannabinoid) anandamide is principally degraded by the integral membrane enzyme fatty acid amide hydrolase (FAAH). Pharmacological blockade of FAAH has emerged as a potentially attractive strategy for augmenting endocannabinoid signaling and retaining the beneficial effects of cannabinoid receptor activation, while avoiding the undesirable side effects, such as weight gain and impairments in cognition and motor control, observed with direct cannabinoid receptor 1 agonists. Here, we report the detailed mechanistic and pharmacological characterization of N-pyridazin-3-yl-4-(3-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzylidene)piperidine-1-carboxamide (PF-04457845), a highly efficacious and selective FAAH inhibitor. Mechanistic studies confirm that PF-04457845 is a time-dependent, covalent FAAH inhibitor that carbamylates FAAH's catalytic serine nucleophile. PF-04457845 inhibits human FAAH with high potency (k(inact)/K(i) = 40,300 M(-1)s(-1); IC(50) = 7.2 nM) and is exquisitely selective in vivo as determined by activity-based protein profiling. Oral administration of PF-04457845 produced potent antinociceptive effects in both inflammatory [complete Freund's adjuvant (CFA)] and noninflammatory (monosodium iodoacetate) pain models in rats, with a minimum effective dose of 0.1 mg/kg (CFA model). PF-04457845 displayed a long duration of action as a single oral administration at 1 mg/kg showed in vivo efficacy for 24 h with a concomitant near-complete inhibition of FAAH activity and maximal sustained elevation of anandamide in brain. Significantly, PF-04457845-treated mice at 10 mg/kg elicited no effect in motility, catalepsy, and body temperature. Based on its exceptional selectivity and in vivo efficacy, combined with long duration of action and optimal pharmacokinetic properties, PF-04457845 is a clinical candidate for the treatment of pain and other nervous system disorders.

Topics: Amidohydrolases; Animals; Enzyme Inhibitors; Humans; Inflammation; Male; Mice; Mice, Inbred C57BL; Pain; Piperidines; Pyridazines; Rats; Rats, Sprague-Dawley; Urea

Inflammatory bowel diseases (IBDs) are chronic inflammatory conditions for which new therapeutic approaches are needed. Genetic and pharmacological data point to a protective role of CB(1) and CB(2) cannabinoid receptor activation in IBD experimental models. Therefore, increasing the endogenous levels of 2-arachidonoylglycerol, the main full agonist of these receptors, should have beneficial effects on colitis. 2-Arachidonoylglycerol levels were raised in the trinitrobenzene sulfonic acid (TNBS)-induced colitis mouse model by inhibiting monoacylglycerol lipase (MAGL), the primary enzyme responsible for hydrolysis of 2-arachidonoylglycerol, using the selective inhibitor JZL184. MAGL inhibition in diseased mice increased 2-arachidonoylglycerol levels, leading to a reduction of macroscopic and histological colon alterations, as well as of colonic expression of proinflammatory cytokines. The restored integrity of the intestinal barrier function after MAGL inhibition resulted in reduced endotoxemia as well as reduced peripheral and brain inflammation. Coadministration of either CB(1) (SR141716A) or CB(2) (AM630) selective antagonists with JZL184 completely abolished the protective effect of MAGL inhibition on TNBS-induced colon alterations, thus demonstrating the involvement of both cannabinoid receptors. In conclusion, increasing 2-arachidonoylglycerol levels resulted in a dramatic reduction of colitis and of the related systemic and central inflammation. This could offer a novel pharmacological approach for the treatment of IBD based on the new protective role of 2-arachidonoylglycerol described here.

Topics: Animals; Arachidonic Acids; Benzodioxoles; Colitis; Disease Models, Animal; Endocannabinoids; Endotoxemia; Enzyme Inhibitors; Glycerides; Humans; Indoles; Inflammation; Inflammation Mediators; Inflammatory Bowel Diseases; Male; Mice; Mice, Inbred C57BL; Monoacylglycerol Lipases; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant; Trinitrobenzenesulfonic Acid

Retinol-binding protein 4 (RBP4) is an adipocyte-secreted hormone proposed to link obesity with insulin resistance. However, the role of RBP4 in cardiovascular complications is yet to be fully understood. The present study is aimed to decipher the association between RBP4 with pro-inflammatory cytokines and low-density lipoprotein (LDL) cholesterol in diet-induced obese and hyperlipidaemic mice. To understand the correlation, rimonabant, an anti-obesity drug, has been used to relieve the atherosclerotic predisposition.. Adipose and/or aortic tissue expressions of RBP4, pro-inflammatory cytokine genes and circulating LDL levels were measured in high fat (HF)-fed female C57BL/6 and high cholesterol (HC)-fed apolipoprotein E3 (ApoE3) Leiden mice.. Mice fed a HF diet had a significantly increased adipose expression of RBP4, TNF-α and monocyte chemoattractant protein 1 (MCP-1) and down-regulated adiponectin mRNA levels. A significant increase in aortic RBP4 and MCP-1 expression and circulating levels of LDL and C-reactive protein (CRP) was found in the ApoE3 mice fed a HC diet. Interestingly, rimonabant treatment lowered the elevated aortic RBP4, MCP-1 expressions and significantly reduced the serum levels of LDL, CRP, RBP4 and MCP-1.. Our results indicate that RBP4 is positively associated with markers of inflammation in obese and pro-atherogenic conditions and could play a role in a predisposition to atherosclerosis. Furthermore, our results indicate that rimonabant may improve vascular function by modulating RBP4 along with pro-inflammatory cytokines.

Topics: 3T3-L1 Cells; Adipokines; Animals; Apolipoprotein E3; Atherosclerosis; Base Sequence; Cardiovascular Diseases; Cholesterol; DNA Primers; Female; Gene Expression Regulation; Hypercholesterolemia; Inflammation; Mice; Mice, Inbred C57BL; Obesity; Piperidines; Pyrazoles; Real-Time Polymerase Chain Reaction; Retinol-Binding Proteins, Plasma; Rimonabant

This study was to investigate the effects of the novel cannabinoid receptor - G protein-coupled receptor 55 (GPR55) - and its ligands O-1602 and cannabidiol (CBD) on gastrointestinal (GI) motility in rodents.. Lipopolysaccharide (LPS) was used in vivo to produce the model of septic ileus. The intestinal motility was measured by recording myoelectrical activity of jejunum in rats, and by measuring GI transit with a charcoal marker in mice, in presence of O-1602 or CBD. Inflammatory response was assessed serologically and histologically. The expression and distribution of GPR55 in the different parts of rat intestine were investigated by real-time PCR and immunohistochemistry. In vitro, the effects of the drugs on the GI movement were investigated by measuring the contraction of the intestinal muscle strips in organ bath, and the intracellular responses of the muscle cells with microelectrode technique.. G protein-coupled receptor 55 was expressed in different parts of rat intestine. Lipopolysaccharide significantly inhibited the intestinal motility, increased inflammatory cytokines and GPR55 expression. Pretreatment with CBD normalized LPS-induced hypomotility and improved the inflammatory responses serologically and histologically. Both O-1602 and CBD counteracted LPS-induced disturbances of the gut contraction, but had no effect on the membrane potential of the muscle cells, while cannabinoid type 1 receptor antagonist AM251 and cannabinoid type 2 receptor antagonist AM630 increased the potential.. G protein-coupled receptor 55 existed throughout the whole intestine of rats. O-1602 or CBD selectively normalized the motility disturbances. Possible mechanisms involved systemic anti-inflammation and the regulation of myoelectrical activity of the intestine.

Topics: Animals; Cannabidiol; Electromyography; Gastrointestinal Motility; Gastrointestinal Transit; Indoles; Inflammation; Interleukin-6; Intestines; Ligands; Lipopolysaccharides; Membrane Potentials; Mice; Mice, Inbred C57BL; Myocytes, Smooth Muscle; Piperidines; Pyrazoles; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, Cannabinoid; Receptors, G-Protein-Coupled; Tumor Necrosis Factor-alpha

Roxatidine is a novel, specific, competitive H(2) -receptor antagonist that is used to treat gastric and duodenal ulcers, and which is known to suppress the growth of several tumors by reducing vascular endothelial growth factor (VEGF) expression. Nevertheless, it remains unclear whether roxatidine has anti-inflammatory effects. In this study, we the authors investigated the anti-inflammatory effect of roxatidine in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells. It was found that roxatidine dose-dependently inhibited the productions of prostaglandin E(2) (PGE(2)), nitric oxide (NO), and histamine, and the protein and mRNA expressions of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and histidine decarboxylase (HDC). In addition, roxatidine reduced the productions and expressions of VEGF-1 and pro-inflammatory cytokines, including those of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). Electrophoretic mobility shift assays (EMSA) and reporter gene assays revealed that treatment with roxatidine attenuated the LPS-induced DNA-binding and transcriptional activity of nuclear factor kappa B (NF-κB). In addition, it was found that pretreatment with roxatidine significantly inhibited the nuclear translocations of the p65 and p50 subunits of NF-κB, and these inhibitions were not found to be associated with decreases in the phosphorylation or degradation of inhibitory kappa B-α (IκBα). Furthermore, roxatidine suppressed the phosphorylation of p38 MAP kinase, but not of IκB kinase-α/β (IKKα/β), c-Jun NH(2) -terminal kinase (JNK), or extracellular signal-regulated kinase (ERK). Taken together, these results indicate that the anti-inflammatory properties of roxatidine in LPS-treated RAW 264.7 macrophages are mediated by the inhibition of NF-κB transcriptional activity and the p38 MAP kinase pathway.

Topics: Animals; Cell Line; Electrophoretic Mobility Shift Assay; Histamine H2 Antagonists; Humans; Inflammation; Lipopolysaccharides; Macrophages; Mice; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Piperidines; Reverse Transcriptase Polymerase Chain Reaction

The cannabinoid system (CS) is implicated in the regulation of hepatic fibrosis, steatosis and inflammation, with cannabinoid receptors 1 and 2 (CB1 and CB2) being involved in regulation of pro- and antifibrogenic effects. Daily cannabis smoking is an independent risk factor for the progression of fibrosis in chronic hepatitis C and a mediator of experimental alcoholic steatosis. However, the role and function of CS in alcoholic liver fibrosis (ALF) is unknown so far. Thus, human liver samples from patients with alcoholic liver disease (ALD) were collected for analysis of CB1 expression. In vitro, hepatic stellate cells (HSC) underwent treatment with acetaldehyde, Δ9-tetrahydrocannabinol H₂O₂, endo- and exocannabinoids (2-arachidonoylglycerol (2-AG) and [THC]), and CB1 antagonist SR141716 (rimonabant). In vivo, CB1 knockout (KO) mice received thioacetamide (TAA)/ethanol (EtOH) to induce fibrosis. As a result, in human ALD, CB1 expression was restricted to areas with advanced fibrosis only. In vitro, acetaldehyde, H₂O₂, as well as 2-AG and THC, alone or in combination with acetaldehyde, induced CB1 mRNA expression, whereas CB1 blockage with SR141716 dose-dependently inhibited HSC proliferation and downregulated mRNA expression of fibrosis-mediated genes PCα1(I), TIMP-1 and MMP-13. This was paralleled by marked cytotoxicity of SR141716 at high doses (5-10 μmol/L). In vivo, CB1 knockout mice showed marked resistance to alcoholic liver fibrosis. In conclusion, CB1 expression is upregulated in human ALF, which is at least in part triggered by acetaldehyde (AA) and oxidative stress. Inhibition of CB1 by SR141716, or via genetic knock-out protects against alcoholic-induced fibrosis in vitro and in vivo.

Topics: Acetaldehyde; Animals; Apoptosis; Cannabinoids; Cell Hypoxia; Cell Proliferation; Collagen; Female; Hepatic Stellate Cells; Humans; Hydrogen Peroxide; Inflammation; Liver; Liver Cirrhosis, Alcoholic; Male; Matrix Metalloproteinases; Mice; Middle Aged; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant; RNA, Messenger; Up-Regulation

Nucleus cuneiformis (NCF) along with periaqueductal gray (PAG) and rostral ventromedial medulla (RVM) is a part of descending system for pain modulation. Cannabinoids have analgesic effects on the PAG and RVM. This study investigates the possible role of cannabinoids in pain modulation in the NCF. Cannabinoid agonist, WIN55,212-2 (5, 10 and 20μg/0.3μl DMSO per side), and selective cannabinoid CB1 receptor antagonist, AM251(1, 5 and 10μg/0.3μl DMSO per side), were microinjected alone or in succession. As models of acute and inflammatory pain, tail-flick and formalin test were utilized to examine the effects of these drugs on pain modulation in 5min time blocks for 60min. Results of tail-flick and formalin tests demonstrated a dose-dependent analgesic effects for WIN55,212-2, with the most significant response at the dose of 20μg/side. The analgesic responses were more effective during the first 45-min period of the tail-flick test (P<0.001) and during the late phase (P<0.001) of formalin test, compared to the early phase (P<0.05). These analgesic effects were blocked in the presence of AM251 (1μg/0.3μl DMSO per side) in both tests. Administration of AM251 alone did not have any effect on nociceptive responses in either test. The cannabinoid-mediated analgesia demonstrated in this study suggests the presence of a cannabinoid-sensitive nociceptive modulatory system in the NCF.

Topics: Analgesics; Analysis of Variance; Animals; Area Under Curve; Benzoxazines; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Disease Models, Animal; Dose-Response Relationship, Drug; Formaldehyde; Hot Temperature; Inflammation; Male; Medulla Oblongata; Microinjections; Morpholines; Motor Activity; Naphthalenes; Pain; Pain Measurement; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptors, Cannabinoid; Time Factors

Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes irreversible joint damage and significant disability. However, the fundamental mechanisms underlying how inflammation and joint destruction in RA develop and are sustained chronically remain largely unknown. Here, we show that signal transducer and activator of transcription 3 (STAT3) is the key mediator of both chronic inflammation and joint destruction in RA. We found that inflammatory cytokines highly expressed in RA patients, such as IL-1β, tumor necrosis factor alpha and IL-6, activated STAT3 either directly or indirectly and in turn induced expression of IL-6 family cytokines, further activating STAT3 in murine osteoblastic and fibroblastic cells. STAT3 activation also induced expression of receptor activator of nuclear factor kappa B ligand (RANKL), a cytokine essential for osteoclastogenesis, and STAT3 deficiency or pharmacological inhibition promoted significant reduction in expression of both IL-6 family cytokines and RANKL in vitro. STAT3 inhibition was also effective in treating an RA model, collagen-induced arthritis, in vivo through significant reduction in expression of IL-6 family cytokines and RANKL, inhibiting both inflammation and joint destruction. Leukemia inhibitory factor expression and STAT3 activation by IL-1β were mainly promoted by IL-6 but still induced in IL-6-deficient cells. Thus, our data provide new insight into RA pathogenesis and provide evidence that inflammatory cytokines trigger a cytokine amplification loop via IL-6-STAT3 that promotes sustained inflammation and joint destruction.

Topics: Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Chronic Disease; Enzyme Inhibitors; Fibroblasts; Gene Expression; Humans; Inflammation; Interleukin-1beta; Interleukin-6; Joints; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Osteoclasts; Piperidines; Pyrimidines; Pyrroles; RANK Ligand; Signal Transduction; STAT3 Transcription Factor; Tumor Necrosis Factor-alpha

Postoperative stress produces an inflammatory response. Recent studies have shown that narcotic analgesics suppress the immune system. Nutritional management during perioperative care has also been reported to affect inflammation. We therefore examined whether remifentanil or glucose administration could ameliorate postsurgical inflammatory responses using a rat model of surgical stress.. We divided male Wistar rats randomly into five groups: (1) control, (2) sevoflurane+lactated Ringer's solution, (3) sevoflurane+lactated Ringer's solution with 1% glucose, (4) sevoflurane+remifentanil+lactated Ringer's solution, and (5) sevoflurane+remifentanil+ lactated Ringer's solution with 1% glucose. In all groups, serum samples were obtained at various time points after surgery, and secreted cytokine concentrations were determined. In addition, we assessed the activation of protein kinase B (Akt) and forkhead/winged helix box class O (FOXO3), which play a role in gluconeogenesis/stress responses.. Surgical stress increased the serum concentrations of tumor necrosis factor-α and interleukin-6. Groups receiving remifentanil with anesthesia showed an attenuated inflammatory response. The inflammatory response was also reduced by administering 1% glucose. Furthermore, 1% glucose induced Akt and FOXO3 phosphorylation in the quadriceps femoris muscle 12 h after surgery.. Anesthesia based on remifentanil and perioperative administration of lactated Ringer's solution containing 1% glucose may be able to control inflammatory responses caused by surgical stress.

Topics: Anesthetics, Inhalation; Animals; Blood Glucose; Forkhead Box Protein O3; Forkhead Transcription Factors; Glucose; Hypnotics and Sedatives; Inflammation; Interleukin-6; Isotonic Solutions; Male; Methyl Ethers; Models, Animal; Phosphorylation; Piperidines; Postoperative Complications; Proto-Oncogene Proteins c-akt; Quadriceps Muscle; Rats; Rats, Wistar; Remifentanil; Ringer's Lactate; Sevoflurane; Stress, Physiological; Tumor Necrosis Factor-alpha

Dipeptidyl-peptidase 4 (DPP-4) inhibitors are increasingly used to accomplish glycemic targets in patients with type II diabetes mellitus. Because DPP-4 is expressed in inflammatory cells, we hypothesized that its inhibition will exert favorable effects in atherosclerosis.. Male LDLR(-/-) mice (6 weeks) were fed a high-fat diet or normal chow diet for 4 weeks and then randomized to vehicle or alogliptin, a high-affinity DPP-4 inhibitor (40 mg · kg(-1) · d(-1)), for 12 weeks. Metabolic parameters, blood pressure, vascular function, atherosclerosis burden, and indexes of inflammation were obtained in target tissues, including the vasculature, adipose, and bone marrow, with assessment of global and cell-specific inflammatory pathways. In vitro and in vivo assays of DPP-4 inhibition (DPP-4i) on monocyte activation/migration were conducted in both human and murine cells and in a short-term ApoE(-/-) mouse model. DPP-4i improved markers of insulin resistance and reduced blood pressure. DPP-4i reduced visceral adipose tissue macrophage content (adipose tissue macrophages; CD11b(+), CD11c(+), Ly6C(hi)) concomitant with upregulation of CD163. DPP-4 was highly expressed in bone marrow-derived CD11b(+) cells, with DPP-4i downregulating proinflammatory genes in these cells. DPP-4i decreased aortic plaque with a striking reduction in plaque macrophages. DPP-4i prevented monocyte migration and actin polymerization in in vitro assays via Rac-dependent mechanisms and prevented in vivo migration of labeled monocytes to the aorta in response to exogenous tumor necrosis factor-α and DPP-4.. DPP-4i exerts antiatherosclerotic effects and reduces inflammation via inhibition of monocyte activation/chemotaxis. These findings have important implications for the use of this class of drugs in atherosclerosis.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Blood Pressure; Cell Movement; Chemotaxis; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Glucose; Inflammation; Insulin Resistance; Male; Metabolism; Mice; Mice, Knockout; Monocytes; Piperidines; Receptors, LDL; Time Factors; Uracil

Phospholipase A(2)(PLA(2)) enzymes are considered the primary source of arachidonic acid for cyclooxygenase (COX)-mediated biosynthesis of prostaglandins. Here, we show that a distinct pathway exists in brain, where monoacylglycerol lipase (MAGL) hydrolyzes the endocannabinoid 2-arachidonoylglycerol to generate a major arachidonate precursor pool for neuroinflammatory prostaglandins. MAGL-disrupted animals show neuroprotection in a parkinsonian mouse model. These animals are spared the hemorrhaging caused by COX inhibitors in the gut, where prostaglandins are instead regulated by cytosolic PLA(2). These findings identify MAGL as a distinct metabolic node that couples endocannabinoid to prostaglandin signaling networks in the nervous system and suggest that inhibition of this enzyme may be a new and potentially safer way to suppress the proinflammatory cascades that underlie neurodegenerative disorders.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Benzodioxoles; Brain; Cannabinoid Receptor Modulators; Cyclooxygenase 1; Cytokines; Eicosanoids; Endocannabinoids; Enzyme Inhibitors; Glycerides; Hydrolysis; Inflammation; Inflammation Mediators; Lipopolysaccharides; Liver; Lung; Metabolomics; Mice; Mice, Inbred C57BL; Monoacylglycerol Lipases; Neuroprotective Agents; Parkinsonian Disorders; Phospholipases A2; Piperidines; Prostaglandins; Signal Transduction

Orofacial pain disorders are frequent in the general population and their pharmacological treatment is not always adequately resolved. Cannabinoids have demonstrated their analgesic effect in several pain conditions, both in animal models and in clinical situations. The aim of the present study was to evaluate the cannabinoid-mediated antinociception in two inflammatory models of orofacial pain (orofacial and temporomandibular joint (TMJ) formalin test) and to compare it with a spinal inflammatory model (paw formalin test). WIN 55,212-2 (0.5, 1mg/kg), a synthetic cannabinoid agonist, was intraperitoneally (i.p.) administered prior to formalin and significantly reduced the nociceptive behavioural responses in these inflammatory tests. To elucidate which subtype of receptor could be involved in such effect, two selective cannabinoid antagonists were administered prior to WIN. SR141716A (1mg/kg i.p.), the CB1 receptor-selective antagonist, was able to prevent the cannabinoid-induced analgesia in all three models, whereas SR144528 (1mg/kg i.p.), the CB2 receptor-selective antagonist, only prevented it in the paw formalin test. A comparison with the antinociceptive effects of morphine (2.5, 5, 10mg/kg, i.p.), indomethacin (2.5, 5mg/kg, i.p.) and ketamine (25, 50mg/kg, i.p.) was also performed. Morphine displayed a dose-dependent reduction of acute and inflammatory pain in all three models, whereas indomethacin and ketamine only attenuated inflammatory pain at the highest tested doses. These results indicate that the cannabinoid-induced antinociception in the orofacial region is mediated by activation of CB1 cannabinoid receptor. Moreover WIN was as effective as morphine and more effective than indomethacin and ketamine, in oral inflammatory pain.

Topics: Analgesics; Analgesics, Opioid; Anesthetics, Dissociative; Animals; Anti-Inflammatory Agents, Non-Steroidal; Behavior, Animal; Benzoxazines; Camphanes; Facial Pain; Formaldehyde; Indomethacin; Inflammation; Ketamine; Male; Morphine; Morpholines; Motor Activity; Naphthalenes; Pain; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant; Temporomandibular Joint Disorders

Although neurogenic inflammation of the airways via activation of C-fibers is thought to be important in the pathogenesis of asthma, the mechanisms regulating C-fiber activity remain uncertain.. The influence of a cannabinoid receptor agonist, WIN 55,212-2, on C-fiber activation in guinea pig airways was investigated, as was the mechanism by which cannabinoids regulate antigen-induced airway inflammation.. The inhibitory effect of WIN 55,212-2 on antigen-induced plasma extravasation was assessed in guinea pig tracheal tissues by photometric measurement of extravasated Evans blue dye after extraction with formamide.. Pretreatment with WIN 55,212-2 (0.001, 0.01 or 0.1 mg/kg) significantly and dose-dependently reduced tracheal plasma extravasation induced by inhaling a 5% ovalbumin solution for 2 min after pretreatment with a neutral endopeptidedase inhibitor (phosphoramidon at 2.5 mg/kg i.v.). A cannabinoid CB2 receptor antagonist (SR144528) blunted the inhibitory effect of WIN 55,212-2, while a cannabinoid CB1 antagonist (SR141716A) did not. Pretreatment with a neurokinin-1 receptor antagonist (FK888) significantly reduced ovalbumin-induced extravasation of Evans blue dye. Pretreatment with the combination of WIN 55,212-2 and FK888 reduced antigen-induced plasma extravasation more markedly than FK888 alone.. These findings suggest that WIN 55,212-2 inhibits C-fiber activation via the cannabinoid CB2 receptor and thus suppresses antigen-induced inflammation in guinea pig airways.

Topics: Animals; Antigens; Benzoxazines; Camphanes; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Capillary Permeability; Dipeptides; Evans Blue; Extravasation of Diagnostic and Therapeutic Materials; Guinea Pigs; Immunization; Indoles; Inflammation; Male; Morpholines; Naphthalenes; Neurokinin-1 Receptor Antagonists; Ovalbumin; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Respiratory Hypersensitivity; Rimonabant; Trachea

Macrophage infiltration into adipose tissue (AT-MP) is thought to induce insulin resistance and diabetes in obesity. Here, we investigated the effect of the antiobesity drug SR141716 (a CB1 antagonist) on macrophage-mediated inhibition of insulin signaling in adipocytes. THP1 macrophages (THP1) were stimulated in vitro with lipopolysaccharide (LPS) and SR141716 or vehicle. The resulting conditioned medium (CM) was analyzed and incubated on human adipocytes. CM from LPS-stimulated THP1 inhibited insulin-induced AKT phosphorylation in adipocytes, in contrast to CM from nonactivated THP1. Moreover, it contained higher concentrations of tumor necrosis factor-α (TNFα) and lower levels of the anti-inflammatory cytokine IL-10. SR141716 reduced TNFα production and increased IL-10 secretion, resulting in a rescue of insulin signaling in adipocytes. To confirm these findings in vivo, AT-MP CM from cafeteria diet-fed or Zucker diabetic fatty (ZDF) rats that had received SR141716 for 3 weeks were isolated, analyzed, and incubated with adipocytes. Cafeteria diet induced macrophage-mediated inhibition of insulin signaling in adipocytes. Interestingly, SR141716 rescued insulin-induced glucose uptake in adipocytes. Finally, AT-MP CM from obese ZDF rats inhibited insulin-stimulated glucose uptake in adipocytes in contrast to AT-MP CM from lean ZDF rats. After treatment with SR141716, AT-MP CM rescued insulin-induced glucose uptake in adipocytes. In summary, our data indicate that CB1 receptor antagonism in macrophages modified their cytokine production and improved the insulin responsiveness of adipocytes that had been incubated with macrophage CM. Thus, SR141716 ameliorated adipose tissue insulin resistance by direct action on AT-MP demonstrating a novel peripheral mode of action of CB1 antagonism.

Topics: Adipocytes; Adipose Tissue; Animals; Anti-Obesity Agents; Blood Glucose; Cell Line; Culture Media, Conditioned; Diabetes Mellitus, Experimental; Dietary Fats; Female; Humans; Hypoglycemic Agents; Inflammation; Insulin; Insulin Resistance; Interleukin-10; Lipopolysaccharides; Macrophages; Male; Mice; Obesity; Phosphorylation; Piperidines; Pyrazoles; Rats; Rats, Wistar; Rats, Zucker; Receptor, Cannabinoid, CB1; Rimonabant; Signal Transduction; Tumor Necrosis Factor-alpha

The aim of this study is to investigate the effect of rimonabant, which has antiatherosclerotic and antiinflammatory properties, on peripheral neuropathy in a diabetic rat. Diabetic rat models were induced by treatment with streptozotocin and then either normal or diabetic rats were treated with an oral dose of 10mg/kg/day rimonabant or placebo for 24 weeks. We quantified the densities of intraepidermal (PGP9.5+) nerve fiber and total skin (RECA-1+) capillary length. We also measured the current perception threshold, as defined by the intensity of sine-wave stimulus, skin blood flow after treadmill running and TNF-alpha level in spinal cord tissue or plasma. After 24 weeks, rimonabant reduced the body weight and food intake in both diabetic and normal rats, but it had no effect on blood sugar levels. In addition, rimonabant treatment significantly improved the decreased intraepidermal nerve fiber density (5.53+/-0.12 vs. 4.36+/-0.27/mm, P<0.05) and alleviated the increased current perception threshold in rimonabant-treated versus control diabetic rats. These responses were closely associated with the attenuation of skin capillary loss (1.98+/-0.07 vs. 1.67+/-0.10 mm/mm(2), P<0.05), increase in skin blood flow (14.93+/-1.08 vs. 12.07+/-0.87 TPU, P<0.05) and reduction in TNF-alpha level in tissue (70.10+/-4.99 vs. 91.18+/-3.34 pg/mg, P<0.05) in rimonabant-treated diabetic rats compared with placebo. These findings suggest that rimonabant can be beneficial for treatment of diabetic peripheral neuropathy, possibly due to its potential role in micro- and macrovessel protection and its anti-inflammatory properties.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Disease Models, Animal; Glucose Tolerance Test; Immunohistochemistry; Inflammation; Male; Neurons; Peripheral Nerves; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Rimonabant; Skin; Streptozocin; Time Factors; Tumor Necrosis Factor-alpha

Opioids provide effective analgesia in adult patients with painful inflammatory diseases. The proposed mechanism of action is the activation of peripheral opioid receptors, which may be up-regulated in such conditions. Here, by using a chronic inflammation model, namely subplantar injection of Complete Freund's adjuvant, we show a peripheral synergistic interaction between the histamine H(3) receptor agonist R-(alpha)-methylhistamine and fentanyl on the inhibition of thermal hyperalgesia and of peripheral substance P accumulation. Firstly, dose-related effects obtained for the subplantar antinociceptive effect of fentanyl (0.05-1 microg) in the presence of a fixed dose of R-(alpha)-methylhistamine (12.5 microg) showed a shift to the left when compared to that obtained with fentanyl alone. In a similar way, the subcutaneous administration of fentanyl (0.005-0.1mg/kg) plus a fixed dose of R-(alpha)-methylhistamine (0.5mg/kg) induced a supra additive effect on the inhibition of substance P accumulation in the hind-paw skin of inflamed mice. Interestingly, when a neurokinin-1 receptor antagonist was co-administered, the antinociceptive effects of the combined treatment were potentiated. The peripheral adjuvant effect of R-(alpha)-methylhistamine on fentanyl antinociception and inhibition of substance P accumulation was also demonstrated by means of opioid and histamine H(3) receptors selective antagonists: first, naloxone blockade of fentanyl-mediated effects were partially reversed by co-administration of R-(alpha)-methylhistamine, and second, thioperamide partially antagonised the combined R-(alpha)-methylhistamine/fentanyl effects. Overall, our results clearly show that R-(alpha)-methylhistamine enhances fentanyl effects at peripheral sites, and that the control of substance P levels might be one of the mechanisms responsible of such interaction.

Topics: Analgesics; Animals; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Fentanyl; Freund's Adjuvant; Histamine Agonists; Hyperalgesia; Inflammation; Male; Methylhistamines; Mice; Naloxone; Pain; Piperidines; Receptors, Histamine H3; Skin; Substance P

Rimonabant (SR141716) is a specific antagonist of the cannabinoid-1 receptor. Activation of the receptor initiates multiple effects on central nervous system function, metabolism, and body weight. The hypothesis that rimonabant has protective effects against vascular disease associated with the metabolic syndrome was tested using JCR:LA-cp rats. JCR:LA-cp rats are obese if they are cp/cp, insulin resistant, and exhibit associated micro- and macrovascular disease with end-stage myocardial and renal disease. Treatment of obese rats with rimonabant (10 mg.kg(-1).day(-1), 12-24 wk of age) caused transient reduction in food intake for 2 wk, without reduction in body weight. However, by 4 wk, there was a modest, sustained reduction in weight gain. Glycemic control improved marginally compared with controls, but at the expense of increased insulin concentration. In contrast, rimonabant normalized fasting plasma triglyceride and reduced plasma plasminogen activator inhibitor-1 and acute phase protein haptoglobin in cp/cp rats. Furthermore, these changes were accompanied by reduced postprandial intestinal lymphatic secretion of apolipoprotein B48, cholesterol, and haptoglobin. While macrovascular dysfunction and ischemic myocardial lesion frequency were unaffected by rimonabant treatment, both microalbuminuria and glomerular sclerosis were substantially reduced. In summary, rimonabant has a modest effect on body weight in freely eating obese rats and markedly reduces plasma triglyceride levels and microvascular disease, in part due to changes in intestinal metabolism, including lymphatic secretion of apolipoprotein B48 and haptoglobin. We conclude that rimonabant improves renal disease and intestinal lipid oversecretion associated with an animal model of the metabolic syndrome that appears to be independent of hyperinsulinemia or macrovascular dysfunction.

Topics: Animals; Biomarkers; Blood Vessels; Body Weight; Cannabinoid Receptor Antagonists; Disease Models, Animal; Eating; Inflammation; Insulin Resistance; Intestinal Mucosa; Kidney Diseases; Kidney Glomerulus; Lipid Metabolism; Male; Metabolic Syndrome; Myocardial Ischemia; Piperidines; Prediabetic State; Pyrazoles; Rats; Rats, Mutant Strains; Renal Circulation; Rimonabant; Sclerosis; Thrombosis

Accumulating recent evidence suggests that cannabinoid-1 (CB(1)) receptor activation may promote inflammation and cell death and its pharmacological inhibition is associated with anti-inflammatory and tissue-protective effects in various preclinical disease models, as well as in humans.. In this study, using molecular biology and biochemistry methods, we have investigated the effects of genetic deletion or pharmacological inhibition of CB(1) receptors on inflammation, oxidative/nitrosative stress and cell death pathways associated with a clinically relevant model of nephropathy, induced by an important chemotherapeutic drug cisplatin.. Cisplatin significantly increased endocannabinoid anandamide content, activation of p38 and JNK mitogen-activated protein kinases (MAPKs), apoptotic and poly (ADP-ribose)polymerase-dependent cell death, enhanced inflammation (leucocyte infiltration, tumour necrosis factor-alpha and interleukin-1beta) and promoted oxidative/nitrosative stress [increased expressions of superoxide-generating enzymes (NOX2(gp91phox), NOX4), inducible nitric oxide synthase and tissue 4-hydroxynonenal and nitrotyrosine levels] in the kidneys of mice, accompanied by marked histopathological damage and impaired renal function (elevated creatinine and serum blood urea nitrogen) 3 days following its administration. Both genetic deletion and pharmacological inhibition of CB(1) receptors with AM281 or SR141716 markedly attenuated the cisplatin-induced renal dysfunction and interrelated oxidative/nitrosative stress, p38 and JNK MAPK activation, cell death and inflammatory response in the kidney.. The endocannabinoid system through CB(1) receptors promotes cisplatin-induced tissue injury by amplifying MAPK activation, cell death and interrelated inflammation and oxidative/nitrosative stress. These results also suggest that inhibition of CB(1) receptors may exert beneficial effects in renal (and most likely other) diseases associated with enhanced inflammation, oxidative/nitrosative stress and cell death.

Topics: Animals; Arachidonic Acids; Cell Death; Cisplatin; Disease Models, Animal; Endocannabinoids; Glycerides; Inflammation; Kidney; Male; Mice; Mice, Knockout; Morpholines; Nephritis; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Signal Transduction

In contrast to the numerous reports on the pharmacological effects of Δ(9)-tetrahydrocannabinol (THC), the pharmacological activity of another substituent of Cannabis sativa, cannabichromene (CBC) remains comparatively unknown. In the present study, we investigated whether CBC elicits cannabinoid activity in the tetrad assay, which consists of the following four endpoints: hypomotility, antinociception, catalepsy, and hypothermia. Because cannabinoids are well documented to possess anti-inflammatory properties, we examined CBC, THC, and combination of both phytocannabinoids in the lipopolysaccharide (LPS) paw edema assay. CBC elicited activity in the tetrad that was not blocked by the CB(1) receptor antagonist, rimonabant. Moreover, a behaviorally inactive dose of THC augmented the effects of CBC in the tetrad that was associated with an increase in THC brain concentrations. Both CBC and THC elicited dose-dependent anti-inflammatory effects in the LPS-induced paw edema model. The CB(2) receptor, SR144528 blocked the anti-edematous actions of THC, but not those produced by CBC. Isobolographic analysis revealed that the anti-edematous effects of these cannabinoids in combination were additive. Although CBC produced pharmacological effects, unlike THC, its underlying mechanism of action did not involve CB(1) or CB(2) receptors. In addition, there was evidence of a possible pharmacokinetic component in which CBC dose-dependently increased THC brain levels following an i.v. injection of 0.3mg/kg THC. In conclusion, CBC produced a subset of behavioral activity in the tetrad assay and reduced LPS-induced paw edema through a noncannabinoid receptor mechanism of action. These effects were augmented when CBC and THC were co-administered.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Camphanes; Cannabinoids; Cannabis; Catalepsy; Dose-Response Relationship, Drug; Dronabinol; Hallucinogens; Hypothermia; Inflammation; Male; Mice; Mice, Inbred ICR; Motor Activity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant

Piperine, a main component of Piper longum Linn. and Piper nigrum Linn., is a plant alkaloid with a long history of medical use. Piperine exhibits anti-inflammatory activity; however, the underlying mechanism remains unknown. We examined the effects of piperine on lipopolysaccharide (LPS)-induced inflammatory responses. Administration of piperine inhibited LPS-induced endotoxin shock, leukocyte accumulation and the production of tumor necrosis factor-alpha (TNF-alpha), but not of interleukin (IL)-1beta and IL-6. In peritoneal macrophages, piperine inhibited LPS/poly (I:C)/CpG-ODN-induced TNF-alpha production. Piperine also inhibited LPS-induced endotoxin shock in TNF-alpha knockout (KO) mice. To clarify the inhibitory mechanism of LPS-induced endotoxin shock, type 1 interferon (IFN) mRNA expression was determined. Piperine inhibited LPS-induced expression of type 1 IFN mRNA. Piperine inhibited the levels of interferon regulatory factor (IRF)-1 and IRF-7 mRNA, and the phosphorylation and nuclear translocation of IRF-3. Piperine also reduced activation of signal transducer and activator of transcription (STAT)-1. In addition, activation of STAT-1 was inhibited in IFN-alpha/beta-treated cells by piperine. These results suggest that piperine inhibits LPS-induced endotoxin shock through inhibition of type 1 IFN production.

Topics: Alkaloids; Animals; Benzodioxoles; Female; Gene Knockout Techniques; Inflammation; Interferon Type I; Lipopolysaccharides; Macrophages, Peritoneal; Mice; Mice, Inbred C57BL; Piperidines; Polyunsaturated Alkamides; Shock, Septic; STAT1 Transcription Factor; Tumor Necrosis Factor-alpha

Donepezil, a reversible acetylcholinesterase inhibitor, improves cognitive function of Alzheimer's disease. Stimulation of cholinergic system was reported to improve long-term survival of rats with chronic heart failure and to attenuate inflammatory response in mice with lipopolysaccharide-induced sepsis. We sought to determine whether the pharmacological stimulation of cholinergic system by donepezil reduces atherogenesis in apolipoprotein (Apo) E-knockout (KO) mice.. Male ApoE-KO mice (10-week-old) were fed a high-fat diet and received infusion of angiotensin (Ang) II (490 ng/kg/day). Donepezil or physostigmine was administered for 4 weeks. Oral administration of donepezil (5 mg/kg/day) or infusion of physostigmine (2 mg/kg/day) significantly attenuated atherogenesis (Oil Red O-positive area) without significant changes in heart rate, blood pressure and total cholesterol levels. Administration of donepezil suppressed expression of monocyte chemoattractant protein-1 and tumor necrosis factor-α, NADPH oxidase activity and production of reactive oxygen species in the aorta.. The present study revealed novel anti-oxidative and anti-atherosclerotic effects of pharmacological stimulation of cholinergic system by donepezil. Donepezil may be used as a novel therapeutics for the atherosclerotic cardiovascular diseases.

Topics: Alzheimer Disease; Animals; Apolipoproteins E; Atherosclerosis; Cardiovascular Diseases; Cholinesterase Inhibitors; Cytokines; Donepezil; Indans; Inflammation; Lipopolysaccharides; Male; Mice; Mice, Knockout; Oxidative Stress; Piperidines; Sepsis

δ-Opioid receptors are G-protein-coupled receptors that regulate nociceptive and emotional responses. It has been well established that distinct agonists acting at the same G-protein-coupled receptor can engage different signaling or regulatory responses. This concept, known as biased agonism, has important biological and therapeutic implications. Ligand-biased responses are well described in cellular models, however, demonstrating the physiological relevance of biased agonism in vivo remains a major challenge. The aim of this study was to investigate the long-term consequences of ligand-biased trafficking of the δ-opioid receptor, at both the cellular and behavioral level. We used δ agonists with similar binding and analgesic properties, but high [SNC80 ((+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide)]- or low [ARM390 (N,N-diethyl-4-(phenyl-piperidin-4-ylidenemethyl)-benzamide)]-internalization potencies. As we found previously, a single SNC80-but not ARM390-administration triggered acute desensitization of the analgesic response in mice. However, daily injections of either compound over 5 d produced full analgesic tolerance. SNC80-tolerant animals showed widespread receptor downregulation, and tolerance to analgesic, locomotor and anxiolytic effects of the agonist. Hence, internalization-dependent tolerance developed, as a result of generalized receptor degradation. In contrast, ARM390-tolerant mice showed intact receptor expression, but δ-opioid receptor coupling to Ca²+ channels was abolished in dorsal root ganglia. Concomitantly, tolerance developed for agonist-induced analgesia, but not locomotor or anxiolytic responses. Therefore, internalization-independent tolerance was produced by anatomically restricted adaptations leading to pain-specific tolerance. Hence, ligand-directed receptor trafficking of the δ-opioid receptor engages distinct adaptive responses, and this study reveals a novel aspect of biased agonism in vivo.

Topics: Analgesics; Animals; Benzamides; Brain; Calcium; Cell Membrane; Disease Models, Animal; Drug Interactions; Drug Tolerance; Female; Freund's Adjuvant; Ganglia, Spinal; Green Fluorescent Proteins; Guanosine 5'-O-(3-Thiotriphosphate); Hyperalgesia; Inflammation; Ligands; Locomotion; Male; Maze Learning; Membrane Potentials; Mice; Mice, Inbred C57BL; Mice, Transgenic; Pain; Pain Threshold; Patch-Clamp Techniques; Piperazines; Piperidines; Protein Binding; Protein Transport; Receptors, Opioid, delta; Sensory Receptor Cells; Spinal Cord; Statistics, Nonparametric; Sulfur Isotopes; Time Factors

The objective of this study was to determine whether the potent selective cannabinoid receptor-1 antagonist rimonabant has antiatherosclerotic properties.. Rimonabant (50 mg/kg/d in the diet) significantly reduced food intake (from 3.35+/-.04 to 2.80+/-0.03 g/d), weight gain (from 14.6+/-0.7 g to -0.6+/-0.3 g), serum total cholesterol (from 8.39+/-0.54 to 5.32+/-0.18 g/L), and atherosclerotic lesion development in the aorta (from 1.7+/-0.22 to 0.21+/-0.037 mm(2)) and aortic sinus (from 101,000+/-7800 to 27,000+/-2900 microm(2)) of LDLR(-/-) mice fed a Western-type diet for 3 months. Rimonabant also reduced plasma levels of the proinflammatory cytokines MCP-1 and IL12 by 85% (P<0.05) and 76% (P<0.05), respectively. Pair-fed animals had reduced weight gain (6.2+/-0.6 g gain), but developed atherosclerotic lesions which were as large as those of untreated animals, showing that the antiatherosclerotic effect of rimonabant is not related to reduced food intake. Interestingly, rimonabant at a lower dose (30 mg/kg/d in the diet) reduced atherosclerosis development in the aortic sinus (from 121,000+/-20,000 to 62,000+/-11,000 microm(2), 49% reduction, P<0.05), without affecting serum total cholesterol (7.8+/-0.7 g/L versus 8.1+/-1.3 g/L in the control group). Rimonabant decreased lipopolysaccharide (LPS)- and IL1beta-induced proinflammatory gene expression in mouse peritoneal macrophages in vitro as well as thioglycollate-induced recruitment of macrophages in vivo (10 mg/kg, p.o. bolus).. These results show that rimonabant has antiatherosclerotic effects in LDLR(-/-) mice. These effects are partly unrelated to serum cholesterol modulation and could be related to an antiinflammatory effect.

Topics: Animals; Atherosclerosis; Cannabinoids; Chemokine CCL2; Cholesterol; Cytokines; Energy Intake; Female; Inflammation; Interleukin-12; Mice; Mice, Knockout; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, LDL; Rimonabant

Temporomandibular disorders represent one of the major challenges in dentistry therapeutics. This study was undertaken to evaluate the time course of carrageenan-induced inflammation in the rat temporomandibular joint (TMJ) and to investigate the role of tachykinin NK(1) receptors. Inflammation was induced by a single intra-articular (i.art.) injection of carrageenan into the left TMJ (control group received sterile saline). Inflammatory parameters such as plasma extravasation, leukocyte influx and mechanical allodynia (measured as the head-withdrawal force threshold) and TNFalpha and IL-1beta concentrations were measured in the TMJ lavages at selected time-points. The carrageenan-induced responses were also evaluated after treatment with the NK(1) receptor antagonist SR140333. The i.art. injection of carrageenan into the TMJ caused a time-dependent plasma extravasation associated with mechanical allodynia, and a marked neutrophil accumulation between 4 and 24h. Treatment with SR140333 substantially inhibited the increase in plasma extravasation and leukocyte influx at 4 and 24h, as well as the production of TNFalpha and IL-1beta into the joint cavity, but failed to affect changes in head-withdrawal threshold. The results obtained from the present TMJ-arthritis model provide, for the first time, information regarding the time course of this experimental inflammatory process. In addition, our data show that peripheral NK(1) receptors mediate the production of both TNFalpha and IL-1beta in the TMJ as well as some of the inflammatory signs, such as plasma extravasation and leukocyte influx, but not the nociceptive component.

Topics: Animals; Carrageenan; Data Interpretation, Statistical; Extravasation of Diagnostic and Therapeutic Materials; Inflammation; Interleukin-1beta; Leukocyte Count; Male; Neurokinin-1 Receptor Antagonists; Pain; Peroxidase; Piperidines; Quinuclidines; Radiopharmaceuticals; Rats; Rats, Wistar; Receptors, Neurokinin-1; Serum Albumin, Radio-Iodinated; Substance P; Temporomandibular Joint Disorders; Tumor Necrosis Factor-alpha

Inflammation is known to be associated with changes in tachykinin expression both in human and animal models: substance P and NK(1) receptor expression are increased in patients with inflammatory bowel disease, and similar changes are reported in experimental models of inflammation. We investigated the effect of the tachykinin NK(1) receptor antagonist SR140333 (10 mg/kg orally) on 2,4-dinitrobenzene sulfonic acid (DNBS)-induced colitis in rats. Colonic damage was assessed by means of macroscopic and microscopic scores, myeloperoxidase activity (MPO) and TNF-alpha tissue levels on day 6 after induction of colitis. An enzyme immunoassay technique was used to measure colonic substance P levels. DNBS administration impaired body weight gain and markedly increased all inflammatory parameters as well as colonic tissue levels of substance P. Treatment with SR140333 significantly counteracted the impairment in body weight gain, decreased macroscopic and histological scores and reduced colonic myeloperoxidase activity and TNF-alpha tissue levels. Colonic tissue levels of substance P were also reduced by SR140333, although this effect did not reach statistical significance. In conclusion, treatment with SR140333 protects from DNBS-induced colitis in rats. These results suggest a role for NK(1) receptors and substance P in the development of intestinal inflammation and indicate tachykinin receptors as a potential pharmacological target in the treatment of inflammatory bowel disease.

Topics: Animals; Colitis; Dinitrofluorobenzene; Humans; Inflammation; Intestinal Mucosa; Intestines; Male; Piperidines; Quinuclidines; Rats; Rats, Sprague-Dawley; Receptors, Tachykinin; Substance P; Substrate Specificity; Tumor Necrosis Factor-alpha

DMTI-II is a Kunitz-type inhibitor isolated from Dimorphandra mollis seeds that causes rat inflammatory edema by mechanisms involving activation of mast cells and sensory C-fibers. The present study aimed to further explore the inflammatory mechanisms involved in DMTI-II-induced inflammation, focusing to the leukocyte migration in vivo. Male Wistar rats (250-280 g) were injected with DMTI-II (1-100microg/cavity), and at 4-24h thereafter the leukocyte counts in peritoneal lavage were evaluated. DMTI-II caused dose- and time-dependent accumulation of neutrophils and eosinophils. The peritoneal neutrophil influx initiated at 4h, achieving maximal responses at 16 h after DMTI-II injection (16- and 22-fold increase, respectively). The DMTI-II-induced eosinophil recruitment was observed as early as 4h achieving the maximal responses at 16 h (12- and 17-fold increase, respectively). The mononuclear cell number increased at 4h and 16 h (1.5-fold and 1.6-increase, respectively). Prior treatments with dexamethasone, the cyclooxygenase (COX) inhibitors indomethacin and celecoxib, as well as the PAF receptor antagonist PCA4248 largely reduced the neutrophil and eosinophil accumulation. The selective lypoxygenase inhibitor AA861, the tachykinin NK(1) antagonist SR-140333 and the nitric oxide inhibitor L-NAME reduced only the eosinophil number. The eotaxin levels were significantly higher in DMTI-II-injected rats compared with control animals. In conclusion, DMTI-II causes an early migration of eosinophils and neutrophils by mechanisms involving COX-2- and lipoxygenase-derived metabolites, PAF, substance P and NO. The capacity of DMTI-II to recruit eosinophils at early times is likely to reflect the allergen properties of proteinase inhibitors belonging to Kunitz family.

Topics: Analysis of Variance; Animals; Benzoquinones; Celecoxib; Cell Movement; Dexamethasone; Fabaceae; Indomethacin; Inflammation; Leukocytes; Male; NG-Nitroarginine Methyl Ester; Peptides; Peritoneal Lavage; Piperidines; Plant Proteins; Pyrazoles; Quinuclidines; Rats; Rats, Wistar; Seeds; Sulfonamides

We investigated the participation of cyclin-dependent kinase-5 (Cdk5)-mediated N-methyl-D-aspartate receptor (NMDAR) NR2B subunit phosphorylation in cross-organ reflex sensitization caused by colon irritation. The external urethral sphincter electromyogram (EUSE) reflex activity evoked by the pelvic afferent nerve test stimulation (TS, 1 stimulation/30s) and protein expression in the spinal cord and dorsal root ganglion tissue (T13-L2 and L6-S2 ipsilateral to the stimulation) in response to colon mustard oil (MO) instillation were tested in anesthetized rats. When compared with a baseline reflex activity with a single action potential evoked by the TS before the administration of test agents, MO instillation into the descending colon sensitized the evoked activity characterized by elongated firing in the reflex activity in association with increased protein levels of Cdk5, PSD95, and phosphorylated NR2B (pNR2B) but not of total NR2B (tNR2B) in the spinal cord tissue. Both cross-organ reflex sensitization and increments in protein expression were reversed by intra-colonic pretreatments with ruthenium red (a non-selective transient receptor potential vanilloid, TRPV, antagonist), capsaizepine (a TRPV1-selective antagonist), lidocaine (a nerve conduction blocker) as well as by the intra-thecal pretreatment with APV (a NRMDR antagonist) Co-101244 (a NR2B-selective antagonist) and roscovitine (a Cdk5 antagonist). Moreover, compared with the control group, both the increase in pNR2B and the cross-organ reflex sensitization were attenuated in the si-RNA of NR2B rats. All these results suggested that Cdk-dependent NMDAR NR2B subunit phosphorylation mediates the development of cross-organ pelvic-urethra reflex sensitization caused by acute colon irritation which could possibly underlie the high concurrence of pelvic pain syndrome with irritable bowel syndrome.

Topics: Animals; Colon; Cyclin-Dependent Kinase 5; Electric Stimulation; Excitatory Amino Acid Agents; Glutamic Acid; Inflammation; Male; Mustard Plant; Pelvis; Piperidines; Plant Oils; Protein Kinase Inhibitors; Purines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Reflex; RNA, Small Interfering; Roscovitine; TRPV Cation Channels; Urethra

The objective of this study was to determine the anti-inflammatory, nociceptive, and antiarthritic effects of piperine, the active phenolic component in black pepper extract.. The in vitro anti-inflammatory activity of piperine was tested on interleukin 1beta (IL1beta)-stimulated fibroblast-like synoviocytes derived form patients with rheumatoid arthritis. The levels of IL6, matrix metalloproteinase (MMPs), cyclo-oxygenase 2 (COX-2), and prostaglandin E2 (PGE2) were investigated by ELISA and RT-PCR analysis. The analgesic and antiarthritic activities of piperine were investigated on rat models of carrageenan-induced acute paw pain and arthritis. The former were evaluated with a paw pressure test, and the latter by measuring the squeaking score, paw volume, and weight distribution ratio. Piperine was administrated orally to rats at 20 and 100 mg/kg/day for 8 days.. Piperine inhibited the expression of IL6 and MMP13 and reduced the production of PGE2 in a dose dependant manner at concentrations of 10 to 100 microg/ml. In particular, the production of PGE2 was significantly inhibited even at 10 microg/ml of piperine. Piperine inhibited the migration of activator protein 1 (AP-1), but not nuclear factor (NF)kappaB, into the nucleus in IL1beta-treated synoviocytes. In rats, piperine significantly reduced nociceptive and arthritic symptoms at days 8 and 4, respectively. Histological staining showed that piperine significantly reduced the inflammatory area in the ankle joints.. These results suggest that piperine has anti-inflammatory, antinociceptive, and antiarthritic effects in an arthritis animal model. Thus, piperine should be further studied with regard to use either as a pharmaceutical or as a dietary supplement for the treatment of arthritis.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents; Arthritis, Experimental; Benzodioxoles; Cyclooxygenase 2; Dinoprostone; Enzyme-Linked Immunosorbent Assay; Fibroblasts; Humans; Hyperalgesia; Inflammation; Interleukin-1beta; Interleukin-6; Male; Matrix Metalloproteinases; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Synovial Membrane

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin induce gastric mucosal lesions in part by the activation of inflammatory cells and the production of proinflammatory cytokines. The activation of adenosine A(2A) receptors inhibits inflammation by increasing cyclic AMP in leukocytes and reducing both the production of various proinflammatory cytokines and neutrophil chemotaxis. The aim of present study was to determine whether administration of an orally active adenosine A(2A) receptor agonist (4-[3-[6-amino-9-(5-cyclopropylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl]-piperidine-1-carboxylic acid methyl ester; ATL-313) ameliorated indomethacin-induced gastric mucosal lesions in rats.. Gastric lesions were produced by oral gavage of indomethacin (30 mg/kg). ATL-313 (1-10 microg/kg) was given orally just before the indomethacin administration.. The ulcer index induced by indomethacin was significantly (>50%) reduced by pretreatment with ATL-313 and this effect was blocked completely by the addition of equimolar ZM241385, a selective A(2A) receptor antagonist. The gastric content of myeloperoxidase (MPO) and proinflammatory cytokines was significantly reduced by 10 microg/kg ATL-313, but gastric mucosal prostaglandin 2 (PGE2) was not affected.. We conclude that ATL-313 does not inhibit the mucosal damaging effect of indomethacin, but it does block secondary injury due to stomach inflammation. A(2A) agonists may represent a class of new therapeutic drugs for NSAID-induced gastric ulcers.

Topics: Adenosine A2 Receptor Agonists; Adenosine A2 Receptor Antagonists; Animals; Anti-Inflammatory Agents, Non-Steroidal; Chemokine CXCL1; Dinoprostone; Gastric Mucosa; Indomethacin; Inflammation; Interleukin-1beta; Male; Peroxidase; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Adenosine A2A; Stomach Ulcer; Triazines; Triazoles; Tumor Necrosis Factor-alpha

Central neurotensin (NT) administration results in a naloxone-insensitive antinociceptive response in animal models of acute and persistent pain. Both NTS1 and NTS2 receptors were shown to be required for different aspects of NT-induced analgesia. We recently demonstrated that NTS2 receptors were extensively associated with ascending nociceptive pathways, both at the level of the dorsal root ganglia and of the spinal dorsal horn. Then, we found that spinally administered NTS2-selective agonists induced dose-dependent antinociceptive responses in the acute tail-flick test. In the present study, we therefore investigated whether activation of spinal NTS2 receptors suppressed the persistent inflammatory pain symptoms observed after intraplantar injection of formalin.. We first demonstrated that spinally administered NT and NT69L agonists, which bind to both NTS1 and NTS2 receptors, significantly reduced pain-evoked responses during the inflammatory phase of the formalin test. Accordingly, pretreatment with the NTS2-selective analogs JMV-431 and levocabastine was effective in inhibiting the aversive behaviors induced by formalin. With resolution at the single-cell level, we also found that activation of spinal NTS2 receptors reduced formalin-induced c-fos expression in dorsal horn neurons. However, our results also suggest that NTS2-selective agonists and NTS1/NTS2 mixed compounds differently modulated the early (21-39 min) and late (40-60 min) tonic phase 2 and recruited endogenous pain inhibitory mechanisms integrated at different levels of the central nervous system. Indeed, while non-selective drugs suppressed pain-related behaviors activity in both part of phase 2, intrathecal injection of NTS2-selective agonists was only efficient in reducing pain during the late phase 2. Furthermore, assessment of the stereotypic pain behaviors of lifting, shaking, licking and biting to formalin also revealed that unlike non-discriminative NTS1/NTS2 analogs reversing all nociceptive endpoint behaviors, pure NTS2 agonists specifically inhibited paw lifting, supporting a role of NTS2 in spinal modulation of persistent nociception.. The present study provides the first demonstration that activation of NTS2 receptors produces analgesia in the persistent inflammatory pain model of formalin. The dichotomy between these two classes of compounds also indicates that both NTS1 and NTS2 receptors are involved in tonic pain inhibition and implies that these two NT receptors modulate the pain-induced behavioral responses by acting on distinct spinal and/or supraspinal neural circuits. In conclusion, development of NT agonists targeting both NTS1 and NTS2 receptors could be useful for chronic pain management.

Topics: Animals; Formaldehyde; Histamine H1 Antagonists, Non-Sedating; Inflammation; Male; Neurotensin; Pain; Peptide Fragments; Piperidines; Posterior Horn Cells; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptors, Neurotensin; Spinal Nerves; Time Factors

The midbrain periaqueductal grey (PAG) is a structure known for its roles in pain transmission and modulation. Noxious stimuli potentiate the glutamate synaptic transmission and enhance glutamate NMDA receptor expression in the PAG. However, little is known about roles of NMDA receptor subunits in the PAG in processing the persistent inflammatory pain. The present study was undertaken to investigate NR2A- and NR2B-containing NMDA receptors in the PAG and their modulation to the peripheral painful inflammation. Noxious stimuli induced by hind-paw injection of complete Freund's adjuvant (CFA) caused up-regulation of NR2B-containing NMDA receptors in the PAG, while NR2A-containing NMDA receptors were not altered. Whole-cell patch-clamp recordings revealed that NMDA receptor mediated mEPSCs were increased significantly in the PAG synapse during the chronic phases of inflammatory pain in mice. PAG local infusion of Ro 25-6981, an NR2B antagonist, notably prolonged the paw withdrawal latency to thermal radian heat stimuli bilaterally in rats. Hyperoside (Hyp), one of the flavonoids compound isolated from Rhododendron ponticum L., significantly reversed up-regulation of NR2B-containing NMDA receptors in the PAG and exhibited analgesic activities against persistent inflammatory stimuli in mice. Our findings provide strong evidence that up-regulation of NR2B-containing NMDA receptors in the PAG involves in the modulation to the peripheral persistent inflammatory pain.

Topics: Afferent Pathways; Animals; Anti-Inflammatory Agents, Non-Steroidal; Chronic Disease; Disease Models, Animal; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Freund's Adjuvant; Glutamic Acid; Inflammation; Male; Mice; Mice, Inbred C57BL; Nociceptors; Organ Culture Techniques; Pain Measurement; Pain, Intractable; Patch-Clamp Techniques; Periaqueductal Gray; Phenols; Piperidines; Quercetin; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Synaptic Transmission; Up-Regulation

In this study, we investigated the effects of the selective ET(A) (BQ-123) and ET(B) (BQ-788) receptor antagonists for endothelin-1 (ET-1) against several flogistic agent-induced paw edema formation and ovalbumin-induced allergic lung inflammation in mice. The intraplantar injection of BQ-123, but not BQ-788, significantly inhibited carrageenan-, PAF-, ET-1- and bradykinin-induced paw edema formation. The obtained inhibitions (1h after the inflammatory stimulus) were 79+/-5%, 55+/-4%, 55+/-6% and 74+/-4%, respectively. In carrageenan-induced paw edema, the mean ID(50) value for BQ-123 was 0.77 (0.27-2.23)nmol/paw. The neutrophil influx induced by carrageenan or PAF was reduced by BQ-123, with inhibitions of 55+/-2% and 72+/-4%, respectively. BQ-123 also inhibited the indirect macrophage influx induced by carrageenan (55+/-6%). However, BQ-788 failed to block the cell influx caused by either of these flogistic agents. When assessed in the bronchoalveolar lavage fluid in a murine model of asthma, both BQ-123 and BQ-788 significantly inhibited ovalbumin-induced eosinophil recruitment (78+/-6% and 71+/-8%), respectively. Neither neutrophil nor mononuclear cell counts were significantly affected by these drugs. Our findings indicate that ET(A), but not ET(B), selective ET-1 antagonists are capable of preventing the acute inflammatory responses induced by carrageenan, PAF, BK and ET-1. However, both ET(A) and ET(B) receptor antagonists were found to be effective in inhibiting the allergic response in a murine model of asthma.

Topics: Animals; Anti-Allergic Agents; Antihypertensive Agents; Asthma; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Female; Inflammation; Male; Mice; Mice, Inbred BALB C; Oligopeptides; Peptides, Cyclic; Piperidines

We have previously demonstrated antinociceptive effects of fatty acid amide hydrolase (FAAH) inhibition that were accompanied by increases in the levels of endocannabinoids (ECs) in the hind paw. Here, the effects of the FAAH inhibitor URB597 (3'-carbamoyl-biphenyl-3-yl-cyclohexylcarbamate) on responses of spinal neurons were studied.. Extracellular single-unit recordings of dorsal horn neurons were made in anaesthetized rats with hind paw inflammation induced by lambda-carrageenan. Effects of intraplantar pre-administration of URB597, or vehicle, on carrageenan-evoked expansion of peripheral receptive fields of spinal neurons and mechanically evoked responses of neurons were studied. The cannabinoid receptor type 1 (CB(1)) antagonist AM251 (N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide) and the peroxisome proliferator-activated receptor (PPAR)-alpha antagonist GW6471 ([(2S)-2-[[(1Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl]amino]-3-[4-[2-(5-methyl-2-phenyl-4-oxa zolyl)ethoxy]phenyl]propyl]-carbamic acid ethyl ester) were used to investigate the roles of these receptors in mediating the effects of URB597.. URB597 (25 microg in 50 microL) pretreatment significantly inhibited carrageenan-evoked receptive field expansion and this was significantly reversed by co-administration of the PPAR-alpha antagonist but not the CB(1) antagonist. Pretreatment with the PPAR-alpha receptor agonist WY14643 ([[4-chloro-6-[(2,3-dimethylphenyl)amino]-2-pyrimidinyl]thio]acetic acid) also significantly inhibited receptive field expansion. URB597 (25 or 100 microg in 50 microL) had no significant effect on mechanically evoked responses of spinal neurons.. URB597 inhibited receptive field expansions but not mechanically evoked responses of spinal neurons in rats with hind paw inflammation. These effects were blocked by PPAR-alpha receptor antagonism. These data support the contention that URB597 exerts its antinociceptive effects by indirect inhibition of sensitization of neuronal responses at least partly through PPAR-alpha activation due to enhanced EC levels.

Topics: Amidohydrolases; Analgesia; Animals; Benzamides; Carbamates; Carrageenan; Disease Models, Animal; Inflammation; Oxazoles; Pain; Piperidines; PPAR gamma; Pyrazoles; Rats; Receptor, Cannabinoid, CB1; Tyrosine

The endocannabinoid pathway plays an important role in the regulation of appetite and body weight, hepatic lipid metabolism, and fibrosis. Blockade of the endocannabinoid receptor CB1 with SR141716 promotes weight loss, reduces hepatocyte fatty acid synthesis, and is antifibrotic. D-4F, an apolipoprotein A-1 mimetic with antioxidant properties, is currently in clinical trials for the treatment of atherosclerosis. C57BL/6J mice were fed a high-fat diet for 7 months, followed by a 2.5-month treatment with either SR141716 or D-4F. SR141716 markedly improved body weight, liver weight, serum transaminases, insulin resistance, hyperglycemia, hypercholesterolemia, hyperleptinemia, and oxidative stress, accompanied by the significant prevention of fibrosis progression. D-4F improved hypercholesterolemia and hyperleptinemia without improvement in body weight, steatohepatitis, insulin resistance, or oxidative stress, and yet, there was significant prevention of fibrosis. D-4F prevented culture-induced activation of stellate cells in vitro. In summary, C57BL/6J mice given a high-fat diet developed features of metabolic syndrome with nonalcoholic steatohepatitis and fibrosis. Both SR141716 and D-4F prevented progression of fibrosis after onset of steatohepatitis, ie, a situation comparable to a common clinical scenario, with D-4F seeming to have a more general antifibrotic effect. Either compound therefore has the potential to be of clinical benefit.

Topics: Actins; Animals; Apolipoprotein A-I; Body Weight; Cells, Cultured; Diet; Disease Models, Animal; Fatty Liver; Hepatocytes; Inflammation; Liver; Liver Cirrhosis; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Organ Size; Piperidines; Pyrazoles; Rimonabant

Previous studies have demonstrated that locally administered cannabinoids attenuate allodynia and hyperalgesia through activation of peripheral cannabinoid receptors (CB(1) and CB(2)). However, it is currently unknown if cannabinoids alter the response properties of nociceptors. In the present study, correlative behavioral and in vivo electrophysiological studies were conducted to determine if peripheral administration of the cannabinoid receptor agonists arachidonyl-2'-chloroethylamide (ACEA) or (R)-(+)-methanandamide (methAEA) could attenuate mechanical allodynia and hyperalgesia, and decrease mechanically evoked responses of Adelta nociceptors. Twenty-four hours after intraplantar injection of complete Freund's adjuvant (CFA), rats exhibited allodynia (decrease in paw withdrawal threshold) and hyperalgesia (increase in paw withdrawal frequency), which were attenuated by both ACEA and methAEA. The antinociceptive effects of these cannabinoids were blocked by co-administration with the CB(1) receptor antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophen yl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) but not with the CB(2) receptor antagonist 6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-y l](4-methoxyphenyl)methanone (AM630). ACEA and methAEA did not produce antinociception under control, non-inflamed conditions 24 h after intraplantar injection of saline. In parallel studies, recordings were made from cutaneous Adelta nociceptors from inflamed or control, non-inflamed skin. Both ACEA and methAEA decreased responses evoked by mechanical stimulation of Adelta nociceptors from inflamed skin but not from non-inflamed skin, and this decrease was blocked by administration of the CB(1) receptor antagonist AM251. These results suggest that attenuation of mechanically evoked responses of Adelta nociceptors contributes to the behavioral antinociception produced by activation of peripheral CB(1) receptors during inflammation.

Topics: Action Potentials; Analysis of Variance; Animals; Arachidonic Acids; Cannabinoids; Dose-Response Relationship, Drug; Drug Interactions; Freund's Adjuvant; Inflammation; Male; Nerve Fibers, Myelinated; Neural Conduction; Nociceptors; Pain Measurement; Pain Threshold; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Reaction Time; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Skin

Starting from 2, several highly potent C5a receptor antagonists were synthesised through alpha-amide substitution. Attempts to increase the polarity of these compounds through the introduction of basic centres or incorporation into weakly basic heterocycles is described.

Topics: Administration, Oral; Amides; Binding Sites; Chemistry, Pharmaceutical; Complement C5a; Drug Design; Humans; Hydrolysis; Inflammation; Inhibitory Concentration 50; Models, Chemical; Molecular Structure; Peptides; Piperidines; Protein Binding

Endothelins are well known as modulators of inflammation in the periphery, but little is known about their possible role in brain inflammation. Stimulation of astrocyte prostaglandin, an inflammatory mediator, synthesis was shown so far only by endothelin 3 (ET-3). By contrast, several studies showed no change or slight decrease of basal nitric oxide synthesis after treatment of astrocytes with endothelin 1 (ET-1) and ET-3. However, a significant increase in astrocytic and microglial nitric oxide synthase (NOS) was observed after exposure to ET-1 and ET-3 in a model of forebrain ischaemia. Here we demonstrate that all three endothelins (ET-1, ET-2, ET-3) significantly enhanced the synthesis of prostaglandin E(2) and nitric oxide in glial cells. Each of the selective antagonists for ETA and ETB receptors (BQ123 and BQ788 respectively), significantly inhibited endothelins-induced production of both nitric oxide and prostaglandin E(2). These results suggest a regulatory mechanism of endothelins, interacting with both endothelin receptors, on glial inflammation. Therefore, inhibition of endothelin receptors may have a therapeutic potential in pathological conditions of the brain, when an uncontrolled inflammatory response is involved.

Topics: Animals; Astrocytes; Cells, Cultured; Dinoprostone; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Endothelin-2; Endothelin-3; Inflammation; Neuroglia; Nitric Oxide; Nitric Oxide Synthase; Oligopeptides; Peptides, Cyclic; Piperidines; Rats; Receptor, Endothelin A; Receptor, Endothelin B

The pathophysiology of sepsis is due in part to early systemic inflammation. Here we describe molecular and cellular responses, as well as survival, in A 2A adenosine receptor (AR) agonist treated and untreated animals during experimental sepsis.. Sepsis was induced in mice by intraperitoneal inoculation of live bacteria (Escherichia coli or Staphylococcus aureus) or lipopolysaccharide (LPS). Mice inoculated with live bacteria were treated with an A 2A AR agonist (ATL313) or phosphate buffered saline (PBS), with or without the addition of a dose of ceftriaxone. LPS inoculated mice were treated with ATL313 or PBS. Serum cytokines and chemokines were measured sequentially at 1, 2, 4, 8, and 24 hours after LPS was administered. In survival studies, mice were followed until death or for 7 days.. There was a significant survival benefit in mice infected with live E. coli (100% vs. 20%, p = 0.013) or S. aureus (60% vs. 20%, p = 0.02) when treated with ATL313 in conjunction with an antibiotic versus antibiotic alone. ATL313 also improved survival from endotoxic shock when compared to PBS treatment (90% vs. 40%, p = 0.005). The serum concentrations of TNF-alpha, MIP-1 alpha, MCP-1, IFN-gamma, and IL-17 were decreased by ATL313 after LPS injection (p < 0.05). Additionally, ATL313 increased the concentration of IL-10 under the same conditions (p < 0.05). Circulating white blood cell concentrations were higher in ATL313 treated animals (p < 0.01).. Further studies are warranted to determine the clinical utility of ATL313 as a novel treatment for sepsis.

Topics: Animals; Anti-Inflammatory Agents; Ceftriaxone; Cytokines; Disease Models, Animal; Escherichia coli Infections; Female; Inflammation; Leukocytes; Lipopolysaccharides; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Piperidines; Receptor, Adenosine A2A; Sepsis; Staphylococcal Infections; Survival Analysis

Leukotriene B(4) (LTB(4)), formed by the sequential actions of the 5-lipoxygenase (5-LO) and leukotriene A(4) hydrolase (LTA(4)H), is a pro-inflammatory mediator implicated in the pathogenesis of inflammatory bowel disease. However, inhibitors of 5-LO have not proved to be consistent in their therapeutic efficacy in colitis. Another approach to inhibiting LTB(4) synthesis is through the use of inhibitors of LTA(4)H, such as the novel, potent and selective compound, JNJ 26993135.. The effect of oral administration of JNJ 26993135 has been evaluated in a rat model of colitis provoked by colonic instillation of trinitrobenzenesulphonic acid (TNBS). The extent and severity of the macroscopic inflammatory response, the colonic levels of myeloperoxidase (MPO) and LTB(4) and of the pro-inflammatory cytokines, tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were measured.. Oral administration of JNJ 26993135 (5, 15 and 30 mg kg(-1), twice a day) dose-dependently reduced both the extent and intensity of the colonic inflammatory damage observed 3 days after TNBS challenge. JNJ 26993135 also dose-dependently reduced the elevated colonic levels of LTB(4), as well as the inflammatory biomarkers, MPO, IL-6 and TNF-alpha. This dosing regimen was supported by the pharmacokinetic profile of JNJ 26993135, along with the demonstration of the inhibition of ex vivo production of LTB(4) in whole blood following oral administration.. These results with JNJ 26993135 in the rat TNBS model support the role of LTB(4) in colitis and the potential value of targeting LTA(4)H for the treatment of inflammatory bowel diseases.

Topics: Administration, Oral; Animals; Benzothiazoles; Colitis; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Delivery Systems; Enzyme Inhibitors; Epoxide Hydrolases; Inflammation; Interleukin-6; Male; Peroxidase; Piperidines; Rats; Rats, Wistar; Severity of Illness Index; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

N-acylethanolamines, which include the endocannabinoid anandamide and the cannabinoid receptor-inactive saturated compounds N-palmitoyl ethanolamine and N-stearoyl ethanolamine, are ethanolamines of long-chain fatty acids degraded by fatty acid amide hydrolase (FAAH) known to accumulate in degenerating tissues and cells. Whilst much evidence supports a protective anti-inflammatory role of both anandamide and N-palmitoyl ethanolamine, very little information is available with regard to the bioactivity of N-stearoyl ethanolamine. Employing a murine model of passive IgE-induced cutaneous anaphylaxis, we have found that N-stearoyl ethanolamine is endowed with marked anti-inflammatory properties in vivo, supporting the hypothesis that endogenous N-stearoyl ethanolamine is, in analogy to N-palmitoyl ethanolamine, a bioactive signalling lipid capable of downregulating allergic inflammation in the skin. This effect, although mimicked by synthetic, non-selective, CB(1)/CB(2) receptor agonists, such as WIN55, 212-2, was not sensitive to CB(1) or CB(2) receptor antagonists, but rather was fully reversed by capsazepine, a competitive antagonist of the TRPV1 receptor. Moreover, CB(1) receptor antagonists, although effective in antagonising the WIN55,212-2-induced hypothermia, did not reduce the anti-inflammatory effect of WIN55,212-2, whilst CB(2) receptor antagonists, per se inactive, potentiated the WIN55,212-2 effect, suggesting an involvement of non-CB(1)/CB(2) receptors in the anti-inflammatory action of WIN55,212-2. All this, together with demonstration of FAAH as a major regulator of the in vivo concentrations of saturated N-stearoyl ethanolamine, in addition to N-palmitoyl ethanolamine, raise the speculation that pharmacological treatments with saturated N-acylethanolamines such as N-stearoyl ethanolamine, or alternatively FAAH inhibitors able to increase their local concentration, rather than selective CB receptor agonists, might be of promising therapeutic benefit in reducing allergic inflammation in the skin.

Topics: Amides; Animals; Anti-Inflammatory Agents; Benzoxazines; Body Temperature; Camphanes; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Cannabinoids; Ear Auricle; Edema; Endocannabinoids; Ethanolamines; Fatty Acids; Female; Inflammation; Mice; Mice, Inbred BALB C; Morpholines; Naphthalenes; Palmitic Acids; Passive Cutaneous Anaphylaxis; Piperidines; Pyrazoles; Rimonabant; Stearic Acids; Time Factors

The endocannabinoid system modulates many pathophysiological functions, including the brain pathways involved in the regulation of body weight and adipose tissue function. The selective cannabinoid CB(1) receptor antagonist, rimonabant, has undergone phase III clinical testing as anti-obesity drug. Obesity is considered a mild inflammatory condition and predisposes individuals to an increased risk of developing many diseases. It has been recently suggested that a successful intervention to treat obesity is a therapy combining weight-reducing drugs with anti-inflammatory ones. In this scenario, rimonabant's anti-obesity action is accompanied by favorable changes in markers for insulin resistance, C-reactive protein, adiponectin, tumor necrosis factor alpha (TNFalpha). The results reported by Croci and Zarini in this issue highlight the anti-inflammatory and anti-hyperalgesic effect of rimonabant in obese animals, so suggesting that it could provide a more general and aggressive strategy to protect obese patients from many pathological risks.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Anti-Obesity Agents; Arthritis; Humans; Hyperalgesia; Inflammation; Obesity; Pain Measurement; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

Obesity is a risk factor for several inflammation-based diseases including arthritis. We investigated the anti-nociceptive and anti-inflammatory effects of the cannabinoid CB1 receptor antagonist rimonabant in lean and diet-induced obese female rats with arthritis induced by complete Freund's adjuvant (CFA) injected in the right hind-paw.. The effect of oral rimonabant was assessed in rat paws on thermal hyperalgesia, mechanical allodynia, oedema, global arthritis score, nitrite/nitrate levels and ankle widths.. After 7 but not after 14 days, the inflammatory response to CFA was significantly higher in obese than lean rats; however, the nociceptive response (thermal hyperalgesia and mechanical allodynia) was similar. Oral rimonabant (3 or 10 mg kg-1, once a day for 1 week from day 7 after CFA) only reduced the global arthritic score and joint width in obese rats, with no effect on the paw oedema. It also markedly reduced thermal hyperalgesia and mechanical allodynia in both lean and obese rats, with a greater effect in the latter.. Rimonabant appears to be a potent inhibitor of sensorial hypersensitivity associated with CFA-induced arthritis in obese rats, in which the inflammatory reaction is more severe than in lean rats. It may thus have therapeutic potential in obesity-associated inflammatory diseases, particularly in the treatment of the pain associated with arthritis.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Anti-Obesity Agents; Arthritis, Experimental; Body Weight; Edema; Female; Freund's Adjuvant; Hot Temperature; Hyperalgesia; Inflammation; Joints; Nitric Oxide; Obesity; Pain Measurement; Pain Threshold; Piperidines; Pyrazoles; Rats; Reaction Time; Receptor, Cannabinoid, CB1; Rimonabant; Time Factors; Touch

Leukotriene A(4) hydrolase (LTA(4)H) catalyzes production of the proinflammatory lipid mediator, leukotriene (LT) B(4), which is implicated in a number of inflammatory diseases. We have identified a potent and selective inhibitor of both the epoxide hydrolase and aminopeptidase activities of recombinant human LTA(4)H (IC(50), approximately 10 nM). In a murine model of arachidonic acid-induced ear inflammation, the LTA(4)H inhibitor, JNJ-26993135 (1-[4-(benzothiazol-2-yloxy)-benzyl]-piperidine-4-carboxylic acid), dose-dependently inhibited ex vivo LTB(4) production in blood, in parallel with dose-dependent inhibition of neutrophil influx (ED(50), 1-3 mg/kg) and ear edema. In murine whole blood and in zymosan-induced peritonitis, JNJ-26993135 selectively inhibited LTB(4) production, without affecting cysteinyl leukotriene production, while maintaining or increasing production of the anti-inflammatory mediator, lipoxin (LX) A(4). The 5-lipoxygenase (5-LO) inhibitor zileuton showed inhibition of LTB(4), LTC(4), and LXA(4) production. Although zileuton inhibited LTB(4) production in the peritonitis model more effectively than the LTA(4)H inhibitor, the influx of neutrophils into the peritoneum after 1 and 2 h was significantly higher in zileuton- versus JNJ-26993135-treated animals. This difference may have been mediated by the increased LXA(4) levels in the presence of the LTA(4)H inhibitor. The selective inhibition of LTB(4) production by JNJ-26993135, while increasing levels of the anti-inflammatory mediator, LXA(4), may translate to superior therapeutic efficacy versus 5-LO or 5-LO-activating protein inhibitors in LTB(4)-mediated inflammatory diseases.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Ascitic Fluid; Benzothiazoles; Dogs; Ear; Edema; Eicosanoids; Enzyme Inhibitors; Epoxide Hydrolases; Female; Humans; Hydroxyurea; Inflammation; Leukotriene B4; Leukotriene C4; Lipoxins; Lipoxygenase Inhibitors; Mice; Mice, Inbred BALB C; Mice, Inbred Strains; Neutrophil Infiltration; Peritonitis; Piperidines; Recombinant Proteins

Inflammation has been recently implicated in pathogenesis of dementia disorders. Effect of anti-dementia (Acetylcholinesterase inhibitor) drugs tacrine, rivastigmine and donepezil were studied on neuroinflammation induced by intraperitoneal administration of lipopolysaccharide (LPS) in mice. Interleukin-2 (IL-2) and isoforms of acetylcholinesterase (AChE) were estimated in different brain areas as marker for neuroinflammation and cholinergic activity respectively. LPS significantly increased the level of IL-2 in all the brain areas while enhancement of AChE activity varied in brain areas. It was found that administration of tacrine, rivastigmine and donepezil in mice significantly attenuated the LPS induced increased levels of IL-2 along with the significant reduction of AChE activity predominantly in salt soluble (SS) fraction as compared to the detergent soluble (DS) fraction in a dose dependent manner. In vitro effect of LPS was also studied in different brain areas. LPS significantly increased the AChE activity in SS fractions but the significant increase was not found in DS fractions. The present study indicate that cholinesterase inhibitor anti-dementia drugs are effective against LPS induced neuroinflammation that may be linked to enhanced cholinergic activity.

Topics: Acetylcholinesterase; Analysis of Variance; Animals; Brain; Cholinesterase Inhibitors; Dementia; Donepezil; Dose-Response Relationship, Drug; Indans; Inflammation; Injections, Intraperitoneal; Interleukin-2; Lipopolysaccharides; Mice; Phenylcarbamates; Piperidines; Rivastigmine; Tacrine

Cannabinoids, such as anandamide, are involved in pain transmission. We evaluated the effects of AM404 (N-(4-hydroxyphenyl)-5Z,8Z,11Z,14Z-eicosatetraenamide), an anandamide reuptake inhibitor, monitoring the expression of c-fos, a marker of activated neurons and the pain-related behaviours using formalin test. The study was carried out in an experimental model of inflammatory pain made by a single injection of formalin in rat hind paws. Formalin test showed that the antinociceptive effect of AM404 was evident in phase I. We found that Fos-positive neurons in dorsal superficial and deep laminae of the lumbar spinal cord increased in formalin-injected animals and that AM404 significantly reduced Fos induction. Co-administration of cannabinoid CB(1) receptor antagonist (AM251), cannabinoid CB(2) receptor antagonist (AM630) and transient receptor potential vanilloid type 1 (TRPV-1) antagonist (capsazepine), attenuate the inhibitory effect of AM404 and this effect was higher using cannabinoid CB(2) and vanilloid TRPV-1 receptor antagonists. These results suggest that AM404 could be a useful drug to reduce inflammatory pain in our experimental model and that cannabinoid CB(2) receptor and vanilloid TRPV-1 receptor, and to a lesser extent, the cannabinoid CB(1) receptor are involved.

Topics: Animals; Arachidonic Acids; Capsaicin; Endocannabinoids; Immunohistochemistry; Indoles; Inflammation; Male; Pain; Pain Measurement; Piperidines; Polyunsaturated Alkamides; Proto-Oncogene Proteins c-fos; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Spinal Cord; TRPV Cation Channels

Tecastemizole, a major metabolite of astemizole, is a potent and selective H1 receptor antagonist. Evidence suggests that this and certain other H1 receptor antagonists may possess anti-inflammatory effects that are, in some cases, independent of H1 receptor antagonism. Objective The aim of this study was to investigate the anti-inflammatory effects of tectastemizole in models of allergic inflammation.. Effects of tecastemizole were assessed in a murine model of allergic lung inflammation, in passive cutaneous anaphylaxis (PCA) responses in guinea-pig skin and in in vitro assays measuring endothelial adhesion molecule expression and leucocyte-endothelial adhesion.. Tecastemizole inhibited antigen-induced eosinophil recruitment to the lungs of allergic mice in a dose-dependent manner. Furthermore, combination of a sub-effective dose of tecastemizole, combined with a sub-effective dose of dexamethasone inhibited eosinophil accumulation in this model. Plasma extravasation in PCA reactions was inhibited by tecastemizole, although by a mechanism that would appear to be H1 receptor-dependent. Cytokine-induced endothelial intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression, as well as mononuclear cell adhesion to human umbilical vein endothelial cells was inhibited by tecastemazole in a manner independent of H1 receptor antagonism.. These data suggest that tecastemizole may have H1 receptor-independent effects in inhibiting late-phase inflammatory responses, while acute responses appear to be inhibited in a H1 receptor-dependent manner. Furthermore, our data suggest an important potential steroid-sparing role for such drugs in the treatment of allergic inflammatory conditions.

Topics: Anaphylaxis; Animals; Anti-Inflammatory Agents; Astemizole; Benzimidazoles; Cell Adhesion; Cell Adhesion Molecules; Cell Movement; Dermatitis, Atopic; Dexamethasone; Disease Models, Animal; Endothelium, Vascular; Eosinophils; Guinea Pigs; Histamine H1 Antagonists; Humans; Inflammation; Intercellular Adhesion Molecule-1; Male; Mice; Mice, Inbred BALB C; Piperidines; Receptors, Histamine H1; Respiratory Hypersensitivity; Umbilical Veins; Vascular Cell Adhesion Molecule-1

This study investigated the effects of rimonabant (SR141716), an antagonist of the cannabinoid receptor type 1 (CB1), on obesity-associated hepatic steatosis and related features of metabolic syndrome: inflammation (elevated plasma levels of tumor necrosis factor alpha [TNFalpha]), dyslipidemia, and reduced plasma levels of adiponectin. We report that oral treatment of obese (fa/fa) rats with rimonabant (30 mg/kg) daily for 8 weeks abolished hepatic steatosis. This treatment reduced hepatomegaly, reduced elevation of plasma levels of enzyme markers of hepatic damage (alanine aminotransferase, gamma glutamyltransferase, and alkaline phosphatase) and decreased the high level of local hepatic TNFalpha currently associated with steatohepatitis. In parallel, treatment of obese (fa/fa) rats with rimonabant reduced the high plasma level of the proinflammatory cytokine TNFalpha and increased the reduced plasma level of the anti-inflammatory hormone adiponectin. Finally, rimonabant treatment also improved dyslipidemia by both decreasing plasma levels of triglycerides, free fatty acids, and total cholesterol and increasing the HDLc/LDLc ratio. All the effects of rimonabant found in this study were not or only slightly observed in pair-fed obese animals, highlighting the additional beneficial effects of treatment with rimonabant compared to diet. These results demonstrate that rimonabant plays a hepatoprotective role and suggest that this CB1 receptor antagonist potentially has clinical applications in the treatment of obesity-associated liver diseases and related features of metabolic syndrome.

Topics: Animals; Cannabinoid Receptor Antagonists; Fatty Liver; Inflammation; Liver; Male; Metabolic Syndrome; Obesity; Piperidines; Pyrazoles; Rats; Rats, Zucker; Reverse Transcriptase Polymerase Chain Reaction; Rimonabant; RNA; Tumor Necrosis Factor-alpha

2-arachidonoylglycerol (2-AG) is an endocannabinoid whose hydrolysis is predominantly catalysed by the enzyme monoacylglycerol lipase (MAGL). The development of MAGL inhibitors could offer an opportunity to investigate the anti-inflammatory and anti-nociceptive role of 2-AG, which have not yet been elucidated. On these bases, URB602, a MAGL inhibitor, was tested in a murine model of inflammation/inflammatory pain.. Acute inflammation was induced by intraplantar injection of lambda-carrageenan into mice. The highest dose to be employed has been selected performing the tetrad assays for cannabimimetic activity in mice. URB602 anti-inflammatory and anti-nociceptive efficacy (assessed by plethysmometer and plantar test, respectively) was evaluated both in a preventive regimen (drug administered 30 min before carrageenan) and in a therapeutic regimen (URB602 administered 30 min after carrageenan). To elucidate the cannabinoid receptor involvement, rimonabant and SR144528, CB1 and CB2 selective antagonists, respectively, were given 15 min before URB602.. Systemic administration of URB602 elicited a dose-dependent anti-oedemigen and anti-nociceptive effect that was reversed exclusively by the CB2 receptor antagonist. The efficacy of URB602 persisted also when the compound was administered in a therapeutic regimen, suggesting the ability of URB602 to improve established disease.. The present report highlighted the ability of the selective MAGL inhibitor, URB602, to prevent and treat an acute inflammatory disease without producing adverse psychoactive effects. The data presented herein also contributed to clarify the physiological role of 2-AG in respect to inflammatory reactions, suggesting its protective role in the body.

Topics: Acute Disease; Animals; Biphenyl Compounds; Body Temperature; Camphanes; Carrageenan; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Hindlimb; Hyperalgesia; Inflammation; Injections, Intraperitoneal; Male; Mice; Mice, Inbred C57BL; Monoacylglycerol Lipases; Pain; Pain Measurement; Pain Threshold; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant

Pharmacological activation of histamine H3 receptors is known to reduce the release of inflammatory peptides, thereby reducing pain and inflammation, but the site(s) and mechanism(s) of these effects are currently unknown. The present study addressed these questions by examining the effects of the H3 agonist immepip and the H3 antagonist thioperamide on nociceptive behaviors and swelling produced during the rat formalin test. Systemic administration of immepip (5 and 30 mg/kg, s.c.) significantly attenuated formalin-induced flinching but not licking responses during both phases. This attenuation was reversed by either systemic (15 mg/kg, i.p.) or intrathecal (20 or 50 microg) administration of thioperamide. Furthermore, immepip (30 mg/kg, s.c.) significantly inhibited formalin-induced swelling, an action which was completely reversed by systemic (15 mg/kg, i.p.), but not intrathecal (50 microg) thioperamide. Also consistent with this pattern, intrathecal immepip (50 microg) reduced flinching responses, but had no effect on formalin-induced paw swelling. The present findings suggest that activation of H3 receptors located on peripheral and spinal terminals of deep dermal fibers attenuates formalin-induced swelling and flinching, respectively. Pharmacological stimulation of H3 receptors could be an important therapeutic approach for many disorders related to deep dermal or inflammatory pain.

Topics: Animals; Behavior, Animal; Brain; Edema; Formaldehyde; Histamine Agonists; Histamine Antagonists; Imidazoles; Inflammation; Injections, Spinal; Male; Nerve Endings; Nerve Fibers; Neurons, Afferent; Pain Measurement; Peripheral Nervous System; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Histamine H3; Skin; Spinal Cord

1. Although cannabinoid receptor agonists have analgesic activity in chronic pain states, they produce a spectrum of central cannabinoid CB(1) receptor-mediated motor and psychotropic side-effects. The actions of endocannabinoids, such as anandamide, are terminated by uptake and subsequent intracellular enzymatic degradation. In the present study, we examined the effect of acute administration of the anandamide transport inhibitor AM404 in rat models of chronic neuropathic and inflammatory pain. 2. Systemic administration of AM404 (10 mg/kg) reduced mechanical allodynia in the partial sciatic nerve ligation (PNL) model of neuropathic pain, but not in the complete Freund's adjuvant (CFA) model of inflammatory pain. 3. The effect of AM404 in the PNL model was abolished by coapplication with the selective cannabinoid CB(1) receptor antagonist AM251 (1 mg/kg). AM404 did not produce a reduction in motor performance in either the PNL or CFA models. 4. These findings suggest that acute administration of AM404 reduces allodynia in a neuropathic pain model via cannabinoid CB(1) receptor activation, without causing the undesirable motor disruption associated with cannabinoid receptor agonists.

Topics: Analgesics; Animals; Arachidonic Acids; Cannabinoid Receptor Modulators; Carrier Proteins; Disease Models, Animal; Endocannabinoids; Freund's Adjuvant; Inflammation; Ligation; Male; Motor Activity; Pain; Pain Measurement; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Sciatic Nerve; Sciatic Neuropathy; Time Factors

Tachykinins including substance P (SP) are well known to play a role in influencing oedema formation and leukocyte accumulation during tissue insult and inflammation. Cutaneous inflammatory models to characterize a TNFalpha-dependent mechanism where endogenous SP act via the NK1 receptor to promote leukocyte accumulation in the absence of oedema formation were used. We found that TNFalpha induced dose-dependent leukocyte accumulation at 4 h, which returned towards basal levels at 8 h in NK1+/+ mice. This response was absent in both the NK1+/+ mice treated with an NK1 receptor antagonist and NK1-/- mice. At the highest dose IL-6 induced a significant accumulation in NK1+/+ and NK1-/- mice but IL-12 was ineffective. SP induced skin oedema but none of the cytokines did. Either co-injection of SP with low dose of TNFalpha (0.3 pmol/site) or SP previously injected (30 min) to TNFalpha evoked a significant increase in MPO activity when compared with that induced by the cytokine alone. In contrast, SP injected i.d. 3.5 h after TNFalpha failed to produce additive response. Control, but not capsaicin-pretreated rats (to deplete sensory nerves), exhibited a marked increase in MPO activity in response to TNFalpha. Histological analysis showed that TNFalpha caused tissue infiltrate of leukocytes in NK1+/+ mice, whilst leukocytes accumulated at intravascular sites in NK1-/- mice, but did not appear to emigrate, suggesting a defect in trans-endothelial migration. Interestingly, monocytes in addition to neutrophils accumulated 4 h post TNFalpha injection. In conclusion, the NK1 receptor plays a functional role in mediating leukocyte accumulation independently of the historically important NK1 mediated oedema formation. It seems that TNFalpha directly activates sensory nerve in addition to its chemoattractant activity. The NK1 receptor agonist influences the accumulation of monocytes in addition to that of PMN by 4 h, thus revealing an important influence of the NK1 receptor on TNFalpha mediated events in mouse skin.

Topics: Albumins; Analysis of Variance; Animals; Capsaicin; Dose-Response Relationship, Drug; Female; Glycoproteins; Immunohistochemistry; Inflammation; Injections, Intradermal; Iodine Isotopes; Leukocytes; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophils; Peroxidase; Piperidines; Quinuclidines; Receptors, Neurokinin-1; Skin; Substance P; Tachykinins; Time Factors; Tumor Necrosis Factor-alpha

Activation of protease-activated receptors (PAR) can induce vasodilation (VD) and increase of vascular permeability either directly by stimulating endothelial cells or indirectly via activation of nociceptors and subsequent release of neuropeptides (neurogenic inflammation). We aimed to estimate the relative contribution of the two pathways for stimulation with endogenous activators of PAR-2 (trypsin) and of PAR-1, 3 and 4 (thrombin) using in vivo dermal microdialysis in rats. Protein extravasation (PE) was assessed by increase of protein concentration in the dialysate, and VD was quantified by laser Doppler scanning. Both trypsin (10(-8)-10(-4) M) and thrombin (10(-6), 10(-5.5) and 10(-5) M) provoked PE and local VD in a dose-dependent manner. Trypsin (10(-4) M)-induced PE was inhibited by 87.2 +/- 21% due to the substance P (SP) NK1 receptor antagonist SR140333. VD was blocked by 58.15 +/- 10.1% in response to the calcitonin gene-related peptide (CGRP) receptor antagonist CGRP(8-37). By contrast, CGRP(8-37) did not affect thrombin-induced VD, while blockade of SP receptors prevented the PE elicited only by low doses of thrombin (10(-6) M), being ineffective at higher thrombin concentrations. In conclusion, intradermal trypsin elicits a neurogenic inflammation in rat, probably mediated via PAR-2 activation on nociceptors and subsequent SP and CGRP release. Thrombin-induced PE and VD are mediated mainly by a non-neurogenic mechanism.

Topics: Animals; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Capillary Permeability; Inflammation; Male; Neurogenic Inflammation; Neurokinin-1 Receptor Antagonists; Peptide Fragments; Piperidines; Quinuclidines; Rats; Rats, Wistar; Receptors, Proteinase-Activated; Skin; Thrombin; Trypsin; Vasodilation

Topics: Animals; Anti-Obesity Agents; Anxiety; Arachidonic Acids; Blood Pressure; Brain; Cannabinoid Receptor Antagonists; Cannabinoid Receptor Modulators; Controlled Clinical Trials as Topic; Drug Evaluation, Preclinical; Endocannabinoids; Humans; Inflammation; Neurons; Obesity; Osteoporosis; Pain; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Receptors, Cannabinoid; Rimonabant; Smoking Cessation

Anandamide, an endocannabinoid, is degraded by the enzyme fatty acid amide hydrolase which can be inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs). The present work was designed to study the peripheral interactions between anandamide and ibuprofen (a non-specific cyclooxygenase inhibitor) in the rat formalin test. We first determined the ED50 for anandamide (0.018 microg +/- 0.009), ibuprofen (0.18 microg +/- 0.09), and their combination (0.006 microg +/- 0.002). Drugs were given 15 min before a 2.5% formalin injection into the dorsal surface of the right hind paw. Results were analyzed using isobolographic analysis. The antinociceptive interaction between anandamide and ibuprofen was synergistic. To further investigate the mechanisms by which the combination of anandamide with ibuprofen produced their antinociceptive effects, we used specific antagonists for the cannabinoid CB1 (AM251; 80 microg) and CB2 (AM630; 25 microg) receptors. We demonstrated that the antinociceptive effects of ibuprofen were not antagonized by either AM251 or AM630 and that those of anandamide were antagonized by AM251 but not by AM630. The synergistic antinociceptive effects of the combination of anandamide with ibuprofen were completely antagonized by AM251 but only partially inhibited by AM630. In conclusion, locally (hind paw) injected anandamide, ibuprofen or combination thereof decreased pain behavior in the formalin test. The combination of anandamide with ibuprofen produced synergistic antinociceptive effects involving both cannabinoid CB1 and CB2 receptors. Comprehension of the mechanisms involved needs further investigation.

Topics: Acute Disease; Analysis of Variance; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acids; Area Under Curve; Cannabinoid Receptor Modulators; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Combinations; Drug Interactions; Endocannabinoids; Ibuprofen; Indoles; Inflammation; Male; Pain; Pain Measurement; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Random Allocation; Rats

In the study of anti-proinflammation by 7-[2-[4-(2-chlorobenzene)piperazinyl] ethyl]-1,3-dimethylxanthine (KMUP-1) and 7-[2-[4-(4-nitrobenzene)piperazinyl]ethyl]-1,3-dimethylxanthine (KMUP-3), exposure of rat tracheal smooth muscle cells (TSMCs) to tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine, increased the expression of inducible nitric-oxide synthase (iNOS) and NO production and decreased the expression of soluble guanylate cyclase alpha1 (sGCalpha1), soluble guanylate cyclase beta1 (sGCbeta1), protein kinase G (PKG), and the release of cGMP in TSMCs. The cell-permeable cGMP analog 8-Br-cGMP, xanthine-based KMUP-1 and KMUP-3, and the phosphodiesterase 5 inhibitor zaprinast all inhibited TNF-alpha-induced increases of iNOS expression and NO levels and reversed TNF-alpha-induced decreases of sGCalpha1, sGCbeta1, and PKG expression. These results imply that cGMP enhancers could have anti-proinflammatory potential in TSMCs. TNF-alpha also increased protein kinase A (PKA) expression and cAMP levels, cyclooxygenase-2 (COX-2) expression, and activated productions of prostaglandin (PG) E2 and 6-keto-PGF1alpha (stable PGI2 metabolite). Dexamethasone and N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methane sulfonamide (NS-398; a selective COX-2 inhibitor) attenuated TNF-alpha-induced expression of COX-2 and activated productions PGE2 and PGI2. However, KMUP-1 and KMUP-3 did not affect COX-2 activities and did not further enhance cAMP levels in the presence of TNF-alpha. It is suggested that TNF-alpha-induced increases of PKA expression and cAMP levels are mediated by releasing PGE2 and PGI2, the activation products of COX-2. In conclusion, xanthine-based KMUP-1 and KMUP-3 inhibit TNF-alpha-induced expression of iNOS in TSMCs, involving the sGC/cGMP/PKG expression pathway but without the involvement of COX-2.

Topics: Animals; Cells, Cultured; Cyclic AMP-Dependent Protein Kinase Type II; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP-Dependent Protein Kinases; Cyclooxygenase 2; Guanylate Cyclase; Inflammation; Male; Models, Biological; Myocytes, Smooth Muscle; Nitrates; Nitric Oxide; Nitric Oxide Synthase Type II; Nitrites; Nucleotides, Cyclic; Piperidines; Prostaglandins; Rats; Rats, Wistar; Solubility; Trachea; Tumor Necrosis Factor-alpha; Xanthines

Activation of cannabinoid CB1 and CB2 receptors is known to attenuate nociception and hyperalgesia in somatic inflammatory conditions. The aim of this study was to determine whether cannabinoids modulate colonic sensitivity in basal and inflammatory conditions. The effects of CB1 and CB2 receptor agonists and antagonists on the abdominal contractile response to colorectal distension (CRD) in basal conditions and after 2,4,6-trinitrobenzenesulphonic acid-induced colitis were investigated. As previously described, colitis triggered a hypersensitivity to CRD. In basal conditions, both CB1 (WIN 55212-2) and CB2 (JWH 015) agonists reduced the abdominal response to CRD at a dose of 1 mg kg(-1), i.p. Both compounds were active at a lower dose (0.1 mg kg(-1)) abolishing the hypersensitivity induced by colitis. Administered alone, CB1 (Rimonabant) and CB2 (SR 144528) receptor antagonists (10 mg kg(-1)) had no effect on basal sensitivity. In contrast, the CB1, but not the CB2, receptor antagonist enhanced colitis-induced hyperalgesia. It is concluded that colonic inflammation enhances the antinociceptive action of CB1 and CB2 receptor agonists, and activates an endogenous, CB1 receptor mediated, antinociceptive pathway.

Topics: Animals; Benzoxazines; Calcium Channel Blockers; Camphanes; Colitis; Colon; Dose-Response Relationship, Drug; Indoles; Inflammation; Male; Manometry; Morpholines; Muscle Contraction; Muscle, Smooth; Naphthalenes; Nociceptors; Pain; Piperidines; Pressure; Pyrazoles; Rats; Rats, Wistar; Receptors, Cannabinoid; Rimonabant; Trinitrobenzenesulfonic Acid

Starting with our previously described(20) class of CC chemokine receptor-3 (CCR3) antagonist, we improved the potency by replacing the phenyl linker of 1 with a cyclohexyl linker and by replacing the 4-benzylpiperidine with a 3-benzylpiperidine. The resulting compound, 32, is a potent and selective antagonist of CCR3. SAR studies showed that the 3-acetylphenyl urea of 32 could be replaced with heterocyclic ureas or heterocyclic-substituted phenyl ureas and still maintain the potency (inhibition of eotaxin-induced chemotaxis) of this class of compounds in the low-picomolar range (IC(50) = 10-60 pM), representing some of the most potent CCR3 antagonists reported to date. The potency of 32 for mouse CCR3 (chemotaxis IC(50) = 41 nM) and its oral bioavailability in mice (20% F ) were adequate to assess the efficacy in animal models of allergic airway inflammation. Oral administration of 32 reduced eosinophil recruitment into the lungs in a dose-dependent manner in these animal models. On the basis of its overall potency, selectivity, efficacy, and safety profile, the benzenesulfonate salt of 32, designated DPC168, entered phase I clinical trials.

Topics: Animals; Biological Availability; Caco-2 Cells; Calcium; Chemotaxis, Leukocyte; CHO Cells; Cricetinae; Cyclohexanes; Eosinophils; Female; Humans; Hypersensitivity; In Vitro Techniques; Inflammation; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Permeability; Phenylurea Compounds; Piperidines; Receptors, CCR3; Receptors, Chemokine; Stereoisomerism; Structure-Activity Relationship; Urea

Delta-9 tetrahydrocannabinol (Delta(9)-THC) and (-)-cannabidiol ((-)-CBD) are major constituents of the Cannabis sativa plant with different pharmacological profiles: (Delta(9)-THC activates cannabinoid CB(1) and CB(2) receptors and induces psychoactive and peripheral effects. (-)-CBD possesses no, or very weak affinity for these receptors. We tested a series of (+)- and (-)-CBD derivatives for central and peripheral effects in mice. None of the (-)-CBD derivatives were centrally active, yet most inhibited intestinal motility. Of the five (+)-CBD derivatives, all with CB(1) receptor affinity, only (+)-7-OH-CBD-DMH (DMH=1,1-dimethylheptyl), acted centrally, while all five arrested defecation. The effects of (+)-CBD-DMH and (+)-7-OH-CBD-DMH were inhibited by the CB(1) receptor antagonist SR141716. The CB(2) receptor antagonist SR144528, and the vanilloid TRPV1 receptor antagonist capsazepine, had no influence. Further, the (-)-CBD derivatives (-)-7-COOH-CBD and (-)-7-COOH-CBD-DMH, displayed antiinflammatory activity. We suggest that (+)-CBD analogues have mixed agonist/antagonist activity in the brain. Second, (-)-CBD analogues which are devoid of cannabinoid receptor affinity but which inhibit intestinal motility, suggest the existence of a non-CB(1), non-CB(2) receptor. Therefore, such analogues should be further developed as antidiarrheal and/or antiinflammatory drugs. We propose to study the therapeutic potential of (-)- and (+)-CBD derivatives for complex conditions such as inflammatory bowel disease and cystic fibrosis.

Topics: Animals; Binding, Competitive; Body Temperature; Camphanes; Cannabidiol; Capsaicin; Drug Interactions; Ear, External; Gastrointestinal Motility; Inflammation; Mice; Mice, Inbred ICR; Mice, Inbred Strains; Motor Activity; Pain Measurement; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant

Astrocytes play a key role regulating aspects of inflammation in the central nervous system (CNS). Several enzymes, such as the inducible nitric oxide synthase (iNOS) or the cyclooxygenase-2 (COX-2), along with different inflammatory mediators such as the free radical nitric oxide (NO) or proinflammatory cytokines, have been proposed to be involved in the cell damage associated with neuroinflammation. Recent studies suggest that the endogenous cannabinoid system (ECS) may be involved in the regulation of neuroinflammation. Cannabinoid agonists decrease neurotoxicity and release of proinflammatory factors from activated glial cells and anandamide itself is able to promote antiinflammatory responses in astrocytes via CB1 cannabinoid receptors. The present study is aimed at studying whether UCM707, a potent and selective anandamide uptake inhibitor, is able to inhibit the production of proinflammatory mediators by LPS-stimulated astrocytes. Our findings indicate that UCM707 is able to reduce NO release, iNOS expression, and the production of the proinflammatory cytokines tumoral necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) in a significant manner, while producing a slight increase in IL-6 levels. These effects can be reproduced by administration of the synthetic agonist HU210 and partially or totally blocked by administration of CB1 or CB2 selective antagonists, further supporting the involvement of the ECS. These results confirm the ability of UCM707 to reinforce the beneficial effects induced by anandamide and make it an attractive candidate for the management of those pathologies with neuroinflammation as one of their hallmarks.

Topics: Animals; Arachidonic Acids; Astrocytes; Cells, Cultured; Cytokines; Endocannabinoids; Furans; Inflammation; Lipopolysaccharides; Nitric Oxide; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant

The anti-inflammatory effect (AI) induced by peripheral injection of diluted bee venom (dBV) involves activation of spinal cord circuits and is mediated by catecholamine release from adrenal medulla, but the precise neuronal mechanisms involved are not fully understood. In a recent study, we demonstrated that an increase in spinal acetylcholine is involved in mediating the anti-inflammatory effect of dBV and that this mediation also involves adrenomedullary activation. The present study utilized the mouse air pouch inflammation model to evaluate the involvement of spinal acetylcholine receptors and sympathetic preganglionic neurons (SPNs) in dBV's anti-inflammatory effect (dBVAI). Intrathecal (IT) pretreatment with atropine (muscarinic cholinergic antagonist) but not hexamethonium (nicotinic cholinergic antagonist) significantly suppressed dBVAI on zymosan-evoked leukocyte migration. Subsequent experiments showed that IT pretreatment with methoctramine (a muscarinic receptor type 2; M(2) antagonist), but not pirenzepine (an M(1) antagonist) or 4-DAMP (an M(3) antagonist), suppressed the dBVAI. In addition, dBV stimulation specifically increased Fos expression in SPNs of the T7-T11, but not the T1-T6 or T12-L2 spinal cord segments, in animals with zymosan-induced inflammation. Moreover, IT methoctramine pretreatment suppressed this dBV-induced Fos expression specifically in SPNs of T7-T11 level. Peripheral sympathetic denervation using 6-hydroxydopamine (6-OHDA) treatment (which spares sympathetic adrenal medullary innervation) did not alter dBVAI. Collectively these results indicate that dBV stimulation leads to spinal cord acetylcholine release that in turn acts on spinal M(2) receptors, which via a hypothesized disinhibition mechanism activates SPNs that project to the adrenal medulla. This activation ultimately leads to the release of adrenal catecholamines that contribute to dBVAI.

Topics: Animals; Animals, Newborn; Anti-Inflammatory Agents; Atropine; Autonomic Fibers, Preganglionic; Bee Venoms; Catecholamines; Cell Count; Choline O-Acetyltransferase; Disease Models, Animal; Drug Interactions; Exudates and Transudates; Hexamethonium; Immunohistochemistry; Inflammation; Leukocytes; Male; Mice; Mice, Inbred ICR; Muscarinic Antagonists; Neurons; Nicotinic Antagonists; Oncogene Proteins v-fos; Oxidopamine; Piperidines; Pirenzepine; Receptor, Muscarinic M2; Spinal Cord; Sympathectomy, Chemical

We studied morphology of the regeneratory process in gingival tissues during treatment of exacerbation of chronic generalized periodontitis. Richlocaine treatment led to more pronounced activation of neoangiogenesis in inflammatory cellular infiltrate in comparison with traditional drug treatment. Richlocaine stimulated vascularization of regenerating tissues, promoted more extensive normalization of the structure of the gingival mucosa, and prevented the development of fibrosclerotic changes.

Topics: Biopsy; Fibrosis; Gingiva; Humans; Inflammation; Models, Theoretical; Mouth Mucosa; Neovascularization, Pathologic; Periodontitis; Piperidines; Regeneration; Treatment Outcome

Endothelin receptors have been involved in inflammatory, neuropathic and tumoral pain. In the case of inflammatory hyperalgesia, some previous papers have pointed towards the involvement of ETB receptors, although the stimulation of ETA receptors seems to participate in the development of the inflammatory reaction. We have studied the effect of ETA and ETB receptor antagonists in the thermal and mechanical hyperalgesia induced in a model of acute (induced by carrageenan) and chronic (induced by complete Freund's adjuvant, CFA) inflammation in mice. The i.pl. administration of the selective ETA antagonist BQ-123 (1-10 nmol) antagonized the thermal hyperalgesia detected by the unilateral hot plate test, observed in both inflammatory models, whereas the i.pl. administration of the ETB selective antagonist BQ-788 (17.7 nmol) failed to modify this. In contrast, both BQ-123 (3-17.7 nmol) and BQ-788 (3-17.7 nmol) antagonized the mechanical hyperalgesia, as assessed by the Randall-Selitto test in carrageenan- and CFA-treated mice. Both BQ-123 and BQ-788 were able to antagonize the mechanical hyperalgesia induced by ET-1 (200 pmol; i.pl.) in the same dose range. Thus, ETA receptors are involved in both thermal and mechanical hyperalgesia whereas ETB receptors are only involved in mechanical hyperalgesia in these inflammatory models. In conclusion, the role of ETB receptors in inflammatory pain is further supported and new insights into the participation of ETA receptors in inflammatory hyperalgesia are given.

Topics: Animals; Carrageenan; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Freund's Adjuvant; Hot Temperature; Hyperalgesia; Inflammation; Male; Mice; Oligopeptides; Pain Measurement; Peptides, Cyclic; Physical Stimulation; Piperidines; Receptor, Endothelin A; Receptor, Endothelin B; Time Factors

We characterized the effect of a novel selective histamine H1 receptor antagonist, (R)-1-(3-(10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5-ylidene)-1-propyl)-3-piperidine carboxylic acid (ReN-1869), on the responses of dorsal horn neurons in anesthetized rats after carrageenan induced-inflammation and peripheral neuropathy (L5/6 spinal nerve ligation; SNL). ReN-1869 was administered systemically (0.1-4 mg/kg), and drug effects were assessed using a wide range of peripheral electrical and natural stimuli (brush, von Frey filaments, and heat). Comparisons were made between unoperated naive groups and either carrageenan inflamed or SNL rats. ReN-1869 produced little effect on the electrically evoked responses (wind-up, Abeta-, Adelta-, and C-fiber-evoked responses); however, it significantly attenuated neuronal responses to noxious heat in carrageenan and SNL rats. A robust effect was seen with the low-threshold mechanical punctate (von Frey 9 g) stimuli, which were selectively inhibited by ReN-1869 after tissue and nerve injury. These inhibitory actions were in marked contrast to the naive animal group, where only nonsignificant effects were observed. To investigate whether the actions of ReN-1869 are mediated via the antagonism of histamine H1 receptors, the effects of this novel compound were compared with that of another H1 receptor antagonist, mepyramine (1-20 mg/kg). Systemic mepyramine produced strong inhibitions of the 9-g von Frey-evoked responses in carrageenan and SNL rats. The similar pharmacological profile of these two compounds suggests for a similar mechanism of action. We propose that ReN-1869 may represent a novel agent for the treatment of certain modalities of persistent pain states, in particular for the treatment of mechanical allodynia.

Topics: Analgesics; Animals; Disease Models, Animal; Electrophysiology; Histamine H1 Antagonists; Inflammation; Male; Neurons; Pain; Peripheral Nervous System Diseases; Piperidines; Posterior Horn Cells; Pyrilamine; Rats; Rats, Sprague-Dawley; Spinal Cord

Topics: Analgesics; Burning Mouth Syndrome; Europe; Facial Pain; Humans; Inflammation; Pain; Peripheral Nerve Injuries; Piperidines; Pyridines; Temporomandibular Joint Disorders; Trust

A neurogenic component has been suggested to play a pivotal role in a range of inflammatory/immune diseases. Mustard oil (allyl-isothiocyanate) has been used in studies of inflammation to mediate neurogenic vasodilatation and oedema in rodent skin. The aim of the present study was to analyse mustard oil-induced oedema and neutrophil accumulation in the mouse ear focussing on the roles of neurokinin 1 (NK(1)) and vanilloid (TRPV1) receptors using normal (BALB/c, C57BL/6) as well as NK(1) and TRPV1 receptor knockout mice. A single or double treatment of 1% mustard oil on the BALB/c mouse ear induced ear oedema with responses diminished by 6 h. However a 25-30% increase in ear thickness was maintained by the hourly reapplication of mustard oil. Desensitisation of sensory nerves with capsaicin, or the NK(1) receptor antagonist SR140333, inhibited oedema but only in the first 3 h. Neutrophil accumulation in response to mustard oil was inhibited neither by SR140333 nor capsaicin pre-treatment. An activating dose of capsaicin (2.5%) induced a large oedema in C57BL/6 wild-type mice that was minimal in TRPV1 receptor knockout mice. By comparison, mustard oil generated ear swelling was inhibited by SR140333 in wild-type and TRPV1 knockout mice. Repeated administration of mustard oil maintained 35% oedema in TRPV1 knockout animals and the lack of TRPV1 receptors did not alter the leukocyte accumulation. In contrast repeated treatment caused about 20% ear oedema in Sv129+C57BL/6 wild-type mice but the absence of NK(1) receptors significantly decreased the response. Neutrophil accumulation showed similar values in both groups. This study has revealed that mustard oil can act via both neurogenic and non-neurogenic mechanisms to mediate inflammation in the mouse ear. Importantly, the activation of the sensory nerves was still observed in TRPV1 knockout mice indicating that the neurogenic inflammatory component occurs via a TRPV1 receptor independent process.

Topics: Animals; Capillary Permeability; Capsaicin; Dose-Response Relationship, Drug; Ear; Edema; Inflammation; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Mustard Plant; Neurokinin-1 Receptor Antagonists; Piperidines; Plant Extracts; Plant Oils; Quinuclidines; Receptors, Drug; Receptors, Neurokinin-1; Staining and Labeling; Time Factors; TRPV Cation Channels

Ras farnesyltransferase inhibitor (FTI) exhibit antiproliferative and antiangiogenic effects through a mechanism that is poorly understood. Because of the known role of Ras in the activation of transcription factor NF-kappaB and because NF-kappaB-regulated genes can control cell survival and angiogenesis, we postulated that FTI mediates its effects in part by modulating NF-kappaB activation. Therefore, in the present study we investigated the effect of FTI, SCH 66336, on NF-kappaB and NF-kappaB-regulated gene expression activated by a variety of inflammatory and carcinogenic agents. We demonstrate by DNA-binding assay that NF-kappaB activation induced by tumor necrosis factor (TNF), phorbol 12-myristate 13-acetate, cigarette smoke, okadaic acid, and H(2)O(2) was completely suppressed by SCH 66336; the suppression was not cell type-specific. This FTI suppressed the activation of IkappaBalpha kinase (IKK), thus abrogating the phosphorylation and degradation of IkappaBalpha. Additionally, TNF-activated Ras and SCH 66336 inhibited the activation. Also, overexpression of Ras (V12) enhanced TNF-induced NF-kappaB activation, and adenoviral dominant-negative Ras (N17) suppressed the activation, thus suggesting the critical role of Ras in TNF signaling. SCH 66336 also inhibited the NF-kappaB-dependent reporter gene expression activated by TNF, TNFR1, TRADD, TRAF2, NIK, and IKK but not that activated by the p65 subunit of NF-kappaB. The TNF-induced NF-kappaB-regulated gene products cyclin D1, COX-2, MMP-9, survivin, IAP1, IAP2, XIAP, Bcl-2, Bfl-1/A1, TRAF1, and FLIP were all down-regulated by SCH 66336, which potentiated apoptosis induced by TNF and doxorubicin. Overall, our results indicate that SCH 66336 inhibited activation of NF-kappaB and NF-kappaB-regulated gene expressions induced by carcinogens and inflammatory stimuli, which may provide a molecular basis for the ability of SCH 66336 to suppress proliferation and angiogenesis.

Topics: Active Transport, Cell Nucleus; Alkyl and Aryl Transferases; Apoptosis; Blotting, Western; Carcinogens; Cell Division; Cell Line, Tumor; Cell Survival; Cytoplasm; DNA; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Inhibitors; Gene Expression Regulation, Neoplastic; Humans; Hydrogen Peroxide; I-kappa B Kinase; Immunohistochemistry; In Situ Nick-End Labeling; Inflammation; Jurkat Cells; Models, Chemical; Neovascularization, Pathologic; NF-kappa B; Okadaic Acid; Phosphorylation; Piperidines; Protein Binding; Protein Serine-Threonine Kinases; Pyridines; ras Proteins; Smoking; Time Factors; Tumor Necrosis Factor-alpha; Up-Regulation

1. We describe here the alterations in the nociceptive sensitivity of Swiss CD1 mice receiving an intraplantar (i.pl.) administration of XC Rous sarcoma-virus-transformed rat fibroblasts (XC cells). 2. Histological studies reveal that XC cells remain at the injection site 2-3 weeks after implantation, a time at which an inflammatory reaction is also detected. No tumoral growth was found and 5 weeks after inoculation neither XC cells nor inflammatory reaction were observed. 3. Measures to different types of noxious stimuli were performed. At week 1 after XC cell inoculation, hyperalgesia to thermal, but not mechanical, stimuli as well as to capsaicin injection is present in the implanted paw. At week 5 after XC cell implantation, only thermal hyperalgesia is present, and this enhanced reactivity persisted for even 25 weeks after the disappearance of XC tumoral cells. 4. Pharmacological studies on thermal hyperalgesia were conducted at two different stages, week 1 and week 5 after XC cell inoculation. The systemic administration of morphine (1-10 mg/kg i.p. (intraperitoneal); 30 min before testing) prevents this thermal hyperalgesic reaction both at week 1 and week 5. The endothelin type A (ETA) receptor antagonist BQ-123 (10 nmol; i.pl.; 90 min before testing) abolishes both the early (week 1) and the late (week 5) thermal hyperalgesia. In contrast, the selective endothelin type B (ETB) receptor antagonist, BQ-788 (10 nmol; i.pl.; 90 min before) abolishes thermal hyperalgesia only at week 1, but not at week 5 after XC cell inoculation. 5. It might be concluded that endothelins are probably involved in this type of long-term thermal hyperalgesia produced by the transitory presence of the XC tumoral cell line.

Topics: Animals; Avian Sarcoma Viruses; Capsaicin; Cell Line, Transformed; Cell Line, Tumor; Chronic Disease; Endothelin Receptor Antagonists; Endothelins; Fibroblasts; Genetic Vectors; Hindlimb; Hyperalgesia; Inflammation; Male; Mice; Morphine; Neoplasm Regression, Spontaneous; Neoplasm Transplantation; Nociceptors; Oligopeptides; Pain Measurement; Peptides, Cyclic; Piperidines; Rats; Reaction Time; Receptors, Endothelin

Cannabidiol (CBD), a nonpsychoactive marijuana constituent, was recently shown as an oral antihyperalgesic compound in a rat model of acute inflammation. We examined whether the CBD antihyperalgesic effect could be mediated by cannabinoid receptor type 1 (CB1) or cannabinoid receptor type 2 (CB2) and/or by transient receptor potential vanilloid type 1 (TRPV1). Rats received CBD (10 mg kg(-1)) and the selective antagonists: SR141716 (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide) for CB1, SR144528 (N-[(1S)-endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)pyrazole-3 carboxamide) for CB2 and capsazepine (CPZ) for TRPV1 receptors. The intraplantar injection of carrageenan in rats induced a time-dependent thermal hyperalgesia, which peaked at 3 h and decreased at the following times. CBD, administered 2 h after carrageenan, abolished the hyperalgesia to the thermal stimulus evaluated by plantar test. Neither SR141716 (0.5 mg kg(-1)) nor SR144528 (3 and 10 mg kg(-1)) modified the CBD-induced antihyperalgesia; CPZ partially at the lowest dose (2 mg kg(-1)) and fully at the highest dose (10 mg kg(-1)) reversed this effect. These results demonstrate that TRPV1 receptor could be a molecular target of the CBD antihyperalgesic action.

Topics: Administration, Oral; Animals; Camphanes; Cannabidiol; Capsaicin; Carrageenan; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Therapy, Combination; Hyperalgesia; Inflammation; Italy; Male; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Receptors, Drug; Rimonabant; Time Factors

Effects of the CB2-selective cannabinoid agonist AM1241 on activity evoked in spinal wide dynamic range (WDR) neurons by transcutaneous electrical stimulation were evaluated in urethane-anesthetized rats. Recordings were obtained in both the absence and the presence of carrageenan inflammation. AM1241, administered intravenously or locally in the paw, suppressed activity evoked by transcutaneous electrical stimulation during the development of inflammation. Decreases in WDR responses resulted from a suppression of C-fiber-mediated activity and windup. Abeta- and Adelta-fiber-mediated responses were not reliably altered. The AM1241-induced suppression of electrically evoked responses was blocked by the CB2 antagonist SR144528 but not by the CB1 antagonist SR141716A. AM1241 (33 microg/kg intraplantar [i.p.l.]), administered to the carrageenan-injected paw, suppressed activity evoked in WDR neurons relative to groups receiving vehicle in the same paw or AM1241 in the opposite (noninflamed) paw. The electrophysiological effects of AM1241 (330 microg/kg intravenous [i.v.]) were greater in rats receiving i.p.l. carrageenan compared with noninflamed rats receiving an i.p.l. injection of vehicle. AM1241 failed to alter the activity of purely nonnociceptive neurons recorded in the lumbar dorsal horn. Additionally, AM1241 (330 microg/kg i.v. and i.p.l.; 33 microg/kg i.p.l.) reduced the diameter of the carrageenan-injected paw. The AM1241-induced decrease in peripheral edema was blocked by the CB2 but not by the CB1 antagonist. These data demonstrate that activation of cannabinoid CB2 receptors is sufficient to suppress neuronal activity at central levels of processing in the spinal dorsal horn. Our findings are consistent with the ability of AM1241 to normalize nociceptive thresholds and produce antinociception in inflammatory pain states.

Topics: Analgesics; Animals; Camphanes; Cannabinoids; Carrageenan; Edema; Electric Stimulation; Inflammation; Male; Nerve Fibers, Unmyelinated; Nociceptors; Piperidines; Posterior Horn Cells; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB2; Rimonabant

Peripheral cannabinoid 2 receptors (CB2 receptors) modulate immune responses and attenuate nociceptive behaviour in models of acute and persistent pain. The aim of the present study was to investigate whether peripheral CB2 receptors modulate spinal processing of innocuous and noxious responses and to determine whether there are altered roles of CB2 receptors in models of persistent pain. Effects of local administration of the CB2 receptor agonist JWH-133 (5 and 15 microg/50 microL) on mechanically evoked responses of spinal wide dynamic range (WDR) neurons in noninflamed rats, rats with carrageenan-induced hindpaw inflammation, sham operated rats and spinal nerve-ligated (SNL) rats were determined in anaesthetized rats in vivo. Mechanical stimulation (von Frey filaments, 6-80 g) of the peripheral receptive field evoked firing of WDR neurons. Mechanically evoked responses of WDR neurons were similar in noninflamed, carrageenan-inflamed, sham-operated and SNL rats. Intraplantar injection of JWH-133 (15 microg), but not vehicle, significantly (P < 0.05) inhibited innocuous and noxious mechanically evoked responses of WDR neurons in all four groups of rats. In many cases the selective CB2 receptor antagonist, SR144528 (10 microg/50 microL), attenuated the inhibitory effects of JWH-133 (15 microg) on mechanically evoked WDR neuronal responses. The CB1 receptor antagonist, SR141716A, did not attenuate the inhibitory effects of JWH-133 on these responses. Intraplantar preadministration of JWH-133 also inhibited (P < 0.05) carrageenan-induced expansion of peripheral receptive fields of WDR dorsal horn neurons. This study demonstrates that activation of peripheral CB2 receptors attenuates both innocuous- and noxious-evoked responses of WDR neurons in models of acute, inflammatory and neuropathic pain.

Topics: Action Potentials; Animals; Camphanes; Cannabinoids; Carrageenan; Disease Models, Animal; Inflammation; Ligation; Male; Neural Inhibition; Neuralgia; Nociceptors; Peripheral Nervous System Diseases; Physical Stimulation; Piperidines; Posterior Horn Cells; Pyrazoles; Rats; Rats, Sprague-Dawley; Reaction Time; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant; Sensory Receptor Cells; Spinal Nerves

We report a patient who presented with multiple small submucosal nodules with granulomatous inflammation in the minor salivary glands of the oral cavity. A 43-year-old woman presented with a 1-week history of multiple small submucosal nodules in her oral cavity after having taken medicine for abdominal pain. The patient did not have a history of fever, rectal bleeding, skin lesions or arthritis, but did have a history of drug allergy and bronchial asthma. Histopathological examination of the submucosal nodules showed sialadenitis with marked infiltration of lymphocytes, eosinophilic cells, macrophages and Langhans-type or foreign-body-type multinucleate giant cells. The macrophages tended to be aggregated and appeared to have caused immature granuloma formation without caseous necrosis. Degranulated eosinophilic cells were numerous. Sarcoidosis, Crohn's disease, tuberculosis and atypical mycobacterial infection were not identified by medical examination. Three weeks after discontinuing the medication the patient was seen again at a follow-up visit. Multiple submucosal small nodules and other symptoms were not evident at that time. This case report may represent a new entity of salivary gland disease that we tentatively refer to as 'allergic granulomatous sialadenitis'.

Topics: Abdominal Pain; Adult; Anti-Ulcer Agents; Diagnosis, Differential; Enzymes; Female; Granuloma; Humans; Hypersensitivity; Inflammation; Liver Diseases; Piperidines; Ranitidine; Salivary Glands, Minor; Sialadenitis

The present studies were conducted to test the hypothesis that systemically inactive doses of cannabinoids suppress inflammation-evoked neuronal activity in vivo via a peripheral mechanism. We examined peripheral cannabinoid modulation of spinal Fos protein expression, a marker of neuronal activity, in a rat model of inflammation. Rats received unilateral intraplantar injections of carrageenan (3%). In behavioral studies, carrageenan induced allodynia and mechanical hyperalgesia in response to stimulation with von Frey monofilaments. The cannabinoid agonist WIN55,212-2 (30 microg intraplantarly), administered concurrently with carrageenan, attenuated carrageenan-evoked allodynia and hyperalgesia relative to control conditions. In immunocytochemical studies, WIN55,212-2 suppressed the development of carrageenan-evoked Fos protein expression in the lumbar dorsal horn of the spinal cord relative to vehicle treatment. The same dose administered systemically or to the noninflamed contralateral paw failed to alter either carrageenan-evoked allodynia and hyperalgesia or carrageenan-evoked Fos protein expression, consistent with a peripheral site of action. The suppressive effects of WIN55,212-2 (30 microg intraplantarly) on carrageenan-evoked Fos protein expression and pain behavior were blocked by local administration of either the CB(2) antagonist SR144528 (30 microg intraplantarly) or the CB(1) antagonist SR141716A (100 microg intraplantarly). WIN55,212-3, the enantiomer of the active compound, also failed to suppress carrageenan-evoked Fos protein expression. These data provide direct evidence that a peripheral cannabinoid mechanism suppresses the development of inflammation-evoked neuronal activity at the level of the spinal dorsal horn and implicate a role for CB(2) and CB(1) in peripheral cannabinoid modulation of inflammatory nociception.

Topics: Analgesics; Animals; Behavior, Animal; Benzoxazines; Camphanes; Cannabinoids; Carrageenan; Disease Models, Animal; Drug Administration Routes; Drug Interactions; Edema; Functional Laterality; Gene Expression Regulation; Immunohistochemistry; Inflammation; Male; Mechanoreceptors; Morpholines; Naphthalenes; Pain; Pain Measurement; Physical Stimulation; Piperidines; Proto-Oncogene Proteins c-fos; Pyrazoles; Rats; Rats, Sprague-Dawley; Rimonabant; Spinal Cord; Time Factors

Activation of colonic proteinase-activated receptor-2 (PAR-2) provokes colonic inflammation and increases mucosal permeability in mice. The mechanism of inflammation is under debate and could be neurogenic and/or the consequence of tight-junction opening with passage of exogenous pathogens into the lamina propria. The present study aimed to further characterize the inflammatory effect of PAR-2 activation by investigating: 1) the role of NO, 2) the role of afferent neurons, and 3) a possible cause and effect relationship between colonic paracellular permeability changes and mucosal inflammation. Thus, intracolonic infusion to mice of the PAR-2-activating peptide, SLIGRL, increased both myeloperoxidase (MPO) activity and damage scores indicating colonic inflammation, and enhanced colonic permeability to (51)Cr-EDTA from 2 to 4 h after its infusion. NO synthase inhibitors, L-NAME and aminoguanidine, as well as the neurotoxin capsaicin and NK1, calcitonin gene-related peptide (CGRP) receptor antagonists, SR140333 and CGRP(8-37), prevented SLIGRL-induced MPO and damage score increases and permeability. In contrast, although the tight-junction blocker, 2,4,6-triaminopyrimidine, and the myosin L chain kinase inhibitor, ML-7, prevented SLIGRL-induced increase in permeability, they did not prevent MPO and damage score increases. Taken together our data show that both NO and capsaicin-sensitive afferent neurons are involved in PAR-2-mediated colonic inflammation and paracellular permeability increase. Nevertheless, the inflammation process is not a consequence of increased permeability which results at least in part from the activation of myosin L chain kinase.

Topics: Administration, Rectal; Animals; Antigens; Antigens, Surface; Azepines; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Cell Membrane Permeability; Colon; Denervation; Enzyme Inhibitors; Inflammation; Injections, Intraperitoneal; Intercellular Junctions; Intestinal Mucosa; Lectins, C-Type; Male; Mice; Myosin-Light-Chain Kinase; Naphthalenes; Neurons, Afferent; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; NK Cell Lectin-Like Receptor Subfamily B; Oligopeptides; Peptide Fragments; Piperidines; Proteins; Pyrimidines; Quinuclidines; Receptor, PAR-2; Receptors, Thrombin

In our study, the effects of the compound 3-benzoyl-1-methyl-4-phenyl-4-piperidinol hydrochloride (C1) and also an anti-inflammatory drug, indomethacin, tested by carrageenan-induced paw edema and cotton pellet granuloma tests, for their effects on acute and chronic phases of inflammation, respectively. Their effects on vascular permeability were also tested by hyaluronidase-induced capillary permeability. C1 decreased the carrageenan-induced paw edema 61.98, 80.84, and 90.32% at 50, 100, and 200mgkg(-1) doses, respectively, while this decrease was 89.93% by indomethacin at 20mgkg(-1) dose. Antiproliferative effects of C1 at 100mgkg(-1) and indomethacinin at 20mgkg(-1) doses were 46.1 and 43.1%, respectively, in cotton pellet test. C1 and indomethacin both significantly inhibited the hyaluronidase-induced increase in capillary permeability.

Topics: Analysis of Variance; Animals; Anti-Inflammatory Agents, Non-Steroidal; Capillary Permeability; Carrageenan; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Granuloma, Foreign-Body; Hyaluronoglucosaminidase; Indomethacin; Inflammation; Male; Piperidines; Rats; Rats, Wistar

Activation of cannabinoid CB(2) receptors attenuates thermal nociception in untreated animals while failing to produce centrally mediated effects such as hypothermia and catalepsy [Pain 93 (2001) 239]. The present study was conducted to test the hypothesis that activation of CB(2) in the periphery suppresses the development of inflammatory pain as well as inflammation-evoked neuronal activity at the level of the CNS. The CB(2)-selective cannabinoid agonist AM1241 (100, 330 micrograms/kg i.p.) suppressed the development of carrageenan-evoked thermal and mechanical hyperalgesia and allodynia. The AM1241-induced suppression of carrageenan-evoked behavioral sensitization was blocked by the CB(2) antagonist SR144528 but not by the CB(1) antagonist SR141716A. Intraplantar (ipl) administration of AM1241 (33 micrograms/kg ipl) suppressed hyperalgesia and allodynia following administration to the carrageenan-injected paw but was inactive following administration in the contralateral (noninflamed) paw, consistent with a local site of action. In immunocytochemical studies, AM1241 suppressed spinal Fos protein expression, a marker of neuronal activity, in the carrageenan model of inflammation. AM1241 suppressed carrageenan-evoked Fos protein expression in the superficial and neck region of the dorsal horn but not in the nucleus proprius or the ventral horn. The suppression of carrageenan-evoked Fos protein expression induced by AM1241 was blocked by coadministration of SR144528 in all spinal laminae. These data provide evidence that actions at cannabinoid CB(2) receptors are sufficient to suppress inflammation-evoked neuronal activity at rostral levels of processing in the spinal dorsal horn, consistent with the ability of AM1241 to normalize nociceptive thresholds and produce antinociception in inflammatory pain states.

Topics: Analgesics; Animals; Camphanes; Cannabinoids; Carrageenan; Disease Models, Animal; Drug Interactions; Hyperalgesia; Inflammation; Male; Nociceptors; Pain; Pain Threshold; Piperidines; Posterior Horn Cells; Proto-Oncogene Proteins c-fos; Pyrazoles; Rats; Rats, Sprague-Dawley; Reaction Time; Receptor, Cannabinoid, CB2; Receptors, Cannabinoid; Receptors, Drug; Rimonabant

Mast cell activation, bronchoconstriction, inflammation and airway hyperreactivity are prominent features of non-atopic hypersensitivity reactions in mouse airways. We studied the role of tachykinin receptors in mice that were skin-sensitized with dinitrofluorobenzene (or vehicle) and challenged intranasally with dinitrobenzene sulfonic acid. Tachykinin NK1 receptor blockade, by treatment with the antagonist RP67580, or absence of the tachykinin NK1 receptor resulted in a strong reduction in the accumulation of neutrophils in the bronchoalveolar lavage fluid, and in the development of tracheal hyperreactivity in mice 48 h after challenge. In contrast, treatment with the tachykinin NK2 receptor antagonist SR48968 did not affect the dinitrofluorobenzene-induced hypersensitivity reaction. We have previously shown that mast cells play a crucial role in the development of non-atopic asthma. However, we did not observe an inhibitory effect of the tachykinin receptor antagonists or the genetic absence of tachykinin NK1 receptors on mast cell protease release. In conclusion, distal from mast cell activation, the tachykinin NK1 receptor is crucial for the infiltration of pulmonary neutrophils and the development of tracheal hyperreactivity in non-atopic asthma.

Topics: Administration, Intranasal; Airway Obstruction; Animals; Benzamides; Dinitrofluorobenzene; Hypersensitivity; In Vitro Techniques; Indoles; Inflammation; Isoindoles; Leukocytes; Male; Mast Cells; Mice; Mice, Inbred BALB C; Mice, Knockout; Neurokinin-1 Receptor Antagonists; Piperidines; Receptors, Neurokinin-1; Receptors, Neurokinin-2; Trachea

This study investigated the role of neurokinin 1 receptors (NK1R) in inflammatory cutaneous orofacial pain. The effects of subcutaneous and intracisternal administration of the NK1R antagonist SR140333 on the face rubbing response provoked by injection of 50 micro l of 1.5% formalin into the vibrissa pad were examined. Subcutaneous administration of SR140333 (5, 15, 30 mg/kg) induced a dose-related depressant effect on both the first and second phases of the formalin test. In contrast, intracisternal administration of SR140333 (10, 30, 60, 90 microg) produced a decrease only on the second phase with an apparent ceiling effect at approximately 50%. These data suggest that persistent nociceptive effects associated with orofacial cutaneous inflammation depend at least in part on the activation of NK1R.

Topics: Animals; Behavior, Animal; Cisterna Magna; Dose-Response Relationship, Drug; Facial Pain; Formaldehyde; Inflammation; Injections; Male; Neurokinin-1 Receptor Antagonists; Pain Measurement; Piperidines; Postural Balance; Quinuclidines; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-1

Proteinase-activated receptor-2 (PAR2) activation induces colonic inflammation by an unknown mechanism. We hypothesized that PAR2 agonists administered intracolonically in mice induce inflammation via a neurogenic mechanism. Pretreatment of mice with neurokinin-1 and calcitonin-gene-related peptide (CGRP) receptor antagonists or with capsaicin showed attenuated PAR2-agonist-induced colitis. Immunohistochemistry demonstrated a differential expression of a marker for the type-1 CGRP receptor during the time course of PAR2-agonist-induced colitis, further suggesting a role for CGRP. We conclude that PAR2-agonist-induced intestinal inflammation involves the release of neuropeptides, which by acting on their receptors cause inflammation. These results implicate PAR2 as an important mediator of intestinal neurogenic inflammation.

Topics: Animals; Calcitonin Gene-Related Peptide; Capsaicin; Colitis; Enteric Nervous System; Inflammation; Mice; Neurons, Afferent; Neuropeptides; Oligopeptides; Piperidines; Quinuclidines; Receptor, PAR-2; Receptors, Neurokinin-1

The presence of cannabinoid1 (CB1) receptors on primary afferent fibres may provide a novel target for cannabinoid analgesics. The present study investigated the ability of peripheral CB1 receptors to modulate innocuous and noxious transmission in noninflamed rats and rats with peripheral carrageenan inflammation. Effects of peripheral injection of arachidonyl-2-choroethylamide (ACEA; 10 and 30 micro g in 50 micro L), a selective CB1 receptor agonist, on mechanically evoked responses of dorsal horn neurons were studied in noninflamed rats and rats with peripheral carrageenan inflammation. Peripheral injection of ACEA (30 micro g in 50 micro L) significantly inhibited innocuous (12 g) mechanically evoked responses of spinal neurons in noninflamed (27 +/- 4% of control; P < 0.01) and inflamed (12 +/- 8% of control; P < 0.05) rats. Similarly, noxious (80 g) mechanically evoked responses of spinal neurons were inhibited by peripheral injection of ACEA (30 micro g in 50 micro L) in noninflamed rats (51 +/- 9% of control; P < 0.01) and rats with peripheral carrageenan inflammation (21 +/- 8% of control; P < 0.01). Inhibitory effects of ACEA were significantly greater in rats with peripheral carrageenan inflammation than in noninflamed rats (P < 0.05). Inhibitory effects of ACEA were significantly blocked by coadministration of the CB1 receptor antagonist SR141716A in both groups of rats. Peripheral injection of SR141716A alone did not alter mechanically evoked responses of spinal neurons in either group of rats. These data demonstrate that activation of peripheral CB1 receptors can inhibit innocuous and noxious somatosensory processing. Furthermore, following peripheral inflammation there is an enhanced inhibitory effect of a peripherally administered CB1 receptor agonist on both innocuous and noxious mechanically evoked responses of spinal neurons.

Topics: Animals; Arachidonic Acids; Carrageenan; Diterpenes; Dose-Response Relationship, Drug; Drug Interactions; Evoked Potentials; Hindlimb; Inflammation; Male; Neural Inhibition; Physical Stimulation; Piperidines; Posterior Horn Cells; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptors, Drug; Rimonabant; Spinal Cord; Time Factors

The local anesthetic richlocaine decreased the area of necrosis in the skin flap under conditions of reduced blood flow by 29.5%. Improved survival of skin flap after richlocaine treatment alleviated endogenous intoxication, reduced secondary inflammatory reaction, improved liver function, and normalized the ratio between vasoconstricting and vasodilating prostaglandins. This effect was most pronounced after combination therapy with richlocaine and direct-action antihypoxant energostim.

Topics: Alanine Transaminase; Animals; Antioxidants; Aspartate Aminotransferases; Cell Survival; Cytochromes c; Drug Combinations; Endotoxemia; Erythrocytes; Histamine; Hydroxyproline; Hypoxia; Inflammation; Inosine; Keratinocytes; Lactates; Male; NAD; Necrosis; Piperidines; Rats; Regional Blood Flow; Serotonin; Skin; Surgical Flaps; Time Factors; Vasodilator Agents

Release of human lung mast cell tryptase may be important in the pathophysiology of asthma. We examined the effect of the reversible, nonelectrophilic tryptase inhibitor MOL 6131 on airway inflammation and hyper-reactivity in a murine model of asthma. MOL 6131 is a potent selective nonpeptide inhibitor of human lung mast cell tryptase based upon a beta-strand template (K(i) = 45 nM) that does not inhibit trypsin (K(i) = 1,061 nM), thrombin (K(i) = 23, 640 nM), or other serine proteases. BALB/c mice after i.p. OVA sensitization (day 0) were challenged intratracheally with OVA on days 8, 15, 18, and 21. MOL 6131, administered days 18-21, blocked the airway inflammatory response to OVA assessed 24 h after the last OVA challenge on day 22; intranasal delivery (10 mg/kg) had a greater anti-inflammatory effect than oral delivery (10 or 25 mg/kg) of MOL 6131. MOL 6131 reduced total cells and eosinophils in bronchoalveolar lavage fluid, airway tissue eosinophilia, goblet cell hyperplasia, mucus secretion, and peribronchial edema and also inhibited the release of IL-4 and IL-13 in bronchoalveolar lavage fluid. However, tryptase inhibition did not alter airway hyper-reactivity to methacholine in vivo. These results support tryptase as a therapeutic target in asthma and indicate that selective tryptase inhibitors can reduce allergic airway inflammation.

Topics: Animals; Asthma; Bridged Bicyclo Compounds, Heterocyclic; Bronchial Diseases; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Cell Movement; Cytokines; Eosinophils; Humans; Inflammation; Lung; Mice; Mice, Inbred BALB C; Models, Molecular; Mucus; Ovalbumin; Piperidines; Pulmonary Edema; Pulmonary Eosinophilia; Serine Endopeptidases; Serine Proteinase Inhibitors; Tryptases; Vascular Cell Adhesion Molecule-1

Hypohalites (OCl-, OBr-) are formed at inflammation sites as antimicrobial agents. OCl- is also used for the disinfection of water supplies and the association of drinking chlorinated water with cancer risk is pointed out. In this study, OCl- itself induced 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) formation, while OBr- damaged DNA only when glutathione (GSH) was added. OCl- caused oxidative DNA damage more efficiently than OBr-/GSH. In experiment with 32P-labeled DNA fragments, OCl- strongly caused piperidine-labile sites at guanine residues than piperidine-inert 8-oxodG, whereas OBr-/GSH caused no piperidine-labile sites. Endogenous OCl- may play a role in genotoxicity close to the site of inflammation.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Bromates; Carcinogens; Cattle; Cell Line; Deoxyguanosine; Dimethyl Sulfoxide; DNA; DNA Damage; Electron Spin Resonance Spectroscopy; Genes, p53; Genes, ras; Genes, Tumor Suppressor; Glutathione; Humans; Inflammation; Neoplasms; Oxidation-Reduction; Phosphorus Isotopes; Piperidines; Sodium Hypochlorite

Impending upper airway obstruction due to odontogenic facial and cervical spreading infection is a potential fatal situation that requires urgent treatment. In particular, securing the threatened airway is a priority and a precondition to the pressing need for surgery. The best approach to establish the difficult airway is awake fiberoptic intubation or scheduled tracheotomy under local anesthesia. We report a critical case of severe swelling of the neck in a morbidly obese patient with no alternative to awake fiberoptic intubation. The primary goals of optimal safety for the patient and appropriate intubating conditions for the anesthesiologist made us to consider a new method of patient medication.

Topics: Airway Obstruction; Analgesics, Opioid; Fiber Optic Technology; Hemodynamics; Humans; Inflammation; Intubation, Intratracheal; Male; Middle Aged; Neck; Obesity, Morbid; Piperidines; Remifentanil; Respiratory Mechanics; Tomography, X-Ray Computed

Inflammation is one of the leading causes of the many pathological states associated with oxidative stress. A crucial role in the development of inflammation-induced oxidative stress is played by reactive oxidant species (ROS), which are very difficult to detect in vivo. One of the most sensitive and definitive methods in the detection of ROS is electron spin resonance, especially as used in conjunction with spin trapping. Unfortunately, the commonly used nitrone spin traps have a very low efficacy for trapping superoxide radicals, and their radical adducts are not stable. To address this deficiency, we have developed negatively charged cyclic hydroxylamines such as 1-hydroxy-4-phosphonooxy-2,2,6,6-tetramethylpiperidine (PP-H) for the detection of reactive oxidant species as a diagnostic tool for extracellular inflammation-induced oxidative stress. We used inflammation induced by a bacterial endotoxin lipopolysaccharide (LPS) as a model. ROS formation was tested in cultured macrophages, in blood and in vivo. PP-H reacts with reactive oxidant species generating the stable nitroxide radical 4-phosphonooxy-TEMPO. It was shown that a 5-h treatment of macrophages with LPS (1 microg/ml) leads to a threefold increase in superoxide formation as demonstrated using superoxide dismutase. Formation of reactive oxidant species 5 h after LPS (1 mg/kg) treatment of Fischer rats was analyzed in arterial blood; formation of reactive oxidant species in LPS-treated animals increased by a factor of 2.2 and was dependent upon the LPS dose. Diphenyleneiodonium (0.1 mM) inhibited formation of LPS-stimulated reactive oxidant species by 80%. We suggest that this test could be used as a noninvasive diagnostic tool for inflammation-induced oxidative stress.

Topics: Animals; Cells, Cultured; Cyclic N-Oxides; Electron Spin Resonance Spectroscopy; Extracellular Space; Free Radical Scavengers; Inflammation; Lipopolysaccharides; Macrophages; Male; Organophosphates; Oxidative Stress; Piperidines; Rats; Rats, Inbred F344; Reactive Oxygen Species; Spin Labels; Superoxides

Nuclear factor kappaB (NF-kappaB) is a transcriptional factor which may be pivotal in the pathogenesis of atherosclerosis. Endothelin-1 (ET-1) is a peptide with proatherogenic properties. We hypothesized that ET-1 may act through activation of NF-kappaB and degradation of IkappaB-alpha, the cytosolic inhibitor of NF-kappaB activation, to create an atherogenic environment. The human monocytic cell line THP-1 was stimulated with ET-1 +/- the ET antagonist, BQ788 and the proteosome inhibitor, PSI. LPS was used as a positive control. Gel shift assays for NF-kappaB activity and Western blot analysis for IkappaB-alpha were performed. Both LPS and ET-1 led to activation of NF-kappaB in nuclear extracts [3.4 +/- 0.45 (LPS) and 2.9 +/- 0.26 (ET-1) fold increase in Arbitrary Densitometric Units (ADU) compared with negative control (P < 0.005 in both cases)]. In the presence of the ETB antagonist, BQ788, NF-kappaB activation was attenuated and not different from control (1.7 +/- 0.24 fold DU compared with negative control; P = NS). In addition, both LPS and ET-1 mediated NF-kappaB activation were attenuated by preincubation with the proteosome inhibitor, PSI (1.3 +/- 0.58 and 1.1 +/- 0.3 fold increase in ADU compared with negative control respectively). Both LPS and ET-1 led to a decrease in the amount of IkappaB-alpha present in the THP-1 cytoplasmic extracts (2.1 +/- 1.5% and 54 +/- 15.7% of ADU vs negative control (P < 0.05). NF-kappaB is activated by ET-1 in human THP-1 monocytes. This data supports a role for the ETs in the development of inflammation in the vessel wall in atherosclerosis.

Topics: Antihypertensive Agents; Arteriosclerosis; Blotting, Western; Cell Line; Cell Nucleus; Cysteine Endopeptidases; Cytoplasm; Cytosol; DNA-Binding Proteins; Endothelin-1; Humans; I-kappa B Proteins; Inflammation; Macrophages; Monocytes; Multienzyme Complexes; NF-kappa B; NF-KappaB Inhibitor alpha; Oligopeptides; Peptides; Piperidines; Proteasome Endopeptidase Complex; Protein Binding

1. We have studied the effect of palmitoylethanolamide (PEA, 2.5 - 30 mg kg(-1), i.p.) on upper gastrointestinal transit in control mice and in mice with chronic intestinal inflammation induced by croton oil. 2. PEA significantly and dose-dependently decreased intestinal transit. The inhibitory effect of PEA (10 mg kg(-1)) was not modified by the cannabinoid CB(1) receptor antagonist SR141716A (0.3 mg kg(-1), i.p.), the cannabinoid CB(2) receptor antagonist SR144528 (1 mg kg(-1), i.p.), N(G)-nitro-L-arginine methyl ester (L-NAME, 25 mg kg(-1), i.p.), yohimbine (1 mg kg(-1), i.p.), naloxone (2 mg kg(-1), i.p.) or hexamethonium (1 mg kg(-1), i.p.). 3. PEA levels were significantly decreased in the small intestine of croton oil-treated mice. In these animals, PEA also inhibited motility and this effect was not counteracted by SR141716A (0.3 mg kg(-1)), or SR144528 (1 mg kg(-1)). 4. Pre-treatment of mice with the amidase inhibitor phenylmethyl sulphonil fluoride (PMSF, 30 mg kg(-1), i.p.) did not modify the inhibitory effect of PEA, either in control or in mice with inflammation. 5. It is concluded that PEA inhibits intestinal motility with a peripheral mechanism independent from cannabinoid receptor activation. The decreased levels of PEA in croton oil-treated might contribute, at least in part, to the exaggerated transit observed during chronic intestinal inflammation.

Topics: Adrenergic alpha-Antagonists; Amides; Animals; Anti-Inflammatory Agents, Non-Steroidal; Camphanes; Croton Oil; Dose-Response Relationship, Drug; Endocannabinoids; Enzyme Inhibitors; Ethanolamines; Gastrointestinal Motility; Gastrointestinal Transit; Hexamethonium; Inflammation; Intestine, Small; Male; Mice; Mice, Inbred ICR; Naloxone; NG-Nitroarginine Methyl Ester; Nicotinic Antagonists; Nitric Oxide Synthase; Palmitic Acids; Phenylmethylsulfonyl Fluoride; Piperidines; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Yohimbine

1. Roles of histamine in the production of vascular endothelial growth factor (VEGF) in the carrageenin-induced granulation tissue in rats were analysed in vitro and in vivo. 2. Incubation of the minced granulation tissue in the presence of histamine (1 and 10 microM) increased the content of VEGF protein in the conditioned medium in a time- and concentration-dependent manner. The levels of VEGF mRNA in the minced granulation tissue were also increased by histamine in a concentration-dependent manner. 3. The increase in the content of VEGF protein in the conditioned medium by histamine (10 microM) was suppressed by the H(2) receptor antagonist cimetidine (IC(50) 0.37 microM), but not by the H(1) receptor antagonist pyrilamine maleate, the H(3) receptor antagonist thioperamide or the cyclo-oxygenase inhibitor indomethacin. 4. The histamine-induced increase in the content of VEGF protein in the conditioned medium was inhibited by the cyclic AMP antagonist Rp-cAMP (IC(50) 6.8 microM), and the protein kinase A inhibitor H-89 (IC(50) 12.5 microM), but not by the protein kinase C inhibitors Ro 31-8425 and calphostin C or the tyrosine kinase inhibitor genistein. 5. Simultaneous injection of cimetidine (400 microg) and indomethacin (100 microg) into the air pouch of rats additively reduced the carrageenin-induced increase in VEGF protein levels and angiogenesis in the granulation tissue as assessed by using carmine dye. 6. These findings indicate that histamine has an activity to induce VEGF production in the granulation tissue via the H(2) receptor-cyclic AMP-protein kinase A pathway and augments angiogenesis in the granulation tissue.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Cells, Cultured; Cimetidine; Cyclic AMP-Dependent Protein Kinases; Dose-Response Relationship, Drug; Endothelial Growth Factors; Enzyme Inhibitors; Fibroblasts; Gene Expression Regulation; Granulation Tissue; Histamine; Histamine Antagonists; Immunohistochemistry; Indoles; Indomethacin; Inflammation; Isoquinolines; Lymphokines; Macrophages, Peritoneal; Male; Maleimides; Naphthalenes; Neovascularization, Pathologic; Piperidines; Protein Kinase C; Pyrilamine; Rats; Rats, Sprague-Dawley; Receptors, Histamine H2; RNA, Messenger; Specific Pathogen-Free Organisms; Sulfonamides; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Hindpaw injection of dilute formalin produces brief (Phase 1) and persistent (Phase 2) nociceptive responses in the rat. We recently showed that systemically-administered remifentanil during Phase 1 interacted with peripheral opioid receptors to delay the onset and termination of Phase 2 (Taylor et al., 1997b). To test the hypothesis that opioid inhibition of proinflammatory events during Phase 1 contributed to this delay, we evaluated the effects of remifentanil on the time course of formalin-induced inflammation. We found that formalin increased paw thickness (edema), plasma extravasation and local blood flow within minutes of its injection, i.e. during Phase 1. Each of these responses was blocked during remifentanil administration (30 microg/kg i.v. bolus, followed 90 s later with a 15 microg/kg/min infusion for 13.5 min), indicating that opioids inhibit Phase 1 inflammation. Opioid blockade of the blood flow response could be reversed with a peripherally-acting opioid antagonist, naloxone methiodide, indicating that remifentanil acted upon peripheral opioid receptors. Although the administration of remifentanil during Phase 1 did not reduce the magnitude of inflammatory responses during Phase 2, it did delay the onset and termination of edema during Phase 2. As this corresponds to the effects of remifentanil on nociceptive responses during Phase 2, we suggest that opioid analgesics act upon peripheral sites to inhibit inflammation during Phase 1, leading to a delay in the temporal profile of inflammatory (and likely nociceptive) responses during Phase 2.

Topics: Analgesics, Opioid; Animals; Capillary Permeability; Edema; Formaldehyde; Hindlimb; Inflammation; Laser-Doppler Flowmetry; Male; Piperidines; Plasma; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Remifentanil; Skin Temperature; Ultrasonography

To elucidate the interaction between nitric oxide (NO) and substance P (SP) in neurogenic inflammatory responses, we measured the change in the degree of Evans blue leakage and NO levels in perfusate from the subcutaneous space in the rat instep following noxious heat stimulation (47 degrees C for 30 min). Furthermore, the effects of drugs affecting nitric oxide synthase were examined. Noxious heat stimulation caused on an increase in NOx, or NO2- and NO3- into the perfusate in parallel with plasma extravasation. Nw-nitro-L-arginine methylester (L-NAME: 100 mg/kg once daily.) intraperitoneally (i.p.) given five times (chronic treatment) significantly suppressed the increase in Evans blue extravasation induced by heat stimulation, whereas acute treatments with L- and D-NAME (100 mg/kg once, i.p.) did not show any significant effect. NO release induced by heating also was significantly suppressed by chronic pretreatment with L-NAME, but not by acute treatment. SP (10(-5) M) applied into the perfusate caused a remarkable increase in the NOx release into the perfusate. Intra-arterial injection of RP67580 (1 mg/kg) on the perfused side, but not SR48968 (1 mg/kg), significantly attenuated the increases in Evans blue leakage and NOx release during heat stimulation. These results suggest that heat-induced SP release from the peripheral endings of small-diameter afferent fibers causes NO generation through NK-1R, and that this gas act to elicit or enhance inflammatory responses.

Topics: Analgesics; Animals; Benzamides; Evans Blue; Forelimb; Hyperthermia, Induced; Indoles; Inflammation; Isoindoles; Male; Neurons, Afferent; NG-Nitroarginine Methyl Ester; Nitric Oxide; Piperidines; Rats; Rats, Sprague-Dawley; Skin; Substance P

Piperine is an inhibitor of various hepatic and other enzymes involved in the biotransformation of drugs. Preliminary pharmacokinetic studies conducted by us suggested the increased bioavailability of nimesulide co-administered with piperine. The present study was, thus, conducted to evaluate the antinociceptive, anti-inflammatory and toxicity profile of a new nimesulide-piperine combination administered orally as compared with nimesulide alone. Antinociceptive efficacy was tested using an acetic acid writhing test and tail flick latency test (TFL). The ED50 value of a nimesulide-piperine combination in writhing test was calculated to be significantly lower (1.5 mg kg(-1)) as compared to (11.2 mg kg(-1)) of nimesulide alone. The antinociceptive effect was lesser in the tail flick latency test as compared to what was observed in the writhing test indicating the peripheral action of the Non-Steriodal Anti-Inflammatory Drug (NSAID). In carrageenan-induced inflammatory tests, the nimesulide-piperine combination was found to be dose-to-dose superior than nimesulide alone. Acute toxicity studies on mice revealed a reduction in lethal dose (LD50) of the combination (980 mg kg(-1)) as compared to nimesulide (1500 mg kg(-1)) alone. Results from the present study suggest a better therapeutic index for the nimesulide-piperine combination indicating that this combination would further reduce the frequency of adverse effects associated with nimesulide alone.

Topics: Administration, Oral; Alkaloids; Analgesics, Non-Narcotic; Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzodioxoles; Drug Combinations; Drug Interactions; Female; Inflammation; Lethal Dose 50; Male; Mice; Nociceptors; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Sulfonamides

The airways of the genetically hypertensive rat (GH) are hyperinnervated by substance P-containing sensory nerves and exhibit reduced inflammatory responsiveness to substance P and to capsaicin. The present study measured tracheal inflammation to resiniferatoxin (1.0 microgram/kg i.v.), a capsaicin analogue, which lacks the hypotensive action of capsaicin itself, alone or after the neuronal nitric oxide synthase inhibitor 1-(2-trifluoromethylphenyl)imidazole (TRIM) (50 mg/kg i.p.). The inflammatory response to resiniferatoxin alone was 50% lower in untreated GH than in control rats, a similar strain difference to that seen previously with capsaicin. Pre-treatment with TRIM had no effect on inflammation in either strain. Binding kinetics of the tachykinin NK(1) receptor antagonist [3H](S)-1-(2-[3-(3, 4-dichlorophenyl)-1-(3-isopropoxyphenylacetyl)piperidin-3-yl]ethyl)-4- phenyl-l-azoniabicyclo[2,2,2,]octane chloride ([3H]SR140333)(0.125-16.0 nM) showed 50% reduction of B(max) in GH versus control tracheae (74+/-13 cf.165+/-26 fmol/mg protein). Our results indicate that the reduced neurogenic inflammatory responsiveness in GH rats can be attributed entirely to reduced tachykinin NK(1) receptor numbers.

Topics: Animals; Binding, Competitive; Capillary Permeability; Diterpenes; Hypertension; Inflammation; Male; Membranes; Piperidines; Quinuclidines; Radioligand Assay; Rats; Rats, Inbred Strains; Receptors, Neurokinin-1; Spinal Cord; Substance P; Trachea; Tritium

The endocannabinoid anandamide has affinity for cannabinoid and vanilloid receptors, which have opposing effects on nociceptive transmission. Effects of spinal administration of anandamide on innocuous and noxious evoked spinal neuronal responses in non-inflamed and carrageenin-inflamed rats were studied. Anandamide (0.1-50 microg/50 microl) had inconsistent effects in non-inflamed rats. Following carrageenin inflammation, anandamide (50 microg/50 microl) significantly reduced evoked neuronal responses, C-fibre mediated non-potentiated and post-discharge responses of neurones reduced to 65 +/- 5% and 57 +/- 10% of control, respectively. Effects of anandamide were blocked by SR141716A, a selective CB1 receptor antagonist. Spinal SR141716A (0.001-1 ng/50 microl) alone did not influence neuronal responses in inflamed rats. Spinal anandamide inhibited nociceptive transmission via CB1 receptors; following inflammation there is evidence for a loss of spinal endogenous cannabinoid tone.

Topics: Animals; Arachidonic Acids; Cannabinoid Receptor Modulators; Carrageenan; Electric Stimulation; Endocannabinoids; Hindlimb; Inflammation; Injections, Spinal; Nociceptors; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptors, Cannabinoid; Receptors, Drug; Reference Values; Rimonabant; Synaptic Transmission

Topics: Angina, Unstable; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Coronary Disease; Humans; Inflammation; Methylprednisolone; Oximes; Piperidines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Randomized Controlled Trials as Topic

Although both pre- and postsynaptic mechanisms have been implicated in the analgesia produced by mu-opioids at the spinal cord, it is not known under what conditions these different controls come into play. Because the mu-opioid receptor (MOR) can be visualized in individual lamina II excitatory interneurons and internalizes into endosomes on ligand binding, we tested whether MOR internalization could be monitored and used to measure postsynaptic MOR signaling. To test whether endogenous opioids modulate these lamina II interneurons during noxious stimulation, we next assessed the magnitude of postsynaptic MOR internalization under a variety of nociceptive conditions. As observed in other systems, we show that MOR internalization in dorsal horn interneurons is demonstrated readily in response to opioid ligands. The MOR internalization is dose-dependent, with a similar dose-response to that observed for opioid-induced increases in potassium conductance. We demonstrate that MOR internalization in lamina II neurons correlates precisely with the extent of analgesia produced by intrathecal DAMGO. These results suggest that MOR internalization provides a good marker of MOR signaling in the spinal cord and that postsynaptic MORs on lamina II interneurons likely participate in the analgesia that is produced by exogenous opioids. We found, however, that noxious stimuli, under normal or inflammatory conditions, did not induce MOR internalization. Thus, endogenous enkephalins and endomorphins, thought to be released during noxious peripheral stimuli, do not modulate nociceptive messages via postsynaptic MORs on lamina II interneurons. We suggest that any endogenous opioids that are released by noxious stimuli target presynaptic MORs or delta-opioid receptors.

Topics: Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Drug Implants; Electric Stimulation; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; In Vitro Techniques; Inflammation; Injections, Spinal; Injections, Subcutaneous; Interneurons; Ligands; Morphine; Narcotics; Oligopeptides; Pain Measurement; Piperidines; Posterior Horn Cells; Potassium; Rats; Receptors, Opioid, mu; Remifentanil; Signal Transduction; Substantia Gelatinosa; Synapses

The precise nature of neurokin receptor involvement in human immune cell chemotaxis is unclear. This study therefore sought to directly compare the chemotactic effects of neurokinins on human T lymphocytes and monocytes. Substance P was found to have a similar dose-dependent chemotactic action on T lymphocyte and monocyte populations. In contrast, T lymphocytes were found to be more responsive than monocytes both to the highly selective NK-1 agonist, [Sar(9)Met O(2)(11)]-substance P, and also to the NK-2 selective agonist, beta-alanine neurokinin A((4-10)). Consistent with these findings, substance P-induced chemotaxis of both T lymphocyte and monocytes was attenuated by the selective NK-1 antagonist LY303870. However, the selective NK-2 antagonist MEN 10,376 was only effective in inhibiting the T lymphocyte response. The study confirms that neurokinins have chemotactic actions on immune cells and indicates important functional differences between human T lymphocyte and monocyte responses. This provides a potential mechanism by which the nervous system can selectively influence cellular recruitment in inflammatory disease.

Topics: Chemotaxis, Leukocyte; Dose-Response Relationship, Drug; Humans; Indoles; Inflammation; Monocytes; Neurokinin A; Neurokinin-1 Receptor Antagonists; Peptide Fragments; Piperidines; Receptors, Neurokinin-1; Receptors, Neurokinin-2; Substance P; T-Lymphocytes

Neutrophils are considered to be involved in the pathogenesis of Helicobacter pylori-associated gastroduodenal diseases on account of their potent biological functions as effector cells. Troxipide, a new antiulcer compound used for patients with gastric ulcer or gastritis, has been shown to inhibit migration and activation of guinea pig neutrophils, but little is known about the pharmacological effects on human neutrophils.. To study the effects of troxipide on chemotactic migration and superoxide generation by human neutrophils.. The chemotactic response of neutrophils was determined in a multi-well chamber with a polycarbonate filter and the generation of O2- by neutrophils was measured using a chemiluminescence method. Concentrations of troxipide in gastric mucosa were measured by high-performance liquid chromatography.. Incubation of neutrophils with 10(-6) to 10(4) M troxipide caused inhibition of recombinant interleukin-8-induced migration. These concentrations of troxipide also inhibited superoxide generation by neutrophils stimulated by formyl-methionyl-leucyl-phenylalanine or platelet activating factor. These phenomena were not simply due to the direct cytotoxic effects since the above concentrations of troxipide did not induce neutrophil apoptosis. The concentrations of troxipide detected in the gastric mucosa after oral administration were in the range able to inhibit chemotactic migration and superoxide generation by neutrophils in vitro.. These results suggest that troxipide may exert its therapeutic effect in patients with gastric ulcer or gastritis by inhibiting inflammatory responses and mucosal injury mediated by neutrophils in gastric mucosa.

Topics: Adult; Anti-Ulcer Agents; Cell Culture Techniques; Cell Movement; Chemotaxis; Chromatography, High Pressure Liquid; Helicobacter Infections; Humans; Inflammation; Intestinal Mucosa; Neutrophils; Piperidines; Stomach Ulcer; Superoxides

The etiology of inflammation, edema, and smooth muscle contraction characteristic of inflammatory bowel disease is not clearly understood. There is evidence that several neuropeptides, including substance P (SP), may play a role. In this study we evaluated the ability of a SP-antagonist (SR140333) to modify the course of experimental colitis induced in the rat by trinitrobenzene sulfonic acid (TNB). Colitis was induced in 24 rats using TNB applied by intrarectal enema. Twelve TNB-treated rats received SR140333, 0.1 mg/kg intraperitoneally, 30 min before the administration of TNB and every 48 hr until death. Twelve rats receiving only intrarectal 0.9% saline served as controls. Rats of each group were killed after 14 days. At day 14, the control group showed no signs of inflammation whereas the TNB-treated rats without SR140333 treatment exhibited a well-established colitis. The TNB-treated group had a higher level of inflammation, as seen histologically and by the significantly greater weight of colon strips, compared to the controls (0.30 +/- 0.09 g vs 0.13 +/- 0.03 g, P < 0.001) and to the SR140333-treated rats (0.30 +/- 0.09 g vs 0.14 +/- 0.05 g, P < 0.001). In addition, smooth muscle contractility was significantly reduced in the inflamed colons of TNB-treated rats when compared with the controls (carbachol: 42.7 +/- 20.3 vs 254.2 +/- 69.78 mg/mm2; SP: 18.5 +/- 10.02 vs 89.45 +/- 23.17 mg/mm2; KCl: 11.4 +/- 2.2 vs 98.32 +/- 33.57 mg/mm2, P < 0.01). However, SR140333-treated rats showed a recovery from inflammation and motor alterations caused by TNB (carbachol: 150.9 +/- 46.1 mg/mm2, P < 0.01; SP: 32.5 +/- 9.4 mg/mm2, P < 0.05; KCl: 125.7 +/- 36.1 mg/mm2, P < 0.01). In conclusion, treatment with SP antagonist SR140333 reduces the severity of colitis and has beneficial effects on the concomitant alterations of contractility. Thus, the blockade of substance P may represent a possibility in the treatment of intestinal inflammation.

Topics: Animals; Colitis; Colon; Inflammation; Male; Muscle Contraction; Muscle, Smooth; Neurokinin-1 Receptor Antagonists; Piperidines; Quinuclidines; Rats; Rats, Sprague-Dawley; Stereoisomerism; Substance P; Trinitrobenzenesulfonic Acid

The effect of the non-peptide selective tachykinin NK1 receptor antagonist SR140333 has been investigated on oedema formation and neutrophil accumulation induced by thermal injury (50 degrees C for 5 min), mustard oil, substance P, the tachykinin NK1 agonist GR73632, and interleukin-1beta in the abdominal skin of the anaesthetised rat. SR140333 significantly inhibited (120 nmol/kg i.v.) or prevented (240 nmol/kg i.v.) the early oedema formation (0-10 min) induced by thermal injury. However, a dosing strategy which blocked NK1 receptors for 5 h (SR140333, 240 nmol/kg i.v. + 240 nmol/kg s.c.) failed to influence neutrophil accumulation measured 5 h after thermal injury. Thus, the neurogenic component mediated by NK1 receptors is important to elicit the early oedema formation, but does not influence subsequent neutrophil accumulation. Topical application of mustard oil (2%), a neurogenic inflammation stimulant, caused NK1 receptor-mediated early neurogenic plasma extravasation, but did not induce cutaneous neutrophil accumulation over 5 h. Substance P and GR73632 at high doses (1 nmol/site) also failed to elicit neutrophil accumulation. Neutrophil accumulation induced by interleukin-1beta (0.03-3 pmol i.d.) was not affected by SR140333 pretreatment. In conclusion, despite an early pronounced tachykinin NK1 receptor-dependent oedema response after thermal injury, the results suggest that subsequent neutrophil accumulation is not mediated by NK1 receptors. Furthermore, we have not obtained any evidence to suggest that either endogenous or exogenous tachykinins can directly induce neutrophil accumulation in the rat cutaneous microvasculature.

Topics: Abdomen; Animals; Bradykinin; Burns; Dose-Response Relationship, Drug; Edema; Hindlimb; Histamine; Inflammation; Interleukin-1; Male; Microcirculation; Mustard Plant; Neurokinin-1 Receptor Antagonists; Neutrophils; Peptide Fragments; Piperidines; Plant Extracts; Plant Oils; Quinuclidines; Rats; Rats, Wistar; Receptors, Neurokinin-1; Skin; Substance P; Time Factors

1. In a guinea-pig model of allergic asthma, we investigated the involvement of the tachykinin NK2 receptors in allergen-induced early (EAR) and late (LAR) asthmatic reactions, airway hyperreactivity (AHR) after these reactions and inflammatory cell influx in the airways, using the selective non-peptide NK2 receptor antagonist SR48968. 2. On two different occasions, separated by a 1 week interval, ovalbumin (OA)-sensitized guinea-pigs inhaled either vehicle (3 min) or SR48968 (100 nM, 3 min) at 30 min before as well as at 5.5 h after OA provocation (between the EAR and LAR) in a random crossover design. 3. SR48968 had no significant effect on the EAR, but significantly attenuated the LAR by 44.2+/-16.4% (P<0.05) compared to saline control. 4. The NK2 receptor antagonist did not affect the OA-induced AHR to histamine after the EAR at 5 h after OA challenge (3.59+/-0.59 fold increase in histamine reactivity vs 3.79+/-0.61 fold increase in the controls, NS), but significantly reduced the AHR after the LAR at 23 h after OA challenge (1.59+/-0.24 fold increase vs 1.93+/-0.15 fold increase, respectively, P<0.05). 5. Bronchoalveolar lavage studies performed at 25 h after the second OA provocation showed that SR48968 significantly inhibited the allergen-induced infiltration of neutrophils (P<0.05) and lymphocytes (P<0.01) in the airways. 6. These results indicate that NK2 receptor activation is importantly involved in the development of the allergen-induced late (but not early) asthmatic reaction and late (but not early) AHR to histamine, and that NK2 receptor-mediated infiltration of neutrophils and lymphocytes in the airways may contribute to these effects.

Topics: Allergens; Animals; Asthma; Benzamides; Bronchial Hyperreactivity; Bronchoconstriction; Female; Guinea Pigs; Histamine; Inflammation; Lymphocytes; Male; Neutrophils; Piperidines; Receptors, Neurokinin-2

Severe traumatic injuries and infections are frequently accompanied by life-threatening shock and are associated with increases in the proinflammatory cytokines, particularly tumor necrosis factor alpha (TNF-alpha). The body's first perception of injury is the nociceptive or pain response. This response is induced at the site of injury and is transmitted systemically by sensory neuropeptides, the tachykinins, released from sensory afferent c-fiber neurons. We studied the role of tachykinins in regulating the production of proinflammatory cytokines induced by the administration of bacterial lipopolysaccharide. Destruction of terminal sensory nerve endings before lipopolysaccharide administration abrogates tachykinin synthesis and down-regulates TNF-alpha transcription and secretion. In contrast, the responses of interleukins-1 and -6 are unaffected. Pretreating animals with an antagonist for the substance P-specific NK-1 receptor also down-regulated the TNF-alpha response, whereas blockade of the NK-2 receptor had no effect. These findings indicate that substance P contributes to the induction of those cytokines that are involved in precipitating the shock response.

Topics: Animals; Capsaicin; Cytokines; Endotoxins; Female; Gene Expression Regulation; Inflammation; Lipopolysaccharides; Liver; Mice; Mice, Inbred BALB C; Neurokinin-1 Receptor Antagonists; Piperidines; Quinuclidines; Spleen; Tachykinins; Time Factors; Transcription, Genetic; Tumor Necrosis Factor-alpha

We have developed a guinea pig model for cough related to allergic airway inflammation. Unanesthetized animals were exposed to capsaicin aerosols for 10 min, and cough frequency was counted during this period. The cough evaluation was performed by the following three methods: visual observation, acoustic analysis, and monitoring of pressure changes in the body chamber. These analyses clearly differentiated a cough from a sneeze. To elucidate the relationship between cough response and airway inflammation, animals were immunosensitized and multiple challenged. Sensitized guinea pigs presented no specific changes microscopically, but multiple-challenged animals showed an increased infiltration of inflammatory cells into the airway. Cough number in response to capsaicin increased significantly from 4.7 +/- 1.4 coughs/10 min in normal animals to 10.6 +/- 2.0 coughs/10 min in sensitized animals and further to 22.8 +/- 1.3 coughs/10 min in multiple-challenged animals. This augmented cough frequency was significantly inhibited by the inhalation of tachykinin-receptor antagonists and by oral ingestion, but not inhalation, of codeine phosphate. The results suggest that airway inflammation potentiates an elevation of cough sensitivity in this model.

Topics: Animals; Antitussive Agents; Benzamides; Bronchoalveolar Lavage Fluid; Capsaicin; Codeine; Cough; Dipeptides; Female; Guinea Pigs; Indoles; Inflammation; Peptides, Cyclic; Piperidines; Quinuclidines; Receptors, Neurokinin-2; Receptors, Tachykinin; Respiratory Hypersensitivity; Respiratory Tract Diseases

Human trials for the treatment of cystic fibrosis lung disease with adenoviral vectors have been complicated by acute inflammatory reactions of unknown etiology. Because replicating respiratory viruses can potentiate tachykinin-mediated neurogenic inflammatory responses in airways, we studied whether the endotracheal administration of a replication-deficient adenoviral vector potentiated this response. The vector Ad5CMVLacZ was administered endotracheally to rats and the leakage of Evans blue dye was used to measure the capsaicin-induced neurogenic albumin extravasation. These studies show that neurogenic albumin extravasation is significantly potentiated in the airways of rats after administration of Ad5CMVLacZ. This inflammatory response can be blocked by selective antagonists of the substance P receptor or by glucocorticoids. Therefore, (1) the acute airway inflammation observed in patients after exposure to adenoviral vectors may exhibit a neurogenic component, which can be blocked pharmacologically, and (2) preclinical adenoviral vector safety studies of other organs innervated by the tachykinin system, e.g., coronary arteries and gastrointestinal tract, should include assessment of neurogenic inflammation.

Topics: Adenoviruses, Human; Animals; Capillary Permeability; Capsaicin; Dexamethasone; Ficusin; Gene Transfer Techniques; Genetic Vectors; Glucocorticoids; Hot Temperature; Inflammation; Male; Neurokinin-1 Receptor Antagonists; Neurons, Afferent; Photosensitizing Agents; Piperidines; Protein Denaturation; Rats; Rats, Inbred F344; Receptors, Neurokinin-1; Respiratory System; Substance P; Ultraviolet Rays

In this study, we have characterized the phenotype of mast cells in rat dura mater and their topological and functional relationships with C-fibers in normal and inflammatory conditions. Three mast cell populations with different size, morphology and localization were characterized by their content of specific neutral serine proteases. They showed immunoreactivity corresponding to rat mast cell protease I, rat mast cell protease II, or both proteases. Using confocal microscopy, all three mast cell types were observed in close apposition (distance less than 100 nm) to calcitonin gene-related peptide- and substance P-immunoreactive nerve fibers in both controls and rats infected with the nematode Nippostrongylus brasiliensis. After nematode infection or neonatal treatment with capsaicin, a large increase in the number of rat mast cell protease II-immunoreactive mast cells was found within dura mater segments (+1478% and +596%, respectively), without concomitant changes of rat mast cell protease I- or rat mast cell protease I/II-immunoreactive mast cells. Under both these conditions, the increase in mast cell number was accompanied by a significant increase in rat mast cell protease II level within tissue extracts (+281% after nematode infection and +36% after capsaicin treatment). The functional interaction of mast cells with sensory nerve fibers in the dura mater was assessed by evaluating [3H]histamine synthesis after administration of L-[3H]histidine, an index of mast cell activity. The H3 receptor agonist (R)-alpha-methylhistamine (15 mg/kg, i.p.) had no effect, but administration of the H3 receptor antagonist, thioperamide (10 mg/kg, i.p.), resulted in a significant increase of [3H]histamine synthesis (+62%). This effect was reduced in neonatal capsaicin-treated rats, but not completely suppressed (+35%), very likely because of partial denervation, as assessed by monitoring calcitonin gene-related peptide immunoreactivity. It is concluded that, in the dura mater, as in peripheral tissues, sensory nerve fibers and mast cells actively synthesizing and releasing histamine form a short inhibitory feedback loop involving prejunctional H3 receptors that could regulate the release of pro-inflammatory mediators, thus limiting the extent of inflammatory reactions.

Topics: Animals; Animals, Newborn; Capsaicin; Cerebral Cortex; Chymases; Denervation; Dura Mater; Enzyme-Linked Immunosorbent Assay; Histamine; Histamine Antagonists; Inflammation; Male; Mast Cells; Methylhistamines; Nerve Fibers; Neurons, Afferent; Nippostrongylus; Piperidines; Rats; Rats, Wistar; Reference Values; Sensitivity and Specificity; Serine Endopeptidases; Strongylida Infections

The serotonin (5-HT) receptor subtype mediating inhibition of neurogenic dural inflammation in guinea pigs was investigated using a series of serotonin agonists with differing affinities for the 5-HT1B, 5-HT1D and 5-HT1F receptors. When agonist potencies for inhibiting neurogenic inflammation were compared with affinities for these receptor subtypes, a significant positive correlation was seen only with the 5-HT1F receptor. The potency of agonists in inhibiting adenylate cyclase in cells transfected with human 5-HT1F receptor was also highly correlated with their potency in the animal model of migraine. In situ hybridization demonstrated 5-HT1F receptor mRNA in guinea pig trigeminal ganglion neurons. These data suggest that the 5-HT1F receptor is a rational target for migraine therapeutics.

Topics: Animals; Benzamides; Carbazoles; Disease Models, Animal; Guinea Pigs; In Situ Hybridization; Indoles; Inflammation; Male; Piperidines; Pyrazoles; Rabbits; Receptor, Serotonin, 5-HT1F; Receptors, Serotonin; RNA, Messenger; Serotonin Receptor Agonists; Trigeminal Ganglion; Tryptamines

Bradykinin caused a dose-related increase in cell influx 4 h after its administration into the mouse pleural cavity (ED50 = 3.2 nmol/cav., 95% confidence limits = 0.6-15.5). Cell influx peaked at 4 h and remained elevated for up to 72 h, whereas exudation was detected between 2 and 6 h after bradykinin administration. Both HOE 140 (D-Arg-[Hyp3,Thi5,D-Tic7, Oic8]bradykinin) and NPC 17731 (D-Arg0-[Hyp3 D-HypE(transpropyl7)Oic8]bradykinin) inhibited bradykinin-induced cell influx (ID50 0.028 (0.05-0.16) and 0.4 (0.3-0.7) pmol/cav., respectively). Des-Arg9-[Leu8]bradykinin (0.1 and 3.0 nmol/cav., 30 min before) did not inhibit the effects of bradykinin. Pre-treatment of animals with either indomethacin, terfenadine, dexamethasone, N(omega)-nitro-L-arginine benzyl ester, cromolyn, theophylline, salbutamol, FK 888 (N2-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl)carbonyl-L-propyl]N-met hyl-N-phenyl-methyl-3-(2-naphthyl)-L-alaninamide) or SR 142801 ((N)-(1-[3-[1-benzoyl-3-(3,4-dichloro-phenyl)-piperidin-3-yl]pr opy l]-4-phenyl-piperidin-4-yl)-N-methyl-acetamide) significantly inhibited cell migration (P < 0.01). These results indicate that bradykinin had a significant pro-inflammatory effect on the pleural cavity of the mice. This effect seems to be primarily mediated via activation bradykinin B2 receptors which trigger the release of other mediators.

Topics: Animals; Benzamides; Bradykinin; Bradykinin Receptor Antagonists; Cell Movement; Dipeptides; Dose-Response Relationship, Drug; Female; Indoles; Inflammation; Leukocyte Count; Male; Mice; Neutrophils; Oligopeptides; Piperidines; Pleura; Pleurisy; Receptor, Bradykinin B2; Time Factors

The preparation of a series of N-heteroarylpiperidine ether-based human NK1 antagonists is described. Two of the compounds 3-[-(2S,3S)-3-(((3,5-bis(trifluoromethyl)phenyl)methyl)oxy)- 2-phenylpiperidino}methyl]-1,2,4-triazole (11) and 5-[¿(2S,3S)-3-(((3,5-bis(trifluoromethyl)-phenyl)methyl)oxy)-2- phenylpiperidino}methyl]-3-oxo-1,2,4-triazolone (12)), in particular, are orally bioavailable and exhibited significant improvements in potency, both in vitro and in vivo, over the lead (carboxamidomethyl)piperidine ether 1. Rat liver microsome studies on a selected number of compounds from this series show the triazolone heterocycle to be considerably more stable than the others. Furthermore, both 11 and 12 have been profiled in a number of assays that may be predictive of the clinical utility of substance P antagonists.

Topics: Animals; Biological Availability; Drug Stability; Ferrets; Guinea Pigs; Humans; Inflammation; Macaca mulatta; Male; Microsomes, Liver; Migraine Disorders; Neurokinin-1 Receptor Antagonists; Piperidines; Rats; Receptors, Neurokinin-1; Triazoles; Vomiting

To test in vivo the effect of previously observed inhibition of collagen type I transcription by the plant alkaloid Halofuginone, deep flexor tendons of 12 chickens were severed and sutured, and Halofuginone was applied topically at the site of surgery. Intact tendons, and severed but untreated tendons served as controls. The effect of the treatment was assessed by histological, biochemical, and biomechanical examinations of the operated and intact tendons three weeks after surgery. The results indicated an almost complete absence of fibrous peritendinous adhesions in the histologic sections of the Halofuginone treated tendons. There was a statistically significant decrease in collagen contents of and in both force and energy required to pull out the Halofuginone treated tendons from their sheath, relative to the untreated controls. Halofuginone had no effect on the cellularity of the healing tissue. We conclude that Halofuginone is a potent inhibitor of fibrous peritendinous adhesions with potentially important clinical applications.

Topics: Animals; Chickens; Collagen; Gene Expression Regulation; Hydroxyproline; Inflammation; Piperidines; Protein Synthesis Inhibitors; Quinazolines; Quinazolinones; Statistics, Nonparametric; Tendon Injuries; Tissue Adhesions

An autoradiographic technique was used to study the distribution of changes in pulmonary NK1 and NK2 receptors in guinea pig lung after repeated antigen challenge. Specific labeling of [3H]CP96345 (NK1 receptors) and [3H]SR48968 (NK2 receptors) was localized over the tracheal and bronchial smooth muscle; the density of binding increased towards smaller airways with a higher density for [3H]CP96345 binding. Bronchial epithelium and pulmonary blood vessels were also labeled densely with [3H]CP96345. No remarkable difference in the pattern of distribution of pulmonary NK1 and NK2 tachykinin receptors was observed between control, vehicle-challenged, and repeatedly antigen-challenged (weekly for three times) guinea pigs. A significant reduction in specific labeling of [3H]CP96345 (p < 0.01) and [3H]SR48968 (p < 0.05) over pulmonary structures was observed in antigen-challenged compared to control or vehicle-challenged animals. This study provides evidence that NK1 and NK2 tachykinin receptors are both localized to smooth muscle of all sizes in guinea pig airways and provides further evidence for a discrete distribution of NK1 and NK2 tachykinin receptors, consistent with their relative functional activities. In an established model of airway inflammation a decrease in the expression of NK1 and NK2 tachykinin receptors was evident on several different cell types within the lung, and this could influence airway and vascular reactivity.

Topics: Animals; Antigens; Autoradiography; Benzamides; Binding Sites; Biphenyl Compounds; Guinea Pigs; Inflammation; Lung; Male; Neurokinin-1 Receptor Antagonists; Ovalbumin; Piperidines; Receptors, Neurokinin-1; Receptors, Neurokinin-2; Tissue Distribution

Dispase-dissociated primary cultures of human conjunctival epithelial (HCE) cells were stimulated with histamine and the generation of inositol phosphates ([3H]IPs) from [3H]phosphoinositide (PI) hydrolysis and the mobilization of intracellular calcium ([Ca2+]i) were studied using ion exchange chromatography and Fura-2 fluorescence techniques, respectively. Histamine (100 microM) maximally stimulated PI turnover in HCE cells by 210 +/- 10% (n = 21) above basal levels and with a potency (EC50) of 3.3 microM (n = 4). Histamine (EC50 = 5.8 microM, n = 3) rapidly mobilized [Ca2+]i which peaked within 10 sec but which was still significantly elevated 20 min after stimulation. The histamine-induced [Ca2+]i responses did not desensitize upon repeated applications of histamine. The effects of histamine (100 microM) on PI turnover and [Ca2+]i were potently antagonized by the H1-antagonists, emedastine (IC50 = 1.6-2.9 nM), triprolidine (IC50 = 3.1 nM) and levocabastine (IC50 = 8 nM), but weakly by the H2-(ranitidine/cimetidine) and H3-(thioperamide) antagonists (IC50s = 10-100 microM). In conclusion, HCE cells have been shown to possess functional H1-histamine receptors that couple to inositol phosphates generation which then mobilize intracellular calcium. These intracellular signaling mechanisms may be intimately linked with the process of inflammatory cytokine secretion from the HCE cells after stimulation by histamine released from the conjunctival mast cells. The current results strongly suggest that the HCE cells are active participants in mediating, and perhaps amplifying, the pro-inflammatory and allergic effects of histamine which is released from conjunctival mast cells during ocular allergic and inflammatory reactions.

Topics: Benzimidazoles; Calcium; Cells, Cultured; Chromatography, Ion Exchange; Conjunctiva; Cytokines; Epithelium; Eye Diseases; Histamine; Histamine Antagonists; Humans; Hypersensitivity; Inflammation; Phosphatidylinositols; Piperidines; Receptors, Histamine H1; Stimulation, Chemical; Triprolidine

Prostaglandin E1 (PGE1) is known to possess various actions in vivo. Of these actions, the contraction of the ileum and inflammation are undesirable side effects. We previously proposed a hypothesis concerning the receptors for human blood platelet aggregation and its inhibition, and the contraction of the ileum and uterus based on a study of structure-activity relationships. If the same principle can be applied to contraction of the ileum and inflammation induced by PGE1, compounds that suppress the side effects of PGE1 can be developed. The antihistamine diphenylpyraline and the anticholinergic atropine antagonized PGE1-induced contraction of the ileum in guinea pigs. Papaverine, which is a smooth muscle relaxant, also acted as an antagonist. Gabexate mesylate (FOY), a non-peptide proteinase inhibitor, inhibits guinea pig ileum contraction induced by PGE1, but epsilon-guanidinocaproic acid (GCA), a metabolite of FOY, does not. Increased microvascular permeability of the abdominal skin in rats induced by the local injection of PGE1 and histamine was suppressed by atropine, papaverine and diphenylpyraline. FOY, not GCA, had a weak inhibitory action. We demonstrate the possibility of suppressing the side effects of PGE1 based on the results obtained in the present and previous studies.

Topics: Alprostadil; Animals; Atropine; Capillary Permeability; Gabexate; Guanidines; Guinea Pigs; Histamine; Ileum; Inflammation; Male; Muscle Contraction; Papaverine; Piperidines; Rats

Tachykinins released from sensory airway nerves have been shown to increase vascular permeability and plasma-protein extravasation (PPE) in rodent airways. We previously demonstrated that in Fisher (F344) rats, tachykinins cause bronchoconstriction mainly by indirect mechanisms involving the activation of NK1 receptor and mast cells, whereas in the less responsive BDE rats tachykinins have a direct NK2 receptor-mediated effect on bronchial smooth muscle. Using Evans blue dye as an intravascular marker, we demonstrated that F344 rats are hyperresponsive for the PPE induced by substance P (SP) and capsaicin. The NK1 receptor antagonist RP 67,580 reduced the neurogenic PPE in both strains, whereas the NK2 receptor antagonist SR 48,968 had no effect, indicating that only NK1 receptors are involved in the PPE. Pretreatment with the 5-HT antagonist methysergide decreased the neurogenic PPE in F344 rats but not in BDE rats. In F344 rats depleted of mast-cell mediators with compound 48/80, the SP-induced PPE was significantly reduced. Pretreatment with the H1 antagonist mepyramine and the H2 antagonist cimetidine caused a similar reduction in SP-induced PPE in main bronchi of both strains. Pretreatment with atropine, indomethacin, or the leukotriene antagonist ICI 198,615 did not affect the SP-induced PPE. In conclusion, neurogenic PPE in rat airways involves the activation of NK1 receptors. In F344 but not in BDE rats, an additional indirect mechanism involving 5-HT release and mast-cell activation participates in the neurogenic PPE.

Topics: Animals; Benzamides; Blood Pressure; Bronchi; Capillary Permeability; Capsaicin; Cimetidine; Coloring Agents; Dose-Response Relationship, Drug; Evans Blue; Histamine Antagonists; Indoles; Inflammation; Isoindoles; Methysergide; Neurokinin-1 Receptor Antagonists; Piperidines; Pyrilamine; Rats; Rats, Inbred F344; Rats, Inbred Strains; Receptors, Neurokinin-1; Serotonin; Serotonin Antagonists; Substance P; Trachea

The effects of 2-(2-(4-(diphenylmethyl)-1-piperadinyl) ethoxy) benzoic acid malate (ZCR-2060) on allergic airway inflammation and inflammatory cell activation in guinea-pigs were studied. Allergic airway inflammation was induced by inhalation of antigen into actively-sensitized animals and the increase in inflammatory cells into bronchoalveolar lavage fluid (BALF) was measured. Aeroantigen-induced infiltration of inflammatory cells, especially eosinophils and neutrophils, in BALF gradually increased, and reached a peak at 6 or 9 h after the challenge. ZCR-2060 (1 mg kg-1 p.o.) clearly inhibited the increase of eosinophil numbers in BALF. Moreover, the effect of ZCR-2060 on inflammatory cell activation in terms of chemotaxis and superoxide generation in-vitro was studied. ZCR-2060 (10(-6)-10(-4) M) inhibited the platelet-activating factor (PAF)-induced chemotaxis of eosinophils and neutrophils, but did not inhibit the leukotriene B4-induced chemotaxis of eosinophils and the formyl-Met-Leu-Phe-induced chemotaxis of neutrophils. PAF-induced superoxide anion generation by eosinophils, neutrophils and alveolar macrophages was inhibited by ZCR-2060 (10(-6)-10(-4) M). However, ZCR-2060 did not affect phorbol myristate acetate-induced superoxide anion generation by eosinophils, neutrophils and alveolar macrophages. These results indicate that ZCR-2060 inhibits allergic airway inflammation, and PAF-induced inflammatory cell activation in guinea-pigs. ZCR-2060 may prove useful for the treatment of allergic airway inflammation or allergic disorders, especially inflammatory cell infiltration and activation.

Topics: Animals; Benzoates; Bronchoalveolar Lavage Fluid; Chemotaxis, Leukocyte; Eosinophils; Guinea Pigs; Inflammation; Leukotriene B4; Macrophages, Alveolar; Male; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Piperidines; Platelet Activating Factor; Respiratory Hypersensitivity; Superoxides; Tetradecanoylphorbol Acetate

There is increased recognition that lung mast cell mediators not only produce the symptoms of acute asthma, but also result in the recruitment and activation of additional proinflammatory cells, such as eosinophils. Histamine, one of the major mast cell mediators, is known to have numerous effects on eosinophil function. These effects of histamine are mediated by distinct receptors on the surface of eosinophils, only some of which have been characterized. Prior studies have suggested that eosinophils have non-H1, non-H2 histamine receptors which mediate the chemotactic effects of histamine. We observed previously that the histamine-induced increase in cytosolic calcium in human eosinophils could not be blocked by classic H1 or H2 antagonists, but could be inhibited by the H3 antagonist thioperamide. The purpose of this study was to further characterize the pharmacologic properties of this calcium-linked histamine receptor. Using Fura-2 loaded eosinophils to measure the concentration of cytosolic calcium, we examined the effect of additional histamine receptor antagonists and agonists. We found that the pKb for the H3 antagonists thioperamide, impromidine, and burimamide (8.1, 7.6, and 7.2, respectively), were similar to those reported for H3 receptors in the central nervous system, suggesting that the eosinophil histamine receptor was similar to H3 receptors. However, when the known H3 agonists were tested for activity ([R]-alpha-methylhistamine, N alpha-methylhistamine), the potencies of these compounds were much less than the potency of histamine itself, indicating a significant difference between H3 receptors and this eosinophil histamine receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Anticonvulsants; Asthma; Burimamide; Calcium; Eosinophils; Fura-2; Histamine Agonists; Histamine Antagonists; Humans; Impromidine; Inflammation; Intracellular Fluid; Mast Cells; Methylhistamines; Phosphatidylethanolamines; Piperidines; Platelet Aggregation Inhibitors; Receptors, Histamine

We studied the effect of neurogenic inflammation on airway blood flow in anesthetized F-344 rats. Three successive determinations of blood flow were made by injecting radionuclide-labeled microspheres suspended in 70% dextrose into the left ventricle. A selective agonist of the tachykinin receptor neurokinin 1 (NK1) increased airway blood flow, but NK2- and NK3-selective agonists were without effect. The natural agonist of NK1 receptors, substance P (1 micrograms/kg), increased airway blood flow, an effect that was abolished by the selective NK1 receptor antagonist CP-99,994 [(+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine] but not by the (2R,3R)-enantiomer CP-100,263. Capsaicin (25 micrograms/kg), a drug that releases tachykinins and calcitonin gene-related peptide from sensory nerves, increased airway blood flow, and again this effect was abolished by CP-99,994. We also studied the effect of a selective inhibitor (captopril, 2.5 mg/kg) of the tachykinin-degrading enzyme kininase II [or angiotensin-converting enzyme (ACE)] on substance P-induced airway vasodilation. Captopril potentiated and prolonged the vasodilator effect of substance P. We conclude that neurogenic vasodilation in rat airways is due to the release of substance P, acts via NK1 receptors, and may be modulated by ACE.

Topics: Animals; Capsaicin; Inflammation; Male; Microspheres; Neurons, Afferent; Peptidyl-Dipeptidase A; Piperidines; Rats; Rats, Inbred F344; Receptors, Neurokinin-2; Receptors, Neurotransmitter; Regional Blood Flow; Respiratory System; Respiratory Tract Diseases; Substance P; Tachykinins; Vasodilation

The role of tachykinins released from sensory nerves in bronchoconstriction induced by antigen was studied in sensitized guinea pigs anesthetized with pentobarbital sodium and pretreated with atropine. The combination of NK2 (SR-48968) and NK1 (CP-96,345) tachykinin-receptor antagonists abolished the increase in total pulmonary resistance (RL) evoked by intravenous capsaicin but did not affect the response evoked by intravenous histamine. A small dose of aerosolized ovalbumin (OVA, 0.1%) produced a small increase in RL that was further increased and markedly prolonged by the neutral endopeptidase (NEP) inhibitor phosphoramidon; this bronchoconstrictor effect of OVA was markedly reduced by the NK2-receptor antagonist and was abolished by the combination of the NK1 and NK2-receptor antagonists together. When a larger dose of OVA (0.5%) was used, a maximal bronchoconstrictor response was obtained. Phosphoramidon did not potentiate this response significantly. The combination of NK1- and NK2-receptor antagonists blunted the response at 5 min only slightly but markedly attenuated the later (10-20 min) response. These results show that tachykinins released from sensory nerves play a significant role in antigen-induced bronchoconstriction in guinea pigs. This effect is exaggerated when the normal modulation of neuropeptides by NEP is inhibited and is mediated predominantly by NK2-receptor activation, with a smaller contribution by NK1 receptors.

Topics: Aerosols; Animals; Atropine; Benzamides; Biphenyl Compounds; Bronchoconstriction; Capsaicin; Glycopeptides; Guinea Pigs; Histamine; Immunization; Inflammation; Lung; Male; Neurokinin-1 Receptor Antagonists; Ovalbumin; Piperidines; Pulmonary Circulation; Receptors, Neurokinin-2; Vascular Resistance

Carrageenin induced rat paw oedema shows a direct co-relationship with liver lipid peroxidation and not with kidney or brain. Pretreatment with piperine or oxyphenylbutazone reduced the liver lipid peroxidation, acid phosphatase and oedema induced by carrageenin. However, no such co-relationship was observed with treatment of these anti-inflammatory agents in control animals. It is, therefore, suggested that the inhibition of these liver enzymes is non specific in nature.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzodioxoles; Carrageenan; Inflammation; Lipid Peroxidation; Piperidines; Polyunsaturated Alkamides; Rats

Piperine (1-peperoyl piperidine) was isolated from Piper nigrum Linn for the evaluation of anti-inflammatory activity in rats. Different acute and chronic experimental models like carrageenin-induced rat paw edema, cotton pellet granuloma, and croton oil-induced granuloma pouch, were employed. Simultaneously, biochemical estimations were made to elucidate the underlying mechanism of the action. Piperine acted significantly on early acute changes in inflammatory processes and chronic granulative changes. It also acted partially through stimulation of pituitary adrenal axis. Exudative changes in both acute and chronic models, however, were insignificant.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzodioxoles; Disease Models, Animal; Drug Evaluation, Preclinical; Granuloma; Inflammation; Male; Piperidines; Pituitary-Adrenal System; Polyunsaturated Alkamides; Rats

Aloperine, an alkaloid isolated from Sophora alopecuroides L, showed a marked suppressive effect on the swelling of the rat's hind paw induced by injecting carrageenin, macostatin, PGE2, histamine, 5-HT, on the rat's scald oedema induced by scalding its hind paw, and on the increased permeability of capillaries caused by histamine and the leukocytic migratory response. The swelling induced by injecting carrageenin into the hind paw of adrenolectomized rats was still significantly inhibited. Noticeably, aloperine reduced the content of PGE and histamine in the exudate formed after injecting carrageenin and dextran into the rat's hind paw, and increased the stability of red cell membranes, the activity of catalase (CAT) in hepatic tissue of mice, and reduced the content of malondialdehyde (MDA) in hepatic tissue of intoxicated mice. It had no apparent effect either on the activity of superoxide dismutase (SOD) in mice serum or on the phagocytosis of the monocyte-macrophage system, or on Forssman cutaneous vasculitis and the content of immune complex in serum of rats with Arthus reaction. But it had certain inhibitory effect on the PCA reaction and significant inhibitory effect upon such allergic reaction as Arthus reaction, reversible passive Arthus reaction, the delayed hypersensitivity reaction induced by tuberculin in rats, and adjuvant arthritis.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Arthus Reaction; Cell Migration Inhibition; Female; Hypersensitivity, Delayed; Inflammation; Male; Mice; Piperidines; Quinolizidines; Rats

Topics: Albuterol; Anaphylaxis; Animals; Anura; Bronchial Spasm; Cardiovascular System; Chlorpheniramine; Dogs; Drug Evaluation, Preclinical; Female; Gastric Juice; Guinea Pigs; Histamine H1 Antagonists; Inflammation; Male; Mice; Muscle, Smooth; Piperidines; Pizotyline; Rats; Respiration; Stomach Ulcer; Thiophenes

Topics: Animals; Anti-Inflammatory Agents; Chemistry, Pharmaceutical; Drug Evaluation, Preclinical; Inflammation; Oxazines; Piperidines; Rats

Topics: Anti-Inflammatory Agents; Azoles; Humans; Inflammation; Muscles; Phenothiazines; Piperidines