mocetinostat and Inflammation

Intracellular myeloperoxidase (MPO) plays a specific role in the innate immune response; however, upon release into the extracellular space in the setting of inflammation, drives oxidative tissue injury. Extracellular MPO has recently been shown to be abundant in unstable atheroma and causally linked to plaque destabilization, erosion, and rupture, identifying it as a potential target for the surveillance and treatment of vulnerable atherosclerosis. Through the compartmentalization of MPO's protective and deleterious effects, extracellular MPO can be selectively detected using non-invasive molecular imaging and targeted by burgeoning pharmacotherapies. Given its causal relationship to plaque destabilization coupled with an ability to preserve its beneficial properties, MPO is potentially a superior translational inflammatory target compared with other immunomodulatory therapies and imaging biomarkers utilized to date. This review explores the role of MPO in plaque destabilization and provides insights into how it can be harnessed in the management of patients with vulnerable atherosclerotic plaque.

Topics: Arteries; Atherosclerosis; Humans; Inflammation; Peroxidase; Plaque, Atherosclerotic

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

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Myeloperoxidase is a heme-peroxidase which makes up approximately 5% of the total dry cell weight of neutrophils where it is predominantly found in the primary (azurophilic) granules. Other cell types, such as monocytes and certain macrophage subpopulations also contain myeloperoxidase, but to a much lesser extent. Initially, the function of myeloperoxidase had been mainly associated with its ability as a catalyzer of reactive oxidants that help to clear pathogens. However, over the past years non-canonical functions of myeloperoxidase have been described both in health and disease. Attention has been specially focused on inflammatory diseases, in which an exacerbate infiltration of leukocytes can favor a poorly-controlled production and release of myeloperoxidase and its oxidants. There is compelling evidence that myeloperoxidase derived oxidants contribute to tissue damage and the development and propagation of acute and chronic vascular inflammation. Recently, neutrophils have attracted much attention within the large diversity of innate immune cells that are part of the tumor microenvironment. In particular, neutrophil-derived myeloperoxidase may play an important role in cancer development and progression. This review article aims to provide a comprehensive overview of the roles of myeloperoxidase in the development and progression of cancer. We propose future research approaches and explore prospects of inhibiting myeloperoxidase as a strategy to fight against cancer.

Topics: Humans; Inflammation; Neoplasms; Neutrophils; Oxidants; Peroxidase; Tumor Microenvironment

Polymorphonuclear neutrophils (PMNs) figure prominently in host defense against infection and in noninfectious inflammation. Mobilized early in an inflammatory response, PMNs mediate immediate cellular defense against microbes and orchestrate events that culminate in cessation of inflammation and restoration of homeostasis. Failure to terminate the inflammatory response and its causes can fuel exuberant inflammation characteristic of many human diseases, including cystic fibrosis (CF), an autosomal recessive genetic disease caused by mutations in the CF transmembrane conductance regulator. CF affects multiple end organs, with persistent bacterial infection and chronic neutrophilic inflammation in airways predominating the clinical picture. To match the diverse microbial challenges that they may encounter, PMNs possess a variety of antimicrobial systems to slow or kill invading microorganisms confined in their phagosomes. Prominent among PMN defense systems is their ability to generate hypochlorous acid, a potent microbicide, by reacting oxidants generated by the NADPH oxidase with myeloperoxidase (MPO) released from azurophilic granules in the presence of chloride (Cl-). Products of the MPO-H2O2-Cl system oxidize susceptible biomolecules and support robust antimicrobial action against many, but not all, potential human pathogens. Underscoring that the MPO-H2O2-Cl system is integral to optimal host defense and proper regulation of inflammation, individuals with defects in any component of this system, as seen in chronic granulomatous disease or MPO deficiency, incur increased rates or severity of infection and signs of dysregulated inflammatory responses. We focus attention in this review on the molecular basis for and the clinical consequences of defects in the MPO-H2O2-Cl system because of the compromised Cl transport seen in CF. We will discuss first how the MPO-H2O2-Cl system in healthy PMNs participates in host defense and resolution of inflammation and then review how a defective MPO-H2O2-Cl system contributes to the increased susceptibility to infection and dysregulated inflammation associated with the clinical manifestations of CF.

Topics: Chlorides; Cystic Fibrosis; Humans; Hydrogen Peroxide; Hypochlorous Acid; Inflammation; Leukocyte Disorders; Neutrophils; Peroxidase

Kidney disease is a strong modulator of the composition and metabolism of the intestinal microbiome that produces toxins and inflammatory factors. The primary pathways for these harmful factors are blood vessels and nerves. Although lymphatic vessels are responsible for clearance of interstitial fluids, macromolecules, and cells, little is known about whether and how kidney injury impacts the intestinal lymphatic network.. Kidney injury stimulates intestinal lymphangiogenesis, activates lymphatic endothelial cells, and increases mesenteric lymph flow. The mesenteric lymph of kidney-injured animals contains increased levels of cytokines, immune cells, isolevuglandin (IsoLG), a highly reactive dicarbonyl, and of apolipoprotein AI (apoAI). IsoLG is increased in the ileum of kidney injured animals, and intestinal epithelial cells exposed to myeloperoxidase produce more IsoLG. IsoLG-modified apoAI directly increases lymphatic vessel contractions and activates lymphatic endothelial cells. Inhibition of IsoLG by carbonyl scavenger treatment reduces intestinal lymphangiogenesis in kidney-injured animals. Research from our group and others suggests a novel mediator (IsoLG-modified apoAI) and a new pathway (intestinal lymphatic network) in the cross talk between kidneys and intestines and heart. Kidney injury activates intestinal lymphangiogenesis and increases lymphatic flow via mechanisms involving intestinally generated IsoLG. The data identify a new pathway in the kidney gut-heart axis and present a new target for kidney disease-induced intestinal disruptions that may lessen the major adverse consequence of kidney impairment, namely cardiovascular disease.

Topics: Animals; Apolipoprotein A-I; Cardiovascular Diseases; Cytokines; Endothelial Cells; Humans; Hypertension; Inflammation; Lymphatic Vessels; Peroxidase; Renal Insufficiency, Chronic

Myeloperoxidase (MPO) is one of the most abundantly expressed proteins in neutrophils. It serves as a critical component of the antimicrobial defense system, facilitating microbial killing via generation of reactive oxygen species (ROS). Interestingly, emerging evidence indicates that in addition to the well-recognized canonical antimicrobial function of MPO, it can directly or indirectly impact immune cells and tissue responses in homeostatic and disease states. Here, we highlight the emerging non-canonical functions of MPO, including its impact on neutrophil longevity, activation and trafficking in inflammation, its interactions with other immune cells, and how these interactions shape disease outcomes. We further discuss MPO interactions with barrier forming endothelial and epithelial cells, specialized cells of the central nervous system (CNS) and its involvement in cancer progression. Such diverse function and the MPO association with numerous inflammatory disorders make it an attractive target for therapies aimed at resolving inflammation and limiting inflammation-associated tissue damage. However, while considering MPO inhibition as a potential therapy, one must account for the diverse impact of MPO activity on various cellular compartments both in health and disease.

Topics: Humans; Inflammation; Neoplasms; Neutrophils; Peroxidase; Reactive Oxygen Species

Heme peroxidases are a major source of reactive oxidants at sites of inflammation in biological systems. The formation of some of these oxidants (e.g. hypochlorous acid, HOCl) is important in the innate immune response of activated neutrophils and leukocytes to invading pathogens (e.g. bacteria, yeasts, fungi parasites), and responsible for the anti-microbial activity present in excreted fluids (e.g. hypothiocyanous acid, HOSCN, generated by lactoperoxidase). Other oxidants formed by heme peroxidase family members are important in tissue development (e.g. hypobromous acid, HOBr, formation by peroxidasin) and in the synthesis of thyroid hormones (hypoiodous acid, HOI, synthesized by thyroid peroxidase). However, inadvertent, misplaced or poorly-controlled production of these species can result in host tissue damage, and this underlies the strong association between high levels of some of these enzymes and multiple inflammatory pathologies. As a consequence, there is widespread interest in understanding the kinetics and mechanisms of biomolecule modification by these species, which differ dramatically in their actions, the nature of the products formed (as some of these are specific biomarkers of enzyme activity), and the biological consequences of these reactions in a wide range of diseases associated with acute or chronic inflammation. Increased knowledge of these processes, has allowed the development of a number of alternative and complementary strategies that allow modulation of oxidant formation and subsequent damage. This review discusses developments in these fields and the prospects for tailored inhibition of specific members of this enzyme family.

Topics: Humans; Inflammation; Peroxidase

Chronic systemic inflammation is associated with an increased risk of cardiovascular disease in an environment of low low-density lipoprotein (LDL) and low total cholesterol and with the pathophysiology of neuroprogressive disorders. The causes and consequences of this lipid paradox are explored. Circulating activated neutrophils can release inflammatory molecules such as myeloperoxidase and the pro-inflammatory cytokines interleukin-1 beta, interleukin-6 and tumour necrosis factor-alpha. Since activated neutrophils are associated with atherosclerosis and cardiovascular disease and with major depressive disorder, bipolar disorder and schizophrenia, it seems reasonable to hypothesise that the inflammatory molecules released by them may act as mediators of the link between systemic inflammation and the development of atherosclerosis in neuroprogressive disorders. This hypothesis is tested by considering the association at a molecular level of systemic inflammation with increased LDL oxidation; increased small dense LDL levels; increased lipoprotein (a) concentration; secretory phospholipase A

Topics: Atherosclerosis; Cytokines; Humans; Inflammation; Lipids; Lipoproteins, LDL; Neurodegenerative Diseases; Neutrophils; Peroxidase; Phospholipases A2

The heme peroxidase family generates a battery of oxidants both for synthetic purposes, and in the innate immune defence against pathogens. Myeloperoxidase (MPO) is the most promiscuous family member, generating powerful oxidizing species including hypochlorous acid (HOCl). Whilst HOCl formation is important in pathogen removal, this species is also implicated in host tissue damage and multiple inflammatory diseases. Significant oxidant formation and damage occurs extracellularly as a result of MPO release via phagolysosomal leakage, cell lysis, extracellular trap formation, and inappropriate trafficking. MPO binds strongly to extracellular biomolecules including polyanionic glycosaminoglycans, proteoglycans, proteins, and DNA. This localizes MPO and subsequent damage, at least partly, to specific sites and species, including extracellular matrix (ECM) components and plasma proteins/lipoproteins. Biopolymer-bound MPO retains, or has enhanced, catalytic activity, though evidence is also available for non-catalytic effects. These interactions, particularly at cell surfaces and with the ECM/glycocalyx induce cellular dysfunction and altered gene expression. MPO binds with higher affinity to some damaged ECM components, rationalizing its accumulation at sites of inflammation. MPO-damaged biomolecules and fragments act as chemo-attractants and cell activators, and can modulate gene and protein expression in naïve cells, consistent with an increasing cycle of MPO adhesion, activity, damage, and altered cell function at sites of leukocyte infiltration and activation, with subsequent tissue damage and dysfunction. MPO levels are used clinically both diagnostically and prognostically, and there is increasing interest in strategies to prevent MPO-mediated damage; therapeutic aspects are not discussed as these have been reviewed elsewhere.

Topics: Humans; Hypochlorous Acid; Inflammation; Oxidants; Oxidation-Reduction; Peroxidase

This review provides a practical guide to myeloperoxidase (MPO) and presents to the reader the diversity of its presence in biology. The review provides a historical background, from peroxidase activity to the discovery of MPO, to its role in disease and drug development. MPO is discussed in terms of its necessity, as specific individuals lack MPO expression. An underlying theme presented throughout brings up the question of the benefit and burden of MPO activity. Enzyme structure is discussed, including accurate masses and glycosylation sites. The catalytic cycle of MPO and its corresponding pathways are presented, with a discussion of the importance of the redox couples of the different states of MPO. Cell lines expressing MPO are discussed and practically summarized for the reader, and locations of MPO (primary and secondary) are provided. Useful methods of MPO detection are discussed, and how these can be used for studying disease processes are implied through the presentation of MPO as a biomarker. The presence of MPO in neutrophil extracellular traps is presented, and the activators of the former are provided. Lastly, the transition from drug metabolism to a target for drug development is where the review concludes.

Topics: Biomarkers; Drug Discovery; Humans; Inflammation; Neutrophils; Peroxidase; Pharmaceutical Preparations

For decades, neutrophils were generally regarded as the cells of innate immunity with proinflammatory and phagocytic properties involved in a dual activity, beneficial (antimicrobial) and detrimental (tissue damage). Importantly, until the discovery of toll-like receptors (TLRs), a role of neutrophils in adaptive immunity was limited to the effector stage of humoral response and phagocytosis of opsonized antigens. Moreover, in common opinion, neutrophils, as well as the entire innate immune system, were not functionally associated with adaptive immunity. At the time we demonstrated protein chlorination by HOCl, the major product of neutrophil MPO-halide system enhances protein immunogenicity. Based on this discovery, we proposed, as the first, a new role for neutrophils as APC-accessory cells involved in the induction stage of adaptive immunity. Thereafter, we developed our theory concerning the role of neutrophils as the cells which link innate and adaptive immunity. We proposed that protein modification by HOCl may act as a neutrophildependent molecular tagging system, by which sentinel dendritic cells can faster recognise pathogen- derived antigens. Contemporaneously, it was demonstrated that taurine, the most abundant free amino acid in neutrophil cytosol and the major scavenger of HOCl, is a part of the oxidantantioxidant network and is responsible for the regulation and termination of acute inflammation. Moreover, it has been described, that taurine chloramine (TauCl), the physiological products of the reaction of HOCl with taurine, show anti-microbial and anti-inflammatory properties. In this review, the role of HOCl, taurine and TauCl in innate and adaptive immunity will be discussed.

Topics: Adaptive Immunity; Humans; Hypochlorous Acid; Immunity, Innate; Inflammation; Inflammation Mediators; Neutrophils; Peroxidase

Topics: Animals; Arthritis; Atherosclerosis; Enzyme Inhibitors; Humans; Hypochlorous Acid; Inflammation; Kidney Diseases; Lung Diseases; Neoplasms; Neurodegenerative Diseases; Peroxidase

Myeloperoxidase (MPO) is an immune enzyme found in neutrophils and macrophages. It produces the highly oxidative compound HOCl from H. This article covers the patent literature published on MPO inhibitors from 2013 to 2019, as well as the potential use of these compounds as therapeutics for inflammatory syndromes, especially that plays an important role in the initiation and progression of atherosclerosis.. To date, many MPO inhibitors with different structures have been studied, many of which have prominent inhibitory activities. Furthermore, the specificity of these drugs offers hope for the targeted therapy of inflammatory syndromes. Although many data have proved that MPO can contribute to several chronic inflammatory syndromes, the usefulness of MPO inhibitors in preventing and treating inflammatory disorders is still under investigation.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cardiovascular Diseases; Chronic Disease; Drug Development; Enzyme Inhibitors; Humans; Inflammation; Patents as Topic; Peroxidase

ANCA-associated vasculitis (AAV) is a group of chronic inflammatory diseases of small- and medium-sized vessels, which are broadly subdivided based on organ manifestations and disease-specific autoantibodies. The so called anti-neutrophil cytoplasmic antibodies (ANCA) mostly target one of the enzymes, proteinase 3 (PR3) or myeloperoxidase (MPO). Accumulating genetic data demonstrates that these two autoantibodies discriminate two distinct disease entities, more so than the clinical subdivision which is mainly criteria-based. Treatment of AAV includes heavy immunosuppression and is guided by which organs that are involved. Generally, patients with PR3-ANCA display higher risk for disease relapse than patients with MPO-ANCA. In this review, we will focus on the autoimmune features of PR3+ AAV and our current understanding of its triggers and the potential translation into clinical practice.

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; HLA-DP beta-Chains; Humans; Inflammation; Models, Immunological; Myeloblastin; Peroxidase; T-Lymphocyte Subsets

The heme protein myeloperoxidase (MPO) is a major constituent of neutrophils. As a key mediator of the innate immune system, neutrophils are rapidly recruited to inflammatory sites, where they recognize, phagocytose, and inactivate foreign microorganisms. In the newly formed phagosomes, MPO is involved in the creation and maintenance of an alkaline milieu, which is optimal in combatting microbes. Myeloperoxidase is also a key component in neutrophil extracellular traps. These helpful properties are contrasted by the release of MPO and other neutrophil constituents from necrotic cells or as a result of frustrated phagocytosis. Although MPO is inactivated by the plasma protein ceruloplasmin, it can interact with negatively charged components of serum and the extracellular matrix. In cardiovascular diseases and many other disease scenarios, active MPO and MPO-modified targets are present in atherosclerotic lesions and other disease-specific locations. This implies an involvement of neutrophils, MPO, and other neutrophil products in pathogenesis mechanisms. This review critically reflects on the beneficial and harmful functions of MPO against the background of immune response.

Topics: Animals; Humans; Immunity; Inflammation; Neutrophils; Peroxidase

Autoimmune diseases result from the interplay of cellular effectors like T and B cells, regulatory cells in addition to molecular factors like cytokines and regulatory molecules.. Different electronic databases were searched in a non-systematic way to find out the literature of interest.. Pathogenesis of autoimmune diseases involves typical factors such as genetic background including HLA and non HLA system genes, environmental factors such as infectious agents and inflammatory cells mainly T and B lymphocytes abnormally activated leading to immune dysfunction. Other recently reported less typical factors such as micro-RNAs, circular RNAs, myeloperoxidase, vimentine and microbiome dysbiosis seem to be potential target therapies.. We aimed in this manuscript to review common factors in the pathogenesis of autoimmune diseases.

Topics: Autoimmune Diseases; B-Lymphocytes; Cytokines; Dysbiosis; Humans; Inflammation; Microbiota; MicroRNAs; Peroxidase; RNA, Circular; T-Lymphocytes; Vimentin

Myeloperoxidase (MPO), an abundant hemoprotein present in neutrophils and monocytes, plays a significant role in immune surveillance and host defense mechanisms. However, increased MPO activity has been linked to a number of pathologies with compelling evidence in initiation and progression of inflammatory events. As a result, search for active compounds that can efficiently inhibit MPO activity and subsequently decrease inflammatory events has been focus of the current research. This perspective provides an overview of the development of MPO inhibitors, their mechanism of action and the review of molecules that were in clinical trials as promising MPO inhibitors.

Topics: Animals; Enzyme Inhibitors; Humans; Inflammation; Molecular Structure; Monocytes; Neutrophils; Peroxidase; Structure-Activity Relationship

Myeloperoxidase (MPO) is a member of the superfamily of heme peroxidases that is mainly expressed in neutrophils and monocytes. MPO-derived reactive species play a key role in neutrophil antimicrobial activity and human defense against various pathogens primarily by participating in phagocytosis. Elevated MPO levels in circulation are associated with inflammation and increased oxidative stress. Multiple lines of evidence suggest an association between MPO and cardiovascular disease (CVD) including coronary artery disease, congestive heart failure, arterial hypertension, pulmonary arterial hypertension, peripheral arterial disease, myocardial ischemia/reperfusion-related injury, stroke, cardiac arrhythmia and venous thrombosis. Elevated MPO levels are associated with a poor prognosis including increased risk for overall and CVD-related mortality. Elevated MPO may signify an increased risk for CVD for at least 2 reasons. First, low-grade inflammation and increased oxidative stress coexist with many metabolic abnormalities and comorbidities and consequently an elevated MPO level may represent an increased cardiometabolic risk in general. Second, MPO produces a large number of highly reactive species which can attack, destroy or modify the function of every known cellular component. The most common MPO actions relevant to CVD are generation of dysfunctional lipoproteins with an increased atherogenicity potential, reduced NO availability, endothelial dysfunction, impaired vasoreactivity and atherosclerotic plaque instability. These actions strongly suggest that MPO is directly involved in the pathophysiology of CVD. In this regard MPO may be seen as a mediator or an instrument through which inflammation promotes CVD at molecular and cellular level. Clinical value of MPO therapeutic inhibition remains to be tested.

Topics: Cardiovascular Diseases; Humans; Inflammation; Oxidative Stress; Peroxidase

The review presents the pathobiochemical and molecular mechanisms of sputum formation in patients with cystic fibrosis associated with the pathophysiological features of the disease. Statistical data on the prevalence of this pathology in the world and in the Russian Federation are presented. The mechanisms of sputum formation and disorders of the mucociliary apparatus, leading to the accumulation of viscous bronchopulmonary secret in cystic fibrosis, are considered. The principles of the relationship between the rheological properties of sputum and the formation of inflammation in the lungs with the addition of a concomitant specific microflora in the bronchopulmonary system in patients with cystic fibrosis are presented. Describes the opportunities for biochemical studies of sputum of patients with this pathology: determining the activity of enzymes (myeloperoxidase), the content of proteinase inhibitors (α2-macroglobulin and α1-antitrypsin) and proinflammatory cytokines (IL-8 and TNFa), concentrations of iron and ferriferous proteins (lactoferrin and ferritin), which makes biochemical studies of sputum available, non-invasive, quick and cost-effective method of diagnosis, which can be widely used as an auxiliary laboratory method and makes it possible to use these metabolites as diagnostic markers to assess the severity of inflammation and infection of the lower respiratory tract and predict the development of respiratory complications in patients with cystic fibrosis.

Topics: Cystic Fibrosis; Cytokines; Ferritins; Humans; Inflammation; Lactoferrin; Peroxidase; Protease Inhibitors; Sputum

Myocardial inflammation following acute ischemic injury has been linked to poor cardiac remodeling and heart failure. Many studies have linked myeloperoxidase (MPO), a neutrophil and inflammatory marker, to cardiac inflammation in the setting of acute coronary syndrome (ACS). However, the prognostic role of MPO for adverse clinical outcomes in ACS patients has not been well established.. MEDLINE and Cochrane databases were searched for studies from 1975 to March 2018 that investigated the prognostic value of serum MPO in ACS patients. Studies which have dichotomized patients into a high MPO group and a low MPO group reported clinical outcomes accordingly and followed up patients for at least 30 days to be eligible for enrollment. Data were analyzed using random-effects model. Sensitivity analyses were conducted for quality control.. Our meta-analysis included 13 studies with 9090 subjects and a median follow-up of 11.4 months. High MPO level significantly predicted mortality (odds ratio (OR) 2.03; 95% confidence interval (CI): 1.40-2.94;. Our meta-analysis suggests that high MPO levels are associated with the risk of mortality and that MPO can be incorporated in risk stratification models that guide therapy of high-risk ACS patients.

Topics: Acute Coronary Syndrome; Arrhythmias, Cardiac; Biomarkers; C-Reactive Protein; Female; Heart Failure; Humans; Inflammation; Male; Myocardial Infarction; Odds Ratio; Peroxidase; Predictive Value of Tests; Prognosis; Recurrence; Regression Analysis; Risk Assessment; Sensitivity and Specificity; Sex Factors; Signal Transduction; Smoking; Treatment Outcome

Oxidative stress may cause a wide variety of free radical reactions to produce deleterious modifications in membranes, proteins, enzymes, and DNA. Reactive Oxygen Species (ROS) generated by myeloperoxidase (MPO) can induce lipid peroxidation and also play an important role in the generation of reactive chlorinating and brominating species. As the universal biomarkers, chemical, and immunochemical approach on oxidatively modified and halogenated tyrosines has been carried out. As amido-type adduct biomarkers, chemical, and immunochemical evaluation of hexanoyl- and propanoyl-lysines, hexanoyl- and propanoyl-dopamines and phospholipids were prepared and developed for application of evaluation of novel antioxidative functional food factors. We have also involved in application of oxidatively modified DNAs such as 8-hydroxy- and 8-halogenated deoxyguanosines as the useful biomarkers for age-related diseases using both in vitro and in vivo systems. Application of these oxidative stress biomarkers for novel type of functional food development and recent approach for development of novel evaluation systems are also discussed.

Topics: Biomarkers; DNA; Dopamine; Functional Food; Humans; Inflammation; Lipid Peroxidation; Lipid Peroxides; Lysine; Oxidative Stress; Peroxidase; Phospholipids; Reactive Oxygen Species; Tyrosine

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

Myeloperoxidase (MPO) is a heme-containing peroxidase expressed mainly in neutrophils and to a lesser degree in monocytes. In the presence of hydrogen peroxide and halides, MPO catalyzes the formation of reactive oxygen intermediates, including hypochlorous acid (HOCl). The MPO/HOCl system plays an important role in microbial killing by neutrophils. In addition, MPO has been demonstrated to be a local mediator of tissue damage and the resulting inflammation in various inflammatory diseases. These findings have implicated MPO as an important therapeutic target in the treatment of inflammatory conditions. In contrast to its injurious effects at sites of inflammation, recent studies using animal models of various inflammatory diseases have demonstrated that MPO deficiency results in the exaggeration of inflammatory response, and that it affects neutrophil functions including cytokine production. Given these diverse effects, a growing interest has emerged in the role of this well-studied enzyme in health and disease.

Topics: Animals; Humans; Inflammation; Mice; Mice, Knockout; Neutrophils; Peroxidase

Myeloperoxidase (MPO) is a protein present in azurophilic granules, macrophages, and neutrophils that are released into extracellular fluid (ECF) during inflammation. MPO releases hypochlorous acid (HOCl) and other chlorinated species. It is derived from hydrogen peroxide (H

Topics: Animals; Humans; Hypochlorous Acid; Inflammation; Nervous System Diseases; Neutrophils; Oxidative Stress; Peroxidase

Myeloperoxidase (MPO) is a member of the mammalian peroxidase family. It is mainly expressed in neutrophils, monocytes and macrophages. As a catalyzer of reactive oxidative species and radical species formation, it contributes to neutrophil bactericidal activity. Nevertheless MPO invalidation does not seem to have major health consequences in affected individuals. This suggests that MPO might have alternative functions supporting its conservation during evolution. We will review the available data supporting these non-canonical functions in terms of tissue specific expression, function and enzymatic activity. Thus, we discuss its cell type specific expression. We review in between others its roles in angiogenesis, endothelial (dys-) function, immune reaction, and inflammation. We summarize its pathological actions in clinical conditions such as cardiovascular disease and cancer.

Topics: Adaptive Immunity; Animals; Cardiovascular Diseases; Endothelial Cells; Humans; Immunity, Innate; Inflammation; Neoplasms; Neovascularization, Physiologic; Neutrophils; Peroxidase

The presence of chronic inflammation in the colonic mucosa leads to an increased risk of cancer. Among proteins involved in the regulation of mucosal inflammation and that may contribute both to structural damage of the intestinal mucosa and to intestinal carcinogenesis, there are myeloperoxidase (MPO) and vanins. The infiltration of colonic mucosa by neutrophils may promote carcinogenesis through MPO, a key enzyme contained in the lysosomes of neutrophils that regulates local inflammation and the generation of reactive oxygen species (ROS) and mutagenic species. The human vanin gene family consists of three genes:

Topics: Amidohydrolases; Carcinogenesis; Colorectal Neoplasms; Cysteamine; Enzyme Inhibitors; Humans; Inflammation; Peroxidase; Reactive Oxygen Species

Topics: Animals; Autoimmune Diseases; Autoimmunity; Capillary Permeability; Dendritic Cells; Humans; Inflammation; Mice; Molecular Targeted Therapy; Peroxidase

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

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

Host invasion by Entamoeba histolytica, the pathogenic agent of amebiasis, can lead to the development of amebic liver abscess (ALA). Due to the difficulty of exploring host and amebic factors involved in the pathogenesis of ALA in humans, most studies have been conducted with animal models (e.g., mice, gerbils, and hamsters). Histopathological findings reveal that the chronic phase of ALA in humans corresponds to lytic or liquefactive necrosis, whereas in rodent models there is granulomatous inflammation. However, the use of animal models has provided important information on molecules and mechanisms of the host/parasite interaction. Hence, the present review discusses the possible role of neutrophils in the effector immune response in ALA in rodents. Properly activated neutrophils are probably successful in eliminating amebas through oxidative and non-oxidative mechanisms, including neutrophil degranulation, the generation of free radicals (O2(-), H2O2, HOCl) and peroxynitrite, the activation of NADPH-oxidase and myeloperoxidase (MPO) enzymes, and the formation of neutrophil extracellular traps (NETs). On the other hand, if amebas are not eliminated in the early stages of infection, they trigger a prolonged and exaggerated inflammatory response that apparently causes ALAs. Genetic differences in animals and humans are likely to be key to a successful host immune response.

Topics: Animals; Apoptosis; Cell Degranulation; Cell Hypoxia; Cricetinae; Disease Susceptibility; Entamoeba histolytica; Extracellular Traps; Female; Gerbillinae; Inflammation; Liver Abscess, Amebic; Male; Mice; Mice, SCID; Models, Animal; NADPH Oxidases; Neutrophils; Peroxidase; Rats; Respiratory Burst; Species Specificity

Myeloperoxidase aids in clearance of microbes by generation of peroxidase-mediated oxidants that kill leukocyte-engulfed pathogens. In this review, we will examine 1) strategies for in vitro evaluation of myeloperoxidase function and its inhibition, 2) ways to monitor generation of certain oxidant species during inflammation, and 3) how these methods can be used to approximate the total polymorphonuclear neutrophil chemotaxis following insult. Several optical imaging probes are designed to target reactive oxygen and nitrogen species during polymorphonuclear neutrophil inflammatory burst following injury. Here, we review the following 1) the broad effect of myeloperoxidase on normal physiology, 2) the difference between myeloperoxidase and other peroxidases, 3) the current optical probes available for use as surrogates for direct measures of myeloperoxidase-derived oxidants, and 4) the range of preclinical options for imaging myeloperoxidase accumulation at sites of inflammation in mice. We also stress the advantages and drawbacks of each of these methods, the pharmacokinetic considerations that may limit probe use to strictly cell cultures for some reactive oxygen and nitrogen species, rather than in vivo utility as indicators of myeloperoxidase function. Taken together, our review should shed light on the fundamental rational behind these techniques for measuring myeloperoxidase activity and polymorphonuclear neutrophil response after injury toward developing safe myeloperoxidase inhibitors as potential therapy for chronic obstructive pulmonary disease and rheumatoid arthritis.

Topics: Animals; Humans; Inflammation; Mice; Neutrophils; Peroxidase; Reactive Nitrogen Species; Reactive Oxygen Species; Respiratory Burst

The inhalation injury is usually initiated by uninhibited absorption of smoke, favoring the release of cytokines and other lipid mediators from inflammatory cells in lung airways and parenchyma.. To systematically review, examine, and synthesize the main inflammatory mediators analyzed in published studies in animals subjected to smoke inhalation, as well as oxidative stress.. A comprehensive literature search was conducted through MEDLINE-PubMed, Web of Science, and Scopus.. Studies with animals subjected to lung damage from smoke inhalation that evaluated the presence and the action of inflammatory mediators and oxidative stress.. A total of 1332 studies were initially identified, with only 31 meeting the inclusion criteria. The inflammatory mediators and oxidative stress markers studied and presented in the articles described herein were varied; however, the most cited ones were tumor necrosis factor-alpha (6), IL-8 and IL-6 (both studied in five articles), IL-1β and nuclear factor kappa β (both studied in 4 articles), malondialdehyde (11 studies), and myeloperoxidase (7). It is worth noting that most studies evaluated more than one inflammatory mediator and oxidative stress marker.. Based on this review, we could observe that the main inflammatory mediators and oxidative stress markers analyzed were TNF-α, IL-8, IL-6, IL-1β, nuclear factor kappa β, MDA, and MPO. However, it is necessary to increase the rigor of study design and data, in order to have studies that are more homogeneous and with appropriate methodological quality.

Topics: Animals; Biomarkers; Cytokines; Inflammation; Inflammation Mediators; Interleukin-1beta; Interleukin-6; Interleukin-8; Malondialdehyde; NF-kappa B; Oxidative Stress; Peroxidase; Smoke Inhalation Injury; Tumor Necrosis Factor-alpha

Chronic kidney disease (CKD) is a worldwide public health problem. Patients with CKD have a number of disorders in the organism, and the presence of oxidative stress and systemic inflammation in these patients is the subject of numerous studies. Chronic inflammation joined with oxidative stress contributes to the development of numerous complications: accelerated atherosclerosis process and cardiovascular disease, emergence of Type 2 diabetes mellitus, development of malnutrition, anaemia, hyperparathyroidism, and so forth, affecting the prognosis and quality of life of patients with CKD. In this review we presented the potential role of the myeloperoxidase enzyme in the production of reactive/chlorinating intermediates and their role in oxidative damage to biomolecules in the body of patients with chronic kidney disease and end-stage renal disease. In addition, we discussed the role of modified lipoprotein particles under the influence of prooxidant MPO intermediates in the development of endothelial changes and cardiovascular complications in renal failure.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dyslipidemias; Humans; Hypoalbuminemia; Inflammation; Oxidative Stress; Peroxidase; Reactive Nitrogen Species; Reactive Oxygen Species; Renal Insufficiency, Chronic

The anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are a heterogeneous group of rare syndromes characterized by necrotizing inflammation of small and medium-sized blood vessels and the presence of ANCAs. Several clinicopathological classification systems exist that aim to define homogeneous groups among patients with AAV, the main syndromes being microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) and eosinophilic GPA (EGPA). Two main types of ANCA can be detected in patients with AAV. These ANCAs are defined according to their autoantigen target, namely leukocyte proteinase 3 (PR3) and myeloperoxidase (MPO). Patients with GPA are predominantly PR3-ANCA-positive, whereas those with MPA are predominantly MPO-ANCA-positive, although ANCA specificity overlaps only partially with these clinical syndromes. Accumulating evidence suggests that ANCA specificity could be better than clinical diagnosis for defining homogeneous groups of patients, as PR3-ANCA and MPO-ANCA are associated with different genetic backgrounds and epidemiology. ANCA specificity affects the phenotype of clinical disease, as well as the patient's initial response to remission-inducing therapy, relapse risk and long-term prognosis. Thus, the classification of AAV by ANCA specificity rather than by clinical diagnosis could convey clinically useful information at the time of diagnosis.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Churg-Strauss Syndrome; Granulomatosis with Polyangiitis; Humans; Immunologic Factors; Inflammation; Microscopic Polyangiitis; Myeloblastin; Peroxidase; Predictive Value of Tests; Prognosis; Sensitivity and Specificity

Chlorinated phospholipids are formed by the reaction of hypochlorous acid (HOCl), generated by the enzyme myeloperoxidase under inflammatory conditions, and the unsaturated fatty acyl residues or the head group. In the first case the generated chlorohydrins are both proinflammatory and cytotoxic, thus having a significant impact on the structures of biomembranes. The latter case leads to chloramines, the properties of which are by far less well understood. Since HOCl is also widely used as a disinfecting and antibacterial agent in medicinal, industrial, and domestic applications, it may represent an additional source of danger in the case of abuse or mishandling. This review discusses the reaction behavior of in vivo generated HOCl and biomolecules like DNA, proteins, and carbohydrates but will focus on phospholipids. Not only the beneficial and pathological (toxic) effects of chlorinated lipids but also the importance of these chlorinated species is discussed. Some selected cleavage products of (chlorinated) phospholipids and plasmalogens such as lysophospholipids, (chlorinated) free fatty acids and

Topics: Chlorohydrins; Fatty Acids; Gas Chromatography-Mass Spectrometry; Halogenation; Humans; Hypochlorous Acid; Inflammation; Peroxidase; Phospholipids; Reactive Oxygen Species

Chlorine bleach, or hypochlorous acid, is the most reactive two-electron oxidant produced in appreciable amounts in our bodies. Neutrophils are the main source of hypochlorous acid. These champions of the innate immune system use it to fight infection but also direct it against host tissue in inflammatory diseases. Neutrophils contain a rich supply of the enzyme myeloperoxidase. It uses hydrogen peroxide to convert chloride to hypochlorous acid.. We give a critical appraisal of the best methods to measure production of hypochlorous acid by purified peroxidases and isolated neutrophils. Robust ways of detecting it inside neutrophil phagosomes where bacteria are killed are also discussed. Special attention is focused on reaction-based fluorescent probes but their visual charm is tempered by stressing their current limitations. Finally, the strengths and weaknesses of biomarker assays that capture the footprints of chlorine in various pathologies are evaluated.. Detection of hypochlorous acid by purified peroxidases and isolated neutrophils is best achieved by measuring accumulation of taurine chloramine. Formation of hypochlorous acid inside neutrophil phagosomes can be tracked using mass spectrometric analysis of 3-chlorotyrosine and methionine sulfoxide in bacterial proteins, or detection of chlorinated fluorescein on ingestible particles. Reaction-based fluorescent probes can also be used to monitor hypochlorous acid during phagocytosis. Specific biomarkers of its formation during inflammation include 3-chlorotyrosine, chlorinated products of plasmalogens, and glutathione sulfonamide.. These methods should bring new insights into how chlorine bleach is produced by peroxidases, reacts within phagosomes to kill bacteria, and contributes to inflammation. This article is part of a Special Issue entitled Current methods to study reactive oxygen species - pros and cons and biophysics of membrane proteins. Guest Editor: Christine Winterbourn.

Topics: Animals; Humans; Hypochlorous Acid; Inflammation; Neutrophils; Peroxidase

Myeloperoxidase is an important heme enzyme released by activated leukocytes that catalyzes the reaction of hydrogen peroxide with halide and pseudo-halide ions to form various hypohalous acids. Hypohalous acids are chemical oxidants that have potent antibacterial, antiviral, and antifungal properties and, as such, play key roles in the human immune system. However, increasing evidence supports an alternative role for myeloperoxidase-derived oxidants in the development of disease. Excessive production of hypohalous acids, particularly during chronic inflammation, leads to the initiation and accumulation of cellular damage that has been implicated in many human pathologies including atherosclerosis, neurodegenerative disease, lung disease, arthritis, inflammatory cancers, and kidney disease. This has sparked a significant interest in developing a greater understanding of the mechanisms involved in myeloperoxidase-derived oxidant-induced mammalian cell damage. This article reviews recent developments in our understanding of the cellular reactivity of hypochlorous acid, hypobromous acid, and hypothiocyanous acid, the major oxidants produced by myeloperoxidase under physiological conditions.

Topics: Animals; Bromates; Calcium; Endothelial Cells; Epithelial Cells; Erythrocytes; Humans; Hydrogen Peroxide; Hypochlorous Acid; Inflammation; Intracellular Signaling Peptides and Proteins; Oxidants; Oxidative Stress; Peroxidase; Signal Transduction; Thiocyanates

Atherosclerosis is the proximate cause of arterial thrombosis, leading to acute occlusive cardiovascular syndromes. Thrombosis in atherosclerosis usually results from rupture of the fibrous cap of atherosclerotic plaques with a smaller proportion resulting from superficial endothelial erosion. Ruptured plaques are often associated with intimal and adventitial inflammation, increased size of lipid-rich necrotic core with thinned out collagen-depleted fibrous cap, outward remodeling, increased plaque neovascularity, intraplaque hemorrhage, and microcalcification. By inference, non-ruptured plaques with similar compositional features are considered to be at risk for rupture and hence are labeled vulnerable plaques or high-risk plaques. Identification of vulnerable plaques may help in predicting the risk of acute occlusive syndromes and may also allow targeting for aggressive systemic and possibly local therapies. Plaque rupture is believed to result from extracellular matrix (which comprises the protective fibrous cap) dysregulation due to excessive proteolysis in the context of diminished matrix synthesis. Inflammation is believed to play a key role by providing matrix-degrading metalloproteinases and also by inducing death of matrix-synthesizing smooth muscle cells. Systemic markers of inflammation are thus the most logical forms of potential biomarkers which may predict the presence of vulnerable or high-risk plaques. Several studies have suggested the potential prognostic value of a variety of systemic markers, but regrettably, their overall clinical predictive value is modestly incremental at best, especially for individual subjects compared to groups of patients. Nevertheless, continued investigation of reliable, cost-effective biomarkers that predict the presence of a high-risk plaque and future athero-thrombotic cardiovascular events with greater sensitivity and specificity is warranted.

Topics: Antigens, Human Platelet; Apolipoprotein A-I; Atherosclerosis; Biomarkers; C-Reactive Protein; Coronary Artery Disease; Coronary Thrombosis; Cost-Benefit Analysis; Extracellular Matrix; Humans; Inflammation; Interleukin-18; Interleukin-6; Methylamines; Peroxidase; Plaque, Atherosclerotic; Pregnancy-Associated Plasma Protein-A; Prognosis

Taurine (2-aminoethanesulfonic acid) is the most abundant free amino acid in humans and plays an important role in several essential biological processes such as bile acid conjugation, maintenance of calcium homeostasis, osmoregulation and membrane stabilization. Moreover, attenuation of apoptosis and its antioxidant activity seem to be crucial for the cytoprotective effects of taurine. Although these properties are not tissue specific, taurine reaches particularly high concentrations in tissues exposed to elevated levels of oxidants (e.g., inflammatory cells). It suggests that taurine may play an important role in inflammation associated with oxidative stress. Indeed, at the site of inflammation, taurine is known to react with and detoxify hypochlorous acid generated by the neutrophil myeloperoxidase (MPO)-halide system. This reaction results in the formation of less toxic taurine chloramine (TauCl). Both haloamines, TauCl and taurine bromamine (TauBr), the product of taurine reaction with hypobromous acid (HOBr), exert antimicrobial and anti-inflammatory properties. In contrast to a well-documented regulatory role of taurine and taurine haloamines (TauCl, TauBr) in acute inflammation, their role in the pathogenesis of inflammatory diseases is not clear. This review summarizes our current knowledge concerning the role of taurine, TauCl and TauBr in the pathogenesis of inflammatory diseases initiated or propagated by MPO-derived oxidants. The aim of this paper is to show links between inflammation, neutrophils, MPO, oxidative stress and taurine. We will discuss the possible contribution of taurine and taurine haloamines to the pathogenesis of inflammatory diseases, especially in the best studied example of rheumatoid arthritis.

Topics: Animals; Anti-Infective Agents; Apoptosis; Arthritis, Rheumatoid; Bile Acids and Salts; Calcium; Humans; Inflammation; Osmoregulation; Peroxidase; Taurine

Myeloperoxidase (MPO), a heme protein released by leukocytes, is one of the most widely studied during the last decades molecule that plays a crucial role in inflammation and oxidative stress in the cellular level. It has become increasingly recognized that MPO performs a very important role as part of the innate immune system through the formation of microbicidal reactive oxidants, whilst it affects the arterial endothelium with a number of mechanisms that include modification of net cellular cholesterol flux and impairment of Nitric Oxide (NO)-induced vascular relaxation. In that way, MPO is implicated into both the formation and propagation of atheromatosis and there is substantial evidence that it also promotes ischemia through destabilization of the vulnerable plaque. Numerous studies have added information on the notion that MPO and its oxidant products are part of the inflammatory cascade initiated by endothelial injury and they are significantly overproduced at the site of arterial inflammation. Subsequent studies achieved quantification of this observation showing significant elevations of the systemic levels of MPO in a wide spectrum of cardiovascular disease scenarios with acute coronary syndromes and heart failure being the most studied. This review highlights key-aspects of MPO's pathophysiological properties and summarizes the role of MPO as a diagnostic and prognostic tool for a number of cardiovascular pathologies.

Topics: Animals; Biomarkers; Cardiovascular Diseases; Endothelium, Vascular; Halogens; Heart Failure; Humans; Hydrogen Peroxide; Hypertension; Inflammation; Metabolic Syndrome; Oxidative Stress; Peroxidase; Predictive Value of Tests; Prognosis

  The pharmaceutical effects of non-steroidal anti-inflammatory drugs (NSAIDs) occur through the inhibition of prostaglandin H synthase (PGHS). Prostaglandin H2 is produced from arachidonic acid via peroxidase and cyclooxygenase cycles in PGHS. NSAIDs exhibit different levels of reactivity in these reaction cycles. To prevent the development of side effect while maintaining the beneficial effects of drugs, a therapeutic strategy should be used. A new classification of NSAIDs has been proposed based on reactivity to peroxidase. Class 1 includes the majority of NSAIDs, which react with horseradish peroxidase (HRP) compounds I and II. Also, their drugs exhibit spectral changes induced by PGHS peroxidase and diminished ESR signals of the tyrosyl radical of metmyoglobin. They reduce compounds I and II of HRP and scavenge tyrosyl radicals. The branched chain mechanism by which the porphyrin radical is transferred to the tyrosine residue of the protein might be blocked by these NSAIDs. Class 2 includes salicylic acid derivatives that react only with the porphyrin radical and do not react with HRP compound II (oxoferryl species). Class 3 includes aspirin, nimesulide, tolmetin, and arylpropionic acid derivatives, including ibuprofen and the coxibs such as celecoxib and rofecoxib, which are not substrates for HRP or PGHS peroxidase. It seems that the selectivity of NSAIDs to PGHS1 and PGHS2 depends on their reactivity with cyclooxygenase rather than with the peroxidase of PGHS. The best drug for each inflammatory disease should therefore be selected for therapy.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Humans; Inflammation; Peroxidase; Prostaglandin H2; Prostaglandin-Endoperoxide Synthases

Oxidation of low-density lipoprotein (LDL) has a key role in atherogenesis. Among the different models of oxidation that have been studied, the one using myeloperoxidase (MPO) is thought to be more physiopathologically relevant. Apolipoprotein B-100 is the unique protein of LDL and is the major target of MPO. Furthermore, MPO rapidly adsorbs at the surface of LDL, promoting oxidation of amino acid residues and formation of oxidized lipoproteins that are commonly named Mox-LDL. The latter is not recognized by the LDL receptor and is accumulated by macrophages. In the context of atherogenesis, Mox-LDL accumulates in macrophages leading to foam cell formation. Furthermore, Mox-LDL seems to have specific effects and triggers inflammation. Indeed, those oxidized lipoproteins activate endothelial cells and monocytes/macrophages and induce proinflammatory molecules such as TNF α and IL-8. Mox-LDL may also inhibit fibrinolysis mediated via endothelial cells and consecutively increase the risk of thrombus formation. Finally, Mox-LDL has been involved in the physiopathology of several diseases linked to atherosclerosis such as kidney failure and consequent hemodialysis therapy, erectile dysfunction, and sleep restriction. All these issues show that the investigations of MPO-dependent LDL oxidation are of importance to better understand the inflammatory context of atherosclerosis.

Topics: Apolipoprotein B-100; Atherosclerosis; Endocytosis; Erectile Dysfunction; Fatty Liver; Female; Fibrinolysis; Humans; Hydrogen Peroxide; Inflammation; Interleukin-8; Lipoproteins, LDL; Macrophages; Male; Oxygen; Peroxidase; Pulmonary Disease, Chronic Obstructive; Renal Dialysis; Sleep Wake Disorders; Tumor Necrosis Factor-alpha

The heme-enzyme myeloperoxidase (MPO) is one of the major neutrophil bactericidal proteins and is stored in large amounts inside azurophilic granules of neutrophils. Upon cell activation, MPO is released and extracellular MPO has been detected in a wide range of acute and chronic inflammatory conditions. Recent ADVANCES AND CRITICAL ISSUES: Apart from its role during infection, MPO has emerged as a critical modulator of inflammation throughout the last decade and is currently discussed in the initiation and propagation of cardiovascular diseases. MPO-derived oxidants (e.g., hypochlorous acid) interfere with various cell functions and contribute to tissue injury. Recent data also suggest that MPO itself exerts proinflammatory properties independent of its catalytic activity. Despite advances in unraveling the complex action of MPO and MPO-derived oxidants, further research is warranted to determine the precise nature and biological role of MPO in inflammation.. The identification of MPO as a central player in inflammation renders this enzyme an attractive prognostic biomarker and a potential target for therapeutic interventions. A better understanding of the (patho-) physiology of MPO is essential for the development of successful treatment strategies in acute and chronic inflammatory diseases.

Topics: Cardiovascular Diseases; Humans; Hypochlorous Acid; Infections; Inflammation; Leukocytes; Neutrophils; Peroxidase

Myeloperoxidase (MPO) is a major protein constituent of the primary granules of vertebrate neutrophils. It catalyses the hydrogen peroxide-mediated oxidation of halide ions to hypohalous acids, especially HOCl. These reactive oxygen species can participate in a variety of secondary reactions, leading to modifications of amino acids and many types of biological macromolecules. The classic paradigm views MPO as a component of the phagocyte oxygen-dependent intracellular microbicidal system, and thus an important arm of the effector phase of innate immune responses. However, the limited immunodeficiency associated with lack of MPO in mouse and human models has challenged this paradigm. In this review we examine more recent information on the interaction between MPO, its bioreactive reaction products, and targets within the inflammatory microenvironment. We propose that two assumptions of the current model may require revisiting. First, many important targets of MPO modification are extracellular, rather than present only within the phagolysosome, such as various components of neutrophil extracellular traps. Second, we suggest that the pro-inflammatory pathological role of MPO may be a particular feature of chronic inflammation. In the physiological setting of acute neutrophil-mediated inflammation MPO may also form part of a negative feedback loop which down-regulates inflammation, limits tissue damage, and facilitates the switch from innate to adaptive immunity. This different perspective on this well-studied enzyme may usefully inform further research into its function in health and disease.

Topics: Adaptive Immunity; Animals; Humans; Immunity, Innate; Inflammation; Neutrophils; Oxidation-Reduction; Peroxidase; Reactive Oxygen Species; Tissue Distribution

The mechanisms that deprive HDL of its cardioprotective properties are poorly understood. One potential pathway involves oxidative damage of HDL proteins by myeloperoxidase (MPO) a heme enzyme secreted by human artery wall macrophages. Mass spectrometric analysis demonstrated that levels of 3-chlorotyrosine and 3-nitrotyrosine - two characteristic products of MPO - are elevated in HDL isolated from patients with established cardiovascular disease. When apolipoprotein A-I (apoA-I), the major HDL protein, is oxidized by MPO, its ability to promote cellular cholesterol efflux by the membrane-associated ATP-binding cassette transporter A1 (ABCA1) pathway is diminished. Biochemical studies revealed that oxidation of specific tyrosine and methionine residues in apoA-I contributes to this loss of ABCA1 activity. Another potential mechanism for generating dysfunctional HDL involves covalent modification of apoA-I by reactive carbonyls, which have been implicated in atherogenesis and diabetic vascular disease. Indeed, modification of apoA-I by malondialdehyde (MDA) or acrolein also markedly impaired the lipoprotein's ability to promote cellular cholesterol efflux by the ABCA1 pathway. Tandem mass spectrometric analyses revealed that these reactive carbonyls target specific Lys residues in the C-terminus of apoA-I. Importantly, immunochemical analyses showed that levels of MDA-protein adducts are elevated in HDL isolated from human atherosclerotic lesions. Also, apoA-I co-localized with acrolein adducts in such lesions. Thus, lipid peroxidation products might specifically modify HDL in vivo. Our observations support the hypotheses that MPO and reactive carbonyls might generate dysfunctional HDL in humans. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010).

Topics: Amino Acid Motifs; Animals; Apolipoprotein A-I; ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters; Cardiovascular Diseases; Cholesterol; Halogenation; Humans; Inflammation; Lipoproteins, HDL; Macrophages; Oxidants; Oxidation-Reduction; Peroxidase

Neutrophil accumulation is a critical event in the pathogenesis of inflammation. The generation of hypochlorous acid by myeloperoxidase (MPO) in neutrophils is crucial to the host defense response. MPO-deficient (MPO-KO) mice showed severely reduced cytotoxicity to Candida albicans, Aspergillus fumigatus, Cryptococcus neoformans and other microorganisms, demonstrating that an MPO-dependent oxidative system is important for in vivo host defense against fungi. On the other hand, impaired reactive oxygen species (ROS) production by neutrophils has previously been shown to cause an abnormal inflammatory response. In the present study, we have found that MPO-KO mice exhibit more severe pulmonary inflammation than wild-type mice when challenged with an intranasal administration of zymosan. In addition to measuring the kinetics of neutrophil accumulation, we also measured the production of macrophage inflammatory protein-2 (MIP-2) in the lung, and we correlate the degree of neutrophil accumulation with the production of this mediator. Our results demonstrate that MPO regulates the production of MIP-2, which may modulate neutrophil accumulation during lung inflammation.

Topics: Animals; Chemokine CXCL2; Disease Susceptibility; Humans; Hypochlorous Acid; Inflammation; Lung; Lung Diseases, Fungal; Metabolism, Inborn Errors; NADPH Oxidases; Neutrophil Activation; Neutrophils; Peroxidase; Phagocytes; Reactive Oxygen Species; Zymosan

Several attempts have been made in the last two decades to investigate ulcerative colitis (UC) patients during the natural course of the disease so as to identify appropriate surrogate markers of disease activity. Most patients with quiescent inflammatory bowel disease have low grade inflammation and it is possible that relapse occurs only once the inflammatory process crosses a critical intensity. Since inflammation is a continuous process, its direct assessment may provide us a quantitative pre-symptomatic measure of imminent relapse. If substantial, it may allow targeted treatment early, to avert relapse or formulate newer therapeutic strategies to maintain symptomatic remission. It is clinically very important to identify these patients at a subclinical stage, noninvasively, by various biomarkers. Biomarkers help to gain an objective measurement of disease activity as symptoms are often subjective. Biomarkers also help to avoid invasive procedures which are often a burden to the patient and the health care system. If an ideal biomarker existed for UC, it would greatly facilitate the work of the gastroenterologist treating these patients. Both "classical" and "emerging" biomarkers of relevance for UC have been studied, but the quest for an ideal biomarker still continues. In this brief review we describe various biomarkers of clinical importance.

Topics: Biomarkers; C-Reactive Protein; Colitis, Ulcerative; Feces; Humans; Inflammation; Lactoferrin; Leukocyte L1 Antigen Complex; Peroxidase; Severity of Illness Index

The atheroprotective effects of HDL are mediated by several mechanisms, including its role in reverse cholesterol transport and via its antiinflammatory properties. However, not all HDL is functionally similar. HDL and apolipoprotein A-I may become dysfunctional or even proinflammatory and thus promote atherosclerosis. ApoAI posttranslational modification can have a large impact on its function. Myeloperoxidase modification of apoAI impairs its function as a cholesterol acceptor, and the molecular changes induced by myeloperoxidase have been studied in detail. These studies provide the basis for the development of an oxidant-resistant form of apoAI and clinical measures of HDL modification and dysfunction, which may be useful as a treatment criterion.

Topics: Animals; Apolipoprotein A-I; Atherosclerosis; Biomarkers; Cholesterol; Humans; Hypolipidemic Agents; Inflammation; Lipoproteins, HDL; Peroxidase; Predictive Value of Tests; Protein Conformation; Protein Processing, Post-Translational; Structure-Activity Relationship

Inflammation plays a pivotal role in all stages of atherosclerosis from endothelial dysfunction and plaque formation to plaque destabilization and disruption. Inflammatory biomarkers, originally studied to better understand the pathophysiology of atherosclerosis, have generated increasing interest among clinicians, because of their utility in the challenging problems of diagnosis and risk assessment of patients with suspected or proved coronary heart disease. Moreover, in fascinating perspective, they could be used as therapeutic target, counteracting initiation, progression, and development of complications of atherosclerosis. In this review, we will provide an overview of the more promising inflammatory biomarkers, focusing on their utility and limitations in the clinical setting.

Topics: Acute-Phase Proteins; Biomarkers; CD40 Ligand; Coronary Disease; Cytokines; Humans; Inflammation; Peroxidase; Pregnancy-Associated Plasma Protein-A

Polymorphonuclear leukocytes (PMNs) are important players in innate and acquired immunity. These cells accumulate at inflammatory sites and contribute to host defence, regulation of the inflammatory process, and also to tissue injury. One of the key components of PMNs is the heme-containing enzyme myeloperoxidase (MPO) that is stored in large amount in azurophilic granules of resting cells. Here we review the (patho)physiological role of MPO from the viewpoint of participation of PMNs in immune reactions. Myeloperoxidase is able to catalyse a wide range of one- and two-electron substrate oxidations. With special products, MPO contributes to apoptosis induction in PMNs and other cells, and, thus, to termination of inflammatory response. On the other hand, MPO released from necrotic cells promotes an inflammation by further recruitment of PMNs, and chemical modification of proteins and other tissue constituents. Myeloperoxidase is a fascinating, multifunctional, and challenging enzyme that has not yet revealed all its secrets.

Topics: Adaptive Immunity; Animals; Humans; Immunity, Innate; Inflammation; Models, Molecular; Neutrophils; Peroxidase

The first detailed report of a specific interaction of CP (caeruloplasmin) with another protein described its complex with LF (lactoferrin) in 2000. Since then, several protein-protein interactions involving CP have been reported, mostly concerning iron-containing proteins. The CP-LF complex was studied thoroughly, and evidence of reciprocal effects of CP and LF was obtained. Another specific interaction investigated in detail occurs between CP and MPO (myeloperoxidase). CP-LF, CP-MPO and CP-LF-MPO complexes were found in sera of patients with inflammation. Modelling in vitro allowed understanding of which structural peculiarities of CP and partners allow the modification of their functions in a complex. The present paper reviews the latest data on complexes of CP with LF and MPO, and advances some suggestions about their role in health and disease.

Topics: Animals; Ceruloplasmin; Humans; Inflammation; Inflammation Mediators; Peroxidase; Protein Binding; Proteins

Myeloperoxidase (MPO) is an enzyme found in myeloid cells, particularly in neutrophils, and to a lesser extent in monocytes and tissue macrophages. MPO plays an important role in the host defense against bacteria and viruses. Since MPO is also an important enzyme in the inflammatory process, and inflammation is a key component in the development and progression of atherosclerotic and other forms of cardiovascular disease, there is ongoing interest in the use of MPO as a biomarker in different fields of cardiology. We aimed to review the current state of literature regarding the role of MPO in cardiovascular disease, especially highlighting the practical implications of the fast growing data from clinical studies.

Topics: Cardiology; Cardiovascular Diseases; Coronary Artery Disease; Disease Progression; Heart Failure; Humans; Inflammation; Lipoproteins, LDL; Macrophages; Monocytes; Neutrophils; Peroxidase

Current evidence supports that inflammation is a major driving force underlying the initiation of coronary plaques, their unstable progression, and eventual disruption; patients with a more pronounced vascular inflammatory response have a poorer outcome. Biomarkers are generally considered to be proteins or enzymes - measured in serum, plasma, or blood - that provide independent diagnostic and prognostic value by reflecting an underlying disease state. In the case of coronary artery disease (CAD), inflammatory biomarkers, have been extensively investigated; more evidence exists for C-reactive protein (CRP). Using high sensitivity (hs) assays, epidemiologic data demonstrate an association between hs-CRP and risk for future cardiovascular morbidity and mortality among those at high risk or with documented CAD. Moreover, a series of prospective studies provide consistent data documenting that mild elevation of baseline levels of hs-CRP among apparently healthy individuals is associated with higher long-term risk for cardiovascular events. Yet, the predictive value of hs-CRP is found to be independent of traditional cardiovascular risk factors. Recent studies suggest that, besides CRP, other inflammatory biomarkers such as cytokines [interleukin (IL)-1, IL-6, IL-8, monocyte chemoattractant protein-1 (MCP-1)], soluble CD40 ligand, serum amyloid A (SAA), selectins (E-selectin, P-selectin), myeloperoxidase (MPO), matrix metalloproteinases (MMPs), cellular adhesion molecules [intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1)], placental growth factor (PlGF) and A(2) phospholipases may have a potential role for the prediction of risk for developing CAD and may correlate with severity of CAD. Finally, indications suggest that the increased risk associated with inflammation may be modified with certain preventive therapies and biomarkers may help to identify the individuals who would benefit most from these interventions.

Topics: Biomarkers; C-Reactive Protein; CD40 Ligand; Cell Adhesion Molecules; Coronary Artery Disease; Cytokines; Humans; Inflammation; Inflammation Mediators; Peroxidase; Predictive Value of Tests; Primary Prevention; Risk; Serum Amyloid A Protein

Myeloperoxidase (MPO) is a heme-containing peroxidase abundantly expressed in neutrophils and to a lesser extent in monocytes. Enzymatically active MPO, together with hydrogen peroxide and chloride, produces the powerful oxidant hypochlorous acid and is a key contributor to the oxygen-dependent microbicidal activity of phagocytes. In addition, excessive generation of MPO-derived oxidants has been linked to tissue damage in many diseases, especially those characterized by acute or chronic inflammation. It has become increasingly clear that MPO exerts effects that are beyond its oxidative properties. These properties of MPO are, in many cases, independent of its catalytic activity and affect various processes involved in cell signaling and cell-cell interactions and are, as such, capable of modulating inflammatory responses. Given these diverse effects, an increased interest has emerged in the role of MPO and its downstream products in a wide range of inflammatory diseases. In this article, our knowledge pertaining to the biologic role of MPO and its downstream effects and mechanisms of action in health and disease is reviewed and discussed.

Topics: Animals; Humans; Inflammation; Models, Biological; Peroxidase

Bronchial asthma and chronic obstructive pulmonary disease (COPD) are increasing common diseases. The major pathogenesis of both illnesses is chronic inflammation. However, the inflammatory pattern is distinct in each disease. In asthmatic airways, activated mast cells/eosinophils and T helper 2 lymphocytes (Th2) are predominant. In contrast, macrophages and neutrophils are important in COPD airways/lung. Although nitric oxide (NO) hyperproduction due to inducible NO synthase (iNOS) is observed in asthma and COPD, nitrotyrosine formation via the reaction between NO and O(2)- in addition to the myeloperoxidase-mediated pathway. These distinct inflammatory patterns in both diseases seem to cause pathological differences in asthma and COPD.

Topics: Animals; Asthma; Eosinophils; Humans; Inflammation; Lung; Macrophages; Neutrophils; Nitric Oxide; Nitric Oxide Synthase Type II; Oxygen; Peroxidase; Pulmonary Disease, Chronic Obstructive; Th2 Cells

Although assessment of traditional coronary heart disease risk factors can often stratify individuals into low- or high-risk categories, additional means are needed to more precisely classify people clinically defined as intermediate-risk, to guide the intensity of risk-reducing therapies. The recognition that inflammatory pathways are important in the progression of atherosclerosis and its complications has prompted investigation to identify circulating risk markers that may be useful in risk stratification. This article summarizes recent studies on the current use of an emerging group of inflammatory markers: soluble CD-40 ligand, interleukin-18, myeloperoxidase, B-type natriuretic peptides, secretory phospholipase A(2), lipoprotein-associated phospholipase A(2), and C-reactive protein. The demonstration that lowering C-reactive protein along with low-density lipoprotein cholesterol with statins reduces events beyond cholesterol lowering alone suggests that titration of therapies using other emerging inflammatory markers may further reduce the toll of atherosclerosis in adult populations.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Biomarkers; C-Reactive Protein; CD40 Ligand; Cholesterol, LDL; Coronary Artery Disease; Disease Progression; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Interleukin-18; Natriuretic Peptide, Brain; Peroxidase; Phospholipases A2, Secretory; Risk Assessment; Risk Factors

A marked increase in interest has occurred over the last few years in the role that mammalian heme peroxidase enzymes, primarily myeloperoxidase, eosinophil peroxidase, and lactoperoxidase, may play in both disease prevention and human pathologies. This increased interest has been sparked by developments in our understanding of polymorphisms that control the levels of these enzymes, a greater understanding of the basic chemistry and biochemistry of the oxidants formed by these species, the development of specific biomarkers that can be used in vivo to detect damage induced by these oxidants, the detection of active forms of these peroxidases at most, if not all, sites of inflammation, and a correlation between the levels of these enzymes and a number of major human pathologies. This article reviews recent developments in our understanding of the enzymology, chemistry, biochemistry and biologic roles of mammalian peroxidases and the oxidants that they generate, the potential role of these oxidants in human disease, and the use of the levels of these enzymes in disease prognosis.

Topics: Animals; Eosinophil Peroxidase; Heme; Humans; Inflammation; Lactoperoxidase; Oxidants; Peroxidase; Peroxidases

Myeloperoxidase (MPO) is an enzyme stored in azurophilic granules of polymorphonuclear neutrophils and macrophages and released into extracellular fluid in the setting of inflammatory process. The observation that myeloperoxidase is involved in oxidative stress and inflammation has been a leading factor to study myeloperoxidase as a possible marker of plaque instability and a useful clinical tool in the evaluation of patients with coronary heart disease. The purpose of this review is to provide an overview of the pathophysiological, analytical, and clinical characteristics of MPO and to summarize the state of art about the possible clinical use of MPO as a marker for diagnosis and risk stratification of patients with acute coronary syndrome (ACS).

Topics: Acute Coronary Syndrome; Biomarkers; Humans; Inflammation; Myocardial Ischemia; Oxidative Stress; Peroxidase; Prognosis; Risk Factors

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

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

Inflammation plays a key role in the pathogenesis of atherosclerosis. Understanding the process of inflammation as it pertains to atherosclerosis has provided researchers with multiple opportunities to identify novel markers for use in cardiovascular disease management. This article discusses the inflammatory cascade as it pertains to atherosclerosis and some of the well-studied markers of inflammation. It also discusses the limitations of current risk stratification models and characteristics of a good biomarker.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Area Under Curve; Biomarkers; C-Reactive Protein; Coronary Artery Disease; Endothelium, Vascular; Humans; Inflammation; Peroxidase; Risk Assessment; ROC Curve

Patients with advanced chronic kidney disease are at a greatly increased cardiovascular risk that cannot be explained entirely by traditional cardiovascular risk factors. An increase in oxidative stress is proposed as a non-traditional cardiovascular risk factor in this patient population. Many laboratories have now unequivocally demonstrated that uremia is an increased oxidative stress state. Uremic oxidative stress is characterized biologically by an increase in lipid peroxidation products and reactive aldehyde groups as well as by increased retention of oxidized thiols. The pathophysiology of increased oxidative stress in uremia is multifactorial, but the retention of oxidized solute by the loss of kidney function is probably a major contributor.

Topics: Atherosclerosis; Humans; Inflammation; Kidney Diseases; Oxidative Stress; Peroxidase; Renal Dialysis

The cellular injury that results from irreversible ischemia leads to the alteration of tissue function responsible for the phenomenon that we call left ventricular remodeling. Oxidative stress and inflammation are key elements of this process; in mice as in humans, elevation of markers of inflammation at the time of myocardial infarction (MI) is a predictor of the development of ischemic myopathy and of adverse clinical outcomes. Several leukocyte-derived enzyme systems are responsible for the release of oxidizing agents into the myocardium after ischemic injury and provide a means of better understanding MI. By identifying the oxidation products present after inflammation, the responsible leukocyte-generating oxidant systems can be elucidated. Interestingly, a key leukocyte-derived marker, myeloperoxidase (MPO), was formerly measured routinely by older-generation hematology analyzers. Patients with lower levels of MPO were noted to be at lower risk for untoward cardiovascular events, suggesting that humans are more genomically "hardwired" than previously thought. Studies with genetic knockout mice confirm the importance of these leukocyte-generated oxidants in the pathophysiologic consequences of ischemia. This clearly affects the anatomic extent of damage, the hemodynamic consequences, and ultimately, the clinical correlates and potential outcomes. An understanding of these oxidative processes and their relation to inflammation will be extremely useful in the development and understanding of potential therapeutic agents.

Topics: Animals; Antioxidants; Cardiovascular Diseases; Humans; Inflammation; Leukocytes; Lipid Peroxidation; Myocardial Infarction; Oxidants; Oxidative Stress; Peptide Hydrolases; Peroxidase; Ventricular Remodeling

Although the existence of halogenated lipids in lower organisms has been known for many years, it is only since the 1990s that interest in their occurrence in mammalian systems has developed. Chlorinated (and other halogenated) lipids can arise from oxidation by hypohalous acids, such as HOCl, which are products of the phagocytic enzyme myeloperoxidase and are generated during inflammation. The major species of chlorinated lipids investigated to date are chlorinated sterols, fatty acid and phospholipid chlorohydrins, and alpha-chloro fatty aldehydes. While all of these chlorinated lipids have been shown to be produced in model systems from lipoproteins to cells subjected to oxidative stress, as yet only alpha-chloro fatty aldehydes, such as 2-chlorohexadecanal, have been detected in clinical samples or animal models of disease. alpha-Chloro fatty aldehydes and chlorohydrins have been found to have a number of potentially pro-inflammatory effects ranging from toxicity to inhibition of nitric oxide synthesis and upregulation of vascular adhesion molecules. Thus evidence is building for a role of chlorinated lipids in inflammatory disease, although much more research is required to establish the contributions of specific compounds in different disease pathologies. Preventing chlorinated lipid formation and indeed other HOCl-induced damage, via the inhibition of myeloperoxidase, is an area of growing interest and may lead in the future to antimyeloperoxidase-based antiinflammatory therapy. However, other chlorinated lipids, such as punaglandins, have beneficial effects that could offer novel therapies for cancer.

Topics: Animals; Chlorine Compounds; Drug Delivery Systems; Drug Design; Fatty Acids; Humans; Hydrocarbons, Chlorinated; Inflammation; Lipids; Oxidative Stress; Peroxidase

Myeloperoxidase (MPO), a heme protein abundantly expressed in polymorphonuclear neutrophils (PMN), has long been viewed to function primarily as a bactericidal enzyme centrally linked to innate host defense. Recent observations now extend this perspective and suggest that MPO is profoundly involved in the regulation of cellular homeostasis and may play a central role in initiation and propagation of acute and chronic vascular inflammatory disease. For example, low levels of MPO-derived hypochlorous acid (HOCl) interfere with intracellular signaling events, MPO-dependent oxidation of lipoproteins modulates their affinity to macrophages and the vessel wall, MPO-mediated depletion of endothelial-derived nitric oxide (NO) impairs endothelium-dependent vasodilatation, and nitrotyrosine (NO(2)Tyr) formation by MPO sequestered into the vessel wall may affect matrix protein structure and function. Future studies are needed to further elucidate the significance of MPO in the development of acute and chronic vascular disease and to evaluate MPO as a potential target for treatment.

Topics: Animals; Endothelium, Vascular; Humans; Inflammation; Peroxidase; Vascular Diseases

Inflammation has been recognized as an important factor in cancer development. For the lung, experimental studies with rats, as well as molecular epidemiological studies in humans, have provided evidence that the influx of neutrophils into the airways may be an important process linking inflammation with carcinogenesis. Currently it is believed that the genotoxic capacity of neutrophils is a crucial aetiological factor in this carcinogenic response. In the present review we discuss two major pathways of neutrophil-induced genotoxicity: (i) induction of oxidative DNA damage through release of reactive oxygen species (ROS) and (ii) myeloperoxidase (MPO)-related metabolic activation of chemical carcinogens. So far, direct evidence for a role of neutrophils in pulmonary genotoxicity has largely been derived from in vitro studies using co-cultures of activated neutrophils and target cells. Current evidence from in vivo studies is primarily indirect and additional animal studies are needed to substantiate causality. A further challenge will be to extrapolate results from such studies to humans. Taken together, this will provide a better insight into the role of neutrophils in pulmonary carcinogenicity and may, hence, lead to novel approaches for cancer prevention strategies.

Topics: Animals; Coculture Techniques; DNA Damage; Humans; Inflammation; Models, Biological; Models, Chemical; Mutagenesis; Neoplasms; Neutrophil Activation; Neutrophils; Oxidative Stress; Peroxidase; Reactive Oxygen Species; Respiratory System

The heme enzyme myeloperoxidase (MPO) is released at sites of inflammation by activated leukocytes. A key function of MPO is the production of hypohalous acids (HOX, X = Cl, Br) which are strong oxidants with potent antibacterial properties. However, HOX can also damage host tissue when produced at the wrong place, time or concentration; this has been implicated in several human diseases. Thus, elevated blood and leukocyte levels of MPO are significant independent risk factors for atherosclerosis, and specific markers of HOX-mediated protein oxidation are often present at elevated levels in patients with inflammatory diseases (e.g. asthma). HOX react readily with amino acids, proteins, carbohydrates, lipids, nucleobases and antioxidants. Sulfur-containing amino acids (Cys, Met, cystine) and amines on amino acids, nucleobases, sugars and lipids are the major targets for HOX. Reaction with amines generates chloramines (RNHCl) and bromamines (RNHBr), which are more selective oxidants than HOX and are key intermediates in HOX biochemistry. As these and other products of MPO-derived oxidants are unstable, understanding the role of HOX-induced damage in disease cannot be obtained solely by stable product analysis, and knowledge of the reaction kinetics is essential. This review collates kinetic and product data for HOX, chloramine and bromamine reactions with biological substrates. It highlights how kinetic data may be used to predict the effect of HOX-mediated oxidation on complex biological targets, such as lipoproteins and extracellular matrix in atherosclerosis, or protein-DNA complexes in cancer, thereby providing a basis for unraveling the mechanisms by which these oxidants generate biological damage.

Topics: Atherosclerosis; Humans; Inflammation; Kinetics; Neoplasms; Oxidants; Peroxidase

Topics: Biomarkers; C-Reactive Protein; Cytokines; Fatty Acid-Binding Proteins; Heart Failure; Humans; Inflammation; Myosin Light Chains; Natriuretic Peptide, Brain; Norepinephrine; Nurse's Role; Nursing Assessment; Peroxidase; Prognosis; Risk Assessment; Sensitivity and Specificity; Troponin

Since the first biomarker of myocardial necrosis was described in 1954, cardiac-specific biomarkers have been increasingly identified. This, coupled with dramatic evolution in assay technology and resultant highly sensitive assays, has rendered a remarkable transformation in the medical use of biomarkers. Initially used to aid in diagnosis of myocardial infarction, newer biomarkers of inflammation, plaque instability, and ischemia may complement biomarkers of necrosis by providing tools to diagnose impending myocardial necrosis before irreversible damage occurs, and offering additional information for risk stratification. Importantly, biomarkers of different processes may be combined to enhance risk stratification above that of any single marker.

Topics: Angina, Unstable; Biomarkers; C-Reactive Protein; CD40 Ligand; Humans; Inflammation; Interleukins; Myocardial Infarction; Myocardial Ischemia; Myoglobin; Natriuretic Peptide, Brain; Necrosis; Peroxidase; Pregnancy-Associated Plasma Protein-A; Risk Assessment; Troponin

Cardiovascular disease is common in patients with chronic kidney disease (CKD). As renal function fails, many patients become progressively malnourished, as evidenced by reduced levels of albumin, prealbumin, and transferrin. Malnourished patients have increased levels of C reactive protein (CRP), interleukin-6 (IL-6), and concomitant cardiovascular disease when they reach end stage. Many diseases that cause CKD, diabetes, and hypertension are also associated with cardiovascular disease. Thus the direct effect of renal failure per se directly contributing to the inflammation-malnutrition-atherosclerosis paradigm is not completely established in early stages of CKD. Some aspects of progressive renal failure, however, cause changes in plasma composition and endothelial structure and function that favor vascular injury. As renal function fails, hepatic apo A-I synthesis decreases and HDL levels fall. HDL is an important antioxidant and defends the endothelium from the effects of cytokines. Inflammation causes further structural and functional abnormalities in HDL. Apolipoprotein C III (apo C III), a competitive inhibitor of lipoprotein lipase is increased in CKD. Serum triglyceride levels increase as a result of accumulation of intermediate-density lipoprotein (IDL) comprising VLDL and chylomicron remnants. These impede vascular relaxation and are associated with cardiovascular disease. Activation of the renin angiotensin axis is a component of many renal diseases and adaptation to loss of renal mass. Angiotensin II (AngII) activates NADPH oxidases, leading to production of the superoxide anion and decreased availability of nitric oxide (NO), further impairing vascular function. H(2)O(2), produced as a consequence of superoxide dismutation, stimulates vascular cell proliferation and hypertrophy. Leukocyte-derived myeloperoxidase functions as an "NO Oxidase" in the inflamed vasculature and contributes to decreased NO bioavailability and compromised vascular reactivity. The changes in lipoprotein composition and structure as well as AngII-mediated alterations in endothelial function amplify the effect of subsequent inflammatory events.

Topics: Angiotensins; Animals; Cardiovascular Diseases; Disease Progression; Humans; Inflammation; Kidney Failure, Chronic; Lipoproteins; NADPH Oxidases; Oxidative Stress; Peroxidase; Risk Factors; Severity of Illness Index

The preponderance of epidemiological evidence now points to a strong association between chronic inflammation and cancers of several organs, including the gastrointestinal tract, liver, and lungs. The strongest evidence for a mechanistic link here involves the generation of reactive oxygen and nitrogen species by macrophages and neutrophils that respond to cytokines and other signaling processes arising at sites of inflammation. These reactive species cause oxidation, nitration, halogenation, and deamination of biomolecules of all types, including lipids, proteins, carbohydrates, and nucleic acids, with the formation of toxic and mutagenic products. This review, in honor of Bruce Ames, will focus on recent advances in our understanding of the protein and DNA damage caused by reactive nitrogen species produced by macrophages and neutrophils, with emphasis on nitric oxide, nitrous anhydride, peroxynitrite, and nitrogen dioxide radical.

Topics: Animals; DNA Damage; Humans; Inflammation; Oxygen; Peroxidase; Peroxynitrous Acid; Reactive Nitrogen Species

Topics: Animals; Humans; Inflammation; Lung; Mice; Mice, Knockout; Peroxidase; Reactive Oxygen Species

Topics: 5-Lipoxygenase-Activating Proteins; Animals; Arteriosclerosis; C-Reactive Protein; Carrier Proteins; CD40 Antigens; Cholesterol, HDL; Coronary Disease; Diagnostic Imaging; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Membrane Proteins; Peroxidase; Peroxisome Proliferator-Activated Receptors; Risk Assessment; Thrombosis

Topics: Coronary Artery Disease; Cytokines; Humans; Inflammation; Interleukin-6; Kidney Failure, Chronic; Models, Biological; Nutritional Physiological Phenomena; Oxidative Stress; Peroxidase

Tyrosine nitration is becoming increasingly recognized as a prevalent, functionally significant post-translational protein modification that serves as an indicator of nitric oxide (z.rad;NO)-mediated oxidative inflammatory reactions. Nitration of proteins modulates catalytic activity, cell signaling and cytoskeletal organization. Several reactions mediate protein nitration, and all predominantly depend on z.rad;NO- and nitrite-dependent formation of nitrogen dioxide, a species capable of nitrating aromatic amino acids, nucleotides and unsaturated fatty acids. Here, we review the mechanisms that mediate in vivo protein nitration and how nitration of specific tyrosine residues impacts on protein function.

Topics: Animals; Free Radicals; Humans; Inflammation; Models, Biological; Nitrates; Nitric Oxide; Nitrogen Dioxide; Nitrosation; Peroxidase; Proteins; Signal Transduction; Tyrosine

Inflammatory processes are now recognized to play a central role in the pathogenesis of atherosclerosis and its complications. Plasma levels of several markers of inflammation have been found to be associated with future cardiovascular risk in a variety of clinical settings. These markers include cell adhesion molecules, cytokines, pro-atherogenic enzymes and C-reactive protein (CRP). Initially thought of as an inactive downstream marker of the inflammatory cascade, emerging evidence suggests that CRP may be directly involved in atherogenesis, and that arterial plaque can produce CRP, independent of traditional hepatic pathways. In addition to being a strong predictor of future cardiovascular risk amongst patients presenting with acute coronary syndromes, numerous studies have found that baseline levels of CRP are associated with risk of future myocardial infarction, stroke, peripheral vascular disease and cardiovascular death amongst apparently healthy populations. The combination of measurement of a marker of inflammation with lipid testing may improve upon risk stratification based on lipid testing alone, and intensification of programmes for exercise, weight loss, and smoking cessation is recommended for those with elevated CRP levels. Further trials are needed to confirm the potential benefits of statins amongst individuals with elevated CRP levels.

Topics: Animals; Arteriosclerosis; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Case-Control Studies; Cell Adhesion Molecules; Cohort Studies; Cytokines; Exercise; Female; Humans; Hyperlipidemias; Hypolipidemic Agents; Inflammation; Inflammation Mediators; Interleukin-6; Lipids; Male; Mice; Mice, Knockout; Peroxidase; Prognosis; Prospective Studies; Risk; Risk Assessment; Risk Factors; Smoking; Weight Loss

Nitric oxide (.NO) is a freely diffusible inter- and intracellular messenger produced by a variety of mammalian cells including vascular endothelium, neurons, smooth muscle cells, macrophages, neutrophils, platelets, and pulmonary epithelium. In smooth muscle cells, platelets, and neutrophils, .NO raises intracellular cyclic guanasine 5'-monophosphate levels by reacting with the catalytic heme domain of guanylate cylase, to activate it, thus leading to vasorelaxation, inhibition of platelet aggregation and inhibition of platelet and inflammatory cell adhesion to endothelium. The physiologic actions of .NO are highly dependent on changes in steady-state concentrations of reactive species and tissue-oxidant defense mechanisms. Vessel wall oxidases and oxygenases, in particular, are critical sources of oxygen radical production and can lead to an overall impairment of vascular .NO signaling, via the metalloprotein and free radical-mediated consumption of this vasoactive molecule. Vascular oxidase and oxygenase activities can thus account for the functional inactivation of .NO, leading to a prooxidative milieu and chronic inflammation.

Topics: Animals; Blood Vessels; Cytochrome P-450 Enzyme System; Humans; Inflammation; Lipoxygenase; Models, Molecular; Nitric Oxide; Oxidoreductases; Oxygenases; Peroxidase; Prostaglandin-Endoperoxide Synthases; Reactive Oxygen Species; Signal Transduction; Xanthine Oxidase

Topics: Antibodies, Antineutrophil Cytoplasmic; Apoptosis; Autoantigens; Humans; Inflammation; Macrophage Activation; Myeloblastin; Neutrophil Activation; Peroxidase; Phagocytosis; Serine Endopeptidases; Signal Transduction; Vasculitis

Topics: Biomarkers; Blood Proteins; C-Reactive Protein; Cardiovascular Diseases; Dose-Response Relationship, Drug; Elapid Venoms; Humans; Hypochlorous Acid; Inflammation; Kidney Failure, Chronic; Macrophage Activation; N-Formylmethionine Leucyl-Phenylalanine; Oxidation-Reduction; Oxidative Stress; Peroxidase; Phagocytes; Phagocytosis; Renal Dialysis; Sulfhydryl Compounds; Tetradecanoylphorbol Acetate; Uremia

Optimal oxygen-dependent antimicrobial activity of circulating polymorphonuclear leukocytes reflects the synergistic effects of the myeloperoxidase (MPO)-hydrogen peroxide-halide system. Delivered from its storage compartment to the phagolysosome during fusion of the azurophilic granules, MPO catalyzes the oxidation of chloride in the presence of H2O2, chemistry unique to MPO, and thereby generates an array of highly reactive oxidants. Recent investigations of a wide range of inflammatory disorders have identified biochemical markers of MPO-dependent reactions, thus indirectly implicating MPO in their pathogenesis, progression, or perpetuation. The implied involvement of MPO-dependent events in diseases such as atherosclerosis forces reexamination of several fundamental tenets about MPO that are derived from studies of myeloid cells, most notably factors important in the regulated expression of MPO gene transcription. The evidence supporting a role for MPO in the pathogenesis of atherosclerosis, demyelinating diseases of the central nervous system, and specific cancers is reviewed and some of the new questions raised by these studies are discussed. Lastly, an appreciation for the existence of a broad family of proteins structurally related to MPO and the functional diversity implied by the corresponding structures may provide insights into novel ways in which MPO can function as more than an important antimicrobial component.

Topics: Animals; Anti-Infective Agents; Arteriosclerosis; Central Nervous System Diseases; Humans; Hypochlorous Acid; Inflammation; Peroxidase

This review covers recent advances in the biology of myeloperoxidase. Mechanisms of posttranslational processing and how these fail in some of the common deficiency mutants are discussed. We also review the enzymology that points to myeloperoxidase having a number of physiologic substrates in addition to chloride and the evidence that it produces hypochlorous acid in the neutrophil phagosome in sufficient quantities to be bactericidal. Evidence is accumulating that myeloperoxidase-derived oxidants modify biologic macromolecules and cell-regulatory pathways and that they play a role in atherosclerosis. Investigation of disease incidence in relation to a polymorphism in the promoter region of the gene has produced interesting associations. These links with inflammatory diseases can now be pursued further using specific biomarkers of myeloperoxidase activity.

Topics: Humans; Immunity, Innate; Inflammation; Mutation; Peroxidase; Polymorphism, Genetic; Promoter Regions, Genetic

Topics: Aldehydes; Arteriosclerosis; Chlorine; Humans; Inflammation; Oxidative Stress; Peroxidase; Phagocytes; Tyrosine

Neutrophils, recruited to tissue sites of inflammation, release a variety of oxidants and enzymes, which are responsible for tissue damage. Among the oxidants released are potent chlorinated compounds, such as hypochlorous acid and chloramines, which induce tissue cell damage and inactivate protease inhibitors, particularly alpha 1-antitrypsin, the specific inhibitor of neutrophil elastase. In studying a rational approach to the pharmacological control of neutrophil-mediated tissue injury, we investigated the activity of the anti-inflammatory drug nimesulide. This agent reduced the function of the myeloperoxidase pathway (which generates hypochlorous acid), by exerting a cell-directed inhibitory activity, as shown by measurement of superoxide anion and hydrogen peroxide production. Nimesulide also inactivated hypochlorous acid directly and protected alpha 1-antitrypsin from the neutrophil-mediated oxidation. Thus, neutrophil elastolytic activity may be attenuated by nimesulide-spared alpha 1-antitrypsin. The prevention of oxidative inactivation of alpha 1-antitrypsin by nimesulide strictly correlates with the drug's ability to suppress the extracellular availability of hypochlorous acid. Taken together, these data suggest that nimesulide may prevent tissue injury at sites of inflammation by maintaining natural host protective systems.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Down-Regulation; Humans; Inflammation; Neutrophils; Oxidation-Reduction; Peroxidase; Sulfonamides

Systemic inflammation promotes multiple organ failure through the induction of diffuse microvascular leak. Inflammatory cells such as neutrophils propagate this process. Tissue injury by neutrophils may be viewed as a normal process, inflammation, that has become uncontrolled and generalized. Multiple inflammatory stimuli synergistically promote neutrophil-mediated tissue injury in priming and activation sequences. In some settings, cellular priming is mediated by platelet-activating factor and can be prevented by platelet-activating factor antagonists. Inhibiting cellular priming could be efficacious in the therapy of multiple organ failure.

Topics: Animals; Endotoxins; Humans; Inflammation; Lung; Multiple Organ Failure; Neutrophils; Peroxidase; Platelet Activating Factor; Respiratory Distress Syndrome

Topics: Cytoplasmic Granules; Granulomatous Disease, Chronic; Humans; Inflammation; Macrophage-1 Antigen; Neutrophils; Oxidation-Reduction; Peroxidase; Receptors, Complement

Can the superoxide radical exert deleterious effects independent of participating with H2O2 in the production of the hydroxyl radical? Examination of the superoxide-related literature reveals data suggesting an affirmative answer to this question.

Topics: Animals; Catalase; Catalysis; Chemotactic Factors; Erythrocytes; Ferritins; Glutathione Peroxidase; Hemoglobins; Inflammation; Isoenzymes; L-Lactate Dehydrogenase; Lipid Peroxides; Lung; Macrophages; Molecular Weight; Neutrophils; Oxidation-Reduction; Oxygen; Paraquat; Perfusion; Peroxidase; Peroxidases; Plants; Saccharomyces cerevisiae; Shock, Hemorrhagic; Stem Cells; Superoxide Dismutase; Superoxides; Transketolase

Reactive oxygen metabolic products derived from an activated NADPH oxidase present in the cell membrane of PMNs and mononuclear phagocytic cells play a critical role in the host's defense against bacterial infection. Recent studies have also demonstrated the ability of these toxic products to initiate eukaryotic cell injury and promote the development of the acute inflammatory responses. Experimental studies suggest that neutrophil-derived oxygen metabolites contribute to the development of the tissue injury associated with a variety of disease states, including emphysema, myocardial infarction, adult respiratory distress syndrome, immune complex-mediated vasculitis, and rheumatoid arthritis. Future studies to define further the mechanisms by which reactive oxygen-derived metabolic products mediate tissue injury will provide insight into the development of new therapeutic strategies for the modulation of disease states that are mediated by the recruitment and activation of PMNs.

Topics: Animals; Arthritis, Rheumatoid; Ascorbic Acid; Autoimmune Diseases; Ceruloplasmin; Chemotactic Factors; Cricetinae; Cricetulus; Free Radicals; Humans; Immune Complex Diseases; Inflammation; Lipid Peroxides; Myocardial Infarction; NADH, NADPH Oxidoreductases; NADPH Oxidases; Neutrophils; Oxidation-Reduction; Oxygen; Pancreatic Elastase; Peroxidase; Peroxidases; Peroxides; Phagocytosis; Pulmonary Emphysema; Respiratory Distress Syndrome; Superoxide Dismutase; Superoxides; Vasculitis; Vitamin E

Neutrophils secrete of variety of biologically active compounds, especially when they accumulate at sites of inflammation. Secretory products are delivered to the tissues both by exocytosis of cytoplasmic granules and by metabolic events taking place at the plasma membrane. The release of lysosomal constituents, such as lactoferrin, elastase and collagenases, is associated with the regulation of the turnover of neutrophils, their participation and activity in the inflammatory reaction, and breakdown of cartilage and connective tissues, for example. Generation of cytotoxic oxygen radicals and compounds, e.g. the superoxide anion, hydrogen peroxide and the hydroxyl radical, is initiated by many inflammatory mediators. These two systems, either individually or in collaboration, can cause damage to many types of structures. For instance, when endothelial cells are injured, increased vascular permeability may occur. If such injury involves the pulmonary capillary system a respiratory distress syndrome may supervene. Leukotrienes are potent mediators of inflammation, formed in neutrophils after exposure to various other chemotactic or perturbating compounds. Leukotriene B4 is the most potent of the hitherto described compounds, being a promotor of neutrophil adherence, aggregation and chemotaxis in vitro of similar potency as the formylated synthetic chemotactic peptides, e.g. fMLP, and as the C5a fragment. However, the ability of LTB4 to induce a release of lysosomal enzymes is only half of that of fMLP, and, finally, the capacity to initiate a chemiluminescence response, being a measure of the oxidative metabolism, is only one-tenth of that of fMLP. Thus, leukotrienes of the B series seem to be a signal system whereby activated neutrophils can recruit cellular reinforcements, and, possibly, to act as an intracellular, second messenger system.

Topics: Cell Aggregation; Chemotaxis, Leukocyte; Granulocytes; Humans; Hydrogen Peroxide; Inflammation; Leukotriene B4; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Peroxidase; Superoxides

Topics: Bacteria; Chemotaxis, Leukocyte; Granulomatous Disease, Chronic; Humans; Inflammation; Neutropenia; Neutrophils; Peroxidase; Phagocytosis

One of the most impressive property of the leucocytes is that of changing the oxidative metabolism during various functions. When challenged with phagocytosable particles or with membrane perturbing agents such as chemotactic factors, detergents, lectins and other ligands, granulocytes and mononuclear phagocytes undergo a dramatic increase of oxygen consumption which is associated with the production of superoxide anion (O-2), of hydrogen peroxide (H2O2) and of hydroxyl radical (OH.). These events are referred to as "respiratory burst' . Most of the functions of the inflammatory cells (killing of micro-organisms, tissue damage, amplification of the inflammatory process) are linked to the production, to the fate and to the chemical reactivity of these highly reactive compounds. The authors examine the following aspects: (i) the mechanism responsible for the respiratory burst; (ii) the conditions present in the inflammatory site that induces the metabolic activation of leucocytes; (iii) the variability of the respiratory burst in different types of leucocytes; (iv) the fate, the interrelationships and the reactivity of the intermediate products of oxygen reduction; (v) the relationships between the inflammatory process and the production of free radicals by the inflammatory cells.

Topics: Animals; Cell Membrane; Free Radicals; Guinea Pigs; Hexosephosphates; Hydrogen Peroxide; Inflammation; NADP; Oxygen Consumption; Peroxidase; Phagocytes; Superoxides

Phagocytosis begins with exocytosis--"extrarapid" discharge of bactericidal proteins and factors of permeability into the extracellular medium. A viewpoint was put forward on an "avalanch-like" character of the outcome of cationic proteins from leukocyte granules in inflammation and their participation in formation of a nonphagocytic type of resistance. In phagocytosis bacteria perish due to the myeloperoxidase system, lysozyme, lactoferin and nonenzymic cationic proteins. Hereditary deficit of the above-mentioned substances leads to intraleukocytic microbicidal insufficiency, a drastic decrease in the nonspecific resistance of the organism and to development of fatal granulomatous disease, and to other forms of pathology associated with genetic defects of the bactericidal systems of leukocytes.

Topics: Blood Bactericidal Activity; Blood Proteins; Cell Membrane Permeability; Cytoplasmic Granules; Exocytosis; Glucosephosphate Dehydrogenase Deficiency; Histones; Humans; Immunity; Immunologic Deficiency Syndromes; Inflammation; Lactoferrin; Microscopy, Phase-Contrast; Muramidase; Neutrophils; Peroxidase; Phagocytosis

Topics: Actins; Animals; Bone Marrow; Bone Marrow Cells; Cell Differentiation; Cell Membrane; Cell Nucleus; Cytoplasmic Granules; Endoplasmic Reticulum; Golgi Apparatus; Hematologic Diseases; Hematopoiesis; Histocytochemistry; Humans; Hydrolases; Inflammation; Leukemia; Muramidase; Myosins; Neutrophils; Peroxidase; Peroxidases

Topics: Blood Proteins; Cytoplasm; Cytoplasmic Granules; Glucose; In Vitro Techniques; Inflammation; Lactates; Lactoferrin; Lysosomes; Muramidase; NADH, NADPH Oxidoreductases; Peroxidase; Phagocytes; Phagocytosis

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

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

This individually randomized trial was conducted to estimate the effect of promoting community-initiated Kangaroo Mother Care (ciKMC) in low birth weight (LBW) infants on gut inflammation and permeability. Participants included 200 stable LBW infants (weighing 1,500-2,250 g) in North India enrolled between May and October 2017. The ciKMC intervention included promotion and support of continuous skin-to-skin contact and exclusive breastfeeding through home visits. The mothers in the intervention arm were supported to practice ciKMC until 28 days after birth, i.e., the neonatal period, or till the baby wriggled out of KMC position, if earlier. Infant stool specimens were collected during the first week of birth, and within 1 week after end of the neonatal period. Concentrations of fecal neopterin (nmol/L), myeloperoxidase (ng/mL), and alpha-1-antitrypsin (μg/mL) were determined using ELISA, and composite enteric enteropathy (EE) score at the end of the neonatal period was calculated by principal component analysis. We did not find any substantial difference in means between the ciKMC and control arm infants in the log-transformed values of neopterin (0.03; 95% CI -0.15 to 0.21), myeloperoxidase (0.28; 95% CI -0.05 to 0.61) and alpha-1-antitrypsin (0.02; 95% CI -0.30 to 0.34). The mean (SD) composite EE score was 13.6 (7.5) in the ciKMC and 12.4 (8.3) in the control arm infants, and the adjusted difference in means was, 0.4 (95% CI -1.8 to 2.7). Our findings suggest that the promotion of ciKMC did not affect gut inflammation and permeability in our target population of LBW infants in North India.

Topics: Biomarkers; Child; Female; Humans; Infant; Infant Mortality; Infant, Low Birth Weight; Infant, Newborn; Inflammation; Kangaroo-Mother Care Method; Neopterin; Peroxidase

We have previously shown that multimers of plasma pentraxin-3 (PTX3) were predictive of survival in patients with sepsis. To characterize the release kinetics and cellular source of plasma protein changes in sepsis, serial samples were obtained from healthy volunteers (n = 10; three time points) injected with low-dose endotoxin (lipopolysaccharide [LPS]) and analyzed using data-independent acquisition MS. The human plasma proteome response was compared with an LPS-induced endotoxemia model in mice. Proteomic analysis of human plasma revealed a rapid neutrophil degranulation signature, followed by a rise in acute phase proteins. Changes in circulating PTX3 correlated with increases in neutrophil-derived proteins following LPS injection. Time course analysis of the plasma proteome in mice showed a time-dependent increase in multimeric PTX3, alongside increases in neutrophil-derived myeloperoxidase (MPO) upon LPS treatment. The mechanisms of oxidation-induced multimerization of PTX3 were explored in two genetic mouse models: MPO global knock-out (KO) mice and LysM Cre Nox2 KO mice, in which NADPH oxidase 2 (Nox2) is only deficient in myeloid cells. Nox2 is the enzyme responsible for the oxidative burst in neutrophils. Increases in plasma multimeric PTX3 were not significantly different between wildtype and MPO or LysM Cre Nox2 KO mice. Thus, PTX3 may already be stored and released in a multimeric form. Through in vivo neutrophil depletion and multiplexed vascular proteomics, PTX3 multimer deposition within the aorta was confirmed to be neutrophil dependent. Proteomic analysis of aortas from LPS-injected mice returned PTX3 as the most upregulated protein, where multimeric PTX3 was deposited as early as 2 h post-LPS along with other neutrophil-derived proteins. In conclusion, the rise in multimeric PTX3 upon LPS injection correlates with neutrophil-related protein changes in plasma and aortas. MPO and myeloid Nox2 are not required for the multimerization of PTX3; instead, neutrophil extravasation is responsible for the LPS-induced deposition of multimeric PTX3 in the aorta.

Topics: Animals; Blood Proteins; Endotoxemia; Humans; Inflammation; Lipopolysaccharides; Male; Mice, Knockout; NADPH Oxidase 2; Neutrophils; Peroxidase; Proteome; Proteomics

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

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

To investigate the effects of a low- versus high-intensity aerobic training on biomarkers of inflammation and endothelial dysfunction in adolescents with obesity.. Sixty-two adolescents with obesity [age = 15 (14) y, body mass index = 34.87 (4.22) kg·m. HIT reduced neutrophils [from 4.4 (1.9) to 3.6 (1.3) µL. Both HIT and LIT improved the inflammatory profile. The study, however, indicated that the number of biomarkers and the magnitude of changes were higher in the HIT compared with LIT.

Topics: Adolescent; Biomarkers; Body Mass Index; Cardiorespiratory Fitness; Exercise Therapy; Female; High-Intensity Interval Training; Humans; Inflammation; Insulin Resistance; Intercellular Adhesion Molecule-1; Interleukin-6; Leptin; Male; Monocytes; Neutrophils; Oxygen Consumption; Pediatric Obesity; Peroxidase; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

Topics: Acute Pain; Adenosine Diphosphate; Adult; Anemia, Sickle Cell; Cytokines; Double-Blind Method; Endothelium, Vascular; Eptifibatide; Female; Humans; Inflammation; Male; Middle Aged; P-Selectin; Peroxidase; Platelet Activation; Platelet Aggregation Inhibitors; Young Adult

To study the protective effect of dexmedetomidine against perioperative inflammation and on pulmonary function in patients undergoing radical resection of lung cancer.. From May, 2014 to May, 2016, 124 patients with lung cancer receiving radical surgeries were randomized into experimental group (n=62) and control group (n=62). The patients in the control group received a single anesthetic agent for anesthesia, and additional dexmedetomidine was given in the experimental group. The levels of serum interleukin-1β (IL-1β), IL-10, and tumor necrosis factor-alpha (TNF-α) were measured before the operation (T. At the time points of T. Anesthesia with dexmedetomidine in lung cancer patients undergoing radical surgery can effectively reduce the inflammatory response of the lungs and protect the lung function of the patients.

Topics: Anesthesia; Dexmedetomidine; Enzyme-Linked Immunosorbent Assay; Humans; Inflammation; Interleukin-10; Interleukin-1beta; Lung; Lung Neoplasms; Malondialdehyde; Partial Pressure; Peroxidase; Tumor Necrosis Factor-alpha; Xanthine Oxidase

Although existing research highlights the relationship of OSA and cardiovascular disease, the effect of OSA treatment on cardiovascular biomarkers remains unclear. We evaluated the effect of OSA treatment on oxidative stress/inflammation measures.. We conducted a parallel, randomized controlled trial in moderate to severe OSA (apnea-hypopnea index ≥ 15) patients to examine effects of 2-month CPAP vs sham-CPAP on the primary outcome of oxidative stress/inflammation (F2-isoprostanes: ng/mg) and myeloperoxidase: pmol/L) and secondary oxidative stress measures. Exploratory secondary analyses included vascular and systemic inflammation markers. Linear models adjusted for baseline values examined effect of CPAP on biomarker change (least squares means, 95% CI) including secondary stratified analyses examining CPAP adherence and degree of hypoxia.. Of 153 participants, 76 were randomized to CPAP and 77 to sham-CPAP. In an intent-to-treat analyses, no significant change was observed in the sham and CPAP groups respectively: F2-isoprostanes (-0.02 [-0.12 to 0.10] vs -0.08 [-0.18 to 0.03]) or myeloperoxidase (-3.33 [-17.02 to 10.37] vs -5.15 [-18.65 to 8.35]), nor other oxidative markers; findings that persisted in analyses stratified by adherence and hypoxia. Exploratory analyses revealed percentage reduction of soluble IL-6 receptor (ng/mL) levels (-0.04 [-0.08 to -0.01] vs 0.02 [-0.02 to 0.06], P = .019) and augmentation index (%) (-6.49 [-9.32 to -3.65] vs 0.44 [-2.22 to 3.10], P < .001) with CPAP compared with sham, respectively.. In moderate to severe OSA, 2-month CPAP vs sham did not reduce oxidative stress despite consideration of a broad range of measures, positive airway pressure adherence, and hypoxia burden. These findings suggest that nonoxidative stress pathways primarily modulate OSA-related cardiovascular consequences.. ClinicalTrials.govNCT00607893.

Topics: Adult; Biomarkers; Cardiovascular Diseases; Continuous Positive Airway Pressure; F2-Isoprostanes; Female; Humans; Inflammation; Male; Middle Aged; Oxidative Stress; Peroxidase; Receptors, Interleukin-6; Risk Factors; Sleep Apnea, Obstructive; Statistics as Topic

Re-transfusion of lipid particles and activated leucocytes with shed mediastinal blood (SMB) can aggravate cardiopulmonary bypass-associated inflammation and increase the embolic load. This study evaluated the fat and leucocyte removal capacity of the RemoweLL cardiotomy reservoir.. Forty-five patients undergoing elective on-pump cardiac surgery were randomly allocated to filtration of SMB using the RemoweLL or the Admiral cardiotomy reservoir. The primary outcome was a drop in leucocytes and lipid particles obtained with the two filters. The effect of the filters on other blood cells and inflammatory mediators, such as myeloperoxidase (MPO), was also assessed.. The RemoweLL cardiotomy filter removed 16.5% of the leucocytes (p<0.001) while no significant removal of leucocytes was observed with the Admiral (p=0.48). The percentage reductions in lipid particles were similar in the two groups (26% vs 23%, p=0.2). Both filters similarly affected the level of MPO (p=0.71).. The RemoweLL filter more effectively removed leucocytes from SMB than the Admiral. It offered no advantage in terms of lipid particle clearance.

Topics: Aged; Blood Transfusion, Autologous; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Female; Filtration; Humans; Inflammation; Leukocyte Reduction Procedures; Leukocytes; Lipids; Male; Middle Aged; Peroxidase

In patients with acute coronary syndromes (ACS), early therapy with high-dose statins may reduce short-term adverse clinical outcomes. The mechanisms responsible are not known but could involve anti-inflammatory or anti-thrombotic effects. Compelling evidence from experimental models and clinical studies suggests that the interplay between inflammatory and thrombotic systems, typified by platelet-monocyte and platelet-neutrophil interactions, might be a key regulator of ischemic vascular events. The study sought to determine if early, high-dose administration of the HMG-CoA reductase inhibitor rosuvastatin in the setting of ACS exerts beneficial vascular effects by reducing, and inhibiting biomarkers of thromboinflammation, such as platelet-monocyte and platelet-neutrophil interactions, and biomarkers of myocardial necrosis. A total of 54 patients presenting with ACS within 8 h of symptom onset were randomized to rosuvastatin 40 mg or placebo. Rosuvastatin significantly reduced interactions between platelets and circulating neutrophils (P = 0.015) and monocytes (P = 0.009) within 24 h. No significant effects were observed on platelet aggregation or plasma levels of PF4, sP-selectin, or sCD40L, whereas significant reductions of RANTES occurred over time in both treatment groups. Plasma levels of myeloperoxidase (MPO) declined more rapidly with rosuvastatin therapy than placebo. In a subset of patients with normal cardiac necrosis biomarkers at randomization, rosuvastatin therapy was associated with less myocardial damage as measured by troponin-I or CK-MB. Early administration of high-dose statin therapy in patients with ACS appears to improve biomarkers of inflammation within 8 h, which may translate into fewer ischemic events.

Topics: Acute Coronary Syndrome; Adult; Aged; Biomarkers; Blood Platelets; CD40 Ligand; Cell Communication; Creatine Kinase, MB Form; Dose-Response Relationship, Drug; Early Medical Intervention; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Male; Middle Aged; Monocytes; Neutrophils; P-Selectin; Peroxidase; Platelet Factor 4; Rosuvastatin Calcium; Thrombosis; Treatment Outcome; Troponin I

To evaluate the effects of canrenone compared to placebo on blood pressure control, some non-conventional biomarkers in cardiovascular stratification, and on metalloproteinases in patients affected by metabolic syndrome.. A total of 156 Caucasian patients were treated with placebo or canrenone, 50 mg once a day, for 3 months and then 50 mg twice a day, till the end of the study. We evaluated: systolic (SBP) and diastolic blood pressure (DBP), body weight, body mass index (BMI), fasting plasma glucose (FPG), lipid profile, plasma aldosterone, creatinine, potassium, brain natriuretic peptide (BNP), metalloproteinases 2 and 9 (MMP-2 and -9), lipoprotein (a) (Lp(a)), and serum myeloperoxidase (MPO).. We observed a significant decrease of SBP and DBP in the canrenone group compared to baseline. Canrenone gave a significant decrease of MMP-2 and -9, Lp(a), and MPO compared to baseline, not observed with placebo. Plasma aldosterone, but not BNP, decreased with canrenone, both compared to baseline and to placebo.. Canrenone seems to be effective in reducing blood pressure in patients with metabolic syndrome. Moreover, canrenone seems also to improve MPO, Lp(a), and metalloproteinases in these patients.

Topics: Aged; Aldosterone; Biomarkers; Blood Glucose; Blood Pressure; Body Mass Index; Body Weight; Canrenone; Creatine; Double-Blind Method; Fasting; Female; Humans; Inflammation; Lipids; Lipoproteins; Male; Metabolic Syndrome; Metalloproteases; Middle Aged; Natriuretic Peptide, Brain; Peroxidase; Potassium; White People

This study aimed to determine whether aerobic training could reduce lipid peroxidation and inflammation at rest and after maximal exhaustive exercise in overweight/obese adolescent girls. Thirty-nine adolescent girls (14-19 years old) were classified as nonobese or overweight/obese and then randomly assigned to either the nontrained or trained group (12-week multivariate aerobic training program). Measurements at the beginning of the experiment and at 3 months consisted of body composition, aerobic fitness (VO2peak) and the following blood assays: pre- and postexercise lipid peroxidation (15F2a-isoprostanes [F2-Isop], lipid hydroperoxide [ROOH], oxidized LDL [ox-LDL]) and inflammation (myeloperoxidase [MPO]) markers. In the overweight/ obese group, the training program significantly increased their fat-free mass (FFM) and decreased their percentage of fat mass (%FM) and hip circumference but did not modify their VO2peak. Conversely, in the nontrained overweight/obese group, weight and %FM increased, and VO2peak decreased, during the same period. Training also prevented exercise-induced lipid peroxidation and/or inflammation in overweight/obese girls (F2-Isop, ROOH, ox-LDL, MPO). In addition, in the trained overweight/obese group, exercise-induced changes in ROOH, ox-LDL and F2-Isop were correlated with improvements in anthropometric parameters (waist-to-hip ratio, %FM and FFM). In conclusion aerobic training increased tolerance to exercise-induced oxidative stress in overweight/obese adolescent girls partly as a result of improved body composition.

Topics: Adolescent; Biomarkers; Body Composition; Exercise; Exercise Therapy; Female; Humans; Inflammation; Lipid Peroxidation; Obesity; Overweight; Oxidative Stress; Peroxidase; Treatment Outcome; Young Adult

The transition from late gestation to early lactation is characterized by substantial metabolic stress and altered immune function. The objective of this study was to assess the effects of supplementing a yeast product derived from Saccharomyces cerevisiae on immunity and uterine inflammation in transition cows. Forty multiparous Holstein cows were blocked by expected parturition date and randomly assigned within block to 1 of 4 treatments (n=10) from 21d before expected parturition to 42d postpartum. Rations were top-dressed with a product containing yeast culture plus enzymatically hydrolyzed yeast (YC-EHY; Celmanax, Vi-COR, Mason City, IA) at the rate of 0, 30, 60, or 90g/d throughout the experiment. Cows were injected subcutaneously with ovalbumin on d -21, -7, and 14 to assess their humoral response. Data were analyzed using mixed models with repeated measures over time. Concentrations of colostrum IgG were unaffected by treatments. A treatment × week interaction was observed for somatic cell linear score, reflecting a tendency for a quadratic dose effect on wk 1 (2.34, 2.85, 1.47, and 4.06±0.59 for 0, 30, 60, and 90g/d, respectively) and a quadratic dose effect on wk 5 (1.36, -0.15, -1.07, and 0.35±0.64 for 0, 30, 60, and 90g/d, respectively). Platelet count was increased by YC-EHY. Increasing YC-EHY dose linearly increased plasma anti-ovalbumin IgG levels following 3 ovalbumin challenges, suggesting that treatments enhanced humoral immunity. Increasing YC-EHY dose also quadratically increased fecal IgA concentrations in early lactation, suggesting that 30 and 60g/d doses enhanced mucosal immunity. Uterine neutrophil populations were much greater in samples collected on d 7 compared with those on d 42 (32.1 vs. 7.6±3.5% of cells), reflecting neutrophil infiltration immediately after calving, but no treatment effect was detected. Significant day effects were detected for mRNA of IL-6, IL-8, neutrophil myeloperoxidase (MPO), and neutrophil elastase (ELANE) in the uterine samples, reflecting greater abundance of these transcripts collected on d 7 compared with d 42. A quadratic dose effect was detected for IL-6, indicating that 30 and 60g/d doses decreased uterine IL-6 mRNA. The mRNA abundance of MPO and ELANE was increased linearly by YC-EHY. Supplementation with YC-EHY enhanced measures of humoral and mucosal immunity and modulated uterine inflammatory signals and mammary gland health in transition dairy cows.

Topics: Animals; Cattle; Colostrum; Female; Haptoglobins; Immunity, Humoral; Immunity, Mucosal; Immunoglobulin A; Immunoglobulin G; Inflammation; Interleukin-6; Interleukin-8; Lactation; Milk; Neutrophils; Ovalbumin; Parity; Peroxidase; Postpartum Period; RNA, Messenger; Saccharomyces cerevisiae; Uterine Diseases; Uterus; Yeast, Dried

We studied the effects of diet supplementation with docosahexaenoic (DHA) and in vitro vitamin C (VitC) at physiological concentrations on oxidative and inflammatory neutrophil response to phorbol myristate acetate (PMA). Fifteen male footballers ingested a beverage enriched with DHA or a placebo for 8 weeks in a randomized double-blind study. Neutrophils were isolated from blood samples collected in basal conditions at the end of nutritional intervention. Neutrophils were cultured for 2 hours at 37°C in (a) control media, (b) media with PMA, and (c) media with PMA + VitC. PMA induces neutrophil degranulation with increased extracellular myeloperoxidase and catalase activities, nitric oxide production, expression of the inflammatory genes cyclooxygenase-2, nuclear factor κβ, interleukin 8 and tumor necrosis factor α, and interleukin 6 production. DHA diet supplementation boosts the exit of CAT from neutrophils but moderates the degranulation of myeloperoxidase granules induced by PMA. VitC facilitates azurophilic degranulation of neutrophils and increases gene expression of myeloperoxidase induced by PMA. VitC and DHA diet supplementation prevent PMA effects on inflammatory gene expression, although together they do not produce additional effects. DHA diet supplementation enhances antioxidant defences and anti-inflammatory neutrophil response to in vitro PMA activation. VitC facilitates neutrophil degranulation but prevents an inflammatory response to PMA.

Topics: Ascorbic Acid; Catalase; Dietary Supplements; Docosahexaenoic Acids; Erythrocytes; Gene Expression Regulation; Humans; Inflammation; Interleukin-6; Male; Neutrophil Activation; Neutrophils; Nitrates; Nitrites; Oxidative Stress; Peroxidase; Tetradecanoylphorbol Acetate; Tumor Necrosis Factor-alpha; Young Adult

Leukocytes play a vital role in the host defence and inflammatory systems, the latter being responsible for the pathogenesis of a wide spectrum of acute and chronic diseases. Green tea is a popular beverage, which is consumed worldwide and its active ingredients are epicatechin derivatives, which possess distinct anti-inflammatory properties. The purpose of this study was to investigate if a green tea extract could enhance leukocyte function in humans.. Volunteers were asked to take 300 mg of the green tea extract daily for 14 days and the capacity of circulating leukocytes to release both myeloperoxidase and lactoferrin was assessed. Whole blood from volunteers was stimulated with the bacterial peptide Formyl-Methionine-Leucine-Phenylalanine (fMet-Leu-Phe). Myeloperoxidase an enzyme that converts hydrogen peroxide to hypochlorous acid and is stored and secreted from the granules of neutrophils and monocytes and was measured as well as lactoferrin which is an iron-binding protein stored and secreted from the neutrophils. In conjunction the antioxidant capacity of the blood of the volunteers was also determined using a chemiluminescence method that measures the capacity of plasma to scavenge superoxide.. After 14 days of treatment there was a significant increase in the release of myeloperoxidase and lactoferrin when whole blood was stimulated with fMet-Leu-Phe (p<0.05), which activates a number of leukocytes including mature neutrophils and monocytes. This was mirrored by a significant increase in the total antioxidant status after 14 days of green tea ingestion (p0.05). After the "wash-out" period of 4 weeks, all parameters were consistent with those observed at the start of the trial (day 0). Treatment with the green tea extract also caused a slight but non-significant decrease in the number of circulating leukocytes, but the counts remained within published "normal" ranges for healthy human adults.. This study indicates that a green tea extract when taken as a dietary supplement for 14 days can increase the leukocyte activity and the total plasma antioxidant status and may have role to play in the prevention of inflammatory disease.

Topics: Adult; Anti-Inflammatory Agents; Antioxidants; Camellia sinensis; Catechin; Dietary Supplements; Female; Humans; Inflammation; Lactoferrin; Leukocytes; Male; Middle Aged; Monocytes; Neutrophils; Oxidative Stress; Peroxidase; Phytotherapy; Plant Extracts; Superoxides; Young Adult

Cardiopulmonary bypass (CPB) is related to inflammatory response and pulmonary dysfunction. The aim of this study was to evaluate the effects of CPB leukocyte filtration on inflammation and lung function after coronary artery bypass grafting (CABG). A prospective randomized study was performed to compare CABG patients undergoing CPB leukocyte filtration (n = 9) or standard CPB (n = 11). Computed tomography, oxygenation, leukocyte count, hemodynamic data, PaO2/FiO2, shunt fraction, interleukins, elastase, and myeloperoxidase were evaluated. Data were analyzed using two-factor ANOVA for repeated measurements. The filtered group showed lower neutrophil counts up to 50 min of CPB, lower shunt fraction up to 6 h after surgery, and lower levels of IL-10 at the end of surgery (p < 0.05). There was no statistically significant difference between groups related to other parameters. Leukodepletion during CPB results in neutrophil sequestration by a short time, decreased IL-10 serum levels, and lower worsening of lung function only temporarily.

Topics: Aged; Cardiopulmonary Bypass; Coronary Vessels; Female; Humans; Inflammation; Interleukin-10; Leukocyte Count; Leukocyte Elastase; Leukocyte Reduction Procedures; Lung; Male; Middle Aged; Neutrophils; Peroxidase; Prospective Studies; Respiratory Function Tests

Smoking is responsible for most COPD. Although people with COPD often have concomitant nasal disease, there are few studies that report physiologic or inflammatory changes in the upper airways in young asymptomatic smokers. We investigated physiologic and inflammatory changes in the nasal and lower airways of young smokers and if these changes were related to smoking history.. Seventy-two subjects aged between 18 and 35 years (32 healthy nonsmokers and 40 young smokers) participated in this study. We measured nasal mucociliary clearance (MCC), nasal mucus surface contact angle, cell counts, myeloperoxidase and cytokine concentrations in nasal lavage fluid, exhaled breath condensate (EBC) pH, and lung function.. Smokers had faster MCC, an increased number of cells (macrophages, ciliated cells, and goblet cells), increased lavage myeloperoxidase concentration, and decreased EBC pH compared with nonsmokers. There was a significant inverse relationship between pack-year smoking history and EBC pH. There were no differences in lung function or mucus surface properties comparing smokers to nonsmokers.. Young adult smokers have functional and inflammatory changes in the nasal and lower airways and these correlate with smoking history. However, in these young smokers, smoking history was not associated with pulmonary function decline, probably because it is unlikely that spirometry detects early physiologic changes in the airways.. ClinicalTrials.gov; No.: NCT01877291; URL: www.clinicaltrials.gov.

Topics: Adolescent; Adult; Air; Breath Tests; Cell Count; Exhalation; Female; Humans; Hydrogen-Ion Concentration; Inflammation; Male; Mucociliary Clearance; Nasal Lavage Fluid; Nasal Mucosa; Peroxidase; Respiratory Mucosa; Smoking; Young Adult

More than two-fifths of the world's population uses solid fuels, mostly biomass, for cooking. The resulting biomass smoke exposure is a major cause of chronic obstructive pulmonary disease (COPD) among women in developing countries.. To assess whether lower woodsmoke exposure from use of a stove with a chimney, compared to open fires, is associated with lower markers of airway inflammation in young women.. We carried out a cross-sectional analysis on a sub-cohort of participants enrolled in a randomized controlled trial in rural Guatemala, RESPIRE.. We recruited 45 indigenous women at the end of the 18-month trial; 19 women who had been using the chimney stove for 18-24 months and 26 women still using open fires.. We obtained spirometry and induced sputum for cell counts, gene expression of IL-8, TNF-α, MMP-9 and 12, and protein concentrations of IL-8, myeloperoxidase and fibronectin. Exhaled carbon monoxide (CO) and 48-hr personal CO tubes were measured to assess smoke exposure.. MMP-9 gene expression was significantly lower in women using chimney stoves. Higher exhaled CO concentrations were significantly associated with higher gene expression of IL-8, TNF-α, and MMP-9. Higher 48-hr personal CO concentrations were associated with higher gene expression of IL-8, TNF- α, MMP-9 and MMP-12; reaching statistical significance for MMP-9 and MMP-12.. Compared to using an open wood fire for cooking, use of a chimney stove was associated with lower gene expression of MMP-9, a potential mediator of airway remodeling. Among all participants, indoor biomass smoke exposure was associated with higher gene expression of multiple mediators of airway inflammation and remodeling; these mechanisms may explain some of the observed association between prolonged biomass smoke exposure and COPD.

Topics: Adult; Air Pollutants; Carbon Monoxide; Cohort Studies; Cross-Sectional Studies; Female; Fibronectins; Guatemala; Humans; Inflammation; Interleukin-8; Matrix Metalloproteinase 12; Matrix Metalloproteinase 9; Peroxidase; Pulmonary Disease, Chronic Obstructive; Rural Population; Smoke; Spirometry; Tumor Necrosis Factor-alpha; Young Adult

Cystic fibrosis (CF) airways are characterized by bacterial infections, excess mucus production, and robust neutrophil recruitment. The main CF airway pathogen is Pseudomonas aeruginosa. Neutrophils are not capable of clearing the infection. Neutrophil primary granule components, myeloperoxidase (MPO) and human neutrophil elastase (HNE), are inflammatory markers in CF airways, and their increased levels are associated with poor lung function. Identifying the mechanism of MPO and HNE release from neutrophils is of high clinical relevance for CF. In this article, we show that human neutrophils release large amounts of neutrophil extracellular traps (NETs) in the presence of P. aeruginosa. Bacteria are entangled in NETs and colocalize with extracellular DNA. MPO, HNE, and citrullinated histone H4 are all associated with DNA in Pseudomonas-triggered NETs. Both laboratory standard strains and CF isolates of P. aeruginosa induce DNA, MPO, and HNE release from human neutrophils. The increase in peroxidase activity of neutrophil supernatants after Pseudomonas exposure indicates that enzymatically active MPO is released. P. aeruginosa induces a robust respiratory burst in neutrophils that is required for extracellular DNA release. Inhibition of the cytoskeleton prevents Pseudomonas-initiated superoxide production and DNA release. NADPH oxidase inhibition suppresses Pseudomonas-induced release of active MPO and HNE. Blocking MEK/ERK signaling results in only minimal inhibition of DNA release induced by Pseudomonas. Our data describe in vitro details of DNA, MPO, and HNE release from neutrophils activated by P. aeruginosa. We propose that Pseudomonas-induced NET formation is an important mechanism contributing to inflammatory conditions characteristic of CF airways.

Topics: Adolescent; Adult; Biomarkers; Cystic Fibrosis; DNA; Female; Humans; Inflammation; Male; MAP Kinase Signaling System; NADPH Oxidases; Neutrophils; Peroxidase; Pseudomonas aeruginosa; Superoxides

The purpose of this study was to investigate the effects of different cold-water immersion (CWI) protocols on the inflammatory response to and functional recovery from high-intensity exercise.. Eight healthy recreationally active males completed five trials of a high-intensity intermittent sprint protocol followed by a randomly assigned recovery condition: 1 of 4 CWI protocols (CWI-10 min × 20 °C, CWI-30 min × 20 °C, CWI-10 min × 10 °C, or CWI-30 min × 10 °C) versus passive rest. Circulating mediators of the inflammatory response were measured from EDTA plasma taken pre-exercise (baseline), immediately post-exercise, and at 2, 24, and 48 h post-exercise. Ratings of perceived soreness and impairment were noted on a 10-pt Likert scale, and squat jump and drop jump were performed at these time points.. IL-6, IL-8, and MPO increased significantly from baseline immediately post-exercise in all conditions. IL-6 remained elevated from baseline at 2 h in the CWI-30 min × 20 °C, CWI-10 min × 10 °C, and CWI-30 min × 10 °C conditions, while further increases were observed for IL-8 and MPO in the CWI-30 min × 20 °C and CWI-30 min × 10 °C conditions. Squat jump and drop jump height were significantly lower in all conditions immediately post-exercise and at 2 h. Drop jump remained below baseline at 24 and 48 h in the CON and CWI-10 min × 20 °C conditions only, while squat jump height returned to baseline in all conditions.. Cold-water immersion appears to facilitate restoration of muscle performance in a stretch-shortening cycle, but not concentric power. These changes do not appear to be related to inflammatory modulation. CWI protocols of excessive duration may actually exacerbate the concentration of cytokines in circulation post-exercise; however, the origin of the circulating cytokines is not necessarily skeletal muscle.

Topics: Adult; Humans; Hypothermia, Induced; Immersion; Inflammation; Interleukin-6; Interleukin-8; Male; Peroxidase; Recovery of Function; Running; Tumor Necrosis Factor-alpha; Water

Recent trials of fish oil for the prevention of atrial fibrillation (AF) recurrence have provided mixed results. Notable uncertainties in the existing evidence base include the roles of high-dose fish oil, inflammation, and oxidative stress in patients with paroxysmal or persistent AF not receiving conventional antiarrhythmic (AA) therapy.. The aim of this study was to evaluate the influence of high-dose fish oil on AF recurrence, inflammation, and oxidative stress parameters.. We performed a double-blind, randomized, placebo-controlled, parallel-arm study in 337 patients with symptomatic paroxysmal or persistent AF within 6 months of enrollment. Patients were randomized to fish oil (4 g/day) or placebo and followed, on average, for 271 ± 129 days.. The primary endpoint was time to first symptomatic or asymptomatic AF recurrence lasting >30 s. Secondary endpoints were high-sensitivity C-reactive protein (hs-CRP) and myeloperoxidase (MPO). The primary endpoint occurred in 64.1% of patients in the fish oil arm and 63.2% of patients in the placebo arm (hazard ratio: 1.10; 95% confidence interval: 0.84 to 1.45; p = 0.48). hs-CRP and MPO were within normal limits at baseline and decreased to a similar degree at 6 months (Δhs-CRP, 11% vs. -11%; ΔMPO, -5% vs. -9% for fish oil vs. placebo, respectively; p value for interaction = NS).. High-dose fish oil does not reduce AF recurrence in patients with a history of AF not receiving conventional AA therapy. Furthermore, fish oil does not reduce inflammation or oxidative stress markers in this population, which may explain its lack of efficacy. (Multi-center Study to Evaluate the Effect of N-3 Fatty Acids [OMEGA-3] on Arrhythmia Recurrence in Atrial Fibrillation [AFFORD]; NCT01235130).

Topics: Aged; Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; C-Reactive Protein; Dietary Supplements; Double-Blind Method; Fatty Acids, Omega-3; Female; Fish Oils; Fishes; Humans; Inflammation; Male; Middle Aged; Oxidative Stress; Peroxidase; Proportional Hazards Models; Recurrence; Time Factors; Treatment Outcome

The hemodialysis (HD) procedure induces oxidative stress (OS), which is further aggravated by intravenous (IV) iron administration, aimed at correcting anemia of patients with HD. We have recently shown that 1 year of pomegranate juice (PJ) intake attenuated OS and inflammation in patients with HD. In the current study, we hypothesized that a single dose of PJ can attenuate the enhanced OS and inflammation induced by both the dialysis procedure and IV iron administration during HD session. Twenty-seven patients with HD were randomized to receive PJ or placebo during 1 dialysis session with IV iron. Blood samples were drawn before and after the session to asses OS biomarkers such as advanced oxidation protein products and myeloperoxidase (MPO), whereas polymorphonuclear leukocyte (PMNL) counts served as an indirect measure of inflammation. At the end of the dialysis session, an increase in advanced oxidation protein products and MPO levels as well as a decrease in PMNLs counts were observed in the placebo group, whereas no significant changes occurred in the PJ group. The postdialysis increase in MPO levels in the placebo group is a direct result of PMNL degranulation, associated with postdialysis decrease in PMNL counts. Degranulation of PMNLs leads to the release of other cell moieties, such as inflammatory mediators and proteases that enhance inflammation. We conclude that PJ intake attenuated the increase in systemic OS and inflammation induced by IV iron administration during the dialysis session. These beneficial effects illuminate the previously observed attenuation in OS and inflammation in patients with HD on prolonged PJ intake.

Topics: Administration, Intravenous; Aged; Anemia; Beverages; Biomarkers; Dose-Response Relationship, Drug; Female; Fruit; Humans; Inflammation; Iron; Kidney Failure, Chronic; Lythraceae; Male; Middle Aged; Neutrophils; Oxidative Stress; Peroxidase; Renal Dialysis

Oxidative stress and inflammation persist years after smoking cessation thereby limiting the restoration of vascular endothelial function (VEF). Although short-term smoking cessation improves VEF, no studies have examined co-therapy of antioxidants in combination with smoking cessation to improve VEF. We hypothesized that improvements in γ-tocopherol (γ-T) status during smoking cessation would improve VEF beyond that from smoking cessation alone by decreasing oxidative stress and proinflammatory responses. A randomized, double-blind, placebo-controlled study was conducted in otherwise healthy smokers (22 ± 1 years; mean ± SEM) who quit smoking for 7 days with placebo (n=14) or γ-T-rich supplementation (n=16; 500 mg γ-T/day). Brachial artery flow-mediated dilation (FMD), cotinine, and biomarkers of antioxidant status, oxidative stress, and inflammation were measured before and after 7 days of smoking cessation. Smoking cessation regardless of supplementation similarly decreased plasma cotinine, whereas γ-T-rich supplementation increased plasma γ-T by seven times and its urinary metabolite γ-carboxyethyl hydroxychroman by nine times (P<0.05). Smoking cessation with γ-T-rich supplementation increased FMD responses by 1.3% (P<0.05) beyond smoking cessation alone (4.1 ± 0.6% vs 2.8 ± 0.3%; mean ± SEM). Although plasma malondialdehyde decreased similarly in both groups (P<0.05), plasma oxidized LDL and urinary F2-isoprostanes were unaffected by smoking cessation or γ-T-rich supplementation. Plasma TNF-α and myeloperoxidase decreased (P<0.05) only in those receiving γ-T-rich supplements and these were inversely related to FMD (P<0.05; R=-0.46 and -0.37, respectively). These findings demonstrate that short-term γ-T-rich supplementation in combination with smoking cessation improved VEF beyond that from smoking cessation alone in young smokers, probably by decreasing the proinflammatory mediators TNF-α and myeloperoxidase.

Topics: Adult; alpha-Tocopherol; Antioxidants; Biomarkers; Brachial Artery; Carotid Arteries; Chromans; Cotinine; Dietary Supplements; Double-Blind Method; Endothelium, Vascular; F2-Isoprostanes; Female; Humans; Inflammation; Inflammation Mediators; Lipoproteins, LDL; Male; Malondialdehyde; Oxidative Stress; Peroxidase; Placebos; Smoking; Smoking Cessation; Tumor Necrosis Factor-alpha; Young Adult

The aim of the present study was to investigate leucocyte markers, CD11b, CD16, CD66b, CD68, myeloperoxidase and neutrophil elastase on skeletal muscle biopsies from biceps brachii after unaccustomed eccentric exercise followed by the second bout of exercise 3 weeks later. The subjects (10 subjects received COX-2 inhibitor (Celecoxib) and 13 subjects received placebo) were divided into three categories: mild, moderate and severe effect of eccentric exercise, according to the reduction and recovery of muscle force-generating capacity after performing 70 maximal eccentric actions with elbow flexors on an isokinetic dynamometer. The results showed that the CD66b antibody was applicable for localization of neutrophils in human skeletal muscle, whereas the other studied neutrophil markers recognized also other leucocytes than neutrophils. The number of CD66b positive cells in skeletal muscle was very low and was not affected by the exercise. The macrophage marker CD68 showed reactivity also against satellite cells and fibroblast-like cells in skeletal muscle and therefore cannot be applied as a quantitative value for inflammatory cells. Skeletal muscle fibre injury, shown as dystrophin negative fibres, was observed approximately in half of the biopsies at 4 and 7 days after the first exercise bout in the categories moderate and severe effect of eccentric exercise. These subjects represent the most prominent loss in muscle force-generating capacity both at the category and the individual levels. Furthermore, deformed skeletal muscle fibres were observed in five subjects in these categories after the second bout of exercise. The present results suggest that neutrophils are not involved in skeletal muscle fibre injury and the reduction in muscle force-generating capacity after a single bout of eccentric exercise is a good indirect indicator of muscle damage in humans. Furthermore, prolonged regeneration process could be one of the reasons for impaired peripheral muscle function after high-force eccentric exercise.

Topics: Adult; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Biomarkers; CD11b Antigen; Celecoxib; Cell Adhesion Molecules; Cyclooxygenase 2 Inhibitors; Exercise; Female; GPI-Linked Proteins; Humans; Inflammation; Leukocyte Elastase; Male; Muscle Contraction; Muscle, Skeletal; Peroxidase; Pyrazoles; Receptors, IgG; Sulfonamides

Epidemiological evidence supports a positive relationship between fruit and vegetable (FV) intake, lung function and chronic obstructive pulmonary disease (COPD). Increasing FV intake may attenuate the oxidative stress and inflammation associated with COPD. An exploratory randomised controlled trial to examine the effect of increased consumption of FV on oxidative stress and inflammation in moderate-to-severe COPD was conducted. 81 symptomatically stable patients with a habitually low FV intake (two or fewer portions of FV per day) were randomised to the intervention group (five or more portions of FV per day) or the control group (two or fewer portions of FV per day). Each participant received self-selected weekly home deliveries of FV for 12 weeks. 75 participants completed the intervention. There was a significant between-group change in self-reported FV intake and biomarkers of FV intake (zeaxanthin (p = 0.034) and β-cryptoxanthin (p = 0.015)), indicating good compliance; post-intervention intakes in intervention and control groups were 6.1 and 1.9 portions of FV per day, respectively. There were no significant changes in biomarkers of airway inflammation (interleukin-8 and myeloperoxidase) and systemic inflammation (C-reactive protein) or airway and systemic oxidative stress (8-isoprostane). This exploratory study demonstrated that patients with moderate-to-severe COPD were able to comply with an intervention to increase FV intake; however, this had no significant effect on airway or systemic oxidative stress and inflammation.

Topics: Aged; Aged, 80 and over; Anticarcinogenic Agents; Biomarkers; C-Reactive Protein; Cryptoxanthins; Diet; Dinoprost; Feeding Behavior; Female; Fruit; Humans; Inflammation; Interleukin-8; Male; Middle Aged; Oxidative Stress; Patient Compliance; Peroxidase; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Sputum; Vegetables; Xanthophylls; Zeaxanthins

Endothelial progenitor cells (EPCs) contribute to the maintenance of endothelial integrity and function. We investigated the effects of rosuvastatin and allopurinol on the number of EPCs in patients with heart failure and aimed to provide insight into the molecular inflammatory and oxidative mechanisms that could be responsible for the alterations in EPC levels after treatment.. Sixty patients with systolic heart failure were randomized to receive rosuvastatin 10mg/d, allopurinol 300mg/d or placebo and followed up for 1 month. The number of CD34(+)/KDR(+) and CD34(+)/CD133(+)/KDR(+) EPCs in blood was evaluated by flow cytometry. Endothelial function was assessed by brachial artery flow-mediated dilation. Levels of markers of inflammation and oxidative stress were also determined.. Circulating EPCs were significantly increased after rosuvastatin treatment (from 230 (170-380) and 10 (8-24) to 390 (230-520) and 19 (8-33) cells/10(6) lymphomonocytes, respectively, p=0.004 and p=0.008), whereas they remained unchanged in the other groups. The increase in EPC levels was not associated with the changes in the levels of the measured inflammatory and oxidative markers.. Short-term treatment with rosuvastatin, but not allopurinol, significantly increases the number of circulating EPCs in patients with heart failure providing further insights into its role in these individuals. The impact of rosuvastatin on EPCs is not mediated by changes in inflammatory and oxidative status.

Topics: AC133 Antigen; Aged; Allopurinol; Antigens, CD; Antigens, CD34; Endothelial Cells; Enzyme Inhibitors; Female; Fluorobenzenes; Glycoproteins; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Male; Middle Aged; Oxidative Stress; Peptides; Peroxidase; Pyrimidines; Rosuvastatin Calcium; Stem Cells; Sulfonamides; Vascular Endothelial Growth Factor Receptor-2; Xanthine Oxidase

Intrauterine inflammation is followed by elevated concentrations of inflammation-related proteins in the newborn's blood. Many of these proteins have short half-lives. The persistence of this postnatal inflammation has not previously been investigated. In a sample of 834 infants born before the 28th week of gestation, 12% (103) had grade 1 or 2, and 17% (142) had grade 3, 4, or 5 umbilical cord inflammation. Concentrations of nine proteins previously shown to be associated with umbilical cord inflammation at birth were measured on the first postnatal day and at two weekly intervals after birth. We evaluated the hypothesis that children who had umbilical cord inflammation were no more likely than others to have elevated concentrations of inflammation-related proteins in postnatal blood. The concentrations of seven of the nine proteins [C-reactive protein (CRP), myeloperoxidase (MPO), IL1β, IL8, TNFα, intercellular adhesion molecule-1 (ICAM3), and matrix metalloproteinase (MMP9)] showed a tendency to be elevated on day 7 among infants with funisitis. Adjusting for gestational age, growth restriction, and three postnatal exposures (ventilation on day 7, presumed and definite early bacteremia, and Bell stage III necrotizing endocolitis) did not diminish the elevated odds ratios of concentrations in the top quartile (for gestational age and day the specimen was obtained) of MPO, IL1β, TNFα, IL8, ICAM3, and MMP9. The persistence of a relationship between umbilical cord inflammation and elevated blood concentrations of inflammation-related proteins on postnatal day 7 suggests the existence of phenomena that contribute to a reinforcement loop and thereby sustained systemic inflammation.

Topics: Antigens, CD; Bacteremia; C-Reactive Protein; Cell Adhesion Molecules; Chorioamnionitis; Cytokines; Female; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Inflammation; Matrix Metalloproteinase 9; Peroxidase; Pregnancy; Time Factors; Umbilical Cord

Studies indicate that myeloperoxidase (MPO) is associated with disease progression and severity in heart failure (HF), while it may provide a mechanistic link between inflammation and adverse cardiac remodeling. The mechanisms that regulate MPO are unclear, while it is unknown whether specific treatments such as HMG-CoA reductase inhibitors and xanthine oxidase inhibitors may modify MPO. Therefore in the present study we examined the effects of rosuvastatin and allopurinol on MPO levels in patients HF.. Sixty clinically stable patients with systolic HF were randomized to receive rosuvastatin 10mg/day, allopurinol 300mg/day or placebo and followed up for 1 month. Plasma levels of MPO and serum levels of soluble CD40 ligand, interleukin-6, and oxidized LDL were determined using ELISA. All measurements were made before and after 1-month treatment.. Rosuvastatin significantly reduced plasma levels of MPO (p=0.003), which remained unchanged in the other groups. Furthermore, the change of MPO levels in the rosuvastatin-treated group was significantly different compared with the other groups (p<0.05). Rosuvastatin administration also led to a significant decrease in oxidized LDL (p=0.009), while the other inflammatory markers remained unchanged in all groups. In the total population, a significant correlation was observed between the baseline levels of MPO and hsCRP (r=0.275, p=0.027), fibrinogen (r=0.278, p=0.025), and sCD40L (r=0.288, p=0.021).. Short-term treatment with rosuvastatin regulates inflammatory process in patients with heart failure by significantly reducing plasma levels of MPO. This finding reveals a novel pleiotropic effect of statins in patients with heart failure, and provides further insights into the pathophysiological mechanisms of MPO in heart failure.

Topics: Aged; Allopurinol; Biomarkers; Cholesterol; Cholesterol, LDL; Chronic Disease; Female; Fluorobenzenes; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Male; Peroxidase; Pyrimidines; Rosuvastatin Calcium; Sulfonamides; Triglycerides

The biocompatibility of cardiopulmonary bypass surfaces has been improved by heparin and polymer surface modifications. The present study compared the effect of two such coatings on the inflammatory reactions after open heart surgery.. Thirty patients undergoing elective heart surgery were randomly assigned to receive one of two types of coated circuits: Bioline (n=15) or phosphorylcholine (Phisio, n=15). The platelet and leukocyte counts, neutrophil activation (myeloperoxidase), complement activation (C3a and TCC), concentrations of lactate dehydrogenase, 27 cytokines (including interleukins, chemokines and growth factors), thrombin-antithrombin complexes, and the endothelial cell marker syndecan-1 were analyzed at five predetermined time points until 24 hrs post operatively.. Most measurements were comparable in both groups. However, myeloperoxidase was significantly higher in the Bioline group (p < 0.001). Postoperative lactate dehydrogenase concentrations were significantly higher in the Phisio group (p<0.01) and the maximal concentration of thrombin-antithrombin complexes 2 hours postoperatively tended to be higher in the Phisio group (p=0.08), consistent with a longer aortic cross-clamp and cardiopulmonary bypass time.. The two circuits exhibited a comparable degree of in vivo biocompatibility.

Topics: Aged; Anticoagulants; Antithrombin III; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Coated Materials, Biocompatible; Complement C3a; Cytokines; Female; Hemoglobins; Heparin; Humans; Inflammation; L-Lactate Dehydrogenase; Leukocyte Count; Male; Middle Aged; Peptide Hydrolases; Peptides; Peroxidase; Phosphorylcholine; Platelet Count; Syndecan-1; Thrombosis

This study was to compare the impact of different biocompatible coated circuits on inflammatory response and oxidative stress induced during cardiopulmonary bypass (CPB). Seventy-eight patients undergoing elective coronary artery bypass grafting (CABG) with CPB were randomly assigned to five groups with different biocompatible coated circuits: Trillium, Bioline, Phosphorylcholine, Polymethoxyethyl acrylate (PMEA), and the uncoated control group. Blood was drawn at three different time points: before CPB, 6 and 72 hours post CPB. Unlike the Trillium group, serum levels of TNF-alpha in the Bioline and Phosphorylcholine groups significantly increased only at 72 hours post CPB (p < 0.05). Serum levels of IL-6 significantly increased at 6 and 72 hours post CPB in all groups (p < 0.01). The Trillium group showed a significant increase of IL-10 compared to the control group at 72 hours post CPB (p < 0.05). Serum levels of NOx in the Phosphorylcholine group significantly decreased at 6 hours post CPB compared to baseline (p < 0.05). Both the Bioline and Phosphorylcholine groups showed statistical decreases in serum NOx levels compared with other groups at 6 hours post CPB (p < 0.05). A significant difference in NOx levels between the Bioline and the control group was also observed at 72 hours post CPB. Myeloperoxidase levels were significantly elevated at 6 and 72 hours post CPB in all groups (p < 0.05). Inflammatory response and oxidative stress are elevated during CABG with CPB. Heparin-coated and the Phosphorylcholine-coated circuits induce less inflammatory responses and oxidative stress compared to other circuits.

Topics: Aged; Cardiopulmonary Bypass; Coated Materials, Biocompatible; Coronary Artery Bypass; Female; Humans; Inflammation; Interleukin-10; Interleukin-6; Male; Middle Aged; Myocardial Infarction; Nitric Oxide; Oxidative Stress; Peroxidase; Tumor Necrosis Factor-alpha

The purpose of this study was to test the influence of 2.4 g/d fish oil n-3 polyunsaturated fatty acids (n-3 PUFA) over 6 wk on exercise performance, inflammation, and immune measures in 23 trained cyclists before and after a 3-d period of intense exercise. Participants were randomized to n-3 PUFA (n = 11; 2,000 mg eicosapentaenoic acid [EPA], 400 mg docosahexaenoic acid [DHA]) or placebo (n = 12) groups. They ingested supplements under double-blind methods for 6 wk before and during a 3-d period in which they cycled for 3 hr/d at ~57% W(max) with 10-km time trials inserted during the final 15 min of each 3-hr bout. Blood and saliva samples were collected before and after the 6-wk supplementation period, immediately after the 3-hr exercise bout on the third day, and 14 hr postexercise and analyzed for various immune-function and inflammation parameters. Supplementation with n-3 PUFA resulted in a significant increase in plasma EPA and DHA but had no effect on 10-km time-trial performance; preexercise outcome measures; exercise-induced increases in plasma cytokines, myeloperoxidase, blood total leukocytes, serum C-reactive protein, and creatine kinase; or the decrease in the salivary IgA:protein ratio. In conclusion, 6 wk supplementation with a large daily dose of n-3 PUFAs increased plasma EPA and DHA but had no effect on exercise performance or in countering measures of inflammation and immunity before or after a 3-d period of 9 hr of heavy exertion.

Topics: Adult; Bicycling; C-Reactive Protein; Creatine Kinase; Cross-Over Studies; Cytokines; Docosahexaenoic Acids; Double-Blind Method; Eicosapentaenoic Acid; Fatty Acids, Omega-3; Female; Fish Oils; Humans; Immunoglobulin A; Inflammation; Leukocyte Count; Male; Peroxidase; Physical Endurance; Young Adult

Peripheral arterial disease (PAD) is strongly associated with endothelial dysfunction and inflammation, which portend a high cardiovascular risk. Accordingly, we investigated the effects of omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation on endothelial function and inflammatory status in affected individuals.. PAD patients were randomly divided into two groups. In Group I (n=16) pre-enrollment therapy was not modified, while in Group II (n=16) n-3 PUFAs 1 g b.i.d. for 3 months were added to the previous treatment. Endothelial function was assessed by measuring plasma soluble thrombomodulin (sTM) and brachial artery flow-mediated dilation (FMD), and the inflammatory status by measuring high-sensitivity C-reactive protein and myeloperoxidase.. In Group II, n-3 PUFAs reduced sTM levels from the median value of 33.0 ng/mL (interquartile range 16.7, 37.2) to 17.0 ng/mL (11.2, 33.7) (p=0.04), and improved FMD from 6.7% (3.7, 8.7) to 10.0% (6.2, 14.2) (p=0.02). Conversely, these markers did not change in Group I. After 3 months, the levels of inflammatory markers remained unmodified in both groups.. In PAD, n-3 PUFAs induced a marked improvement in endothelial function. Conversely, they did not affect the inflammatory status. In future, large, prospective studies are needed to investigate whether n-3 PUFAs, by improving endothelial function, would reduce the incidence of ischemic events in a population at high risk.

Topics: Aged; Biomarkers; Blood Flow Velocity; Brachial Artery; C-Reactive Protein; Dietary Supplements; Endothelium, Vascular; Fatty Acids, Omega-3; Female; Humans; Inflammation; Male; Middle Aged; Peripheral Vascular Diseases; Peroxidase; Regional Blood Flow; Risk Assessment; Severity of Illness Index; Single-Blind Method; Thrombomodulin; Treatment Outcome

To study the effect of oral steroids upon clinical response and rectal mucosa secretion of eosinophil cationic protein (ECP), myeloperoxidase (MPO), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and albumin in patients with collagenous colitis (CC).. A segmental perfusion technique was used to collect perfusates from rectum of CC patients once before and twice (one and four weeks) after the start of steroid treatment. Clinical data was monitored and ECP, MPO, bFGF, VEGF and albumin concentrations were analyzed by immunochemical methods in perfusates and in serum.. Steroids reduced the number of bowel movements by more than five times within one week and all patients reported improved subjective well-being at wk 1 and 4. At the same time, the median concentrations of ECP, bFGF, VEGF and albumin in rectal perfusates decreased significantly. MPO values were above the detection limit in only 3 patients before treatment and in none during treatment. VEGF, bFGF, ECP and albumin concentrations correlated with each other with the exception of ECP and albumin. A decrease of serum ECP and VEGF concentrations was also seen even if the overtime reduction was not significant.. Oral steroid treatment in CC patients induced a simultaneous reduction of bowel movements and rectal release of ECP, bFGF, VEGF and albumin, suggesting that these polypeptides and increased mucosal permeability are important components of the pathophysiology in collagenous colitis.

Topics: Adult; Aged; Albumins; Colitis, Collagenous; Colon; Eosinophil Cationic Protein; Female; Fibroblast Growth Factor 2; Humans; Inflammation; Intestinal Mucosa; Male; Middle Aged; Permeability; Peroxidase; Steroids; Vascular Endothelial Growth Factor A

To investigate the effect of N-acetylcysteine on preventing pump-induced oxidoinflammatory response during cardiopulmonary bypass (CPB).. Forty patients undergoing coronary artery bypass grafting (CABG) were randomly divided into a study group (n = 20), given 50 mg kg(-1) N-acetylcysteine intravenously for 3 days, and a control group (n = 20) given saline. Serum samples were collected for measurement of myeloperoxidase (MPO), malondialdehyde (MDA), interleukin-6, Alpha1-acid glycoprotein (AAGP), and C-reactive protein (CRP) during surgery and postoperatively.. The MPO and MDA values showed a similar pattern during and after CPB in the study group, with significantly less variance than in the control group. Interleukin-6 showed similar patterns in the two groups, but the data from 30 min after the start of CPB and from 6 h post-CPB were significantly different. The AAGP and CRP values were both elevated during CPB in the two groups without a significant difference, but 6 and 24 h post-CPB, the values were significantly higher in the control group than in the study group.. N-Acetylcysteine decreased pump-induced oxidoinflammatory response during CPB, suggesting that it could be a novel therapy for assisting in the prevention of CBP-induced oxidoinflammatory damage.

Topics: Acetylcysteine; Acute-Phase Proteins; Antioxidants; C-Reactive Protein; Cardiopulmonary Bypass; Coronary Artery Bypass; Humans; Inflammation; Inflammation Mediators; Interleukin-6; Lipid Peroxidation; Malondialdehyde; Neutrophil Activation; Orosomucoid; Oxidative Stress; Peroxidase

Complement activation contributes to ischemia-reperfusion injury. Patients undergoing thoracoabdominal aortic aneurysm (TAAA) repair suffer extensive ischemia-reperfusion and considerable systemic inflammation.. The degree and mechanism of complement activation and its role in inflammation were investigated in 19 patients undergoing TAAA repair. Patients undergoing open infrarenal aortic surgery (n=5) or endovascular descending aortic aneurysm repair (n=6) served as control subjects. Substantial complement activation was seen in TAAA patients but not in controls. C1rs-C1-inhibitor complexes increased moderately, whereas C4bc, C3bBbP, C3bc, and the terminal SC5b-9 complex (TCC) increased markedly after reperfusion, reaching a maximum 8 hours after reperfusion. Interleukin (IL)-1beta, tumor necrosis factor alpha (TNF-alpha), and IL-8 increased significantly in TAAA patients but not in controls, peaking at 24 hours postoperatively and correlating closely with the degree of complement activation. IL-6 and IL-10 increased to a maximum 8 hours after reperfusion in the TAAA patients, were not correlated with complement activation, and increased moderately in the control subjects. Myeloperoxidase and lactoferrin increased markedly before reperfusion in all groups, whereas sICAM-1, sP-selectin, and sE-selectin were unchanged. No increase was observed in complement activation products, IL-1beta, TNF-alpha, or IL-8 in a mannose-binding lectin (MBL)-deficient TAAA patient, whereas IL-6, IL-10, myeloperoxidase, and lactoferrin increased as in the controls. Two other MBL-deficient TAAA patients receiving plasma attained significant MBL levels and showed complement and cytokine patterns identical to the MBL-sufficient TAAA patients.. The data suggest that complement activation during TAAA repair is MBL mediated, amplified through the alternative pathway, and responsible in part for the inflammatory response.

Topics: Aged; Aged, 80 and over; Aortic Aneurysm, Abdominal; Aortic Aneurysm, Thoracic; Cell Adhesion Molecules; Chemokines; Complement Activation; Cytokines; Female; Humans; Inflammation; Lactoferrin; Male; Mannose-Binding Lectin; Middle Aged; Neutrophil Activation; Peroxidase; Plasma; Prospective Studies; Reperfusion Injury; Vascular Surgical Procedures

Intraoperative blood salvage devices allowing a reinfusion of red blood cells (RBCs) after processing of shed blood and stagnant blood in the mediastinal cavity are more and more used to reduce homologous blood requirements in cardiac surgery with cardiopulmonary bypass (CPB). As the proinflammatory activity of the shed blood also contributes to morbidity during CPB, we conducted a prospective study in order to examine the quality of autologous blood before and after processing with five different devices [BRAT2, Sequestra, Compact Advanced, Cell Saver 5 (CS5), Continuous Autologous Transfusion System (CATS)]. All systems resulted in an excellent haemoconcentration, ranging from 53.7% (Compact) to 68.9% (CATS). The concentrations and elimination rates of several inflammatory markers [IL-1beta, IL-2, IL-8, TNFalpha, myeloperoxidase (MPO), elastase] were examined. Except for the Sequestra, an important increase in concentration of IL-1beta (between 30% and 220%) has been observed after processing with each device. In contrast, the attenuation rate of IL-6 and TNFalpha (95%) was optimal for all investigated blood salvages systems. Regarding IL-8, only the CATS and CS5 systems were able to attenuate this biological parameter with an excellent efficacy. The rate of attenuation in MPO and elastase, as markers of leukocyte activation, was higher than 80% for all devices. In conclusion, the different RBC washing systems tested in this study resulted in a significant attenuation of the inflammatory response. Increased levels of IL-1beta after processing remained, however, unclear. According to the type of protocol, based on inlet haematocrit, fill and wash speeds, and wash volumes, small variations in reducing the inflammatory response have been observed from one device to another.

Topics: Aged; Biomarkers; Blood Component Removal; Blood Transfusion, Autologous; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Cytokines; Female; Humans; Inflammation; Intraoperative Period; Male; Middle Aged; Pancreatic Elastase; Peroxidase

Cardiopulmonary bypass (CPB) is associated with the production of inflammatory responses, which can have significant influence on prognosis. We studied the effects of leucocyte-depletion filters on inflammatory parameters and early postoperative prognosis during coronary revascularization. Twenty patients undergoing elective coronary revascularization were randomly divided into two groups. Ten patients had leucocyte-depletion filters added to the CPB circuit (treatment group) and 10 were used as control cases (control group). Expression of CD11b on neutrophils, and production of myeloperoxidase and lactoferrin, were measured in arterial samples between induction and 3 h postbypass. In addition, clinical parameters were measured during inpatient recovery. CD11b neutrophil expression, and myeloperoxidase and lactoferrin production, were found to be upregulated during CPB and then to decline to preoperative levels by the third postoperative hour. Blood transfusion requirements were reduced in the treatment group, equalling 1.5 +/- 1.2 units, compared to 2.7 +/- 1.1 units for the control group (p value = 0.034) and so were the volumes of crystalloid infused during the first 24 h postoperatively, equalling 3.9 +/- 1.21 in the treatment group and 3.3 +/- 0.71 in the control group (p value = 0.021). Overall, the application of leucocyte depletion produced an early clinical advantage, underlining the need for an improved understanding and manipulation of the inflammatory response to CPB.

Topics: Biomarkers; Blood Loss, Surgical; Blood Transfusion; Cardiopulmonary Bypass; Crystalloid Solutions; Elective Surgical Procedures; Female; Filtration; Humans; Inflammation; Isotonic Solutions; Lactoferrin; Leukocyte Count; Leukocytes; Lymphocyte Depletion; Macrophage-1 Antigen; Male; Middle Aged; Myocardial Revascularization; Neutrophils; Peroxidase; Plasma Substitutes; Postoperative Period; Prognosis; Treatment Outcome

Markers of airway inflammation are needed for prediction of asthma deterioration and evaluation of disease severity. Few studies have focused on the dynamics of airway inflammation as reflected by the activity of the eosinophils and their proteins after withdrawal of inhaled corticosteroids.. Our goal was to investigate the effect of withdrawal of inhaled budesonide on eosinophil count in blood and eosinophil proteins in serum and urine and to relate the levels of these markers to the risk of symptoms of asthma, increased bronchial hyperresponsiveness, and deterioration of lung function.. Thirty-three children were randomly selected to continue or discontinue use of inhaled budesonide in a double-blind, placebo-controlled study. They were followed up for 4 months with regular analysis of blood, serum, and urine samples; lung function; and methacholine challenges. Eosinophil activity markers were analyzed. Age-matched healthy children provided reference data for all parameters measured.. The eosinophil number in blood and eosinophil protein levels in serum (serum eosinophil cationic protein [ECP] and serum eosinophil peroxidase [EPO]) increased significantly in the withdrawal group, and the difference between the groups was significant (P =.02 for all). Twenty-nine percent of the children in the withdrawal group remained symptom free. This subgroup had eosinophil counts at baseline below 350/microL, a serum ECP level below 15 microg/L, and a serum EPO level below 25 microg/L, each of which was related to a low risk of exacerbation (relative risk = 0.37, 0.48, and 0.37 respectively; P <.05 for all). All eosinophil markers were lower in the healthy children than in the symptom-free children with asthma.. Our data indicate that eosinophil count and/or ECP and EPO levels can be used to estimate the short-term risk of deterioration and the need for corticosteroid treatment in cases of mild and moderate allergic asthma.

Topics: Adolescent; Anti-Asthmatic Agents; Antigens, CD; Asthma; Biomarkers; Blood Proteins; Bronchial Hyperreactivity; Bronchial Provocation Tests; Budesonide; Child; Disease Progression; Double-Blind Method; Eosinophil Granule Proteins; Eosinophil Peroxidase; Eosinophil-Derived Neurotoxin; Eosinophils; Female; Forced Expiratory Volume; Humans; Inflammation; Leukocyte Count; Male; Membrane Glycoproteins; Methacholine Chloride; Peroxidase; Peroxidases; Ribonucleases; Skin Tests; Spirometry; Tetraspanin 29

Inhaled nitric oxide is used to treat hypoxia associated with acute lung injury. Endogenous nitric oxide regulates inflammatory responses, but the effect of inhaled nitric oxide therapy is unknown. We hypothesized that inhaled nitric oxide may alter inflammatory responses and endogenous nitric oxide synthase activity.. A randomized, prospective interventional study.. A university hospital's general intensive care unit.. Thirty-two patients with acute lung injury.. Patients who responded to test doses of nitric oxide were randomized to ventilator therapy with and without inhaled nitric oxide. The inhaled concentration of nitric oxide was determined by dose titration at 0, 2, 10, and 40 ppm and the minimum concentration used, which resulted in an increase in the PaO2/FIO2 ratio of at least 25%.. Patients were followed up for 30 days or until death, and bronchoalveolar lavage (BAL) was performed at 0, 24, and 72 hrs. Nitric oxide synthase activity was measured spectrophotometrically, and myeloperoxidase, elastase, interleukin-8, and leukotrienes were measured in BAL fluid by enzyme immunoassay. Total nitrite and lipid peroxides in serum were measured colorimetrically. Nitric oxide synthase activity decreased (p = .01) and total nitrite increased (p = .02) in patients receiving inhaled nitric oxide. Other markers of inflammation in BAL fluid did not change. Lipid peroxide concentrations also did not alter.. The decrease in activity of nitric oxide synthase in patients receiving nitric oxide is likely to be the result of feedback inhibition of the enzyme. This study shows that inhaled nitric oxide has no effect on several markers of the inflammatory response system and does not lead to increased oxidant stress.

Topics: Acute Disease; Administration, Inhalation; Adolescent; Adult; Aged; Aged, 80 and over; Female; Humans; Inflammation; Interleukin-8; Leukotrienes; Lipid Peroxides; Lung; Lung Injury; Male; Middle Aged; Nitric Oxide; Nitric Oxide Synthase; Nitrites; Pancreatic Elastase; Peroxidase; Prospective Studies; Wounds and Injuries

The object of this study was to examine the hypothesis that meter-dosed, inhaled beclomethasone administered to premature infants beginning at birth in a tapering dosage schedule over the first 12 days of life attenuates bronchoalveolar lining fluid oxyradical inflammation concomitant with modulation of bronchopulmonary dysplasia. The design of this study was an unblinded, uncontrolled phase I, pilot investigation of inhaled beclomethasone primarily examining safety and administration. The setting was a tertiary care neonatal intensive care unit. Intubated, premature infants were studied longitudinally to 36 weeks corrected gestational age. Meter-dosed, inhaled beclomethasone was administered in a tapering dosage schedule over the first 12 days of life. Endotracheal tube aspirates were collected on Days 2, 4, and 6 of life and assayed for various markers of bronchoalveolar lining fluid oxyradical stress. Infants were also assessed with regards to a number of relevant clinical variables and presence or absence of bronchopulmonary dysplasia at 36 weeks corrected gestational age. Although no differences in clinical outcome were apparent in comparing nine control infants with nine beclomethasone-treated infants, bronchoalveolar lining fluid from control infants exhibited evidence of apparent phospholipid peroxidation (enhanced polyunsaturated fatty acid consumption) on Day 2 of life compared to beclomethasone-treated infants. Significant differences were noted for percent arachidonic acid, total polyunsaturated fatty acids and ratio of polyunsaturated fatty acids, to saturated fatty acids. The ratio of monohydroxyl linolenic acid to native linoleic acid (a more specific marker of lipid peroxidation) as well as myeloperoxidase activity (a marker of neutrophil oxyradical stress) tended to be higher in the control group but did not achieve statistical significance for this small subject number study. No adverse reactions related to meter-dosed, inhaled beclomethasone were noted in the treatment group; most specifically no evidence of hypothalamic-pituitary-adrenal axis suppression was noted in either control or beclomethasone-treated infants. Meter-dosed, inhaled beclomethasone in the dosage schedule utilized was safe and appeared to moderate bronchoalveolar lining fluid phospholipid peroxidation. Small numbers of infants entered into the present investigation preclude comments on clinical efficacy because of the likelihood of a statistical type 2 error. However

Topics: Administration, Inhalation; Beclomethasone; Bronchoalveolar Lavage Fluid; Bronchopulmonary Dysplasia; Fatty Acids; Female; Gestational Age; Humans; Hypothalamo-Hypophyseal System; Infant, Newborn; Infant, Premature; Inflammation; Interleukin-8; Lipid Peroxidation; Lung Diseases; Male; Nebulizers and Vaporizers; Peroxidase; Phospholipids; Pilot Projects; Pituitary-Adrenal System; Reactive Oxygen Species; Severity of Illness Index

The mechanisms explaining the beneficial effects of glucocorticoid in ventilator-dependent preterm infants are not known. In the present randomized trial, we evaluated the hypothesis that dexamethasone (DEX) treatment of small, preterm infants at risk for chronic lung disease favorably affects the surfactant system. Twenty-three ventilator-dependent infants, with a mean +/- SD gestational age of 26 +/- 2 wk and a mean birth weight of 836 +/- 173 g, received 1 wk of treatment with either DEX (dose 0.5 mg/kg/d) or placebo beginning at 2 wk of age. The airway specimens were analyzed for surfactant components, surface activity, surfactant inhibitors, and inflammatory mediators. The concentrations of these parameters in epithelial lining fluid were calculated using the urea method. DEX treatment decreased the concentration of nonsedimentable protein in epithelial lining fluid within 3 d (p < 0.05). The nonsedimentable fraction of airway specimens decreased the surface activity of surfactant as a function of protein concentration. At a constant protein concentration, the protein from placebo-treated infants inhibited the surface activity of human surfactant in vitro more than protein from DEX-treated infants (p < 0.05). DEX transiently increased the concentration of surfactant protein-A in epithelial lining fluid but had no effect on surface activity of the sedimentable surfactant complex or on concentrations of phosphatidylcholine, IL-1 beta, lactoferrin, or myeloperoxidase. We conclude that the acute beneficial effect of DEX treatment in preterm ventilator-dependent infants may in part be mediated through a decrease in the concentration of non-sedimentable protein and a decrease in the capacity of this protein to inhibit surface activity.

Topics: Blood Proteins; Chronic Disease; Dexamethasone; Female; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature, Diseases; Inflammation; Interleukin-1; Lactoferrin; Lung Diseases; Male; Peroxidase; Pulmonary Surfactants; Risk Factors; Trachea; Treatment Outcome

A 26-year-old Japanese woman was admitted with a 1-month history of diarrhea, a high fever for a few days, and exacerbation of dyspnea. She was treated with an antifibrotic drug and long-term oxygen therapy for Hermansky-Pudlak syndrome-related pulmonary fibrosis. New ground-glass attenuation appeared on chest computed tomography (CT), and a colon biopsy showed an inflammatory cell accumulation with a high titer of myeloperoxidase (MPO)-specific anti-neutrophil cytoplasmic antibodies (ANCA). Systemic inflammation related to MPO-ANCA titer elevation was suspected. Steroid pulse therapy and intravenous cyclophosphamide improved chest CT findings and diarrhea. Therefore, immunosuppressant treatment should be considered for systemic inflammation related to MPO-ANCA.

Topics: Adult; Antibodies, Antineutrophil Cytoplasmic; Diarrhea; Female; Hermanski-Pudlak Syndrome; Humans; Inflammation; Peroxidase

Syk is a cytoplasmic protein tyrosine kinase that plays a role in signaling via B cell and Fc receptors (FcR). FcR engagement and signaling via Syk is thought to be important in antineutrophil cytoplasm antibody (ANCA) IgG-mediated neutrophil activation. This study was undertaken to investigate the role of Syk in ANCA-induced myeloid cell activation and vasculitis pathogenesis.. Phosphorylation of Syk in myeloid cells from healthy controls and ANCA-associated vasculitis (AAV) patients was analyzed using flow cytometry. The effect of Syk inhibition on myeloperoxidase (MPO)-ANCA IgG activation of cells was investigated using functional assays (interleukin-8 and reactive oxygen species production) and targeted gene analysis with NanoString. Total and phosphorylated Syk at sites of tissue inflammation in patients with AAV was assessed using immunohistochemistry and RNAscope in situ hybridization.. We identified increased phosphorylated Syk at critical activatory tyrosine residues in blood neutrophils and monocytes from patients with active AAV compared to patients with disease in remission or healthy controls. Syk was phosphorylated in vitro following MPO-ANCA IgG stimulation, and Syk inhibition was able to prevent ANCA-mediated cellular responses. Using targeted gene expression analysis, we identified up-regulation of FcR- and Syk-dependent signaling pathways following MPO-ANCA IgG stimulation. Finally, we showed that Syk is expressed and phosphorylated in tissue leukocytes at sites of organ inflammation in AAV.. These findings indicate that Syk plays a critical role in MPO-ANCA IgG-induced myeloid cell responses and that Syk is activated in circulating immune cells and tissue immune cells in AAV; therefore, Syk inhibition may be a potential therapeutic option.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Humans; Immunity, Innate; Immunoglobulin G; Inflammation; Peroxidase; Receptors, Fc; Syk Kinase

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Carrageenan; Cyclooxygenase 2; Edema; Female; Inflammation; Mice; Pain; Peroxidase; Piperazines; Plant Extracts; Pleurisy; Zymosan

It was aimed to induce a new experimental colitis model by using acetic acid and trinitrobenzene sulphonic acid together and to investigate the severity of inflammation biochemically and histopathologically in comparison with other models.. Fifty-six Wistar albino male rats were randomly divided into 4 groups as control, acetic acid, trinitrobenzene sulphonic acid, and combined groups, and the animals were sacrificed following the induction of colitis on the third day and on the seventh day. The serum amyloid A and myeloperoxidase were tested in plasma samples, and the tumor necrosis factor-alpha, interleukin 33, and ST2 were assayed in colon tissue samples with enzyme-linked immunosorbent assay in addition to histopathological examination.. There were statistically significant differences between the combined and the control groups both on the third day and on the seventh day in all parameters. There was no difference between the acetic acid group on the seventh day and the control groups in biochemical parameters.. The acetic acid model forms acute colitis. The combined model is found to be more successful in forming inflammation when compared to other models.

Topics: Acetic Acid; Animals; Colitis; Colon; Inflammation; Peroxidase; Rats; Rats, Wistar; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

Atherosclerotic cardiovascular disease and tooth infection are common in primary care, and both significantly reduce quality of life. Our study aimed to examine signs of vascular inflammation associated with loss of tooth vitality before and after a single tooth extraction.. An observational cohort study was performed with adults who had a nonvital tooth and an indicated desire for tooth extraction. Concentrations of total cholesterol, high-density lipoprotein-cholesterol, high-sensitivity C-reactive protein (hs-CRP), myeloperoxidase (MPO), and troponin T were measured in venous blood serum or plasma at baseline and 6-weeks after tooth extraction.. Circulating hs-CRP levels were > 3 mg/dL in 15 participants (68.2%) and MPO levels were > 350 pmol/L in 9 (40.9%) of 22 participants at baseline. After tooth extraction (n = 18), MPO levels decreased significantly compared with baseline (P < .00006) and hs-CRP levels moved directionally downward. The response rate for MPO was 88.9% (confidence interval: 65.1%-98.6%) from visit 1 to visit 2. Those with high MPO levels at baseline demonstrated larger reductions in MPO levels by visit 2 than those with lower baseline MPO levels (r = .81; P < .0001). A total of 13 individuals (72.2%) achieved MPO levels < 350 pmol/L and 11 (61.1%) achieved hs-CRP levels < 3 mg/dL at visit 2. Total cholesterol, high-density lipoprotein-cholesterol, and troponin T levels did not significantly change from visit 1 to visit 2.. A link between dental infection and circulating levels of inflammation was observed, suggesting that oral infection could be a risk factor for atherosclerotic cardiovascular disease.

Topics: Adult; Atherosclerosis; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Cholesterol, HDL; Humans; Inflammation; Peroxidase; Quality of Life; Troponin T

The risk of idiosyncratic drug-induced agranulocytosis (IDIAG) markedly constrains the use of clozapine, a neuroleptic with unparalleled efficacy. Most clozapine patients experience an early inflammatory response, likely a necessary step in IDIAG onset. However, most patients do not progress to IDIAG, presumably because of the requirement of specific human leukocyte antigen (HLA) haplotypes, T cell receptors, and other unknown factors. We established that clozapine activates inflammasomes and that myeloperoxidase bioactivation of clozapine generates neoantigens, but the connection between these early mechanistic events remained unknown and, thus, was the aim of this work. We found that the myeloperoxidase inhibitor PF-1355 attenuated myeloperoxidase activity in phorbol myristate acetate (PMA)-differentiated THP-1 macrophages, and it also attenuated clozapine-induced release of inflammatory mediators (e.g., IL-1β, CXCL1, and C-reactive protein). In vivo, pretreatment of Sprague Dawley rats with PF-1355 significantly attenuated clozapine-induced increases in neutrophil mobilization from the bone marrow to the blood and spleen, as determined using differential blood counts and flow cytometry. Moreover, the clozapine-triggered release of inflammatory mediators (e.g., IL-1β, calprotectin, CXCL1, and α-1-acid glycoprotein) from the liver, spleen, and bone marrow was dampened by myeloperoxidase inhibition. These data support the working hypothesis that oxidation of clozapine to a reactive metabolite by myeloperoxidase is critical for induction of the inflammatory response to clozapine. Ultimately, a better mechanistic understanding of the early events involved in the immune response to clozapine may elucidate ways to prevent IDIAG, enabling safer, more frequent therapeutic use of this and potentially other highly efficacious drugs.

Topics: Animals; Antipsychotic Agents; Clozapine; Coloring Agents; Humans; Inflammation; Inflammation Mediators; Neutropenia; Peroxidase; Rats; Rats, Sprague-Dawley

To the best of our knowledge, systemic sclerosis with overlapping characteristics of both microscopic polyangiitis and giant cell arteritis (i.e. microscopic polyangiitis involving the superficial temporal artery or giant cell arteritis with myeloperoxidase anti-neutrophil cytoplasmic antibody seropositivity) has not been reported previously. An 82-year-old woman with diffuse cutaneous systemic sclerosis experienced dyspnoea on exertion and fever. No signs of infection were observed on computed tomography. Her fever persisted despite antibiotic treatment for occult bacterial infection and secondary Clostridioides difficile-associated diarrhoea. Microscopic polyangiitis was suspected because of myeloperoxidase anti-neutrophil cytoplasmic antibody seropositivity, and giant cell arteritis was suspected as a differential diagnosis due to swelling of the superficial temporal artery. Arterial biopsy revealed inflammatory cell infiltration with granuloma formation. Based on the presence of granulomatous inflammation in the superficial temporal artery, we concluded that giant cell arteritis with myeloperoxidase anti-neutrophil cytoplasmic antibody seropositivity occurred as a complication. After glucocorticoid therapy, her fever and dyspnoea on exertion improved with a gradual decline in the serum myeloperoxidase anti-neutrophil cytoplasmic antibody levels. It is possible that vasculitis occurs as a complication in patients with systemic sclerosis in cases where the fever persists and cannot be explained by systemic sclerosis itself, infectious disease, or malignancy. Clinicians must be careful not to prematurely diagnose microscopic polyangiitis based on myeloperoxidase anti-neutrophil cytoplasmic antibody seropositivity or giant cell arteritis based on the swelling of the superficial temporal artery. Careful evaluation of the presence of granulomatous inflammation in an arterial biopsy specimen is essential to differentiate between microscopic polyangiitis and giant cell arteritis.

Topics: Aged, 80 and over; Antibodies, Antineutrophil Cytoplasmic; Female; Giant Cell Arteritis; Humans; Inflammation; Microscopic Polyangiitis; Peroxidase; Scleroderma, Systemic

The protective effects of Bacillus amyloliquefaciens(CCT7935), Bacillus subtilis(CCT7935), Bacillus licheniformis (CCT 7836), and Bacillus coagulans (CCT 0199) against lipopolysaccharide (LPS)-induced intestinal inflammation were investigated.. Male Swiss mice were assigned into six groups: control group, LPS group, LPS + B. subtilis (CCT7935) group, LPS +   B. licheniformis (CCT 7836) group, LPS +   B. amyloliquefaciens (CCT7935) group, and LPS   + B. coagulans (CCT 0199) group. Each mouse of the groups Bacillus received 1 × 109 colony-forming units of Bacillus once daily by oral gavage during 30 days. Twenty-four hours after the last dose of Bacillus, all groups, except the control group, were intraperitoneally injected with LPS in the single dose of 15 mg kg-1. The mice were euthanized 24 h after the LPS administration. Histological alterations, myeloperoxidase activity, and nitrite levels were analyzed in the gut of mice and the inflammatory cytokines were analyzed in the gut and in the blood. The results demonstrate that the mice challenged with LPS presented the villi shortened and damaged, which were significantly protected by B. coagulans and B. amyloliquefaciens. Furthermore, all Bacillus tested were effective in preventing against the increase of myeloperoxidase activity, while B. amyloliquefaciens and B. subtilis prevented the increase of nitrite and IL-1β levels in the gut of mice induced with LPS was decreased only B. subtilis. LPS also elevated the IL-1 β, IL-6, and IL-10 levels in the blood, and these alterations were significantly suppressed by Bacillus, especially by B. subtilis.. The study suggests that the Bacillus investigated in this study might be effective therapeutic agents for preventing intestinal inflammation, because they decrease the inflammatory process an protect against tissue damage.

Topics: Animals; Bacillus; Inflammation; Lipopolysaccharides; Male; Mice; Nitrites; Peroxidase; Probiotics

Calotropis procera latex protein (CpLP) is a popular anti-inflammatory and therefore we aimed to study its effects on inflammatory bone loss.. Male Wistar rats were subjected to a ligature of molars. Groups of rats received intraperitoneally CpLP (0.3 mg/kg, 1 mg/kg, or 3 mg/kg) or saline (0.9% NaCl) one hour before ligature and then daily up to 11 days, compared to naïve. Gingiva was evaluated by myeloperoxidase activity and interleukin-1 beta (IL-1β) expression by ELISA. Bone resorption was evaluated in the region between the cement-enamel junction and the alveolar bone crest. The histology considered alveolar bone resorption and cementum integrity, leukocyte infiltration, and attachment level, followed by immunohistochemistry bone markers between 1. The periodontitis significantly increased myeloperoxidase activity and the IL-1β level. The increased bone resorption was histologically corroborated by periodontal destruction, leukocyte influx, and attachment loss, as well as the increasing receptor activator of the nuclear factor-kappa B ligand (RANKL)/osteoprotegerin (OPG) ratio, and Tartrate-resistant acid phosphatase (TRAP)+ cells when compared to naïve. CpLP significantly reduced myeloperoxidase activity, level of IL-1β, alveolar bone resorption, periodontal destruction, leukocyte influx, and attachment loss. The CpLp also reduced the RANKL/OPG ratio and TRAP+ cells, when compared with the saline group, and did not affect the systemic parameters.. CpLP exhibited a periodontal protective effect by reducing inflammation and restricting osteoclastic alveolar bone resorption in this rat model.

Topics: Alveolar Bone Loss; Alveolar Process; Animals; Antioxidants; Calotropis; Inflammation; Latex; Male; Osteoprotegerin; Peroxidase; RANK Ligand; Rats; Rats, Wistar

Acute pancreatitis is a systemic inflammatory disorder characterized by the hyperactivation of digestion enzymes and the release of proinflammatory cytokines. Ferulic acid (FA) is a hydroxycinnamic acid derivative that has recently been shown to have antioxidant and anti-inflammatory properties.. The anti-inflammatory effects of FA were investigated in the pancreaticobiliary duct ligation (PBDL)-induced pancreatitis model.. Wistar albino rats (250-300 g; female = male) were divided into sham operation and PBDL groups. Some PBDL-performed animals were given intragastric saline or 250 mg/kg FA or 500 mg/kg FA 30 min before the PBDL and for 3 consecutive days. Moreover, the control group received saline. Blood samples are collected at the 24th, 48th, and 72nd hours to measure serum tumor necrosis factor (TNF)-α, liver, and pancreatic enzymes. At the 72nd hour, rats were euthanized; pancreas, lung, and liver samples were collected, scored microscopically, and analyzed for myeloperoxidase activity, malondialdehyde, and glutathione levels. One-way ANOVA with Tukey-Kramer tests were used for statistical analysis.. FA treatment reduced myeloperoxidase activity and prevented the depletion of glutathione in all three tissues. With FA treatments, high malondialdehyde levels in the pancreas and liver were reduced, as were serum TNF- α, amylase, lipase, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, and total bilirubin levels. Additionally, FA ameliorated microscopic damage in the pancreas and liver significantly.. According to the findings, FA protects endogenous antioxidant content, prevents neutrophil infiltration, and decreases lipid peroxidation in PBDL-induced pancreatitis. Furthermore, FA improves tissue damage induced by pancreatitis with its anti-inflammatory effects.

Topics: Acute Disease; Animals; Antioxidants; Coumaric Acids; Female; Glutathione; Inflammation; Liver; Male; Malondialdehyde; Pancreas; Pancreatitis; Peroxidase; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

Inflammation plays a key role in driving brain aneurysmal instability and rupture, but clinical tools to noninvasively differentiate between inflamed and stable aneurysms are lacking. We hypothesize that imaging oxidative changes in the aneurysmal microenvironment driven by myeloid inflammatory cells may represent a noninvasive biomarker to evaluate rupture risk. In this study, we performed initial evaluation of the oxidatively activated probe Fe-PyC3A as a tool for magnetic resonance imaging (MRI) of inflammation in a rabbit model of saccular aneurysm.. The difference in longitudinal relaxivity ( r1 ) in reduced and oxidized states of Fe-PyC3A was measured in water and blood plasma phantoms at 3 T. A rabbit saccular aneurysm model was created by endovascular intervention/elastinolysis with subsequent decellularization in situ. Rabbits were imaged at 4 weeks (n = 4) or 12 weeks (n = 4) after aneurysmal induction, when luminal levels of inflammation reflected by the presence of myeloperoxidase positive cells are relatively high and low, respectively, using a 3 T clinical scanner. Both groups were imaged dynamically using a 2-dimensional T1-weighted fast field echo pulse MRI sequence before and up to 4 minutes postinjection of Fe-PyC3A. Dynamic imaging was then repeated after an injection of gadobutrol (0.1 mmol/kg) as negative control probe. Rabbits from the 12-week aneurysm group were also imaged before and 20 minutes and 3 hours after injection of Fe-PyC3A using an axial respiratory gated turbo-spin echo (TSE) pulse sequence with motion-sensitized driven equilibrium (MSDE) preparation. The MSDE/TSE imaging was repeated before, immediately after dynamic acquisition (20 minutes postinjection), and 3 hours after injection of gadobutrol. Aneurysmal enhancement ratios (ERs) were calculated by dividing the postinjection aneurysm versus skeletal muscle contrast ratio by the preinjection contrast ratio. After imaging, the aneurysms were excised and inflammatory infiltrate was characterized by fluorometric detection of myeloperoxidase activity and calprotectin immunostaining, respectively.. In vitro relaxometry showed that oxidation of Fe-PyC3A by hydrogen peroxide resulted in a 15-fold increase of r1 at 3 T. Relaxometry in the presence of blood plasma showed no more than a 10% increase of r1 , indicating the absence of strong interaction of Fe-PyC3A with plasma proteins. Dynamic imaging with Fe-PyC3A generated little signal enhancement within the blood pool or adjacent muscle but did generate a transient increase in aneurysmal ER that was significantly greater 4 weeks versus 12 weeks after aneurysm induction (1.6 ± 0.30 vs 1.2 ± 0.03, P < 0.05). Dynamic imaging with gadobutrol generated strong aneurysmal enhancement, but also strong enhancement of the blood and muscle resulting in smaller relative ER change. In the 12-week group of rabbits, MSDE/TSE imaging showed that ER values measured immediately after dynamic MRI (20 minutes postinjection) were significantly higher ( P < 0.05) in the case of Fe-PyC3A (1.25 ± 0.06) than for gadobutrol injection (1.03 ± 0.03). Immunohistochemical corroboration using anticalprotectin antibody showed that leukocyte infiltration into the vessel walls and luminal thrombi was significantly higher in the 4-week group versus 12-week aneurysms (123 ± 37 vs 18 ± 7 cells/mm 2 , P < 0.05).. Magnetic resonance imaging using Fe-PyC3A injection in dynamic or delayed acquisition modes was shown to generate a higher magnetic resonance signal enhancement in aneurysms that exhibit higher degree of inflammation. The results of our pilot experiments support further evaluation of MRI using Fe-PyC3A as a noninvasive marker of aneurysmal inflammation.

Topics: Animals; Contrast Media; Inflammation; Intracranial Aneurysm; Iron; Magnetic Resonance Imaging; Oxidation-Reduction; Peroxidase; Rabbits

Glucagon-like peptide-2 (GLP-2) enhances intestinal repair and attenuates inflammation in preclinical inflammatory bowel disease (IBD) models, making GLP-2 analogues attractive candidates for IBD therapy. Glepaglutide is a long-acting GLP-2 receptor agonist in clinical development for treatment of short bowel syndrome. Here, we investigated if glepaglutide is therapeutically beneficial in rats with small intestinal inflammation.. Small intestinal inflammation was induced with indomethacin in naive Wistar rats, followed by glepaglutide administration at different disease stages. Glepaglutide was administered in co-treatment and post-treatment regimens. Small intestinal length and concentrations of inflammatory markers α-1-acid glycoprotein and myeloperoxidase were used to assess anti-inflammatory effects. Small intestinal mass was evaluated to determine intestinotrophic effects.. Glepaglutide co- and post-treatment significantly reduced severity of small intestinal inflammation, evidenced by reversed small intestinal shortening and decreased α-1-acid glycoprotein and/or myeloperoxidase concentration(s). Co- and post-treatment with glepaglutide also significantly increased small intestinal mass, indicating intestinal regenerative effects. Similar effects were observed in naive rats after glepaglutide treatment.. Glepaglutide has anti-inflammatory and intestinotrophic effects without the need for pre-treatment in a rat model of small intestinal inflammation. Thus, glepaglutide is of potential clinical interest for patients with IBD.

Topics: Animals; Anti-Inflammatory Agents; Glucagon-Like Peptide 2; Glycoproteins; Inflammation; Inflammatory Bowel Diseases; Intestinal Mucosa; Models, Theoretical; Peroxidase; Rats; Rats, Wistar

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

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

Necroptosis is a form of regulated cell death triggered by various host and pathogen-derived molecules during infection and inflammation. The essential step leading to necroptosis is phosphorylation of the mixed lineage kinase domain-like protein by receptor-interacting protein kinase 3. Caspase-8 cleaves receptor-interacting protein kinases to block necroptosis, so synthetic caspase inhibitors are required to study this process in experimental models. However, it is unclear how caspase-8 activity is regulated in a physiological setting. The active site cysteine of caspases is sensitive to oxidative inactivation, so we hypothesized that oxidants generated at sites of inflammation can inhibit caspase-8 and promote necroptosis. Here, we discovered that hypothiocyanous acid (HOSCN), an oxidant generated in vivo by heme peroxidases including myeloperoxidase and lactoperoxidase, is a potent caspase-8 inhibitor. We found HOSCN was able to promote necroptosis in mouse fibroblasts treated with tumor necrosis factor. We also demonstrate purified caspase-8 was inactivated by low concentrations of HOSCN, with the predominant product being a disulfide-linked dimer between Cys360 and Cys409 of the large and small catalytic subunits. We show oxidation still occurred in the presence of reducing agents, and reduction of the dimer was slow, consistent with HOSCN being a powerful physiological caspase inhibitor. While the initial oxidation product is a dimer, further modification also occurred in cells treated with HOSCN, leading to higher molecular weight caspase-8 species. Taken together, these findings indicate major disruption of caspase-8 function and suggest a novel mechanism for the promotion of necroptosis at sites of inflammation.

Topics: Animals; Caspase 8; Catalytic Domain; Fibroblasts; Inflammation; Lactoperoxidase; Mice; Necroptosis; Oxidants; Oxidation-Reduction; Peroxidase; Tumor Necrosis Factors

Topics: Heart Failure; Humans; Inflammation; Peroxidase; Stroke Volume; Ventricular Function, Left

BACKGROUND RLS-0071 is a dual-targeting peptide developed for the regulation of humoral and cellular inflammation via inhibition of neutrophil effectors, including myeloperoxidase and neutrophil extracellular trap formation (NETosis). The safety, pharmacokinetics, and pharmacodynamics of single and multiple doses of RLS-0071 were evaluated in a first-in-human clinical trial in healthy volunteers. Myeloperoxidase is the major peroxidase enzyme present in neutrophilic granules and contributes to cellular inflammation. Extracellular myeloperoxidase has been associated with chronic inflammation in a variety of diseases, including atherosclerosis. RLS-0071 has previously been shown to inhibit extracellular myeloperoxidase function both in vitro and in vivo in animal disease models. CASE REPORT Healthy subjects participating in the RLS-0071-101 study were screened for baseline myeloperoxidase level, leading to the identification of a 21-year-old woman with elevated baseline levels. After randomization, the subject received 9 intravenous infusions of 10 mg/kg RLS-0071. The subject tolerated the peptide infusions well with no adverse changes in vital signs, significantly abnormal clinical laboratory results, or severe adverse events. Analysis of this subject's myeloperoxidase plasma concentrations demonstrated that her myeloperoxidase levels decreased by 43% and myeloperoxidase activity levels decreased 49% after infusions of RLS-0071. The reduction in the patient's plasma myeloperoxidase levels demonstrated a partial return to baseline levels 24 hours after cessation of dosing. There were no other clinically meaningful safety observations for this subject. CONCLUSIONS This observation suggests RLS-0071 has the therapeutic potential to moderate plasma myeloperoxidase levels and activity and modulate diseases in which myeloperoxidase contributes to pathogenesis.

Topics: Adult; Animals; Female; Humans; Inflammation; Infusions, Intravenous; Peroxidase; Young Adult

Despite intensive research on rheumatoid arthritis, the pathomechanism of the disease is still not fully understood and the treatment has not been completely resolved. Previously we demonstrated that the GTPase-activating protein, ARHGAP25 has a crucial role in the regulation of basic phagocyte functions. Here we investigate the role of ARHGAP25 in the complex inflammatory process of autoantibody-induced arthritis.. Wild-type and ARHGAP25 deficient (KO) mice on a C57BL/6 background, as well as bone marrow chimeric mice, were treated i.p. with the K/BxN arthritogenic or control serum, and the severity of inflammation and pain-related behavior was measured. Histology was prepared, leukocyte infiltration, cytokine production, myeloperoxidase activity, and superoxide production were determined, and comprehensive western blot analysis was conducted.. In the absence of ARHGAP25, the severity of inflammation, joint destruction, and mechanical hyperalgesia significantly decreased, similarly to phagocyte infiltration, IL-1β, and MIP-2 levels in the tibiotarsal joint, whereas superoxide production or myeloperoxidase activity was unchanged. We observed a significantly mitigated phenotype in KO bone marrow chimeras as well. In addition, fibroblast-like synoviocytes showed comparable expression of ARHGAP25 to neutrophils. Significantly reduced ERK1/2, MAPK, and I-κB protein signals were detected in the arthritic KO mouse ankles.

Topics: Animals; Arthritis, Experimental; Inflammation; Mice; Mice, Inbred C57BL; Peroxidase; Superoxides

Cardiotoxicity is a major complication of anthracycline therapy that negatively impacts prognosis. Effective pharmacotherapies for prevention of anthracycline-induced cardiomyopathy (AICM) are currently lacking. Increased plasma levels of the neutrophil-derived enzyme myeloperoxidase (MPO) predict occurrence of AICM in humans. We hypothesized that MPO release causally contributes to AICM. Mice intravenously injected with the anthracycline doxorubicin (DOX) exhibited higher neutrophil counts and MPO levels in the circulation and cardiac tissue compared to saline (NaCl)-treated controls. Neutrophil-like HL-60 cells exhibited increased MPO release upon exposition to DOX. DOX induced extensive nitrosative stress in cardiac tissue alongside with increased carbonylation of sarcomeric proteins in wildtype but not in Mpo

Topics: Animals; Anthracyclines; Cardiomyopathies; Doxorubicin; Humans; Induced Pluripotent Stem Cells; Inflammation; Mice; Peroxidase

An assay for the measurement of myeloperoxidase (Mpx) in porcine saliva was developed and validated, and factors influencing Mpx and another two biomarkers of inflammation and immune system, the protein S100A12 and the inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4), were studied. The spectrophotometric method for Mpx measurement validated in this assay showed an adequate analytical performance including precision and accuracy. When a group of twenty healthy pigs was sampled every 4 h from 8 a.m. until 8 p.m., Mpx and S100A12 showed significant increases at 4 p.m., whereas ITIH4 concentration showed a significant decrease at 12 a.m. Increases were also seen in salivary Mpx, S100A12, and ITIH4 levels 24 h after the intramuscular administration of Escherichia coli lipopolysaccharide in five pigs; whereas in a non-septic inflammation after the subcutaneous administration of turpentine oil to five pigs changes were seen in S100A12 at 3 h and in ITIH4 at 48 h. When a stressful situation consisting of the transportation and stay of 4 h to a slaughterhouse of 24 pigs was performed, all analytes were increased after 4 h of lairage in the slaughterhouse compared with the values that were obtained the day before at the same time of the day. Mpx can be measured in the saliva of pigs with the automated assay described in this report. Mpx, S100A12, and ITIH4 salivary levels can change depending on the hour of the day in which the sample is taken, and increases can be produced due to sepsis, non-septic inflammation and stress.

Topics: Animals; Biomarkers; Immune System; Inflammation; Peroxidase; S100A12 Protein; Saliva; Swine; Swine Diseases

Increased myeloperoxidase (MPO) levels in saliva are thought to reflect ongoing periodontal inflammation. Less clear is whether and to what extent salivary MPO is increased as a result of systemic inflammation.. In the present study, we aimed to determine which demographic, anthropometric, biochemical, and dental parameters affect the level of MPO in whole mixed saliva in healthy adults with no apparent inflammatory lesions in the oral cavity. Thus, 113 individuals, aged 20-61 years (including 30.1% men and 23.9% smokers), were examined.. In the univariate analysis, higher levels of MPO in saliva were found to be associated with age, an increased body mass index (BMI), higher levels of cytokines tumour necrosis factor-α and interleukin-6, as well as poorer oral hygiene, gingival status, and lower saliva flow. Multivariate logistic regression analysis determined that the main predictors of MPO concentration in saliva were BMI and stimulated saliva flow rate.. Overall, an increase in MPO in saliva could be related to an increase in BMI, possibly as a result of subclinical chronic microinflammation, which also involves the gingiva.

Topics: Adult; Body Mass Index; Cytokines; Female; Humans; Inflammation; Interleukin-6; Male; Middle Aged; Peroxidase; Saliva; Young Adult

Osteoarthritis (OA) is the most common joint disorder, and disease-modifying OA drugs (DMOADs) represent a major need in OA management. Krüppel-like factor 4 (KLF4) is a central transcription factor upregulating regenerative and protective functions in joint tissues. This study was aimed to identify small molecules activating KLF4 expression and to determine functions and mechanisms of the hit compounds. High-throughput screening (HTS) with 11,948 clinical-stage compounds was performed using a reporter cell line detecting endogenous KLF4 activation. Eighteen compounds were identified through the HTS and confirmed in a secondary screen. After testing in SW1353 chondrosarcoma cells and human chondrocytes, mocetinostat - a class I selective histone deacetylase (HDAC) inhibitor - had the best profile of biological activities. Mocetinostat upregulated cartilage signature genes in human chondrocytes, meniscal cells, and BM-derived mesenchymal stem cells, and it downregulated hypertrophic, inflammatory, and catabolic genes in those cells and synoviocytes. I.p. administration of mocetinostat into mice reduced severity of OA-associated changes and improved pain behaviors. Global gene expression and proteomics analyses revealed that regenerative and protective effects of mocetinostat were dependent on peroxisome proliferator-activated receptor γ coactivator 1-α. These findings show therapeutic and protective activities of mocetinostat against OA, qualifying it as a candidate to be used as a DMOAD.

Topics: Animals; Bone Neoplasms; Histone Deacetylase Inhibitors; Humans; Inflammation; Kruppel-Like Factor 4; Mice; Osteoarthritis

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

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

Inflammation and oxidative stress play a significant role in the pathogenesis of acute myeloid leukemia. While myeloperoxidase carries pro-oxidant effects, HDL-cholesterol and paraoxonase have antioxidant properties. Therefore, we evaluated serum paraoxonase, myeloperoxidase, and HDL-cholesterol levels in cases with acute myeloid leukemia. Myeloperoxidase, paraoxonase, and HDL-cholesterol levels in 40 acute myeloid leukemia patients and 18 healthy individuals were determined. The relationship between these parameters and other prognostic factors, as well as their association with response to chemotherapy, was investigated. Myeloperoxidase levels were higher, while paraoxonase and HDL-cholesterol levels were lower in acute myeloid leukemia cases compared to the control group (p < 0.001, p < 0.001, p = 0.006, respectively). The myeloperoxidase level was significantly negatively correlated with paraoxonase and HDL-c levels (r =  - 0.64, p < 0.001; r =  - 0.27, p = 0.02, respectively). Paraoxonase level was positively correlated with HDL level (r = 0.34, p = 0.04). Lactate dehydrogenase level was negatively correlated with HDL-c and paraoxonase levels and positively correlated with myeloperoxidase level (r =  - 0.37, p = 0.019; r =  - 0.35, p = 0.04; r = 0.45, p = 0.03, respectively). Following complete remission induction treatment, cases with complete remission had lower myeloperoxidase levels and higher HDL-cholesterol and paraoxonase levels compared to other cases (p = 0.03, p = 0.01, p = 0.04, respectively). Myeloperoxidase levels are higher, while paraoxonase and HDL-cholesterol levels are lower in acute myeloid leukemia cases. The obtained findings emphasize the potential importance of inflammation and oxidative stress in the pathogenesis of acute myeloid leukemia. These parameters can be used as biomarkers for prognosis prediction and prediction of response to chemotherapy.

Topics: Aryldialkylphosphatase; Cholesterol, HDL; Humans; Inflammation; Oxidative Stress; Peroxidase

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

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

ANCA-associated vasculitis (AAV) is an autoimmune disease characterized by small blood vessel inflammation, commonly affecting the kidneys and respiratory tract. It is unclear why the incidence of this condition increases with age. Previous studies in a passive antibody transfer system in aged mice have implicated innate effectors. To test the hypothesis that autoimmunity to myeloperoxidase (MPO), an autoantigen responsible for AAV, increases with age, anti-MPO autoimmunity was studied in murine models of active autoimmunity and disease induced by cellular immunity.. Young (8 weeks) and aged (either 15 or 22 months) mice were immunized with whole proteins or peptides from ovalbumin, as a model foreign antigen, or MPO protein or peptides. Mice were subjected to a model of active anti-MPO glomerulonephritis. Cellular and humoral immune responses, and tissue inflammation were assessed.. While cellular immunity to ovalbumin was diminished in aged mice, cellular autoimmunity to MPO and its immunodominant CD4+ and CD8+ T cell epitopes was increased after immunization with either MPO peptides or whole MPO protein, assessed by peptide and antigen-specific production of the pro-inflammatory cytokines IFN-γ and IL-17A. MPO-ANCA titres were not increased in aged mice compared with young mice. In experimental anti-MPO glomerulonephritis, cell-mediated injury was increased, likely due to CD4+ and CD8+ T cells, innate immunity and the increased vulnerability of aged kidneys.. Heightened cellular immunity to MPO develops with ageing in mice and may contribute to the increased incidence and severity of AAV in older people.

Topics: Aged; Aging; Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; CD4-Positive T-Lymphocytes; Female; Glomerulonephritis; Humans; Immunity, Cellular; Inflammation; Male; Mice; Ovalbumin; Peroxidase

The present study investigated the individual and collective effect of organochlorinated fungicide hexachlorobenzene (HCB) and manganese (Mn), a metal, on the hepatorenal function in adult rats. Rats were divided into four groups of rats comprising of control, HCB alone (15 mg/kg), Mn alone (10 mg/kg) and co-exposure group that were orally treated for 25 consecutive days. After sacrifice, hepatorenal damage and antioxidant status markers, myeloperoxidase (MPO) activity, levels of nitric oxide, total antioxidant capacity (TAC), total oxidative stress (TOS) and lipid peroxidation (LPO) were analyzed spectrophotometrically. Levels of tumor necrosis factor alpha (TNF-α), interleukin-1 β (IL-1β) and caspase-3 activity were assessed using ELISA. Results revealed that the HCB administration significantly (

Topics: Animals; Antioxidants; Biomarkers; Caspase 3; Fungicides, Industrial; Hexachlorobenzene; Inflammation; Interleukin-1beta; Liver; Manganese; Nitric Oxide; Oxidative Stress; Peroxidase; Rats; Tumor Necrosis Factor-alpha

Fluorouracil (5-FU) is a widely used chemotherapeutic agent in various malignant tumors. However, intestinal toxicity is considered the irritant unavoidable adverse effect during the course therapy. The aim of the current study was to screen the effect of a new selective histamine receptor 1 blocker and platelet-activating factor (PAF) blocker on 5-FU induced intestinal toxicity. Five groups (6 rats each) of adult male rats (Wistar) were arranged as follows: (1) control group that was treated with carboxymethylcellulose, (2) a group that received rupatadine (higher dose) only, (3) a group that received 5-FU and (4) and (5) groups that received 5-FU plus lower or higher dose rupatadine, respectively. At end of the experiment, we determined intestinal malondialdehyde (MDA), glutathione reduced (GSH), nitric oxide (NO), tumor necrosis factor (TNF-α), interleukin 1β, 6, 10 (IL-1β, IL-6, IL-10), PAF, histamine, myeloperoxidase, cysteine-aspartic acid protease-3 (caspase-3), and nuclear factor kappa B (NF-κB) as well as the histological analysis. 5-FU injection caused marked elevation of MDA, NO, TNF-α, IL-1β, IL-6, PAF, histamine, myeloperoxidase, caspase-3, and NF-κB expressions. The intoxicated animals showed deficient GSH and IL-10 along with significant loss of villi, disorganized crypts, and inflammatory cell infiltration. Rupatadine pretreatment reduced the previously mentioned parameters, preserved a nearly normal intestinal mucosa picture with replenished GSH and elevated IL-10. In conclusion, rupatadine is a dual histamine receptor 1, and a PAF blocker could reduce 5-FU-induced oxidative damage, inflammation, apoptosis, and ulceration of the intestinal epithelium. Rupatadine may be a valuable modality to decrease 5-FU induced intestinal mucositis.

Topics: Animals; Apoptosis; Aspartic Acid Proteases; Carboxymethylcellulose Sodium; Caspase 3; Cysteine; Fluorouracil; Glutathione; Histamine; Inflammation; Interleukin-10; Interleukin-1beta; Interleukin-6; Intestinal Mucosa; Irritants; Male; Malondialdehyde; NF-kappa B; Nitric Oxide; Permeability; Peroxidase; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

Therapeutics that impair the innate immune responses of the liver during the inflammatory cytokine storm like that occurring in COVID-19 are greatly needed. Much interest is currently directed toward Janus kinase (JAK) inhibitors as potential candidates to mitigate this life-threatening complication. Accordingly, this study investigated the influence of the novel JAK inhibitor ruxolitinib (RXB) on concanavalin A (Con A)-induced hepatitis and systemic hyperinflammation in mice to simulate the context occurring in COVID-19 patients. Mice were orally treated with RXB (75 and 150 mg/kg) 2 h prior to the intravenous administration of Con A (20 mg/kg) for a period of 12 h. The results showed that RXB pretreatments were efficient in abrogating Con A-instigated hepatocellular injury (ALT, AST, LDH), necrosis (histopathology), apoptosis (cleaved caspase-3) and nuclear proliferation due to damage (PCNA). The protective mechanism of RXB were attributed to i) prevention of Con A-enhanced hepatic production and systemic release of the proinflammatory cytokines TNF-α, IFN-γ and IL-17A, which coincided with decreasing infiltration of immune cells (monocytes, neutrophils), ii) reducing Con A-induced hepatic overexpression of IL-1β and CD98 alongside NF-κB activation, and iii) lessening Con A-induced consumption of GSH and GSH peroxidase and generation of oxidative stress products (MDA, 4-HNE, NOx) in the liver. In summary, JAK inhibition by RXB led to eminent protection of the liver against Con A-deleterious manifestations primarily via curbing the inflammatory cytokine storm driven by TNF-α, IFN-γ and IL-17A.

Topics: Aldehydes; Animals; Chemical and Drug Induced Liver Injury; Concanavalin A; Cytokine Release Syndrome; Dose-Response Relationship, Drug; Inflammation; Liver; Male; Malondialdehyde; Mice; Mice, Inbred BALB C; Nitrates; Nitriles; Nitrites; Oxidative Stress; Peroxidase; Pyrazoles; Pyrimidines

The smart design of nanoparticles with varying surfaces may open a new avenue for potential biomedical applications. Consequently, several approaches have been established for controlled synthesis to develop the unique physicochemical properties of nanoparticles. However, many of the synthesis and functionalization methods are chemical-based and might be toxic to limit the full potential of nanoparticles. Here, curcumin (a plant-derived material) based synthesis of gold (Au) nanoparticles, followed by the development of a suitable exterior corona using isoniazid (INH, antibiotic), tyrosine (Tyr, amino acid), and quercetin (Qrc, antioxidant), is reported. All these nanoparticles (Cur-Au, Cur-Au

Topics: Animals; Curcumin; Gold; Inflammation; Metal Nanoparticles; Mice; Nanoparticles; Peroxidase; Peroxidases

Polymorphonuclear neutrophils (PMNs) play a key role in host defense. However, their massive accumulation at the site of inflammation can delay regenerative healing processes and can initiate pathological inflammatory processes. Thus, the efficient clearance of PMNs mediated by the induction of regulated cell death is a key process preventing the development of these pathological conditions. Myeloperoxidase (MPO), a highly abundant enzyme in PMN granules, primarily connected with PMN defense machinery, is suggested to play a role in PMN-regulated cell death. However, the contribution of MPO to the mechanisms of PMN cell death remains incompletely characterized. Herein, the process of the cell death of mouse PMNs induced by three different stimuli - phorbol 12-myristate 13-acetate (PMA), opsonized streptococcus (OST), and N-formyl-met-leu-phe (fMLP) - was investigated. MPO-deficient PMNs revealed a significantly decreased rate of cell death characterized by phosphatidylserine surface exposure and cell membrane permeabilization. An inhibitor of MPO activity, 4-aminobenzoic acid hydrazide, did not exhibit a significant effect on PMA-induced cell death compared to MPO deficiency. Interestingly, only the limited activation of markers related to apoptotic cell death was observed (e.g. caspase 8 activation, Bax expression) and they mostly did not correspond to phosphatidylserine surface exposure. Furthermore, a marker characterizing autophagy, cleavage of LC3 protein, as well as histone H3 citrullination and its surface expression was observed. Collectively, the data show the ability of MPO to modulate the life span of PMNs primarily through the potentiation of cell membrane permeabilization and phosphatidylserine surface exposure.

Topics: Animals; Inflammation; Male; Mice; Mice, Inbred C57BL; Neutrophils; Peroxidase; Regulated Cell Death

Morus mesozygia Stapf (Moraceae), otherwise referred to as African mulberry, is utilized domestically as a remedy for a variety of inflammatory disorders including rheumatism.. The anti-arthritic effect of the ethylacetate fraction of M. mesozygia leaf extract (EAFMm) was assessed on complete Freund's adjuvant (CFA)-induced arthritis in male Wistar rats.. Groups of male Wistar rats were injected with CFA (0.2 mL; 10 mg/mL) in the plantar surface of their right hind paws and treated orally with EAFMm (50 and 100 mg/kg) or its vehicle daily for 28 days. The effect on joint inflammation and mechanical nociception threshold, behavioral deficits (spontaneous motor activity in the open field test and depressive-like symptoms in the forced swim test) was evaluated. The levels and activities of the biomarkers of oxidative-nitrosative stress (reduced glutathione, superoxide dismutase, nitrite, and malondialdehyde) and inflammatory markers [TNF-α, IL-6, COX-2, NFκB and myeloperoxidase] were also analysed.. The EAFMm at the doses of 50 and 100 mg/kg produced a dose dependent reduction in joint inflammation and mechanical hyperalgesia, and as well improved behavioral deficits like spontaneous motor activity and depressive-like behavior. The EAFMm also significantly reduced oxido-nitrosative stress response in the joint and brain tissues. It also decreased TNF-α, interleukin-6 levels and myeloperoxidase enzyme activities in joints and brain tissues of rats. Furthermore, EAFMm attenuated the activity of NFκB and reduced the cyclooxygenase -2 protein expression level in joint tissues.. The ethylacetate fraction of Morus mesozygia leaf extract demonstrated anti-arthritic activity and ameliorated co-morbid depressive-like behavior via inhibition of oxidative stress and inflammation in a rat model of arthritis.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Arthritis, Experimental; Cyclooxygenase 2; Freund's Adjuvant; Inflammation; Interleukin-6; Male; Morus; NF-kappa B; Oxidative Stress; Peroxidase; Plant Extracts; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

Environmental enteric dysfunction is a subclinical intestinal disorder characterized by gut inflammation accompanied by morphological changes, such as blunted villi and crypt hyperplasia. This is a common illness in low and middle-income countries. However, environmental enteric dysfunction evidence is limited in Ethiopia. Accordingly, this study was conducted to measure fecal biomarkers of environmental enteric dysfunction and associated factors among children aged 24-59 months in rural northwest Ethiopia.. A community-based cross-sectional study was employed among 235 randomly selected children in a rural setting of the east Dembiya district. Stool samples were collected without fixative and analyzed for fecal biomarkers of environmental enteric dysfunction (Alpha-1-antitrypsin, neopterin, and myeloperoxidase) using commercial enzyme-linked immunosorbent assay kits and analyzed for intestinal parasites using wet mount and Kato-Katz techniques. Child behaviors related with exposure to enteropathogens, condition of the living environment and socio-demographic information were collected using interviewer-administered questionnaire and structure observation. We fitted multivariable linear regression model to assess the association between environmental factors and concentration of fecal biomarkers of environmental enteric dysfunction in the stool. Statistically significant associations were declared based on adjusted betas with the corresponding 95% confidence interval and p-value < 0.05.. The median concentration of fecal markers of environmental enteric dysfunction was 350 μg/ml for Alpha-1-antitrypsin, 3320.2 ng/ml for myeloperoxidase, and 1562 nmol/l for neopterin. The median concentration of Alpha-1-antitrypsin among 161 (68.5%), myeloperoxidase among 168 (71.5%), and neopterin among 188 (80%) of the stool samples were above the normal values in non-tropical settings. Moreover, 100 (42.6%) of the children had high EED disease activity score (above the median score). The elevated concentrations of fecal biomarkers of gut inflammation and the high EED disease activity score were significantly associated with open defecation practice, mouthing of soil contaminated materials, Escherichia coli (E. coli)  contamination of drinking water, E. coli contamination of foods, E. coli contamination of soil, and intestinal parasites.. Overall, Alpha-1-antitrypsin, myeloperoxidase, and neopterin levels among the children in the studied region were highly elevated in comparison to populations in high-income countries. Moreover, the EED disease activity score in significant proportion of children was high, suggesting widespread intestinal inflammation and increased intestinal permeability. Extensive E. coli contamination of the living environment (drinking water, ready-to-eat foods, and courtyard soil), hygiene and sanitation behaviors (such as open defecation and mouthing of soil contaminated materials), and a high burden of intestinal parasites were identified as factors associated with the elevated concentration of fecal biomarkers of environmental enteric dysfunction. Parental care to children to avoid mouthing of soil contaminated materials and other risky behaviors that increase exposure enteric infections, and protecting the living environment (water, food and soil) from fecal contamination are important.

Topics: Biomarkers; Child; Cross-Sectional Studies; Drinking Water; Escherichia coli; Ethiopia; Feces; Humans; Infant; Inflammation; Neopterin; Peroxidase; Soil

Topics: Artificial Intelligence; Biomarkers; Cerebral Small Vessel Diseases; DNA; Humans; Inflammation; Neutrophils; Peroxidase; Platelet Activation

CD8+CD25+Foxp3+ regulatory T cells (Tregs) play an important role in human's immune tolerance. The study was aimed to assess the influence of budesonide nasal spray on CD8+CD25+Foxp3+ Tregs and to evaluate their cellular functions in neutrophilic chronic rhinosinusitis with nasal polyps (CRSwNPs).. Fifteen patients with neutrophilic CRSwNPs were enrolled and received physiological saline or budesonide nasal spray treatment (Saline or Budesonide group) for 3 months. Nasal tissue samples were obtained from normal subjects or those patients and cultured in vitro. CD8+CD25+Foxp3+ Tregs were separated from normal or NP tissues and also cultured in vitro. Then interleukin (IL)-10 and its mRNA were evaluated in the above cell cultures. The cells were applied into NP cultures. Finally, myeloperoxidase (MPO), interferon (IFN)-γ, IL-1β, and tumor necrosis factor (TNF)-α were assessed in the tissue cultures.. CD8+CD25+Foxp3+ Tregs decreased in NP tissues. Budesonide administration did not enhance the percentage of these cells in polypoid tissues. IL-10 and its mRNA were increased in the above cell cultures from NPs. However, there were no statistical differences between the two treatments in the IL-10 expression. Additionally, levels of MPO, IFN-γ, IL-1β, and TNF-α were totally elevated in NP tissue cultures and reduced after the administration of CD8+CD25+Foxp3+ Tregs. However, there were no significant differences in concentrations of these mediators between these two groups of the CD8+CD25+Foxp3+ Tregs treatment in vitro.. The findings indicate that CD8+CD25+Foxp3+ Tregs might regulate the neutrophilic inflammation, and budesonide nasal spray therapy could not ameliorate the inflammation in neutrophilic CRSwNPs.

Topics: Adrenal Cortex Hormones; Budesonide; CD8-Positive T-Lymphocytes; Forkhead Transcription Factors; Humans; Inflammation; Interferons; Interleukin-10; Nasal Polyps; Nasal Sprays; Peroxidase; Rhinitis; RNA, Messenger; Sinusitis; T-Lymphocytes, Regulatory; Tumor Necrosis Factor-alpha

Probiotics and their metabolites appear to be a promising approach that targets both the intestinal inflammation and dysbiosis in bowel diseases. In this context, the emergence of the probiotic cell-free supernatant (CFS) has attracted more attention as a safe and targeted alternative therapy with reduced side effects. The use of nonsteroidal anti-inflammatory drugs (NSAIDs) can cause significant intestinal alterations and inflammation, leading to experimental enterocolopathy resembling Crohn disease. Therefore, we investigated the effect of CFS supplementation on the inflammation and the mucosal intestinal alterations induced by NSAIDs, indomethacin. In the current study, a murine model of intestinal inflammation was generated by the oral gavage (o.g) of indomethacin (10 mg/kg) to BALB/C mice. A group of mice treated with indomethacin was concomitantly treated orally by CFS for 5 days. The Body Health Condition index was monitored, and histological scores were evaluated. Moreover, oxidative and pro-inflammatory markers were assessed. Interestingly, we observed that CFS treatment attenuated the severity of the intestinal inflammation in our enterocolopathy model and resulted in the improvement of the clinical symptoms and the histopathological features. Notably, nitric oxide, tumor necrosis factor alpha, malondialdehyde, and myeloperoxidase levels were down-modulated by CFS supplementation. Concomitantly, an attenuation of NF-κB p65, iNOS, COX2 expression in the ileum and the colon was reported. Collectively, our data suggest that CFS treatment has a beneficial effect in experimental enterocolopathy model and could constitute a good therapeutic candidate for alleviating inflammatory responses and to maintain mucosal homeostasis during chronic and severe conditions of intestinal inflammation.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase 2; Indomethacin; Inflammation; Malondialdehyde; Mice; Mice, Inbred BALB C; NF-kappa B; Nitric Oxide; Oxidative Stress; Peroxidase; Probiotics; Tumor Necrosis Factor-alpha

Inflammatory bowel diseases (IBDs) such as ulcerative colitis (UC) and Crohn's disease (CD) are diseases of the gastrointestinal system involving genetic and environmental factors attributed to oxidative stress and inflammation. Targeting oxidative stress and inflammation by novel dietary compounds of natural origin convincingly appears to be one of the important therapeutic strategies to keep the disease in remission. As there is no permanent cure for IBD except for chronic long-term treatment or surgery, it is therefore imperative to investigate plant-based agents that are receiving attention for their therapeutic benefits to overcome the debilitating clinical conditions of IBD. Lycopodium (LYCO), a plant of tropical and subtropical origin and known by numerous names such as ground pine, club moss, or devil's claw, has been popularly used for centuries in traditional medicine including Chinese and Indian medicines. In the present study, the effect of LYCO has been investigated in an acetic acid (AA)-induced colitis model in Wistar rats. LYCO was orally administered at the dose of 50 mg/kg/day either 3 days before or 30 min after the induction of IBD and continued for 7 days by intrarectal administration of AA. The changes in body weight and macroscopic and microscopic analysis of the colon of rats of different experimental groups were observed on days 0, 2, 4, and 7. The levels of myeloperoxidase (MPO), reduced glutathione (GSH), and malondialdehyde (MDA) were measured. AA caused a significant reduction in body weight and increased macroscopic and microscopic ulcer scores along with a significant decline in antioxidant enzymes, superoxide dismutase (SOD), and catalase and antioxidant substrate, glutathione (GSH). There was a concomitant increased formation of malondialdehyde (MDA), a marker of lipid peroxidation, and raised myeloperoxidase (MPO) activity, a marker of neutrophil activation. Treatment with LYCO significantly improved IBD-induced reduction in body weight, improved histology, inhibited MDA formation, and restored antioxidants along with reduced MPO activity. AA also caused the release of proinflammatory cytokines such as interleukin-1β (IL-1β) and interleukin-23 (IL-23). Furthermore, AA also increased the levels of calprotectin, a protein released by neutrophils under inflammatory conditions of the gastrointestinal tract. LYCO treatment significantly reduced the release of calprotectin and proinflammatory cytokines. The results demonstrate

Topics: Acetic Acid; Animals; Anti-Inflammatory Agents; Antioxidants; Body Weight; Colitis; Colitis, Ulcerative; Cytokines; Glutathione; Inflammation; Inflammatory Bowel Diseases; Intestinal Mucosa; Leukocyte L1 Antigen Complex; Lycopodium; Malondialdehyde; Oxidative Stress; Peroxidase; Rats; Rats, Wistar

Although the merely cutaneous, benign form of the extremely rare disease atrophic papulosis (Köhlmeier-Degos disease) may occasionally develop into the systemic, malignant form with time, it is unclear whether it exhibits any systemic characteristics.. To determine whether benign atrophic papulosis exhibits inflammatory and thrombo-occlusive signals and to classify it according to the Chapel-Hill classification of vasculitis.. In a monocentric, controlled study, levels of cytokines (IL-1β, IL-6, IL-8, IFNγ, MCP-1, VEGF, TNFα, TGF-β1), antiphospholipid antibodies (cardiolipin IgG/A/M, cardiolipin IgG, cardiolipin IgM, β2-glycoprotein IgG/A/M, phosphatidyl choline, phosphatidyl serine, phosphatidyl inositol, phosphatidyl ethanolamine and sphingomyelin A), antibodies against proteinase-3 IgG and myeloperoxidase IgG, antinuclear antibodies and extractable nuclear antigen were assessed in blood samples of six benign atrophic papulosis patients and six age- and sex-matched healthy controls.. IL-8 was only detectable in patients' serum. VEGF was reduced and cardiolipin IgG/A/M and β2-glycoprotein antibodies were increased in the patients' group. ANA were only detected in three patients, and ENA were negative throughout. No differences were detected between the other investigated markers.. This is the first study evaluating systemic inflammatory and thrombo-occlusive vessel signalling in benign atrophic papulosis and provides evidence of a non-antineutrophil cytoplasmatic antibodies immune-complex small vessel vasculitis according to the Chapel-Hill classification. These findings corroborate its systemic character despite the apparent missing involvement of systemic organs.

Topics: Antibodies, Antinuclear; Antibodies, Antiphospholipid; Antigens, Nuclear; Atrophy; Cardiolipins; Connective Tissue Diseases; Ethanolamines; Humans; Immunoglobulin G; Immunoglobulin M; Inflammation; Interleukin-6; Interleukin-8; Malignant Atrophic Papulosis; Peptide Hydrolases; Peroxidase; Phosphatidylcholines; Phosphatidylinositols; Phosphatidylserines; Sphingomyelins; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A; Vasculitis

Nonalcoholic fatty liver disease (NAFLD) is a progressive disease that ranges from simple steatosis to cirrhosis. Obstructive sleep apnea syndrome (OSAS) and chronic intermittent hypoxia (CIH) are implicated in the pathogenesis of NAFLD. However, the overlapping consequences of CIH on liver sinusoidal endothelial function over time in NAFLD are largely unknown. We explored endothelial dysfunction in a rat model of NAFLD with a high-fat diet exposed to CIH [12 h/day, every 30 s to fractional concentration of oxygen ([Formula: see text] 8%-10%]. The livers were isolated and perfused, and the endothelial function was determined by testing the vasodilation of the liver circulation to increased concentrations of acetylcholine and von Willebrand factor (vWF) and intercellular adhesion molecule 1 (ICAM-1) expression. Phosphorylated endothelial nitric oxide synthase (p-eNOS), cGMP, and oxidative stress were assessed to determine nitric oxide bioavailability. Inflammation and fibrosis were evaluated by transaminases, myeloperoxidase activity, hydroxyproline, and histological evaluation. Hypoxia-inducible factors (HIFs) were studied as a marker of hypoxia and after a second insult with acetaminophen. CIH exposure provoked typical systemic features of OSAS and provoked a decreased response in vasodilation to acetylcholine. This was associated with increased oxidative stress and reduced p-eNOS and cGMP. The microcirculation impairment due to CIH preceded significant hepatic inflammation and fibrotic changes, despite the presence of HIF expression. In conclusion, CIH exacerbates endothelial dysfunction in NAFLD rats associated with increased oxidative stress and reduced nitric oxide bioavailability. This occurs before inflammation and fibrosis establish. Our results suggest that with CIH endothelial dysfunction should be considered an early target.

Topics: Acetaminophen; Acetylcholine; Animals; Hydroxyproline; Hypoxia; Inflammation; Intercellular Adhesion Molecule-1; Liver Cirrhosis; Nitric Oxide; Nitric Oxide Synthase Type III; Non-alcoholic Fatty Liver Disease; Oxygen; Peroxidase; Rats; Sleep Apnea, Obstructive; Transaminases; von Willebrand Factor

Topics: Antibodies, Antineutrophil Cytoplasmic; Glomerulonephritis; Granulomatosis with Polyangiitis; Humans; Inflammation; Peroxidase

Gedunin is a bioactive compound, obtained from Entandrophragma angolense (EA), which has limited therapeutic usefulness due to poor aqueous solubility and first-pass effects. Cyclodextrins are cyclic oligosaccharides that form complexes with poorly soluble compounds, thus enhancing their pharmacological activity. In this article, we evaluated the pharmacological activities of gedunin-2-hydroxypropyl-β-cyclodextrin complex (GCD) in rodents. The antinociceptive activity of GCD (50, 100, 200 mg/kg) and Gedunin (50mg/kg) was tested in acetic acid-induced writhing and formalin-induced paw licking in mice. The anti-inflammatory activity was investigated in carrageenan-induced paw oedema and air pouch inflammation models in rats. Leucocytes counts, Tumour Necrosis Factor-alpha (TNF-α) level, nitric oxide, malondialdehyde, reduced glutathione, and myeloperoxidase enzyme activities were assessed in the air pouch exudate. The GCD (200mg/kg) significantly decreased writhing response, reduced licking duration and decreased oedema compared with gedunin and control. Exudate volume and leucocyte count were significantly reduced by GCD (200 mg/kg), it decreased myeloperoxidase activity and inhibited TNF-α release. The carrageenan-induced GSH depletion, increased malondialdehyde and nitrite levels were significantly reversed by GCD (200 mg/kg) relative to gedunin and control.  The GCD complex demonstrated significant antinociceptive and anti-inflammatory activities relative to gedunin alone via mechanisms associated with inhibition of oxidative stress and inflammation in rodents.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Analgesics; Animals; Anti-Inflammatory Agents; Antioxidants; Carrageenan; Edema; Inflammation; Limonins; Malondialdehyde; Mice; Pain; Peroxidase; Plant Extracts; Rats; Rodentia; Tumor Necrosis Factor-alpha

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

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

Intestinal ischemia-reperfusion (I/R) injury is a severe disease associated with high mortality. Stimulator of interferon genes (STING) is an intracellular protein that is activated by cytosolic DNA and is implicated in I/R injury, resulting in transcription of type I interferons (IFN-α and IFN-β) and other proinflammatory molecules. Extracellular cold-inducible RNA-binding protein (eCIRP), a damage-associated molecular pattern, induces STING activation. H151 is a small molecule inhibitor of STING that has not yet been studied as a potential therapeutic. We hypothesize that H151 reduces inflammation, tissue injury, and mortality after intestinal I/R. Methods: In vitro, RAW264.7 cells were pretreated with H151 then stimulated with recombinant murine (rm) CIRP, and IFN-β levels in the culture supernatant were measured at 24 hours after stimulation. In vivo, male C57BL/6 mice were subjected to 60-minute intestinal ischemia via superior mesenteric artery occlusion. At the time of reperfusion, mice were intraperitoneally instilled with H151 (10 mg/kg BW) or 10% Tween-80 in PBS (vehicle). Four hours after reperfusion, the small intestines, lungs, and serum were collected for analysis. Mice were monitored for 24 hours after intestinal I/R to assess survival. Results: In vitro, H151 reduced rmCIRP-induced IFN-β levels in a dose-dependent manner. In vivo, intestinal levels of pIRF3 were increased after intestinal I/R and decreased after H151 treatment. There was an increase in serum levels of tissue injury markers (lactate dehydrogenase, aspartate aminotransferase) and cytokine levels (interleukin 1β, interleukin 6) after intestinal I/R, and these levels were decreased after H151 treatment. Ischemia-reperfusion-induced intestinal and lung injury and inflammation were significantly reduced after H151 treatment, as evaluated by histopathologic assessment, measurement of cell death, chemokine expression, neutrophil infiltration, and myeloperoxidase activity. Finally, H151 improved the survival rate from 41% to 81% after intestinal I/R. Conclusions: H151, a novel STING inhibitor, attenuates the inflammatory response and reduces tissue injury and mortality in a murine model of intestinal I/R. H151 shows promise as a potential therapeutic in the treatment of this disease.

Topics: Animals; Aspartate Aminotransferases; Chemokines; Cytokines; Inflammation; Interferon Type I; Interleukin-1beta; Interleukin-6; Intestines; Lactate Dehydrogenases; Male; Membrane Proteins; Mesenteric Ischemia; Mice; Mice, Inbred C57BL; Peroxidase; Reperfusion Injury; RNA-Binding Proteins

In the current world, a major challenge to diagnose environmental enteric dysfunction (EED) is the lack of validated non-invasive biomarkers. Intestine derived molecules, including intestinal fatty acid binding protein (I-FABP), trefoil factor-3 (TFF3), lactoferrin, lipocalin-2 (LCN2), and mucin-2, have been reported as indicators of intestinal inflammation and gut health. Therefore, we aimed to investigate the levels of these bio-molecules as biomarkers of EED among under-2 children in Bangladesh. A total of 140 children were recruited in a case-control design. All the biomarkers were measured by ELISA. Spearman's rank correlation was performed to see the correlation between the biomarkers and the EED score. Moreover, multivariable linear regression was performed to investigate the association of biomarkers with length-for-age z-score (LAZ). TFF3 correlates positively with myeloperoxidase (r = 0.26, p < 0.05) and EED score (r = 0.17, p < 0.05). Likewise, LCN2 correlates positively with myeloperoxidase (r = 0.37, p < 0.05), neopterin (r = 0.33, p < 0.05) and EED score (r = 0.31, p < 0.05). Moreover, multivariable linear regression revealed a negative association of I-FABP with LAZ of the study participants. Our results imply that TFF3 and LCN2 might be promising biomarkers to diagnose intestinal inflammation and EED, while I-FABP is negatively associated with linear growth of Bangladeshi children.

Topics: Bangladesh; Biomarkers; Child Development; Fatty Acid-Binding Proteins; Humans; Infant; Inflammation; Intestinal Diseases; Lipocalin-2; Peroxidase; Trefoil Factor-3

Acute lung injury (ALI) is commonly accompanied by a severe inflammatory reaction process, and effectively managing inflammatory reactions is an important therapeutic approach for alleviating ALI. Macrophages play an important role in the inflammatory response, and this role is proinflammatory in the early stages of inflammation and anti-inflammatory in the late stages. Oxypeucedanin is a natural product with a wide range of pharmacological functions. This study aimed to determine the effect of oxypeucedanin on lipopolysaccharide (LPS)-induced ALI.. In conclusion, this study demonstrated that the anti-inflammatory mechanism of oxypeucedanin is associated with the inhibition of the activation of PI3K/AKT/NF-κB and MAPK signaling pathways and the maintenance of the integrity of the lung air-blood barrier.

Topics: Acute Lung Injury; Anti-Inflammatory Agents; Blood-Air Barrier; Furocoumarins; Humans; Inflammation; Lipopolysaccharides; Lung; NF-kappa B; Peroxidase; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt

Metabolic syndrome is a cluster of risk factors for cardiovascular disease afflicting more than 1 billion people worldwide and is increasingly being identified in younger age groups and in socioeconomically disadvantaged settings in the global south. Enteropathogen exposure and environmental enteropathy in infancy may contribute to metabolic syndrome by disrupting the metabolic profile in a way that is detectable in cardiometabolic markers later in childhood. A total of 217 subjects previously enrolled in a birth cohort in Amazonian Peru were monitored annually from ages 2 to 5 years. A total of 197 blood samples collected in later childhood were analyzed for 37 cardiometabolic biomarkers, including adipokines, apolipoproteins, cytokines, which were matched to extant early-life markers of enteropathy ascertained between birth and 2 years. Multivariate and multivariable regression models were fitted to test for associations, adjusting for confounders. Fecal and urinary markers of intestinal permeability and inflammation (myeloperoxidase, lactulose, and mannitol) measured in infancy were associated with later serum concentrations of soluble CD40-ligand, a proinflammatory cytokine correlated with adverse metabolic outcomes. Fecal myeloperoxidase was also associated with later levels of omentin-1. Enteric protozoa exposure showed stronger associations with later cardiometabolic markers than viruses, bacteria, and overall diarrheal episodes. Early-life enteropathy markers were associated with altered adipokine, apolipoprotein, and cytokine profiles later in childhood consistent with an adverse cardiometabolic disease risk profile in this cohort. Markers of intestinal permeability and inflammation measured in urine (lactulose, mannitol) and stool (myeloperoxidase, protozoal infections) during infancy may predict metabolic syndrome in adulthood.

Topics: Adipokines; Apolipoproteins; Biomarkers; Birth Cohort; Cardiovascular Diseases; Child, Preschool; Cytokines; Humans; Inflammation; Intestinal Diseases; Lactulose; Ligands; Mannitol; Metabolic Syndrome; Peroxidase; Peru

The mortality of patients on chronic haemodialysis is 10-30 times greater than that of the general population and over 60% of these individuals die within the first 5 years of beginning haemodialysis. Although causes for excessive mortality in haemodialysis patients are not clearly defined, it seems that nutrition, inflammation and oxidative stress play key roles in this regard. Until now, no cohort study has focused on the association between nutritional, inflammatory or oxidative status and risk of complications and adverse outcomes in Iranian haemodialysis patients. Therefore, we sought to fill this gap and designed the Nutritional, Inflammatory, and Oxidative Status in Hemodialysis (NIOS-HD) prospective cohort study to determine the association of dietary factors, malnutrition, anthropometric indices, body composition, inflammation and oxidative stress with quality of life, dialysis access infections, hospitalisation, potential years of life lost and mortality in adults on maintenance haemodialysis in Isfahan, Iran.. The sample size of this cohort was estimated to be 300 participants. At baseline, demographic, medical and dialysis-related data of eligible patients will be recorded. In addition, participants will undergo anthropometric measurements, malnutrition assessment and body composition analysis. Also, their dietary intake and quality of life will be evaluated through interviewer-administered questionnaires. Moreover, their fasting blood samples will be collected and stored for biochemical assays including transthyretin, albumin, serum amyloid A, pentraxin-3, trimethylamine N-oxide, myeloperoxidase, paraoxonase-1 and superoxide dismutase. After baseline evaluation, patients will be followed up to 3 years to update exposure information (except biochemical assays) and measure adverse outcomes. Finally, collected data will be analysed using descriptive and inferential statistics.. The NIOS-HD is in agreement with the Declaration of Helsinki and has been approved by the Ethics Committee of Isfahan University of Medical Sciences (reference number: IR.MUI.. REC.1399.605). Findings of this study will be published in academic journals.

Topics: Adult; Aryldialkylphosphatase; Humans; Inflammation; Iran; Kidney Failure, Chronic; Malnutrition; Nutritional Status; Oxidative Stress; Peroxidase; Prealbumin; Prospective Studies; Quality of Life; Renal Dialysis; Serum Amyloid A Protein; Superoxide Dismutase

Recently, some preclinical and clinical studies have demonstrated the ability of brown seaweeds in reducing the risk factors for metabolic syndrome. Here, we analyzed the beneficial effect of a nutraceutical formulation containing a phytocomplex extracted from seaweeds and chromium picolinate in animal models of liver steatosis of differing severities (rats with non-alcoholic fatty liver disease (NAFLD) and its complication, non-alcoholic steatohepatitis (NASH)). This treatment led to a significant drop in hepatic fat deposition in both models (p < 0.01 vs. untreated animals), accompanied by a reduction in plasma inflammatory cytokines, such as interleukin 6, tumor necrosis factor α, and C reactive protein, and myeloperoxidase expression in liver tissue. Furthermore, a modulation of the molecular pathways involved in lipid metabolism and storage was demonstrated, since we observed the significant reduction of the mRNA levels of fatty acid synthase, diacylglycerol acyltransferases, the sterol-binding protein SREBP-1, and the lipid transporter perilipin-2, in both treated NAFLD and NASH rats in comparison to untreated ones. In conclusion, this nutraceutical product was effective in reducing liver steatosis and showed further beneficial effects on hepatic inflammation and glycemic control, which were particularly evident in rats characterized by a more severe condition, thus representing a therapeutic option for the treatment of NAFLD and NASH patients.

Topics: Animals; C-Reactive Protein; Dietary Supplements; Diglycerides; Fatty Acid Synthases; Inflammation; Interleukin-6; Lipid Metabolism; Liver; Mice; Mice, Inbred C57BL; Models, Theoretical; Non-alcoholic Fatty Liver Disease; Perilipin-2; Peroxidase; Phaeophyceae; Rats; RNA, Messenger; Seaweed; Sterol Regulatory Element Binding Protein 1; Sterols; Tumor Necrosis Factor-alpha

Invasion of the intestinal mucosa by T. gondii elicits a local immune response of variable intensity. These reactions can be lethal in C57BL/6 mice. The tissue damage caused by inflammation and the functional effects depend on the host immunity, strain, and developmental form of the parasite. We investigated the effects of acute oral infection with T. gondii on histoarchitecture, enteric nervous system (ENS), and inflammatory markers in the jejunum and ileum of mice.. Female C57BL/6 mice were divided into a control group and a group orally infected with 1000 sporulated T. gondii oocysts (ME-49 strain). After 5 days, jejunum and ileum were collected and processed for analyzes (e.g., histological and histopathological examinations, ENS, cytokine dosage, myeloperoxidase, nitric oxide activity).. In infected mice, we observed a significant increase in serotonin-immunoreactive cells (5-HT IR) in the intestinal mucosa, as well as cellular infiltrates in the lamina propria, periganglionitis, and ganglionitis in the myenteric plexus. We also noted decreased neuron density in the jejunum, increased population of enteric glial cells in the ileum, histomorphometric changes in the intestinal wall, villi, and epithelial cells, remodeling of collagen fibers, and increased myeloperoxidase activity, cytokines, and nitric oxide in the intestine.. Acute infection of female mice with T. gondii oocysts resulted in changes in ENS and a marked increase in 5-HT. These changes are consistent with its modulatory role in the development of moderate acute inflammation. The use of this experimental model may lend itself to studies aimed at understanding the pathophysiological mechanisms of intestinal inflammation in humans involving ENS.

Topics: Animals; Collagen; Cytokines; Female; Humans; Inflammation; Intestines; Mice; Mice, Inbred C57BL; Nitric Oxide; Oocysts; Peroxidase; Rats; Rats, Wistar; Serotonin; Toxoplasma

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

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

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

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

Globally, Mechanical ventilation is the most commonly used short-term life support technology. Ventilator-induced lung injury (VILI) is an inflammatory injury caused by mechanical ventilation. MicroRNAs (miRNAs) are considered as new gene regulators that play an important role in lung injury and inflammation. However, the role and mechanism of action of miR-9a-5p in VILI remain unclear.. Herein, a rat model of VILI was established. To determine the expression levels of miR-9a-5p and CXCR4 mRNA, real-time quantitative polymerase chain reactions (qRT-PCR) were conducted. As well as western blot (WB) and immunofluorescence analyses, we determined the expression of CXCR4, SDF-1 and MAPK signaling pathway-related kinases. Hematoxylin and eosin (H&E) staining and the wet-dry ratio of the lung tissue were used to evaluate organ injury. An enzyme-linked immunosorbent assay (Elisa) and myeloperoxidase (MPO) activity measurements were performed to evaluate the inflammatory response. In addition, double luciferase reporter assays were used to verify the association between miR-9a-5p and CXCR4.. The expression of miR-9a-5p was low, whereas that of CXCR4 was high in the lung tissues of VILI rats. The overexpression of miR-9a-5p alleviated the degree of pathological injury in the lung tissues of rats with VILI, downregulating inflammatory cytokine expression and MPO activity. In the VILI rat model, miR-9a-5p targeted the negative regulation of CXCR4, and CXCR4 overexpression to reverse the lung-protective and anti-inflammatory effects of miR-9a-5p overexpression in VILI rats. miR-9a-5p also inhibited the phosphorylation of extracellular signal receptor-activated kinase (ERK), a protein related to the MAPK signaling pathway, by downregulating CXCR4 expression.. miR-9a-5p can hinder the activation of the MAPK/ERK signaling pathway and reduce inflammatory reactions and lung injury in VILI rats through the targeted regulation of CXCR4 expression. Therefore, miR-9a-5p could serve as an intervention target to supply a new strategy for the care of VILI.

Topics: Animals; Anti-Inflammatory Agents; Cytokines; Down-Regulation; Eosine Yellowish-(YS); Hematoxylin; Inflammation; MicroRNAs; Peroxidase; Rats; Receptors, CXCR4; RNA, Messenger; Signal Transduction; Ventilator-Induced Lung Injury

Torasemide is a loop diuretic with a molecule that is chemically similar to the sulphonamides described as eosinophilic granulomatosis with polyangiitis (EGPA) triggering drugs. The presented case is probably the first description of torasemide-induced vascular purpura in the course of EGPA. Any diagnosis of vasculitis should be followed by an identification of drugs that may aggravate the disease. A 74-year-old patient was admitted to the Department of Dermatology with purpura-like skin lesions on the upper, and lower extremities, including the buttocks. The lesions had appeared around the ankles 7 days before admission to the hospital and then started to progress upwards. The patient complained on lower limb paresthesia and pain. Other comorbidities included bronchial asthma, chronic sinusitis, ischemic heart disease, mild aortic stenosis, arterial hypertension, and degenerative thoracic spine disease. The woman had previously undergone nasal polypectomy twice. She was on a constant regimen of oral rosuvastatin 5 mg per day, spironolactone 50 mg per day, metoprolol 150 mg per day, inhaled formoterol 12 μg per day, and ipratropium bromide 20 μg per day. Ten days prior to admission, she was commenced on torasemide at a dose of 50 mg per day prescribed by a general practitioner due to high blood pressure. Doppler ultrasound upon admission to the hospital excluded deep venal thrombosis. The laboratory tests revealed leukocytosis (17.1 thousand per mm3) with eosinophilia (38.6%), elevated plasma level of C-reactive protein (119 mg per L) and D-dimers (2657 ng per mm3). Indirect immunofluorescent test identified a low titer (1:80) of antinuclear antibodies, but elevated (1:160) antineutrophil cytoplasmic antibodies (ANCA) in the patient's serum. Immunoblot found them to be aimed against myeloperoxidase (pANCA). A chest X-ray showed increased vascular lung markings, while high-resolution computed tomography revealed peribronchial glass-ground opacities. Microscopic evaluation of skin biopsy taken from the lower limbs showed perivascular infiltrates consisting of eosinophils and neutrophils, fragments of neutrophil nuclei, and fibrinous necrosis of small vessels. Electromyography performed in the lower limbs because of their weakness highlighted a loss of response from both sural nerves, as well as slowed conduction velocity of the right tibial nerve and in both common peroneal nerves. Both clinical characteristics of skin lesions and histopathology suggested a

Topics: Adolescent; Aged; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Antinuclear; Antihypertensive Agents; Asthma; C-Reactive Protein; Churg-Strauss Syndrome; Eosinophilia; Female; Formoterol Fumarate; Granulomatosis with Polyangiitis; Humans; IgA Vasculitis; Inflammation; Ipratropium; Leukotriene Antagonists; Metoprolol; Mycophenolic Acid; Peroxidase; Prednisone; Purpura; Receptors, Fc; Rosuvastatin Calcium; Sodium Potassium Chloride Symporter Inhibitors; Spironolactone; Sulfanilamides; Torsemide

Albeit multiple studies demonstrated that

Topics: Adventitia; Animals; Hyperplasia; Inflammation; Neovascularization, Pathologic; Peroxidase; Rats; Vasa Vasorum

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

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

Acute kidney injury (AKI) is a frequent complication of transcatheter aortic valve implantation (TAVI) and has been linked to preexisting comorbidities, peri-procedural hypotension, and systemic inflammation. The extent of systemic inflammation after TAVI is not fully understood. Our aim was to characterize the inflammatory response after TAVI and evaluate its contribution to the mechanism of post-procedural AKI.. One hundred and five consecutive patients undergoing TAVI at our institution were included. We analyzed the peri-procedural inflammatory and oxidative stress responses by measuring a range of biomarkers (including C-reactive protein [hsCRP], cytokine levels, and myeloperoxidase [MPO]), before TAVI and 6, 24, and 48 hours post-procedure. We correlated this with changes in renal function and patient and procedural characteristics.. We observed a significant increase in plasma levels of pro-inflammatory cytokines (hsCRP, interleukin 6, tumor necrosis factor alpha receptors) and markers of oxidative stress (MPO) after TAVI. The inflammatory response was significantly greater after transapical (TA) TAVI compared to transfemoral (TF). This was associated with a higher incidence of AKI in the TA cohort compared to TF (44% vs. 8%, respectively, p < 0.0001). The incidence of AKI was significantly lower when N-acetylcysteine (NAC) was given peri-procedurally (12% vs. 38%, p < 0.005). In multivariate analysis, only the TA approach and no use of NAC before the procedure were independent predictors of AKI.. TAVI creates a significant post-procedural inflammatory response, more so with the TA approach. Mechanisms of AKI after TAVI are complex. Inflammatory response, hypoperfusion, and oxidative stress may all play a part and are potential therapeutic targets to reduce/prevent AKI.

Topics: Acetylcysteine; Acute Kidney Injury; Aortic Valve; Aortic Valve Stenosis; Biomarkers; C-Reactive Protein; Humans; Inflammation; Interleukin-6; Oxidative Stress; Peroxidase; Transcatheter Aortic Valve Replacement; Treatment Outcome; Tumor Necrosis Factor-alpha

Colorectal cancer (CRC) is one of the most common causes of cancer death in the world. Although genes are considered the most importantcauses that contribute to CRC, the intestinal microorganisms are an important player. Recently, various studies ensured the role of microbial infection and the ensuing inflammation in colon cancer initiation and progression. This present study tries to introduce a cheap nano-peroxidase (an antioxidant enzyme) produced from natural sources as efficient and safe antibacterial and anti-inflammatory agent against bacteria and inflammation related to colorectal cancer.. Silica nanoparticles were prepared from rice straw. Peroxidase extracted from the dry onion scales was then immobilized on the prepared nanosilica (nano-peroxidase). The antibacterial activity of the prepared nano-peroxidase was tested against the four horsemen bacteria in CRC, Fusobacterium nucleatum, Escherichia coli, Bacteroides fragilis, and Salmonella enterica. The in vitro anti-inflammatory activity of the prepared nano-peroxidase also tests through performing inhibition of albumin denaturation test.. The prepared nano-peroxidase showed high antibacterial activity against the tested bacteria in presence of very low concentration of H2O2. Immobilization increased the peroxidase stability and protected it from hydrolysis enzymes produced by the bacteria. The prepared nano-peroxidase interestingly showed significant higher anti-inflammatory activity than that of the standard (Aspirin).. Nano-peroxidase can be considered a promising safe anti-inflammatory and antibacterial agent against bacteria and inflammation related to colorectal cancer.

Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents; Bacteria; Colorectal Neoplasms; Humans; Hydrogen Peroxide; Inflammation; Peroxidase

Andrographis paniculata has been shown to be associated with male reproductive dysfunction, although the available data are scarce and inconsistent, and the associated mechanisms are elusive. Hormonal mechanism via hypothalamic-pituitary-testicular axis, and non-hormonal mechanism primarily through oxidative stress, are involved in the modulation of male reproductive function. We therefore, hypothesized that suppression of hypothalamic-pituitary-testicular axis and/or oxidative stress is involved in Andrographis paniculata-induced reproductive dysfunction. Male Wistar rats received either vehicle or Andrographis paniculata in varying doses of 250, 500, and 1000 mg/kg body weight daily for 8 weeks. Treatment with Andrographis paniculata led to reduced sperm count, motility, and viability. Andrographis paniculata treatment also resulted in distorted spermatogenesis and reduced serum testosterone. On the other hand, Andrographis paniculata led to reduction in the testicular content of malondialdehyde, nitric oxide, TNF-α, and IL-6, and testicular activities of xanthine oxidase and myeloperoxidase, but raised testicular levels of reduced glutathione content and enhanced activity of super oxide dismutase. However, body weight gain, and absolute and relative reproductive organ weights were similar across all the groups. These findings demonstrate that Andrographis paniculata induces reproductive toxicity via suppression of testosterone and not induction of oxidative stress. Therefore, Andrographis paniculata could be a potential and safe male contraceptive.

Topics: Androgens; Andrographis paniculata; Animals; Biomarkers; Contraceptive Agents; Diterpenes; Epididymis; Inflammation; Interleukin-6; Leydig Cells; Male; Malondialdehyde; Nitric Oxide; Organ Size; Oxidative Stress; Peroxidase; Rats, Wistar; Reproduction; Sperm Motility; Spermatogenesis; Spermatozoa; Steroids; Superoxide Dismutase; Testis; Tumor Necrosis Factor-alpha; Weight Gain

Ischemia reperfusion (I/R)‑induced intestinal injury is a pathophysiological process leading to oxidative stress and inflammatory responses, and revealing its underlying mechanisms is essential for developing therapeutic strategies. Cyclooxygenase (COX) has been reported to be involved in I/R injury. Parecoxib sodium, a selective inhibitor for COX‑2, exerts protective effects, such as reducing I/R‑induced injuries in the heart, kidney and brain. However, the potential role of parecoxib sodium in protecting the small intestine against I/R‑induced injury has rarely been investigated. Therefore, the aim of the present study was to elucidate the effects and potential mechanisms of parecoxib sodium in I/R‑induced intestinal injury. In total, 60 Sprague‑Dawley rats were randomly divided into four groups: Control (sham operation) group, intestinal I/R group, 10 mg/kg parecoxib sodium‑pre‑treated I/R (I/R + Pare/10) group and the 20 mg/kg parecoxib sodium‑pre‑treated I/R (I/R + Pare/20) group. A regular I/R model was established to induce the intestinal injury in rats. Parecoxib sodium at 10 or 20 mg/kg was intraperitoneally administered into rats in both I/R + Pare groups once daily for 5 consecutive days prior to ischemia. Blood samples and small intestinal tissues were collected at 2 h after reperfusion. Changes in the levels of malondialdehyde, nitric oxide, interleukin (IL)‑1β, IL‑8, intercellular cell adhesion molecule‑1 and IL‑10, as well as the total antioxidant capacity were determined using ELISA, as were the activities of superoxidase dismutase and myeloperoxidase. Furthermore, the protein expression levels of total caspase‑3, cleaved caspase‑3, Bcl‑2 and Bax were examined via western blot analysis. In addition, the daily survival rate post‑reperfusion was examined for 7 days. It was revealed that parecoxib sodium increased the levels of antioxidants and suppressed the intestinal oxidative injury induced by I/R. Moreover, parecoxib sodium downregulated the expression levels of the proinflammatory factors, but upregulated the expression levels of anti‑inflammatory factors. The results also demonstrated that parecoxib sodium attenuated I/R‑induced apoptosis and increased the survival rate of rats. Thus, administration of parecoxib sodium prior to intestinal I/R attenuated intestinal injury and increased the rat survival rate by inhibiting I/R‑induced inflammation, oxidative stress and apoptosis.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Cyclooxygenase 2 Inhibitors; Inflammation; Isoxazoles; Male; Malondialdehyde; Oxidative Stress; Peroxidase; Protective Agents; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Signal Transduction

Metal-oxide nanoparticles (MO-NPs), such as the highly bioreactive copper-based nanoparticles (CuO-NPs), are widely used in manufacturing of hundreds of commercial products. Epidemiological studies correlated levels of nanoparticles in ambient air with a significant increase in lung disease. CuO-NPs, specifically, were among the most potent in a set of metal-oxides and carbons studied in parallel regarding DNA damage and cytotoxicity. Despite advances in nanotoxicology research and the characterization of their toxicity, the exact mechanism(s) of toxicity are yet to be defined. We identified chlorination toxicity as a damaging consequence of inflammation and myeloperoxidase (MPO) activation, resulting in macromolecular damage and cell damage/death. We hypothesized that the inhalation of CuO-NPs elicits an inflammatory response resulting in chlorination damage in cells and lung tissues. We further tested the protective action of LGM2605, a synthetic small molecule with known scavenging properties for reactive oxygen species (ROS), but most importantly, for active chlorine species (ACS) and an inhibitor of MPO. CuO-NPs (15 µg/bolus) were instilled intranasally in mice and the kinetics of the inflammatory response in lungs was evaluated 1, 3, and 7 days later. Evaluation of the protective action of LGM2605 was performed at 24 h post-challenge, which was selected as the peak acute inflammatory response to CuO-NP. LGM2605 was given daily via gavage to mice starting 2 days prior to the time of the insult (100 mg/kg). CuO-NPs induced a significant inflammatory influx, inflammasome-relevant cytokine release, and chlorination damage in mouse lungs, which was mitigated by the action of LGM2605. Preventive action of LGM2605 ameliorated the adverse effects of CuO-NP in lung.

Topics: Animals; Bronchoalveolar Lavage Fluid; Butylene Glycols; Chlorine; Copper; DNA Damage; Female; Glucosides; Inflammasomes; Inflammation; Lung; Metal Nanoparticles; Mice; Mice, Inbred C57BL; Oxidative Stress; Oxides; Peroxidase; Reactive Oxygen Species

Neutrophil extracellular traps (NETs) are web-like structures consisting of DNA, histones and granule proteins, released from neutrophils in thrombus formation, inflammation, and cancer. We asked if plasma levels of the NET markers myeloperoxidase (MPO)-DNA and citrullinated histone H3 (H3Cit)-DNA, are elevated in liver cirrhosis and hepatocellular carcinoma (HCC) and if the levels correlate with clinical parameters. MPO-DNA, H3Cit-DNA, and thrombin-antithrombin (TAT) complex, as a marker of coagulation activity, were measured using ELISA in plasma from 82 patients with HCC, 95 patients with cirrhosis and 50 healthy controls. Correlations were made to clinical parameters and laboratory data and patients were followed for a median of 22.5 months regarding thrombosis development. H3Cit-DNA was significantly (p < 0.01) elevated in plasma from cirrhosis (66.4 ng/mL) and HCC (63.8 ng/mL) patients compared to healthy controls (31.8 ng/mL). TAT levels showed similar pattern (3.1, 3.7, and 0.0 µg/mL respectively, p < 0.01). MPO-DNA was significantly (p < 0.01) elevated in cirrhosis patients (0.53 O.D.) as compared to controls (0.33 O.D.). Levels of MPO-DNA and H3Cit-DNA correlated positively with Child-Pugh and MELD score. TAT was increased in all Child-Pugh and MELD groups. In multivariable logistic regression, Child B and C liver cirrhosis were independent predictors of elevated H3Cit-DNA in plasma. Levels of MPO-DNA and H3Cit-DNA were similar in patients with or without history of thrombosis, or thrombus formation during follow-up. In conclusion, plasma markers of NET formation are elevated in liver cirrhosis and correlate to the degree of liver dysfunction in patients with liver cirrhosis and/or HCC. The presence of HCC did not further increase the plasma levels of NET markers as compared to patients with cirrhosis only.

Topics: Aged; Antithrombin III; Biomarkers; Carcinoma, Hepatocellular; Case-Control Studies; Citrullination; DNA; Extracellular Traps; Female; Histones; Humans; Inflammation; Liver; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Neutrophils; Peptide Hydrolases; Peroxidase; Thrombosis

Tomatidine, which is isolated from green tomato, can ameliorate inflammation and oxidative stress in cells and animal experiments and has been shown to improve airway inflammation in a murine model of asthma. Here, we investigated whether tomatidine can ameliorate acute lung injury in mice. Mice were given tomatidine by intraperitoneal injection for 7 consecutive days, and then, lung injury was induced via intratracheal instillation of lipopolysaccharide (LPS). Tomatidine reduced inflammatory cytokine expressions in bronchoalveolar lavage fluid (BALF), attenuated neutrophil infiltration in the BALF and lung tissue, increased superoxide dismutase activity and glutathione levels, and alleviated myeloperoxidase expression in the lung tissue of mice with lung injury. Tomatidine also decreased inflammatory cytokine and chemokine gene expression in inflammatory lungs and attenuated the phosphorylation of mitogen-activated protein kinase and nuclear factor kappa B. Furthermore, tomatidine enhanced the production of heme oxygenase-1, decreased the secretion of inflammatory cytokines and chemokines in LPS-stimulated lung epithelial cells, and attenuated THP-1 monocyte adhesion. Our findings suggest that tomatidine attenuates oxidative stress and inflammation, improving acute lung injury in mice.

Topics: A549 Cells; Acute Lung Injury; Animals; Bronchoalveolar Lavage Fluid; Cell Adhesion; Chemokines; Cytokines; Glutathione; Humans; Inflammation; Lipopolysaccharides; Male; MAP Kinase Signaling System; Mice; Mice, Inbred BALB C; Neutrophils; NF-kappa B p50 Subunit; Oxidative Stress; Peroxidase; Pneumonia; Superoxide Dismutase; Tomatine

Acute-on-Chronic Liver Failure (ACLF) is associated with innate immune dysfunction and high short-term mortality. Neutrophils have been identified to influence prognosis in ACLF. Neutrophil biology is under-evaluated in ACLF. Therefore, we investigated neutrophil-specific genes and their association with ACLF outcomes. This is an observational study. Enriched granulocytes, containing neutrophils, isolated from study participants in three groups- ACLF(n = 10), chronic liver disease (CLD, n = 4) and healthy controls (HC, n = 4), were analysed by microarray. Differentially expressed genes were identified and validated by qRT-PCR in an independent cohort of ACLF, CLD and HC (n = 30, 15 and 15 respectively). The association of confirmed overexpressed genes with ACLF 28-day non-survivors was investigated. The protein expression of selected neutrophil genes was confirmed using flow cytometry and IHC. Differential gene expression analysis showed 1140 downregulated and 928 upregulated genes for ACLF versus CLD and 2086 downregulated and 1091 upregulated genes for ACLF versus HC. Significant upregulation of neutrophilic inflammatory signatures were found in ACLF compared to CLD and HC. Neutrophil enriched genes ELANE, MPO and CD177 were highly upregulated in ACLF and their expression was higher in ACLF 28-day non-survivors. Elevated expression of CD177 protein on neutrophil surface in ACLF was confirmed by flow cytometry. IHC analysis in archival post mortem liver biopsies showed the presence of CD177

Topics: Acute-On-Chronic Liver Failure; Adult; Case-Control Studies; Female; Flow Cytometry; GPI-Linked Proteins; Granulocytes; Humans; Inflammation; Isoantigens; Leukocyte Elastase; Liver; Male; Oligonucleotide Array Sequence Analysis; Peroxidase; Receptors, Cell Surface

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

We aimed to study the beneficial property of chrysin (CHR) by targeting its antioxidant and anti-inflammatory effects on nephrotoxicity induced by sodium arsenite (SA).. We have used the 35 male Wistar rats in five equal groups (n = 7). Normal saline in (5 ml/kg; p.o.; 21 days) was given to the control group. Sodium arsenite (10 mg/kg; p.o.; 14 days) was given to the SA group. CHR (25, 50 and 100 mg/kg; p.o.; 21 days) and SA (10 mg/kg; p.o.; 14 days from the 7th day of the experiment) was given to the SA + CHR 25, 50 and 100 groups. On the 22nd day of the experiment, the animals' bloods and kidneys were taken, and then we have performed functional, biochemical and histological assessment.. CHR pre- and alongside administration (more potently at dose of 100 mg/kg) with SA reduced the SA-induced alterations in serum creatinine and blood urine nitrogen levels. Increased levels of protein carbonyl, myeloperoxidase, malondialdehyde and nitric oxide in kidney tissue were decreased by CHR treatment. CHR administration increased the levels of glutathione and activities of glutathione peroxidase, catalase and superoxide dismutase in renal tissue. Moreover, treatment with CHR reduced the levels of inflammatory mediators including interleukin 1 beta and tumor necrosis factor alpha in renal tissue. The renal histological lesions induced SA were mitigated by CHR treatment in dose dependent manner.. The results of present study suggested that administration of CHR before and alongside with SA attenuated the renal toxic effects of SA via antioxidative stress and anti-inflammatory effects.

Topics: Animals; Antioxidants; Arsenites; Catalase; Flavonoids; Glutathione; Glutathione Peroxidase; Inflammation; Interleukin-1beta; Kidney; Male; Malondialdehyde; Nitric Oxide; Oxidative Stress; Peroxidase; Protein Carbonylation; Rats, Wistar; Sodium Compounds; Tumor Necrosis Factor-alpha

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

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

Topics: Animals; Cattle; Cell Death; Cytokines; Female; HEK293 Cells; Humans; Inflammation; Inflammation Mediators; Leukocidins; Mammary Glands, Animal; Mastitis; Mice; Mice, Inbred BALB C; Neutrophils; Peptide Library; Peroxidase; Receptors, Chemokine; Single-Chain Antibodies; Staphylococcal Infections; Staphylococcus aureus

The early diagnosis and monitoring of Crohn's disease (CD) and orofacial granulomatosis (OFG) might be facilitated by assaying potential disease biomarkers in saliva. Markers of oxidative stress and inflammation were assayed in salivas from patients with CD, OFG and concurrent OFG and CD (OFG + CD).. Unstimulated whole mouth saliva was collected from 93 subjects, and immunoglobulin A (IgA), lactoferrin (LF) and myeloperoxidase (MPO) were determined by ELISA. Markers of oxidative stress and antioxidant status were assayed spectrophotometrically.. Immunoglobulin A was significantly (p < .03) higher in experimental groups vs the control group. LF was significantly (p < .01) higher in OFG + CD compared to CTRL and CD. Ferric reducing antioxidant power was lower (p ≤ .009) in all experimental groups, and advanced glycation end products were higher (p ≤ .01) in CD and OFG + CD patients.. Oxidative stress is increased in saliva in CD and OFG. Although MPO, a product of inflammatory cells, was not significantly increased, the other innate immune markers, IgA and LF, which are also secreted by salivary glands, were increased. This study suggests that saliva might be utilized in monitoring CD and OFG but further longitudinal studies focused on analysing a panel of salivary markers are needed.

Topics: Granulomatosis, Orofacial; Humans; Inflammation; Oxidative Stress; Peroxidase; Saliva

COPD is an inflammatory lung disease, which is often exacerbated with microbial infections resulting in worsening of respiratory symptoms. Gallic acid (GA), a naturally occurring phenolic compound is known to possess anti-oxidant/anti-inflammatory activity. We have recently reported that GA protects against the elastase (ET) induced lung inflammation and emphysema and the present work was designed to investigate the beneficial effects of Gallic acid against ET + Lipopolysachharide (LPS) induced COPD exacerbation like condition in mice model. Our data showed that i.t. administration of LPS at 21 days after ET instillation resulted in significant infiltration of inflammatory cells particularly neutrophils (p < 0.0001) into the lungs along with elevated levels of pro-inflammatory cytokines like TNF-α, IL-1β and IL-6 (p < 0.0001). Interestingly, daily administration of GA (200 mg/Kg b. wt.) starting 7 days before ET instillation, significantly blunted the ET + LPS induced inflammation as indicated by reduced number of inflammatory cells particularly neutrophils (p < 0.0001) in BALF along with suppression of myeloperoxidase activity (p = 0.0009) and production of pro-inflammatory cytokines (p < 0.0001). Further, GA also restored the redox imbalance in the lungs towards normal. Additionally, phosphorylation of p65-NF-κB was found to be reduced (p = 0.015), which was associated with downregulation in the gene expression of IL-1β (p = 0.022) and TNF-α (p = 0.04). Conversely, GA treatment resulted in increased protein levels of Nrf2 (p = 0.021) with concomitant increase in transcription of its downstream target genes HO-1 (p = 0.033) and Prdx-1 (p = 0.006). Overall, our data show that GA effectively modulates COPD exacerbation manifestations in mice potentially by restoring redox imbalance in lungs.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Cytokines; Enzyme-Linked Immunosorbent Assay; Gallic Acid; Inflammation; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; Neutrophils; Oxidation-Reduction; Oxidative Stress; Peroxidase; Polyphenols; Pulmonary Disease, Chronic Obstructive

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

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

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

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

The inhalation of carbon monoxide (CO) gas and the administration of CO-releasing molecules were shown to inhibit the development of intestinal inflammation in a murine colitis model. However, it remains unclear whether CO promotes intestinal wound healing. Herein, we aimed to evaluate the therapeutic effects of the topical application of CO-saturated saline enemas on intestinal inflammation and elucidate the underlying mechanism. Acute colitis was induced with trinitrobenzene sulfonic acid (TNBS) in male Wistar rats. A CO-saturated solution was prepared via bubbling 50% CO gas into saline and was rectally administrated twice a day after colitis induction; rats were sacrificed 3 or 7 days after induction for the study of the acute or healing phases, respectively. The distal colon was isolated, and ulcerated lesions were measured. In vitro wound healing assays were also employed to determine the mechanism underlying rat intestinal epithelial cell restitution after CO treatment. CO solution rectal administration ameliorated acute TNBS-induced colonic ulceration and accelerated ulcer healing without elevating serum CO levels. The increase in thiobarbituric acid-reactive substances and myeloperoxidase activity after induction of acute TNBS colitis was also significantly inhibited after CO treatment. Moreover, the wound healing assays revealed that the CO-saturated medium enhanced rat intestinal epithelial cell migration via the activation of Rho-kinase. In addition, the activation of Rho-kinase in response to CO treatment was confirmed in the inflamed colonic tissue. Therefore, the rectal administration of a CO-saturated solution protects the intestinal mucosa from inflammation and accelerates colonic ulcer healing through enhanced epithelial cell restitution. CO may thus represent a novel therapeutic agent for the treatment of inflammatory bowel disease.

Topics: Administration, Rectal; Animals; Carbon Monoxide; Cells, Cultured; Chemokine CXCL1; Colitis; Colon; Inflammation; Intestinal Mucosa; Male; Peroxidase; Rats, Wistar; Re-Epithelialization; rho-Associated Kinases; RNA, Messenger; Signal Transduction; Trinitrobenzenesulfonic Acid; Wound Healing

Seaweed lectins are very promising biotechnological tools that also gain prominence when applied to the pharmacology field. The purpose of the present work was to isolate and characterize lectin from the red algae Amansia multifida and subsequently test it in general inflammation models. The lectin was purified by ion exchange chromatography, characterized with two-dimensional electrophoresis, automated analysis of amino acid sequences and circular dichroism spectroscopy. The pharmacological tests performed were paw edema induced by carrageenan or rapid inflammatory mediators, peritonitis induced by carrageenan and myeloperoxidase leukocyte count assays, glutathione and cytokine concentration. Our results have identified a 30 KDa molecular weight protein that presents a major secondary structure arranged in β-strand elements (~43%). A fragment of 20 amino acid residues was sequenced and presented low identity to the known classes of lectins from marine alga. This lectin was able to modulate inflammatory parameters such as paw edema, leukocyte migration, oxidative stress and proinflammatory cytokines. Thus, the lectin from the seaweed Amansia multifida has evident anti-inflammatory properties because it acts by reducing the formation of edema by modulating the effect of vascular mediators, migration of neutrophils, proinflammatory cytokines and oxidative stress control.

Topics: Animals; Anti-Inflammatory Agents; Carrageenan; Cell Movement; Cytokines; Edema; Inflammation; Inflammation Mediators; Lectins; Leukocytes; Mice; Neutrophils; Oxidation-Reduction; Oxidative Stress; Peritonitis; Peroxidase; Rhodophyta

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

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

Caralluma species are traditional edible herbs used in folkloric medicine as antidiabetic, antioxidant, antipyretic, antirheumatic, anti-inflammatory and anthelmintic agents. C. quadrangula was selected in this study to document the traditional use of the genus as anti-rheumatic treatment and the possible mechanisms of action.. The higher mortality rates and shorter survival among the patients suffering from rheumatoid arthritis (RA) led to the increased interest on searching for new treatments for RA. Russelioside B (RB), a major pregnane glycoside found in C. quadrangula, was evaluated as a new anti-rheumatic agent.. The n-butanol fraction of C. quadrangula was chromatographed on a silica gel column to isolate RB. The adjuvant-induced arthritis (AIA) model was established in rats by intradermal injection of complete Freund's adjuvant (CFA) to evaluate its anti-arthritic effect. Ibuprofen was used as a reference drug. Forty rats were randomly divided into 5 groups (n = 8): normal (NOR); CFA model (CFA); ibuprofen, 5 mg/kg; RB, 25 mg/kg and RB, 50 mg/kg. The treatments were initiated from day 16 when AIA model was established and continued up to day 40. Serum diagnostic rheumatoid markers, inflammatory cytokines, oxidative stress biomarkers, cartilage and bone degeneration enzymes were assessed.. RB at 50 mg/kg b. wt., showed significant decreases in the activities of hyaluronidase and β-glucouronidase enzymes as well significant decreases in the levels of proinflammatory cytokines as nuclear factor-kappa-B (NF-κB), tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) compared to the CFA group; 11.04 ± 0.61 pg/mg protein, 4.35 ± 0.25 pg/mg protein, 3.32 ± 0.13 pg/mg protein & 2.75 ± 0.14 pg/mg protein for RB, 50 mg/kg b. wt. group vs. 25.33 ± 2.13 pg/mg protein, 25.65 ± 2.1 pg/mg protein, 22.20 ± 1.34 pg/mg protein & 13.27 ± 1.40 pg/mg protein for the arthritic group, respectively. The total antioxidant capacity (TAC) was significantly restored to normal values in RB, 50 mg/kg treated rats (4.01 ± 0.09 nmol/mL vs. 3.71 ± 0.27 nmol/mL) and the levels of myeloperoxidase (MPO) reduced by 10-folds of the CFA arthritic group. Bone histomorphometry revealed that RB treatment significantly attenuated the CFA-induced bone loss in a dose-dependent manner.. These findings suggested that the anti-arthritic effect of RB was mediated through the reduction of the rheumatoid markers, anti-inflammatory and antioxidant action, inhibition of cartilage and bone degenerative enzymes as well as attenuation of bone loss and osteoclastogenesis.

Topics: 1-Butanol; Animals; Ankle Joint; Anti-Citrullinated Protein Antibodies; Anti-Inflammatory Agents; Antirheumatic Agents; Apocynaceae; Arthritis, Experimental; Blood Cell Count; Body Weight; Cancellous Bone; Carrier Proteins; Cytokines; Edema; Freund's Adjuvant; Glucuronidase; Glycosides; Hyaluronoglucosaminidase; Inflammation; Male; Medicine, Traditional; Oxidative Stress; Peroxidase; Plant Extracts; Pregnanes; Rats, Wistar; Rheumatoid Factor

The use of natural supplies is a resource to mimic an original extracellular matrix that allows for migration, proliferation, and cellular organization. Chitosan from Brazilian Atlantic Ocean had low protein, minerals percentage and excellent antibacterial activity. The aim of this study was to evaluate and to compare the effectiveness of different types of acids as solvents with Brazilian chitosan-membrane in the healing process of skin lesions. Experimental full-thickness 2 × 2 cm wounds were created on the dorsum skin of Wistar rats. The applied different treatments were saline, collagenase®, microcrystalline chitosan salt membrane (MCSM), microcrystalline chitosan acetic acid membrane (MCAAM), and microcrystalline chitosan hydrochloric acid membrane (MCHAM). The wound repairs were measured morphologically and histologically on days 0, 3, 7, 10, and 14. The exudate formation and the final wound contractions were similar in all of the groups. There were mild exudations in the groups with chitosan-membranes, despite the formation of crust under the membrane. This configured a serum hematic aspect, but there was no impact on the healing process. The MCHAM group had more favorable aspects that histologically showed the healing phases. A significant migration of neutrophils and macrophages seen by myeloperoxidade and Beta-N-Acetylglucosaminidase activities was evident in the chitosan groups, MCHAM and MCSM, respectively. Furthermore, the MCHAM group created its histological arrangement in a dense and more consistent manner.

Topics: Acetylglucosaminidase; Animals; Biocompatible Materials; Chitosan; Collagen; Inflammation; Male; Peroxidase; Rats, Wistar; Wound Healing

Accumulating evidence indicates the association between changes in circulating sex steroid hormone levels and the development of diabetic nephropathy. However, the renal synthesis of steroid hormones during diabetes is essentially unknown. Male Wistar rats were injected with streptozotocin (STZ) or vehicle. After one week, no changes in functional or structural parameters related to kidney damage were observed in STZ group; however, a higher renal expression of proinflammatory cytokines and HSP70 was found. Expression of Steroidogenic Acute Regulatory protein (StAR) and P450scc (CYP11A1) was decreased in STZ kidneys. Incubation of isolated mitochondria with 22R-hydroxycholesterol revealed a marked inhibition in CYP11A1 function at the medullary level in STZ group. The inhibition of these first steps of renal steroidogenesis in early STZ-induced diabetes led to a decreased local synthesis of pregnenolone and progesterone. These findings stimulate investigation of the probable role of nephrosteroids in kidney damage associated with diabetes.

Topics: Animals; Blood Glucose; Carrier Proteins; Cholesterol Side-Chain Cleavage Enzyme; Cytokines; Diabetes Mellitus; Diabetes Mellitus, Experimental; Gene Expression Regulation; HSP70 Heat-Shock Proteins; Inflammation; Inflammation Mediators; Kidney; Lipid Metabolism; Male; Peroxidase; Phosphoproteins; Pregnenolone; Progesterone; Rats, Wistar; Receptors, GABA-A; RNA, Messenger; Steroids; Streptozocin; Testosterone

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

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

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

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

In contrast to mammals, zebrafish (Danio rerio) has the ability to regenerate injured sites such as different tissues present in the fin. It is known that cells of the innate immune system play essential roles in regeneration; however, some aspects of the molecular mechanisms by which these cells orchestrate regeneration remain unknown. This study aimed to evaluate the infiltration dynamics of neutrophils and macrophages in the regenerative process of fin fold in regard to the influence of the redox environment and oxidative pathways. Fin fold amputation was performed on transgenic larvae for macrophage-expressed gene 1 (mpeg1), lysozyme (lyz), myeloperoxidase (mpo) and tumour necrosis factor alpha (TNFα) at 3 days post-fertilization, followed by confocal microscopy imaging and measurement of the activities of oxidant and antioxidant enzymes. We observed initially an increase in the number of neutrophils (lyz:DsRed+/mpx:GFP+) and then macrophages (mpeg1+) in the injury site followed by a decrease in neutrophils at 7 days post-amputation (dpa). Moreover, macrophages switch from a pro-inflammatory to an anti-inflammatory profile throughout the process, while the activity of superoxide dismutase (SOD) increased at 1 dpa and catalase (CAT) at 5 dpa. Higher levels of lipid peroxidation were also detected during regeneration. Despite oxidative stress, there is, therefore, an antioxidant response throughout the regeneration of the caudal fin. The present work can contribute to future studies on the development of cell therapies, achieving greater effectiveness in the treatment of diseases related to the formation of fibrotic tissue.

Topics: Animals; Antioxidants; Inflammation; Lipid Peroxidation; Macrophages; Neutrophils; Oxidation-Reduction; Oxidative Stress; Peroxidase; Phenotype; Regeneration; Superoxide Dismutase; Tumor Necrosis Factor-alpha; Wound Healing; Zebrafish; Zebrafish Proteins

Topics: Allyl Compounds; Animals; Calgranulin A; Cell Line, Tumor; Cell Movement; Epithelial Cells; Extracellular Vesicles; Fibronectins; Inflammation; Interleukin-6; Lung; Lung Neoplasms; Melanoma; Mice; Peroxidase; Sulfides; Toll-Like Receptor 4; Tumor Microenvironment

Stroke is the second leading cause of death worldwide. Patients who have a stroke are susceptible to many gastrointestinal (GI) complications, such as dysphagia, GI bleeding, and fecal incontinence. However, there are few studies focusing on the GI tract after stroke. The current study is to investigate the changes of intestinal structure and function in mice after ischemic stroke. Ischemic stroke was made as a disease model in mice, in which brain and ileal tissues were collected for experiments on the 1

Topics: Actins; Animals; Apoptosis; Blotting, Western; Claudin-1; Inflammation; Intestines; Male; Mice; Mice, Inbred C57BL; Microscopy, Electron, Transmission; Neuroglia; Occludin; Peroxidase; Stroke; Zonula Occludens-1 Protein

Topics: Acute Lung Injury; Animals; CD40 Antigens; Cells, Cultured; Cytokines; Ginkgolides; Hydroxyproline; I-kappa B Kinase; Inflammation; Lactones; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophil Infiltration; Neutrophils; Peroxidase; Signal Transduction; Transcription Factor RelA

The myeloperoxidase index (MPXI), on ADVIA hematology analyzers, reflects the mean neutrophil myeloperoxidase staining. It is used as a marker of inflammation in animals and people, but assay variability and storage stability are unknown.. We aimed to determine MPXI precision and stability with refrigerated storage of canine and equine EDTA-anticoagulated blood and compared MPXI results between two analyzers.. Inter-assay coefficients of variations (CVs) were determined from three human-based controls assayed before and after a 20- or 21-day calibration. Blood from 14-16 dogs and 26 horses was assayed 4-10 times within 1 day for intra-assay CV measurements. Median control and single run results from 18 canine and 35 equine samples were compared between analyzers. Blood from 10-12 dogs and 10-11 horses was analyzed after collection, and 24, 48, and 72 hours of refrigerated storage.. Inter-assay CVs of controls were 10.7%-15.9% and 6.4%-9.6% before and 4.3%-7.7% and 2.8%-17.5% after calibration, for ADVIA 1 and 2, respectively. Calibration altered peroxidase gain settings and improved precision. Intra-assay CVs were 0.6%-64% and 3%-350% for canine and equine samples, respectively. Median MPXI results differed significantly between the analyzers, likely from calibration-associated changes in gains. MPXI decreased with storage, and with variable changes between animals and analyzers. Platelet clumps and lipid contributed to the variability in replicate MPXI measurements.. MPXI has a higher variability in equine samples than in canine samples. Equivalent results might not be obtained between analyzers. Results change unpredictably with repeated analyses over 72 hours. MPXI measurements might only be useful in controlled research settings.

Topics: Animals; Dog Diseases; Dogs; Hematologic Tests; Hematology; Horse Diseases; Horses; Inflammation; Neutrophils; Peroxidase

Familial Mediterranean Fever (FMF) and Pyrin-Associated Autoinflammation with Neutrophilic Dermatosis (PAAND) are clinically distinct autoinflammatory disorders caused by mutations in the pyrin-encoding gene MEFV. We investigated the transcriptional, phenotypical, and functional characteristics of patient neutrophils to explore their potential role in FMF and PAAND pathophysiology.. RNA sequencing was performed to discover transcriptional aberrancies. The phenotypical features, degranulation properties, and phagocytic capacity of neutrophils were assessed by flow cytometry. Production of reactive oxygen species (ROS), myeloperoxidase (MPO) release, and chemotactic responses were investigated via chemiluminescence, ELISA, and Boyden chamber assays, respectively.. Neutrophils from PAAND and FMF patients showed a partially overlapping, activated gene expression profile with increased expression of S100A8, S100A9, S100A12, IL-4R, CD48, F5, MMP9, and NFKB. Increased MMP9 and S100A8/A9 expression levels were accompanied by high plasma concentrations of the encoded proteins. Phenotypical analysis revealed that neutrophils from FMF patients exhibited an immature character with downregulation of chemoattractant receptors CXCR2, C5aR, and BLTR1 and increased expression of Toll-like receptor 4 (TLR4) and TLR9. PAAND neutrophils displayed an increased random, but reduced CXCL8-induced migration. A tendency for enhanced random migration was observed for FMF neutrophils. PAAND neutrophils showed a moderately but significantly enhanced phagocytic activity as opposed to neutrophils from FMF patients. Neutrophils from both patient groups showed increased MPO release and ROS production.. Neutrophils from patients with FMF and PAAND, carrying different mutations in the MEFV gene, share a pro-inflammatory phenotype yet demonstrate diverse features, underscoring the distinction between both diseases.

Topics: Adult; Aged; Calgranulin A; Calgranulin B; Cytokines; Familial Mediterranean Fever; Female; Humans; Inflammation; Male; Matrix Metalloproteinase 9; Middle Aged; Neutrophils; Peroxidase; Phagocytosis; Phenotype; Pyrin; Skin Diseases; Transcriptome; Young Adult

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

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

Topics: Animals; Anti-Inflammatory Agents; Antibodies; Antigens, CD; Inflammation; Inflammation Mediators; Macrophages; Male; Models, Animal; Nanofibers; Peroxidase; Postoperative Complications; Rats; Rats, Sprague-Dawley; Urethra; Wound Healing

Agricultural airborne work exposures are complex in nature and workplace exposures are a risk for respiratory outcomes in workers. Endotoxin and glyphosate are two common agents in agricultural exposures. While endotoxin (lipopolysaccaride, LPS) is a potent inflammatory agent it explains only a portion of the respiratory inflammatory response. The inflammatory potential when LPS is presented with another common agricultural respiratory agent, glyphosate, is not known.. Mice were assigned to four treatment groups: control, LPS alone, glyphosate alone, glyphosate and LPS combined. Treatments were for 1, 5 or 10 days.. Five days of repeated exposure to the comintation of LPS and glyphosate resulted in higher neutrophil counts, myloperoxidase, TNF-α, IL-6, KC levels, and ICAM-1 and TLR-2 expression compared to the same length of treatment to LPS or glyphosate alone. After 10-days of exposure, inflammatory responses decreased, however leukocyte infiltration persisted along with increases in IL-4.. Glyphosate exposure modified LPS induced lung inflammatory responses and TLR-2 may be important in the modulated inflammatory response.

Topics: Animals; Bronchoalveolar Lavage Fluid; Cytokines; Drug Interactions; Glycine; Glyphosate; Herbicides; Inflammation; Leukocyte Count; Lipopolysaccharides; Lung; Lung Diseases; Male; Mice, Inbred C57BL; Peroxidase; Toll-Like Receptor 2

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

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

As a type I interferon response gene, ubiquitin-specific protease 18 (USP18) has been shown to be widely involved in oxidative stress and immune regulation processes. However, the relationship between USP18 and acute lung injury (ALI) is unclear. This study aimed to analyze the role of USP18 in the pathogenesis of ALI. Lipopolysaccharide (LPS) treatment up-regulated the expression of USP18 mRNA and protein in human pulmonary microvascular endothelial cells (hPMVECs). USP18 overexpression increased the viability of LPS-induced hPMVECs, and reduced LPS-induced cell damage. Additionally, USP overexpression increased the activity of SOD and CAT, and reduced the production of NO and MDA in LPS-induced hPMVECs. Moreover, overexpression of USP18 inhibited the secretion of IL-1β, IL-6, TNF-α, and IL-18 in LPS-induced hPMVECs. USP18 overexpression restrained LPS-induced upregulation of TLR4 and the excessive phosphorylation of p65 and IκBα, as well as the production of reactive oxygen species (ROS). TLR4 agonist MPLA attenuated the inhibitory effect of USP18 overexpression on LPS-induced oxidative stress and inflammation in hPMVECs. In addition, USP18 ameliorated LPS induced ALI in vivo. In conclusion, USP18 may resist LPS-induced oxidative stress and inflammatory response in hPMVECs by inhibiting the TLR4/NF-κB/ROS signaling pathway, which may provide new and complementary strategies for ALI treatment.

Topics: Acute Lung Injury; Animals; Bronchoalveolar Lavage Fluid; Cells, Cultured; Cytokines; Endothelial Cells; Humans; Inflammation; Lipopolysaccharides; Lung; Mice, Inbred C57BL; Microvessels; NF-kappa B; Oxidative Stress; Peroxidase; Reactive Oxygen Species; Toll-Like Receptor 4; Ubiquitin Thiolesterase

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

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

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common and devastating clinical disorders with high mortality and no specific therapy. Lipopolysaccharide (LPS) is usually used intratracheally to induce ALI in mice. The aim of this study was to examine the effects of an ultramicronized preparation of palmitoylethanolamide (um-PEA) in mice subjected to LPS-induced ALI. Histopathological analysis reveals that um-PEA reduced alteration in lung after LPS intratracheal administration. Besides, um-PEA decreased wet/dry weight ratio and myeloperoxidase, a marker of neutrophils infiltration, macrophages and total immune cells number and mast cells degranulation in lung. Moreover, um-PEA could also decrease cytokines release of interleukin (IL)-6, interleukin (IL)-1β, tumor necrosis factor (TNF)-α and interleukin (IL)-18. Furthermore, um-PEA significantly inhibited the phosphorylation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation in ALI, and at the same time decreased extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38/MAPK) expression, that was increased after LPS administration. Our study suggested that um-PEA contrasted LPS-induced ALI, exerting its potential role as an adjuvant anti-inflammatory therapeutic for treating lung injury, maybe also by p38/NF-κB pathway.

Topics: Acute Lung Injury; Amides; Animals; Cytokines; Ethanolamines; Immunohistochemistry; Inflammation; Interleukin-18; Interleukin-1beta; Interleukin-6; JNK Mitogen-Activated Protein Kinases; Lipopolysaccharides; Macrophages; Male; MAP Kinase Signaling System; Mast Cells; Mice; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Neutrophils; NF-kappa B; NF-KappaB Inhibitor alpha; p38 Mitogen-Activated Protein Kinases; Palmitic Acids; Peroxidase; Tumor Necrosis Factor-alpha

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

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

Lifestyle modifications such as increase in high-fat food consumption importantly increases the risks for cardiovascular disease. The principal objective of this study is to analyze effects of different high fat diet (HFD) sources on haemodynamic parameters, lipid and oxidative profile, myeloperoxidase activity, and markers of inflammation (IL-6/pentraxin-3). HFD containing 20% of fat, provided by lard (saturated) or soybean oil (unsaturated), as well as control diet were administering to three groups (L, SO and C). Food efficiency ratio and plasma lipids were significantly elevated in both HFD groups. However, only SO group showed an increase in systolic arterial pressure, oxidative stress index, myeloperoxidase activity, liver lipids as well as markers of inflammation: IL-6 and pentraxin-3 (PTX3). In summary, these results indicate inflammogenic potential of excessive soybean oil consumption in triggering liver damage.

Topics: Animals; Biomarkers; C-Reactive Protein; Diet, High-Fat; Dietary Fats; Fatty Acids, Unsaturated; Inflammation; Interleukin-6; Liver; Male; Oxidative Stress; Peroxidase; Rats; Rats, Wistar; Serum Amyloid P-Component; Soybean Oil

Multiple organ failure (MOF) is the main cause of early death in septic shock. Lungs are among the organs that are affected in MOF, resulting in acute lung injury. Inflammation is an important factor that causes immune cell dysfunction in the pathogenesis of sepsis. Autophagy is involved in the process of inflammation and also occurs in response to cell and tissue injury in several diseases. We previously demonstrated that hydrogen alleviated the inflammation-induced cell injury and organ damage in septic mice.. The focus of the present study was to elucidate whether mitophagy mediates the inflammatory response or oxidative injury in sepsis in vitro and in vivo. Furthermore, we evaluated the role of mitophagy in the protective effects of hydrogen against cell injury or organ dysfunction in sepsis.. RAW 264.7 macrophages induced by lipopolysaccharide (LPS) were used as an in vitro model for inflammation, and cecal ligation and puncture (CLP)-induced acute lung injury mice were used as an in vivo model for sepsis. The key protein associated with mitophagy, PTEN-induced putative kinase 1 (PINK1), was knocked down by PINK1 shRNA transfection in RAW 264.7 macrophages or mice.. Hydrogen ameliorated cell injury and enhanced mitophagy in macrophages stimulated by LPS. PINK1 was required for the mitigation of the cell impairment in LPS-stimulated macrophages by hydrogen treatment. PINK1 knockdown abrogated the beneficial effects of hydrogen on mitophagy in LPS-stimulated macrophages. Hydrogen inhibited acute lung injury in CLP mice via activation of PINK1-mediated mitophagy.. These results suggest that PINK1-mediated mitophagy plays a key role in the protective effects of hydrogen against cell injury in LPS-induced inflammation and CLP-induced acute lung injury.

Topics: Acute Lung Injury; Animals; Autophagy; Cell Line; Hydrogen; Inflammation; Lipopolysaccharides; Lung; Male; Membrane Potential, Mitochondrial; Mice; Mice, Inbred C57BL; Mitochondria; Mitophagy; Multiple Organ Failure; Oxidative Stress; Peroxidase; Protein Kinases; RAW 264.7 Cells; RNA, Small Interfering; Sepsis; Ubiquitin-Protein Ligases

Retinal vein occlusion (RVO) is the second most common retinal vascular disorders and causes visual damage in a large population. Neutrophil extracellular traps (NETs) formation (NETosis) is an important cause of vascular diseases, however, the association between NETs related biomarkers and RVO development remained unclear. In this pilot study, a total of 77 RVO cases and 48 controls were included between Jan 2020 and July 2020. Besides, the circulating levels of three NETs related markers, cell-free DNA (cfDNA), myeloperoxidase (MPO)-DNA and citrullinated histone H3 (H3Cit), were detected in all the participants and thus the association between NETosis and RVO incidence was analyzed. Advanced assays were conducted to investigate the inflammation and thrombosis related biomarkers in RVO cases with higher or lower NETs biomarkers. When the results were considered, it was found that NETs biomarkers, including cfDNA, MPO-DNA and H3Cit, were increased in the RVO cases comparing with the controls (P < 0.05). Through the receiver operating characteristic (ROC) analyses, we found that circulating NETs related biomarkers demonstrated potential diagnostic effects for RVO and the AUCs of plasma cfDNA, MPO-DNA and H3Cit were 0.859, 0.871 and 0.928, respectively (P < 0.001). Through analyzing the correlations between circulating NETs markers and RVO stages and durations, inflammatory markers as well as thrombotic indexes, it was found that NETs were related with the RVO subtypes, inflammatory status and thrombus formation. In conclusion, the plasma NETs remnants are significantly increased in RVO cases. Besides, advanced studies demonstrate that inflammation as well as thrombus formation might be involved in this association.

Topics: Aged; Biomarkers; Case-Control Studies; DNA; Extracellular Traps; Female; Histones; Humans; Incidence; Inflammation; Male; Middle Aged; Peroxidase; Pilot Projects; Retinal Vein Occlusion

Superoxide radicals and other reactive oxygen species (ROS) are implicated in influenza A virus-induced inflammation. In this in vitro study, we evaluated the effects of TG6-44, a novel quinazolin-derived myeloperoxidase-specific ROS inhibitor, on influenza A virus (A/X31) infection using THP-1 lung monocytic cells and freshly isolated peripheral blood mononuclear cells (PBMC). TG6-44 significantly decreased A/X31-induced ROS and virus-induced inflammatory mediators in THP-1 cells (IL-6, IFN-γ, MCP-1, TNF-α, MIP-1β) and in human PBMC (IL-6, IL-8, TNF-α, MCP-1). Interestingly, TG6-44-treated THP-1 cells showed a decrease in percent cells expressing viral nucleoprotein, as well as a delay in translocation of viral nucleoprotein into the nucleus. Furthermore, in influenza A virus-infected cells, TG6-44 treatment led to suppression of virus-induced cell death as evidenced by decreased caspase-3 activation, decreased proportion of Annexin V+PI+ cells, and increased Bcl-2 phosphorylation. Taken together, our results demonstrate the anti-inflammatory and anti-infective effects of TG6-44.

Topics: Cell Survival; Chemokine CCL2; Gene Expression Regulation; Humans; Inflammation; Inflammation Mediators; Influenza A virus; Interleukin-6; Interleukin-8; Leukocytes, Mononuclear; Lung; Peroxidase; Quinazolines; Reactive Oxygen Species; Superoxides; Tumor Necrosis Factor-alpha

Ulcerative colitis (UC) is a subcategory of intestinal inflammatory bowel disease characterized by up-regulation of proinflammatory cytokines and oxidative stress. The current study was designed to assess the probable protective effect of the nitric oxide (NO) donor, molsidomine, in experimental colitis model in rats. Rats were haphazardly classified into four groups: control, acetic acid, acetic acid + molsidomine (1 mg/kg) and acetic acid + molsidomine (2 mg/kg). Molsidomine (1 and 2 mg/kg/day) was administered by intra-peritoneal injection for 7 days prior to induction of UC. On the 8th day, colitis was induced by intra-rectal instillation of 2 ml of (4% v/v) acetic acid in normal saline using a pediatric plastic catheter. The rats were sacrificed 1 day following colitis induction, blood samples were obtained; colons and livers were isolated then underwent macroscopic, biochemical, histopathological and immunohistochemical examination. Pretreatment with molsidomine significantly reduced disease activity index, colon mass index, colonic macroscopic and histological damage. Besides, molsidomine significantly reduced the serum levels of alanine transaminase (ALT) (58.7 ± 8.9 & 59.7 ± 8 vs 288.75 ± 31.4 in AA group) and aspartate transaminase (AST) (196.2 ± 37.4 & 204 ± 30 vs 392.7 ± 35.6 in AA group). Moreover, molsidomine effectively decreased malondialdehyde (MDA) and total nitrate/nitrite (NOx) contents, and up regulated the enzymatic activity of superoxide dismutase (SOD) and glutathione level (GSH) in colonic and hepatic tissues. With regard to anti-inflammatory mechanisms, molsidomine suppressed tumor necrosis factor-alpha (TNF-α) (792.5 ± 16.7 & 448 ± 12.1 vs 1352.5 ± 45.8 in AA group) in colonic tissues and (701 ± 19 & 442.5 ± 22.5 vs 1501 ± 26 in AA group) in hepatic tissues as well as nuclear transcription factor kappa B (NF-kB/p65) levels (416.2 ± 4.1 & 185.5 ± 14.2 vs 659.2 ± 11.5 in AA group) in colonic tissues and (358 ± 6.2 & 163.5 ± 9.6 vs 732.5 ± 5.5 in AA group) in hepatic tissues. In addition, molsidomine significantly decreased inducible nitric oxide synthase (iNOS) levels (8.1 ± 0.1 & 4.9 ± 0.1 vs 16 ± 0.1 in AA group) in colonic tissues and (8.6 ± 0.3 & 6.1 ± 0.1 vs 17.8 ± 0.1 in AA group) in hepatic tissues, and myeloperoxidase (MPO) contents (10.5 ± 0.4 & 6.6 ± 0.3 vs 20.9 ± 0.6 in AA group) in colonic tissues and (13.1 ± 0.2 & 6.3 ± 0.06 vs 23.9 ± 1.4 in AA group) in hepatic tissues at p > 0.05. Furthermore, it suppressed apoptosi

Topics: Acetic Acid; Alanine Transaminase; Animals; Anti-Inflammatory Agents; Apoptosis; Apoptosis Regulatory Proteins; Caspase 3; Colitis, Ulcerative; Colon; Glutathione; Inflammation; Liver; Male; Molsidomine; NF-kappa B; Oxidative Stress; Peroxidase; Rats, Sprague-Dawley; Superoxide Dismutase; Tumor Necrosis Factor-alpha

The pathogenesis of acute pancreatitis (AP) initiation and progression is still unknown, and effective treatment is limited to supportive care. Many phytochemicals have the potential to alleviate AP symptoms and may be a useful and effective supplement to standard AP treatment. The objective of the study was to examine the potential role of chlorogenic acid (CGA), a polyphenol known for anti-inflammatory effect, in the treatment of experimental AP in mice.. Two intraperitoneal (ip) injections of L-arginine (dosage 400 mg/100 g BW) were given 1 h apart to generate the AP murine model. Mice were separated into two experimental groups after 12 h from the first L-arginine injection: AP mice treated with CGA (oral gavage (po) every 12 h; 20 mg/kg BW) and non-treated AP mice (po vehicle, 5% dimethyl sulfoxide every 12 h). Every 12 h, control mice were given an equivalent volume of vehicle. At 72 h, mice were slaughtered. Histology, as well as myeloperoxidase (MPO) and amylase activity assays, were performed on pancreatic tissues.. In murine mouse model of AP po administration of CGA decreased MPO vs. AP (40.40 ± 2.10 U vs. 7.39 ± 0.34; p < 0.001) as well as amylase activity vs. AP (1444 ± 56 mU/mL vs. 3340 ± 144 mU/mL, Fig. 2B; p < 0.001). When comparing CGA mice to AP mice, histological research demonstrated that the severity of AP was reduced following CGA treatment.. The current study found that CGA might have anti-inflammatory effect on L-arginine-induced pancreatitis. Dietary intervention with CGA may be advised as a supportive treatment for AP, according to our findings.

Topics: Animals; Arginine; Chlorogenic Acid; Gene Expression Regulation, Enzymologic; Inflammation; Male; Mice; Mice, Inbred C57BL; Pancreatitis; Peroxidase; Random Allocation

Aneurysmal subarachnoid hemorrhage (SAH) is associated with the development of delayed cognitive deficits. Neutrophil infiltration into the central nervous system is linked to the development of these deficits after SAH. It is however unclear how neutrophil activity influences central nervous system function in SAH. The present project aims to elucidate which neutrophil factors mediate central nervous system injury and cognitive deficits after SAH.. Using a murine model of SAH and mice deficient in neutrophil effector functions, we determined which neutrophil effector function is critical to the development of deficits after SAH. In vivo and in vitro techniques were used to investigate possible pathways of neutrophils effect after SAH.. Our results show that mice lacking functional MPO (myeloperoxidase), a neutrophil enzyme, lack both the meningeal neutrophil infiltration (wild type, sham 872 cells/meninges versus SAH 3047, P=0.023; myeloperoxidase knockout [MPOKO], sham 1677 versus SAH 1636, P=NS) and erase the cognitive deficits on Barnes maze associated with SAH (MPOKO sham versus SAH, P=NS). The reintroduction of biologically active MPO, and its substrate hydrogen peroxide (H2O2), to the cerebrospinal fluid of MPOKO mice at the time of hemorrhage restores the spatial memory deficit observed after SAH (time to goal box MPOKO sham versus MPOKO+MPO/H2O2, P=0.001). We find evidence of changes in neurons, astrocytes, and microglia with MPO/H2O2 suggesting the effect of MPO may have complex interactions with many cell types. Neurons exposed to MPO/H2O2 show decreased calcium activity at baseline and after stimulation with potassium chloride. Although astrocytes and microglia are affected, changes seen in astrocytes are most consistent with inflammatory changes that likely affect neurons.. These results implicate MPO as a mediator of neuronal dysfunction in SAH through its effect on both neurons and glia. These results show that, in SAH, the activity of innate immune cells in the meninges modulates the activity and function of the underlying brain tissue.

Topics: Animals; Astrocytes; Calcium Signaling; Cerebral Veins; Cognition Disorders; Hydrogen Peroxide; Inflammation; Maze Learning; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuroglia; Neurons; Neutrophils; Peroxidase; Spatial Memory; Subarachnoid Hemorrhage

Male reproductive toxicity is becoming of growing significance due to clinical chemotherapy usage. Methotrexate (MTX) is an anti-folate used on a large scale for different tumors and autoimmune conditions. Despite its wide clinical use, MTX is associated with severe testicular intoxication. The exact underlying mechanism is unclear.. Our study was conducted to explore the pathogenesis mechanism of MTX-induced testicular damage and the potential testicular protective effects of apocynin (APO) on testicular injury induced by single i.p. MTX (20 mg/kg). APO was administered orally (100 mg/kg) for ten days.. As compared to rats given MTX alone, co-administration of MTX with APO demonstrated multiple beneficial effects evidenced by a marked increase in testosterone, FSH, and LH and significantly restored testes histopathological alterations. Mechanistically, APO restored antioxidant status through up-regulation of Nrf2, cytoglobin, PPAR-γ, SIRT1, AKT, and p-AKT, while effectively lowering Keap-1. Moreover, APO significantly attenuated inflammation by down-regulating NF-κB-p65, iNOS, and TLR4 expressions confirmed by in-silico evidence. Additionally, network pharmacology analysis, a bioinformatics approach, was used to decipher various cellular processes' molecular mechanisms.. The current investigation proves the beneficial effects of APO in MTX-associated testicular damage through activation of cytoglobin, Keap-1/Nrf2/AKT, PPAR-γ, SIRT1, and suppressing of TLR4/NF-κB-p65 signal. Our data collectively encourage extending the investigation to the clinical setting to explore APO effects in MTX-treated patients.

Topics: Acetophenones; Animals; Antioxidants; Biomarkers; Inflammation; Interleukin-6; Kelch-Like ECH-Associated Protein 1; Male; Methotrexate; Molecular Docking Simulation; NF-E2-Related Factor 2; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Oxidants; Oxidative Stress; Peroxidase; PPAR gamma; Protein Interaction Maps; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Signal Transduction; Sirtuin 1; Testis; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

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

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

4-methylesculetin (4 ME) is a natural antioxidant coumarin with protective effects on the intestinal inflammation, in which oxidative stress plays a key role in its aetiology and pathophysiology. Based on this, we examined the antioxidant molecular mechanisms involved in the intestinal anti-inflammatory activity of the 4 ME. For this purpose, we investigated the effects of the 4 ME on the modulation of gene expression and antioxidant-related enzyme activities in TNBS model of intestinal inflammation as well as the molecular interaction between 4 ME and glutathione reductase. Our results showed that 4 ME modulated glutathione-related enzymes, mainly increasing glutathione reductase activity. These effects were related to upregulation of glutathione reductase and Nrf2 gene expression. Fluorescence and nuclear magnetic resonance data showed that interaction between 4 ME and glutathione reductase is collisional, hydrophobic and spontaneous, in which C4 methyl group is the second epitope most buried into glutathione reductase. Molecular modelling calculation showed Lys70-B, Arg81-A, Glu381-B, Asp443-A, Ser444-A, Glu447-B and Ser475-A participated in electrostatic interaction, Lys70-B, Glu381-B and Arg81-A acted in the hydrophobic interactions and Trp73, Phe377 and Ala446 are responsible for the hydrogen bonds. Based on this, our results showed 4 ME acted by different mechanisms to control oxidative stress induced by intestinal damage, controlling the imbalance between myeloperoxidase activity and glutathione production, upregulating the glutathione S-transferase and glutathione reductase activities, preventing the Nrf2 and glutathione gene expression downregulation with consequent glutathione maintenance. Finally, 4 ME interacted at molecular level with glutathione reductase, stabilizing its enzymatic activity and reducing oxidative stress to take place in intestinal inflammatory process.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Coumarins; Glutathione; Glutathione Reductase; Inflammation; Male; Oxidation-Reduction; Oxidative Stress; Peroxidase; Rats; Rats, Wistar; Umbelliferones

Endometritis is an inflammation of the endometrium associated with bacterial infection. The pathogenesis of endometritis in cows is still not completely understood. The combined analysis of the markers of inflammation and oxidative stress has contributed to a better understanding of disease mechanisms, but is still unexplored in uterine disorders. Moreover, research provides evidence about an important role of the vagus nerve in regulating the innate immune function through the cholinergic anti-inflammatory pathway in response to bacterial infections. This new pathway has demonstrated a critical role in controlling the inflammatory system. The aim of this study was to evaluate the activity of cholinesterase in total blood, lymphocytes, and serum of dairy cows with clinical and subclinical endometritis. Sixty-one Holstein cows, between 30 and 45 days in milk, were classified into 3 groups of animals: presenting clinical endometritis (n = 22), subclinical endometritis (n = 17), and healthy (n = 22). Mean leukocyte counts did not differ among groups, but the neutrophil number was significantly higher in cows with clinical endometritis than those in healthy animals. Also, serum concentration of interleukin-1beta (pg/mL) was significantly higher in cows with endometritis. The activity of acetylcholinesterase in blood and lymphocytes increased in both groups with endometritis. Animals with endometritis presented an increase in lipid peroxidation, but the antioxidant enzyme activity (catalase levels) was higher in endometritis groups than in normal cows. In conclusion, the inflammatory process of clinical and subclinical endometritis leads to systemic lipid peroxidation despite the compensatory increase of the antioxidant enzyme. These data also provide evidence of an important role of the cholinergic pathway in regulating dairy cows with clinical and subclinical endometritis.

Topics: Acetylcholinesterase; Animals; Antioxidants; Butyrylcholinesterase; Cattle; Cattle Diseases; Cholinesterases; Cross-Sectional Studies; Cytokines; Endometritis; Endometrium; Female; Immune System; Inflammation; Leukocytes; Lipid Peroxidation; Lymphocytes; Oxidative Stress; Peroxidase; Reactive Oxygen Species; Receptors, Cholinergic; Signal Transduction; Uterus

Myeloperoxidase (MPO), an oxidant-producing enzyme, stored in azurophilic granules of neutrophils has been recently shown to influence red blood cell (RBC) deformability leading to abnormalities in blood microcirculation. Native MPO is a homodimer, consisting of two identical protomers (monomeric MPO) connected by a single disulfide bond but in inflammatory foci as a result of disulfide cleavage monomeric MPO (hemi-MPO) can also be produced. This study investigated if two MPO isoforms have distinct effects on biophysical properties of RBCs. We have found that hemi-MPO, as well as the dimeric form, bind to the glycophorins A/B and band 3 protein on RBC's plasma membrane, that lead to reduced cell resistance to osmotic and acidic hemolysis, reduction in cell elasticity, significant changes in cell volume, morphology, and the conductance of RBC plasma membrane ion channels. Furthermore, we have shown for the first time that both dimeric and hemi-MPO lead to phosphatidylserine (PS) exposure on the outer leaflet of RBC membrane. However, the effects of hemi-MPO on the structural and functional properties of RBCs were lower compared to those of dimeric MPO. These findings suggest that the ability of MPO protein to influence RBC's biophysical properties depends on its conformation (dimeric or monomeric isoform). It is intriguing to speculate that hemi-MPO appearance in blood during inflammation can serve as a regulatory mechanism addressed to reduce abnormalities on RBC response, induced by dimeric MPO.

Topics: Erythrocyte Membrane; HL-60 Cells; Humans; Inflammation; Isoenzymes; Peroxidase; Phosphatidylserines; Protein Multimerization

Ventilator‑induced lung injury (VILI) is a life‑threatening condition caused by the inappropriate use of mechanical ventilation (MV). However, the precise molecular mechanism inducing the development of VILI remains to be elucidated. In the present study, it was revealed that the calcineurin/NFATc4 signaling pathway mediates the expression of adhesion molecules and proinflammatory cytokines essential for the development of VILI. The present results revealed that a high tidal volume ventilation (HV) caused lung inflammation and edema in the alveolar walls and the infiltration of inflammatory cells. The calcineurin activity and protein expression in the lungs were increased in animals with VILI, and NFATc4 translocated into the nucleus following calcineurin activation. Furthermore, the translocation of NFATc4 and lung injury were prevented by a calcineurin inhibitor (CsA). Thus, the present results highlighted the critical role of the calcineurin/NFATc4 signaling pathway in VILI and suggest that this pathway coincides with the release of ICAM‑1, VCAM‑1, TNF‑α and IL‑1β.

Topics: Animals; Calcineurin; Calcineurin Inhibitors; Cell Nucleus; Edema; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-1beta; Male; Nerve Tissue Proteins; NFATC Transcription Factors; Peroxidase; Rats; Rats, Wistar; Signal Transduction; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1; Ventilator-Induced Lung Injury

Sepsis is a life-threatening disease without ideal biomarkers. Some long non-coding RNAs (lncRNAs) are found to be implicated in sepsis. Thus, we investigated the effects of lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) on inflammation in septic mice and the potential mechanisms of the MALAT1/microRNA-23a (miR-23a)/MCEMP1 axis.. The sepsis mice model was generated by cecal ligation and puncture (CLP). Then the expressions of lncRNA MALAT1, mast cell-expressed membrane protein 1 (MCEMP1), and miR-23a in septic mice were determined. The interaction between lncRNA MALAT1, miR-23a and MCEMP1 was confirmed. Loss- and gain-of-function approaches were used to verify the roles of the lncRNA MALAT1, miR-23a, and MCEMP1 in inflammation, cell proliferation and apoptosis in septic mice.. The myeloperoxidase (MPO) activity and the expression of interleukin 6 (IL-6), IL-1β, IL-10, and tumor necrosis factor-α (TNF-α) were detected. High expression of the lncRNA MALAT1 and MCEMP1, as well as low expression of miR-23a, was observed in septic mice. LncRNA MALAT1 competitively bound to miR-23a, and miR-23a targeted MCEMP1. Moreover, the down-regulation of lncRNA MALAT1 repressed the expression of MPO, IL-6, IL-10, TNF-α, and IL-1β. Silencing of lncRNA MALAT1 or overexpression of miR-23a reduced inflammation, inhibited cell proliferation, and promoted cell apoptosis in septic mice. Taken together, MALAT1 promotes the inflammation in septic mice by binding to miR-23a to up-regulate MCEMP1. Therefore, silencing of lncRNA MALAT1 might provide a novel therapeutic target for sepsis.

Topics: Animals; Apoptosis; Cell Proliferation; Down-Regulation; Gene Silencing; Inflammation; Male; Mice; Mice, Inbred BALB C; MicroRNAs; Peroxidase; RNA, Long Noncoding; Sepsis

Staphylococcus aureus is one of the main causative agent of infections acquired in both community and hospital environment. In this context, photodynamic therapy (PDT) consists in using a photosensitizer that, activated by light, evokes the formation of reactive oxygen species (ROS), which lead to the death of microorganisms due to oxidative damage; it is useful tool since this action, harmful to pathogens, does not significantly injure human cells. In view of this, this work proposes a more in-depth study on the use of resveratrol (RSV) as a possible photosensitizer. It was observed, in the intradermal infection model in animals' ear dermis, that photoactivated resveratrol promotes an increase in myeloperoxidase expression with reduced bacterial load in the draining lymph node. Besides that, the draining lymph node of the animals treated with photoactivated RSV controls inflammation through IL-10 production. These are pioneers data and this work being a pilot study; then, other works must be conducted with the objective of elucidate the photoactivated resveratrol mechanism of action.

Topics: Animals; Bacterial Load; Cadherins; Dermis; Ear; Humans; Inflammation; Interleukin-10; Light; Lymph Nodes; Mice, Inbred BALB C; Peroxidase; Pilot Projects; Resveratrol; Staphylococcal Infections; Staphylococcus aureus

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

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

The aim of this study is to investigate whether Flammuliana Velutipes Polysaccharide (FVP) could aid in the prevention of colitis. Effect of FVP on colitis was evaluated using dextran sulfate sodium (DSS)-induced colitis in rats. Influence of FVP on the expression of inflammation related biomarkers and signal pathway element of TLR4\\NF-κB were assessed. The composition and taxonomy of colonic microbiota were analyzed by 16S rDNA high throughput sequencing, and the concentrations of caecal short fatty chain acids were assessed by chromatography-mass spectrometry. Our results showed that FVP treatment could regulate the colonic microbial dysbiosis and promote the levels of caecal short fatty chain acids, leading to down-regulation of TLR4\\NF-κB signal pathway, which finally ameliorate the colitis. Thus, the present study is the first attempt to elucidate the effect of FVP on colitis and support the potential application of FVP as a functional food ingredient or preventive drugs for colitis.

Topics: Amine Oxidase (Copper-Containing); Animals; Cecum; Colitis; Colon; Dextran Sulfate; Dysbiosis; Fatty Acids; Flammulina; Gastrointestinal Microbiome; Inflammation; Intestinal Mucosa; Male; NF-kappa B; Nitric Oxide; Peroxidase; Polysaccharides; Principal Component Analysis; Rats, Sprague-Dawley; Signal Transduction; Superoxide Dismutase; Toll-Like Receptors

Topics: Animals; Blood-Brain Barrier; Brain; Capillaries; Cell Line; Cells, Cultured; Endothelial Cells; Homeostasis; Humans; Inflammation; Mice; Peroxidase; Sepsis; Sphingolipids

This study evaluated the effects of

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

Liver dysfunction impairs immunological homeostasis. Glycine (Gly) has been reported to have antioxidative and anti-inflammatory effects and to regulate apoptosis in various models.. The aim of the present study was to determine whether Gly could attenuate LPS-induced liver injury.. In Experiment 1, 48 6-week-old male C57BL/6 mice were randomly assigned into one of 4 groups: CON (control), GLY [orally administered Gly, 5 g · kg body weight (BW)-1 · d-1 for 6 d], LPS (5 mg/kg BW, intraperitoneally administered), and GLY + LPS (Gly supplementation, and on day 7 LPS treatment). In Experiment 2, mice were untreated, pretreated with Gly as above, or pretreated with Gly + l-buthionine sulfoximine (BSO) (0.5 g/kg BW, intraperitoneally administered every other day) for 6 d. On day 7, mice were injected with LPS as above. Histological alterations, activities of antioxidative enzymes, apoptosis, and immune cell infiltration were analyzed.. In Experiment 1, compared with CON, LPS administration resulted in increased karyolysis and karyopyknosis in the liver by 8- to 10-fold, enhanced serum activities of alanine transaminase (ALT), aspartate transaminase (AST), and lactate dehydrogenase (LDH) by 1- to 1.8-fold, and increased hepatic apoptosis by 5.5-fold. Furthermore, LPS exposure resulted in increased infiltration of macrophages and neutrophils in the liver by 3.2- to 7.5-fold, elevated hepatic concentrations of malondialdehyde and hydrogen peroxide (H2O2), and elevated myeloperoxidase (MPO) activity by 1.5- to 6.3-fold. In Experiment 2, compared with the LPS group, mice in the GLY + LPS group had fewer histological alterations (68.5%-75.9%); lower serum ALT, AST, and LDH activities (24.3%-64.7%); and lower hepatic malondialdehyde and H2O2 concentrations (46.1%-80.2%), lower MPO activity (39.2%), immune cell infiltration (52.3%-85.3%), and apoptosis (69.6%), which were abrogated by BSO. Compared with the GLY + LPS group, mice in the GLY + BSO + LPS group had lower hepatic activities of catalase, superoxide dismutase, and glutathione peroxidase by 33.5%-48.5%; increased activation of NF-κB by 2.3-fold; and impaired nuclear factor (erythroid-derived 2)-like 2 signaling by 38.9%.. Gly is a functional amino acid with an ability to protect the liver against LPS-induced injury in mice.

Topics: Alanine Transaminase; Animals; Apoptosis; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Glycine; Hydrogen Peroxide; Inflammation; L-Lactate Dehydrogenase; Lipopolysaccharides; Liver; Macrophages; Male; Malondialdehyde; Mice; Mice, Inbred C57BL; Neutrophils; Peroxidase

Smoke inhalation causes acute lung injury (ALI), a severe clinical disease with high mortality. Accumulating evidence indicates that microRNA-155 (miR-155) and suppressor of cytokine signaling 1 (SOCS-1), as mediators of inflammatory response, are involved in the pathogenesis of ALI. In this paper, we explored the proinflammatory mechanism of miR-155 in smoke-inhalation-induced ALI. Our data revealed that smoke inhalation induces miR-155 expression, and miR-155 knockout (KO) significantly ameliorates smoke-inhalation-induced lung injury in mice. Neutrophil infiltration and myeloperoxidase (MPO), macrophage inflammatory protein 2 (MIP-2) and keratinocyte chemoattractant (KC) expressions were decreased in miR-155

Topics: Acute Lung Injury; Administration, Inhalation; Animals; Bronchoalveolar Lavage Fluid; Chemokine CXCL2; Gene Expression Regulation; Humans; Inflammation; Keratinocytes; Mice; Mice, Knockout; MicroRNAs; Neutrophil Infiltration; Neutrophils; Peroxidase; Smoke; Suppressor of Cytokine Signaling 1 Protein

Luminol-based bioluminescence imaging allows noninvasive tracking of oxidatively active cells such as neutrophils. Luminol is given intravenously or intraperitoneally, followed by bioluminescence imaging at 425 nm. Here we describe a method for tracking neutrophil extravasation into an inflammatory site, especially focusing on mammary carcinoma.

Topics: Animals; Cell Tracking; Female; Inflammation; Luminescent Measurements; Luminol; Mammary Neoplasms, Animal; Mice; Mice, Inbred BALB C; NADPH Oxidases; Neutrophils; Peroxidase

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

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

Cystic fibrosis (CF) lung disease is characterized by severe bacterial infections, excessive neutrophilic inflammation and oxidative stress. The neutrophil enzyme myeloperoxidase (MPO), which produces hypochlorous acid, is associated with worse disease outcomes. Therefore, pharmacological inhibition of MPO in the airways has therapeutic potential. We investigated whether treating mice with an MPO inhibitor during pulmonary infection decreases oxidative stress and improves infection outcomes in mice with CF-like lung inflammation without impacting on bacterial clearance.. Transgenic β-epithelial sodium channel (βENaC)-overexpressing mice (n = 10) were infected with Burkholderia multivorans and treated twice daily with the MPO inhibitor AZM198 (125 μmol/kg) or vehicle administered by oral gavage for two days. Bodyweight was recorded daily. MPO activity, markers of oxidative stress, inflammatory cytokines and leukocytes numbers were measured in bronchoalveolar lavage fluid (BALF). Bacterial burden was determined in lung tissue homogenates.. During the course of infection, mice treated with AZM198 lost less weight than vehicle-treated mice (p < 0.01). MPO activity and glutathione sulfonamide, a hypochlorous acid-specific glutathione oxidation product, were significantly lower in BALF from AZM198-treated mice (p < 0.05). The inflammatory cytokines CXCL1 and TNF-α in BALF and bacterial burden in the lung were not significantly different between treated and control mice.. Orally administered AZM198 inhibits MPO activity in epithelial lining fluid. Blocking hypochlorous acid production in epithelial lining fluid during pulmonary infections through inhibition of MPO improves morbidity in mice with CF-like lung inflammation without interfering with clearance of bacteria. Pharmacological inhibition of MPO is an approach to limit destructive oxidative stress in cystic fibrosis lung disease in humans.

Topics: Animals; Bronchoalveolar Lavage Fluid; Burkholderia; Cystic Fibrosis; Inflammation; Lung; Mice; Morbidity; Oxidative Stress; Peroxidase; Pneumonia

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

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

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

Inflammation appears to be an important component of concussion pathophysiology. However, its relationship to symptom burden is unclear. Therefore, the purpose of this study was to evaluate the relationship between symptoms and inflammatory biomarkers measured in the blood of male and female athletes following a sport-related concussion (SRC).. Forty athletes (n = 20 male, n = 20 female) from nine interuniversity sport teams at a single institution provided blood samples within one week of an SRC. Twenty inflammatory biomarkers were quantitated by immunoassay. The Sport Concussion Assessment Tool version 5 (SCAT-5) was used to evaluate symptoms. Partial least squares (PLS) analyses were used to evaluate the relationship(s) between biomarkers and symptoms. In males, a positive correlation between interferon (IFN)-γ and symptom severity was observed following SRC. The relationship between IFN-γ and symptoms was significant among all symptom clusters, with cognitive symptoms displaying the largest effect. In females, a significant negative relationship was observed between symptom severity and cytokines IFN-γ, tumor necrosis factor (TNF)-α, and myeloperoxidase (MPO); a positive relationship was observed between symptom severity and MCP-4. Inflammatory mediators were significantly associated with all symptom clusters in females; the somatic symptom cluster displayed the largest effect.. These results provide supportive evidence of a divergent relationship between inflammation and symptom burden in male and female athletes following SRC. Future investigations should be cognizant of the potentially sex-specific pathophysiology underlying symptom presentation.

Topics: Adult; Athletes; Biomarkers; Brain Concussion; Disease Progression; Female; Humans; Inflammation; Interferon-gamma; Male; Peroxidase; Severity of Illness Index; Sex Characteristics; Sex Factors; Tumor Necrosis Factor-alpha; Young Adult

Studies suggest a role of the innate immune system, including the activity of neutrophils, in neurodegeneration related to Alzheimer's disease (AD), but prospective cognitive data remain lacking in humans. We aimed to investigate the predictive relationship between neutrophil-associated inflammatory proteins in peripheral blood and changes in memory and executive function over 1 year in patients with AD.. Participants with AD were identified from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Neutrophil gelatinase-associated lipocalin (NGAL), myeloperoxidase (MPO), interleukin-8 (IL-8), macrophage inflammatory protein-1 beta (MIP-1β), and tumor necrosis factor (TNF) were assayed by luminex immunofluorescence multiplex assay at baseline. Confirmatory factor analysis was used to test an underlying neutrophil associated plasma inflammatory factor. Composite z-scores for memory and executive function were generated from multiple tests at baseline and at 1 year. A multiple linear regression model was used to investigate the association of the baseline inflammatory factor with changes in memory and executive function over 1 year.. Among AD patients (n = 109, age = 74.8 ± 8.1, 42% women, Mini Mental State Examination [MMSE] = 23.6 ± 1.9), the neutrophil-related inflammatory proteins NGAL (λ = 0.595, p < .001), MPO (λ = 0.575, p < .001), IL-8 (λ = 0.525, p < .001), MIP-1β (λ = 0.411, p = .008), and TNF (λ = 0.475, p < .001) were found to inform an underlying factor. Over 1 year, this inflammatory factor predicted a decline in executive function (β = - 0.152, p = 0.015) but not memory (β = 0.030, p = 0.577) in models controlling for demographics, brain atrophy, white matter hyperintensities, the ApoE ε4 allele, concomitant medications, and baseline cognitive performance.. An inflammatory factor constructed from five neutrophil-related markers in peripheral blood predicted a decline in executive function over 1 year in people with mild AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Biomarkers; Chemokine CCL4; Disease Progression; Executive Function; Female; Humans; Inflammation; Interleukin-8; Lipocalin-2; Male; Middle Aged; Neutrophils; Peroxidase; Tumor Necrosis Factor-alpha

The barrier-improving functions of fermented blueberry pomace (FBP) and its potential mechanism were investigated in this study. Polyphenols and the approximate composition of FBP were evaluated according to the National Standard of the People's Republic of China and the UPLC-MS system. Male C57BL/6 mice were fed a control diet (CD) or a high-fat diet (HFD) with or without FBP supplementation. Oxidative stress, inflammation, histological morphology and the expression of functional proteins in the small intestine of mice were evaluated using the enzyme linked immunosorbent assay (ELISA), quantitative polymerase chain reaction (qPCR) and western blotting. The content of protein, fat, soluble dietary fiber, insoluble dietary fiber and carbohydrates (non-dietary fiber) was 114.5 ± 1.5 g kg

Topics: Animals; Blueberry Plants; Diet, High-Fat; Fermentation; Gene Expression Regulation; Ileum; Inflammation; Intestine, Small; Liver; Male; Mice; Mice, Inbred C57BL; Myosin-Light-Chain Kinase; NF-kappa B; Oxidation-Reduction; Oxidative Stress; Peroxidase; Phenol; Signal Transduction; Tumor Necrosis Factor-alpha

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

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

Gastric ulcer is a widespread inflammatory disease with high socio-economic burden. C-phycocyanin is one of the active constituents of Spirulina microalgae, and although it is well known for its antioxidant and anti-inflammatory properties, its protective effects against gastric ulcer have not yet been identified. High-mobility group box 1 (HMGB1) is a nuclear protein that, once secreted extracellularly, initiates several inflammatory reactions, and it is involved in the pathogenesis of gastric ulcer. The aim of the present study was to investigate the anti-inflammatory and anti-ulcerogenic effects of C-phycocyanin against ethanol-induced gastric ulcer targeting HMGB1/NLRP3/NF-κB pathway. Ulcer induction showed increase in HMGB1 expression through activation of nucleotide-binding domain and leucine-rich repeat-containing protein 3 (NLRP3) inflammasome and nuclear factor kappa p65 (NF-κB p65). Moreover, oxidative stress and inflammatory markers were elevated in the ulcer-treated group compared to the normal control group. However, pre-treatment with C-phycocyanin significantly reduced HMGB1 expression via suppression of NLRP3/NF-κB, oxidative markers, IL-1β, tumour necrosis factor-α (TNF-α) and ulcer index value. These results were consistent with histopathological and immunohistochemistry examination. Thus, C-phycocyanin is a potential therapeutic strategy with anti-inflammatory and anti-ulcerogenic effects against ethanol-induced gastric ulcer.

Topics: Animals; Anti-Inflammatory Agents; Ethanol; Gastric Mucosa; HMGB1 Protein; Inflammation; Interleukin-1beta; Male; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Oxidative Stress; Peroxidase; Phycocyanin; Protective Agents; Rats; Rats, Wistar; Receptor for Advanced Glycation End Products; Stomach Ulcer; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

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

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

Inflammatory bowel disease (IBD) is characterized by recurring inflammatory disorders in digestive system, and devoid of effective treatment. Proprotein convertase subtilisin/kexin type 9 (PCSK9), stimulated via inflammation whose inhibition could decrease secretion of inflammatory factors. We then determined whether inhibition of PCSK9 could improve the inflammation. First, rats model of colitis was first established via administration of 2,4,6-trinitrobenzenesulfonic acid (TNBS), and then verified via determination of body weight loss, myeloperoxidase (MPO) activity, and histopathological analysis of colonic damage. Results showed that treatment with TNBS induced a great body weight loss, MPO activity increase, and serious colonic damage, showing an obviously character of IBD. PCSK9 was elevated in TNBS-induced rats, and PCSK9 inhibition delivered by adenovirus vector increased the body weight, decreased MPO activity, and ameliorated histological change of colon. Second, the protective effect of PCSK9 inhibition against TNBS-induced colitis was accompanied by decrease of proinflammatory factors secretion, including tumor necrosis factor-α, interleukin-1β, interleukin-6, intercellular adhesion molecule 1, and monocyte chemoattractant protein-1. TNBS could activate toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling pathway, while PCSK9 inhibition suppressed activation of TLR4/NF-κB in TNBS-induced rats. In conclusion, PCSK9 inhibition attenuated TNBS-induced rat colitis through anti-inflammatory effect under inactivation of TLR4/NF-κB, suggesting potential therapeutic strategy in IBD.

Topics: Adenoviridae; Animals; Body Weight; Chemokine CCL2; Colitis; Colon; Gene Expression Regulation; Genetic Vectors; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-1beta; Interleukin-6; Male; NF-kappa B; PCSK9 Inhibitors; Peroxidase; Proprotein Convertase 9; Rats; Rats, Wistar; RNA, Small Interfering; Signal Transduction; Toll-Like Receptor 4; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

Recent studies have shown an increase of C-reactive-protein (CRP) after exposure to zinc- and copper-containing welding fumes. The objective of this study was to determine the effects of exposure to zinc- and copper-containing welding fumes on leukocytes, their subtypes, and myeloperoxidase (MPO).. Serum samples of male volunteers were examined after exposures to welding fumes in two settings: repeated exposure on 4 consecutive days for 6 hours and single exposures for different times (3, 4, 5 hours).. Neutrophil granulocyte and MPO levels showed increases 24 hours after single and repeated exposures for 6 hours similar to CRP increases reported in literature. Overall leukocyte levels and levels of monocytes and lymphocytes were not significantly affected.. This study indicates the involvement of neutrophil granulocytes in welding fume fever additional to mediator related effects.

Topics: Air Pollutants, Occupational; Biomarkers; Copper; Humans; Inflammation; Inhalation Exposure; Male; Neutrophils; Occupational Exposure; Peroxidase; Welding; Zinc

In heart failure (HF) with preserved ejection fraction (HFpEF), microvascular inflammation is proposed as an underlying mechanism. Myeloperoxidase (MPO) is associated with vascular dysfunction and prognosis in congestive HF.. In HFpEF, MPO-dependent oxidative stress reflected by uric acid and calprotectin is increased, and SDMA is associated with diastolic dysfunction and uric acid with outcome. This suggests microvascular neutrophil involvement mirroring endothelial dysfunction, a central component of the HFpEF syndrome and a potential treatment target.

Topics: Aged; Biomarkers; Female; Heart Failure; Humans; Inflammation; Male; Middle Aged; Peroxidase; Stroke Volume

The microbial communities residing in the child gut are thought to play an important role in child growth, although the relationship is not well understood. We examined a cohort of young children from Mirzapur, Bangladesh, prospectively over 18 months. Four fecal markers of environmental enteropathy (EE) (high levels of alpha-1-antitrypsin, calprotectin, myeloperoxidase, and neopterin) were examined and anthropometric measures obtained from a cohort of 68 children. The 16S rRNA gene of bacterial DNA was sequenced from stool samples and used to estimate amplicon sequence variants (ASVs). We age-matched children with poor growth to children with normal growth within 1 month and compared the change in abundance and diversity of ASVs over time. Elevated EE markers and poor linear growth in children were associated with changes in microbial communities in the gut. There were increased amounts of

Topics: alpha 1-Antitrypsin; Bangladesh; Biomarkers; Case-Control Studies; Child, Preschool; Escherichia; Feces; Female; Gastrointestinal Microbiome; Growth Disorders; Humans; Infant; Inflammation; Intestinal Diseases; Leukocyte L1 Antigen Complex; Male; Neopterin; Peroxidase; Prevotella; Proteobacteria; Retrospective Studies; RNA, Ribosomal, 16S; Shigella

To investigate N-acetyl-cysteine (NAC) would able to alleviate liver injury and systemic inflammatory response caused by microwave ablation (MWA) in rats.. Male Sprague-Dawley rats weighing 150-200 g were randomly divided into sham group (only anesthesia and laparotomy except MWA but with intraperitoneal PBS or NAC solution injection according to different situations), control group (intraperitoneal PBS injection for comparation 2 h prior to MWA), and NAC-treated group (intraperitoneal N-acetyl-cysteine (300 mg/kg) injection 2 h prior to MWA). Experimental rats were sacrificed at 4 h following operation in line with the liver injury severity curve. Liver tissue and serum samples were collected for determination of pathology, apoptosis, macrophages contents and protein expression.. The elevated serum level of liver enzymes, Myeloperoxidase (MPO) and inflammatory factors (TNF-α and CXCL1) in MWA-treated rats revealed injurious and pro- inflammatory effect of MVA. Macrophages aggregation was detected in MWA exposure rats similarly. and NAC pre-conditioning mitigate liver damage and hepatocyte apoptosis, besides macrophages accumulation and following inflammatory response in liver tissue.. Our results demonstrated that N-acetyl-cysteine application alleviate macrophages aggregation and inflammatory response in liver suffering microwave ablation, and mitigating liver injury and cell apoptosis.

Topics: Ablation Techniques; Acetylcysteine; Animals; Anti-Inflammatory Agents; Apoptosis; Carcinoma, Hepatocellular; Humans; Inflammation; Liver; Liver Diseases; Liver Neoplasms; Macrophages; Male; Microwaves; Peroxidase; Rats, Sprague-Dawley

The inflammatory responses associated with polycystic ovary syndrome (PCOS) may play a significant role in the severity of the disease. Emerging evidence report states that the polyunsaturated fatty acids are capable of ameliorating the PCOS condition. The therapeutic effects of γ-linolenic acid (GLA), an omega-6 fatty acid, in various inflammatory diseases have been reported. Yet, its role in PCOS associated inflammatory response remains unexplored. The aim of the study was to decipher the effects of GLA in PCOS and its role in the PPAR-γ pathway. In our study, female Wistar rats were stimulated with daily subcutaneous injections of DHEA (60 mg/kg per day) for 28 days to induce PCOS. Daily doses of GLA(10, 20, and 50 mg/kg) and Pioglitazone (P)(30 mg/kg) were administered orally for 14 days after PCOS induction. The levels of DHEA, leptin, PPAR-γ were measured by ELISA. The gene expression levels of leptin, TNF-α, IL-33, PPAR-γ, C/EBP-β, SREBP-1were determined by Real Time-PCR. We observed that the GLA significantly attenuated the DHEA and leptin levels. GLA treatment also upregulated PPAR-γ expression, when compared to the DHEA group. Further, GLA treatment showed a significant reduction in DHEA induced TNF-α, IL-33, C/EBP-β, and SREBP-1 levels in Wistar rat polycystic ovary tissue samples. The present findings could indicate that GLA is able to reduce the inflammatory response due to DHEA stimulation and thereafter potentially attenuate PCOS via the PPAR-γ pathway.

Topics: Animals; Dehydroepiandrosterone; Female; gamma-Linolenic Acid; Gene Expression; Inflammation; Peroxidase; Polycystic Ovary Syndrome; PPAR gamma; Rats; Rats, Wistar; Signal Transduction

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Biomarkers; Cell Movement; Cytokines; Gracilaria; Inflammation; Magnetic Resonance Spectroscopy; Male; Mice; Molecular Structure; Peroxidase; Polysaccharides; Spectrum Analysis; Structure-Activity Relationship; Sulfates

The widespread use of synthetic cannabinoids (SCs) among youth has become an important public health problem. Several life-threatening side effects of SC have been reported, including cardiovascular, gastrointestinal, neurological, renal, metabolic, ophthalmologic, and pulmonary effects, besides skin toxicity and hepatotoxicity.. Given that high levels of SC can lead to oxidative stress, DNA damage, and inflammation, it has been aimed in this study to investigate the effects of SC in aspects of primary DNA damage, plasma total oxidant status (TOS)/total antioxidant status (TAS), thiol-disulfide homeostasis, myeloperoxidase (MPO) level, and cytokine levels (interleukin 1 beta (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNF-α)) of 40 SC users (SCUs) in Turkey.. Mean plasma TOS levels were significantly higher in the SCUs group than in the healthy group (HG). Similarly, mononuclear leukocyte DNA damage, plasma TOS, MPO activity, disulfide, oxidative stress index levels, IL-1β, IL-6, and TNF-α levels were significantly higher in the SCU group than in the HG, whereas plasma TAS, total, and native thiol levels were significantly lower in the SCU group than in the HG.. It is concluded that SC can cause increase in oxidative stress and in inflammatory processes in addition to its potential for DNA damage. Additional studies with larger sample sizes and longer durations should be held to understand more specific outcomes of SC use.

Topics: Adolescent; Adult; Cannabinoids; Cytokines; DNA Damage; Humans; Inflammation; Male; Middle Aged; Oxidative Stress; Peroxidase; Substance-Related Disorders; Turkey; Young Adult

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

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

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

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

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

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

Toxicological studies have identified polycyclic aromatic hydrocarbons (PAH) in human breast milk, smoked and barbequed food, although the largest contribution of PAH intake into the body are cereals and cereals products. The major effects attributable to PAH appeared to occur in the liver, lungs, the hematopoietic system, and the kidney. Nevertheless, more precise mechanisms by which PAH initiates its pathological features are not fully understood. In the present study, we evaluated levels of myeloperoxidase activity, its association with nitric oxide synthesis (NO), levels of uric acid (UA) in circulating blood and glucose in female rats exposed to environmental toxicants. A higher concentration of hydrogen peroxide activates myeloperoxidase, which acts as a leucocyte attractant, contributing to enhanced iNOS activity. In parallel, uric acid in addition to its pro-inflammatory effects aggravates insulin resistance and hyperglycemia, which worsens the process. Our findings suggest potential intermediate mechanisms involved in the inflammatory effects of PAH, which might give insight for the involvement of environmental toxicants not only in carcinogenesis but also in its association with acute cardiovascular disease and induction of multi-organ damage. The development of iNOS inhibitors might be beneficial in certain inflammatory disorders.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Biomarkers; Blood Glucose; Environmental Pollutants; Female; Inflammation; Inflammation Mediators; Kidney; Lipid Peroxidation; Liver; Nitric Oxide; Oxidative Stress; Peroxidase; Protein Carbonylation; Rats, Wistar; Uric Acid

Neuroinflammation plays a pathogenic role in neurodegenerative diseases and recent findings suggest that it may also be involved in X-linked Dystonia-Parkinsonism (XDP) pathogenesis. Previously, fibroblasts and neuronal stem cells derived from XDP patients demonstrated hypersensitivity to TNF-α, dysregulation in NFκB signaling, and an increase in several pro-inflammatory markers. However, the role of inflammatory processes in XDP patient brain remains unknown. Here we demonstrate that there is a significant increase in astrogliosis and microgliosis in human post-mortem XDP prefrontal cortex (PFC) compared to control. Furthermore, there is a significant increase in histone H3 citrullination (H3R2R8R17cit

Topics: Adult; Aged; Aged, 80 and over; Astrocytes; Autopsy; Cell Survival; Chemokines; Citrullination; Dystonic Disorders; Female; Fibroblasts; Genetic Diseases, X-Linked; Gliosis; Histones; Humans; Inflammation; Leukocyte Elastase; Male; Microglia; Middle Aged; Ornithine; Peroxidase; Prefrontal Cortex; Protein-Arginine Deiminase Type 2; Protein-Arginine Deiminase Type 4

Sepsis causes organ dysfunction due to an infection, and it may impact the central nervous system. Neuroinflammation and oxidative stress are related to brain dysfunction after sepsis. Both processes affect microglia activation, neurotrophin production, and long-term cognition. Fish oil (FO) is an anti-inflammatory compound, and lipoic acid (LA) is a universal antioxidant substance. They exert neuroprotective roles when administered alone. We aimed at determining the effect of FO+LA combination on microglia activation and brain dysfunction after sepsis. Microglia cells from neonatal pups were co-treated with lipopolysaccharide (LPS) and FO or LA, alone or combined, for 24 h. Cytokine levels were measured. Wistar rats were subjected to sepsis by cecal ligation and perforation (CLP) and treated orally with FO, LA, or FO+LA. At 24 h after surgery, the hippocampus, prefrontal cortex, and total cortex were obtained and assayed for levels of cytokines, myeloperoxidase (MPO) activity, protein carbonyls, superoxide dismutase (SOD), and catalase (CAT) activity. At 10 days after surgery, brain-derived neurotrophic factor (BDNF) levels were determined and behavioral tests were performed. The combination diminished in vitro levels of pro-inflammatory cytokines. The combination reduced TNF-α in the cortex, IL-1β in the prefrontal cortex, as well as MPO activity, and decreased protein carbonyls formation in all structures. The combination enhanced catalase activity in the prefrontal cortex and hippocampus, elevated BDNF levels in all structures, and prevented behavioral impairment. In summary, the combination was effective in preventing cognitive damage by reducing neuroinflammation and oxidative stress and increasing BDNF levels.

Topics: Animals; Brain; Brain-Derived Neurotrophic Factor; Catalase; Cells, Cultured; Cognitive Dysfunction; Cytokines; Female; Fish Oils; Inflammation; Kaplan-Meier Estimate; Memory Disorders; Microglia; Open Field Test; Oxidative Stress; Peroxidase; Protein Carbonylation; Rats, Wistar; Sepsis; Superoxide Dismutase; Thioctic Acid

Generalized pustular psoriasis (GPP) is a severe multi-systemic inflammatory disease characterized by neutrophilic pustulosis and triggered by pro-inflammatory IL-36 cytokines in skin. While 19%-41% of affected individuals harbor bi-allelic mutations in IL36RN, the genetic cause is not known in most cases. To identify and characterize new pathways involved in the pathogenesis of GPP, we performed whole-exome sequencing in 31 individuals with GPP and demonstrated effects of mutations in MPO encoding the neutrophilic enzyme myeloperoxidase (MPO). We discovered eight MPO mutations resulting in MPO -deficiency in neutrophils and monocytes. MPO mutations, primarily those resulting in complete MPO deficiency, cumulatively associated with GPP (p = 1.85E-08; OR = 6.47). The number of mutant MPO alleles significantly differed between 82 affected individuals and >4,900 control subjects (p = 1.04E-09); this effect was stronger when including IL36RN mutations (1.48E-13) and correlated with a younger age of onset (p = 0.0018). The activity of four proteases, previously implicated as activating enzymes of IL-36 precursors, correlated with MPO deficiency. Phorbol-myristate-acetate-induced formation of neutrophil extracellular traps (NETs) was reduced in affected cells (p = 0.015), and phagocytosis assays in MPO-deficient mice and human cells revealed altered neutrophil function and impaired clearance of neutrophils by monocytes (efferocytosis) allowing prolonged neutrophil persistence in inflammatory skin. MPO mutations contribute significantly to GPP's pathogenesis. We implicate MPO as an inflammatory modulator in humans that regulates protease activity and NET formation and modifies efferocytosis. Our findings indicate possible implications for the application of MPO inhibitors in cardiovascular diseases. MPO and affected pathways represent attractive targets for inducing resolution of inflammation in neutrophil-mediated skin diseases.

Topics: Adult; Animals; Cytokines; Extracellular Traps; Female; Humans; Inflammation; Interleukin-1; Interleukins; Male; Mice; Mutation; Neutrophils; Peroxidase; Psoriasis; Rare Diseases; Skin; Skin Diseases

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

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

We investigated the activation of pancreatic proenzymes and signs of peripancreatic inflammation in patients with clinically relevant postoperative pancreatic fistulas (POPFs).. An increase of systemic amylase concentration was associated with POPFs. This suggested parallels in the pathomechanisms between the development of POPFs and pancreatitis.. Trypsinogen, procathepsin B, and IL-6 concentrations as well as cathepsin B, myeloperoxidase and trypsin activities were determined throughout the first 7 postoperative days in drain fluids of 128 consecutive patients after pancreas resection. Histology and immunohistochemistry were performed in pancreatic specimens after total pancreatectomy due to complications and after placing experimental pancreatic sutures in the pancreatic tail of C57/Bl6 mice.. Trypsin activity, cathepsin B activity and myeloperoxidase activity on the first postoperative day were elevated and predictive for clinically relevant pancreatic fistulas. Drain fluid stabilized trypsin activity and prevented the activation of the cascade of digestive enzymes. Leukocytes were the source of cathepsin B in drain fluid. Findings differed between fistulas after distal pancreatectomy and pancreatoduodenectomy. Immunohistochemistry of the pancreatic remnant revealed an inflammatory infiltrate expressing cathepsin B, independent of the presence of pancreatic fistulas. The infiltrate could be reproduced experimentally by sutures placed in the pancreatic tail of C57/Bl6 mice.. Trypsinogen activation, increased cathepsin B activity and inflammation around the pancreato-enteric anastomosis on post operative day 1 are associated with subsequent clinically relevant POPFs after pancreatoduodenectomy. The parenchymal damage seems to be induced by placing sutures in the pancreatic parenchyma during pancreatic surgery.

Topics: Amylases; Animals; Cathepsin B; Enzyme Precursors; Female; Humans; Inflammation; Interleukin-6; Male; Mice; Pancreatectomy; Pancreatic Fistula; Peroxidase; Postoperative Complications; Prospective Studies; Trypsin; Trypsinogen

To investigate the role of IL-33 in gouty arthritis.. 174 Balb/c (wild-type) and 54 ST2. Gout was induced by injection of monosodium urate (MSU) crystals in the knee joint of mice. Pain was determined using the electronic von Frey and static weight bearing. Neutrophil recruitment was determined by H&E staining, Rosenfeld staining slides, and MPO activity. ELISA was used for cytokine and sST2 measurement. The priming effect of IL-33 was determined in BMDM.. Synovial fluid of gout patients showed higher IL-33 levels and neutrophil counts than osteoarthritis patients. In mice, the absence of ST2 prevented mechanical pain, knee joint edema, neutrophil recruitment to the knee joint, and lowered IL-1β and superoxide anion levels. In macrophages, IL-33 enhanced the release of IL-1β and TNF-α, and BMDMs from ST2. IL-33 mediates gout pain and inflammation by boosting macrophages production of cytokines upon MSU crystals stimulus.

Topics: Animals; Arthritis, Gouty; Female; Humans; Inflammation; Interleukin-1 Receptor-Like 1 Protein; Interleukin-1beta; Interleukin-33; Macrophages; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Middle Aged; Neutrophil Infiltration; Pain; Peroxidase; Superoxides; Synovial Membrane; Uric Acid

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

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

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

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

In cases of any acute surgical abdominal disease the progression of purulent inflammation can lead to local or diffuse peritonitis. The indicators of the degree and specificity of the inflammatory response in blood such as cytokine concentration, neutrophil activity, plasma antioxidant capacity (thiols concentration) could be considered as potential predictors of complications. The luminol-dependent chemiluminescence (CL) response of blood activated by the phorbol ester (PMA), and the concentration of cytokines IL-6, IL-8, IL-10, myeloperoxidase (MPO) and thiols in plasma were measured in patients with uncomplicated condition (group 1, n=8), local peritonitis (group 2, n=9) or diffuse peritonitis (group 3, n=9) at admission to surgery (before surgical operation, b/o), immediately after surgical operation (a/o) and a day after surgery (1 day) as well as in healthy volunteers (norm, n=12). In all time-points the cytokines and MPO concentrations measured by ELISA, in group 3 were higher than in healthy volunteers and in patients in groups 1 and 2. Blood CL demonstrated a more than 5-fold increase above the normal values in all patients, and was also higher in group 2 as compared to group 1 (b/o and a/o). Patients in group 3 had shown both maximum and minimum of CL values, which could be a consequence of neutrophil priming or exhaustion ("immune paralysis"), respectively. The same patients' plasma exhibited low thiol concentration (≤30% vs normal values). In patients with fatal outcomes (group 3, n=2) within a day after surgery, either a decrease of the CL to zero values concurrently with elevated IL-8 and IL-6 concentrations and low thiol levels was observed, or CL exceeded normal values more than 20 times with concurrent complete exhaustion of the plasma thiol pool. No clear dependency between the plasma parameters and neutrophil activity was found. Hence a parameter set for prognosis and/or early diagnosis of infectious complications in acute abdominal pathology should include different biomarkers of the inflammatory response: cytokine profile (IL-6, IL-8, IL-10), MPO and neutrophil activity, antioxidant plasma capacity (e.g., total thiols concentration).. Progressirovanie gnoĭno-vospalitel'nogo protsessa pri liuboĭ ostroĭ khirurgicheskoĭ abdominal'noĭ patologii privodit k razvitiiu mestnogo ili rasprostranennogo peritonita. Potentsial'nymi prediktorami oslozhneniĭ mogut byt' pokazateli, kharakterizuiushchie stepen' i osobennosti vospalitel'noĭ reaktsii v krovi — soderzhanie tsitokinov, aktivnost' neĭtrofilov, sostoiatel'nost' antioksidantogo zvena. U patsientov s neoslozhnennoĭ patologieĭ (gruppa 1, n=8), mestnym peritonitom (gruppa 2, n=9) i rasprostranennym peritonitom (gruppa 3, n=9) pri postuplenii v khirurgicheskoe otdelenie (do operatsii), nemedlenno posle operatsii i cherez sutki, a takzhe u zdorovykh dobrovol'tsev (norma, n=12) izmeriali liuminol-zavisimuiu khemiliuminestsentsiiu(KhL) krovi, aktivirovannuiu forbol-12-miristat-13-atsetatom, i kontsentratsiiu IL-6, IL-8, IL-10, mieloperoksidazy (MPO) i tiolov v plazme krovi. Po dannym immunofermentnogo analiza, vo vsekh vremennykh tochkakh kontsentratsiia tsitokinov IL-6, IL-8 i IL-10, a takzhe MPO v gruppe 3 byla vyshe, chem u zdorovykh dobrovol'tsev i patsientov grupp 1 i 2. Velichina KhL krovi u vsekh patsientov bolee chem v 5 raz uvelichivalas' po sravneniiu s normoĭ, a u patsientov gruppy 2 — po sravneniiu s gruppoĭ 1. V gruppe 3 vyiavlialis' patsienty kak s maksimal'nymi, tak i s minimal'nymi iz vsekh zaregistrirovannykh znacheniĭ KhL, chto mozhet byt' sledstviem praĭminga i istoshcheniia neĭtrofilov sootvetstvenno. U étikh zhe patsientov soderzhanie tiolov snizhalos' v 3 i bolee raz po sravneniiu s normoĭ. U patsientov s letal'nym iskhodom v techenie pervykh sutok posle operatsii (gruppa 3, n=2) otmecheno libo snizhenie KhL do nulevykh znacheniĭ na fone vysokogo soderzhaniia IL-8 i IL-6 i nizkogo (v 3 i bolee raz nizhe normy) urovnia tiolov, libo KhL otvet, 20-kratno prevyshaiushchiĭ normu, pri polnom istoshchenii pula tiolov v plazme. Odnoznachnoĭ zavisimosti mezhdu pokazateliami v plazme i aktivnost'iu neĭtrofilov ne bylo. Éto oznachaet, chto panel' pokazateleĭ dlia prognoza i/ili ranneĭ diagnostiki infektsionnykh oslozhneniĭ pri ostroĭ khirurgicheskoĭ patologii dolzhna vkliuchat' v sebia razlichnye biomarkery vospalitel'nogo otveta: tsitokinovyĭ profil' (IL-6, IL-8, IL-10), MPO i aktivnost' neĭtrofilov, antioksidantnuiu emkost' plazmy (kontsentratsiiu tiolov).

Topics: Biomarkers; Cytokines; Humans; Inflammation; Peritonitis; Peroxidase

Biocompatibility of hemodialysis (HD) systems have been considerably improved. However, mortality and morbidity rates of patients have remained high, raising questions regarding the biocompatibility of current systems. In the present study, 70 patients on regular HD (51 males; mean age, 63 years; median duration of HD, 18 months) with high-performance membrane (polysulfone, 77%; polymethylmethacrylate, 23%) at Tohoku University Hospital were examined. Blood samples before and after HD, were subjected to measure apoptosis cells of white blood cells, plasma levels of the following molecules: myeloperoxidase (MPO), pentraxin 3 (PTX3), angiogenin, complements, and 17 cytokines. The main findings were as follows: significant decreases in leukocyte counts by dialysis, significant increases in apoptosis-positive leukocytes by dialysis (neutrophils and monocytes), and significant decrease in plasma angiogenin accompanying increase in plasma MPO and PTX3 levels, with no or only marginal changes in plasma pro-inflammatory cytokine levels and complement products by dialysis. The findings underlined the unsolved issue of bio-incompatibility of HD systems, and suggest the possible pathology of neutrophil apoptosis accompanying MPO release for the development of microinflammation in patients on HD.

Topics: Apoptosis; Biocompatible Materials; C-Reactive Protein; Complement System Proteins; Cytokines; Humans; Inflammation; Inflammation Mediators; Male; Middle Aged; Neutrophils; Peroxidase; Renal Dialysis; Ribonuclease, Pancreatic; Serum Amyloid P-Component

Rheumatoid arthritis (RA) is a chronic inflammatory disorder affecting synovial joints. Neutrophils are believed to play an important role in both the initiation and progression of RA, and large numbers of activated neutrophils are found within both synovial fluid (SF) and synovial tissue from RA joints. In this study we analyzed paired blood and SF neutrophils from patients with severe, active RA (DAS28>5.1, n=3) using RNA-seq. 772 genes were significantly different between blood and SF neutrophils. IPA analysis predicted that SF neutrophils had increased expression of chemokines and ROS production, delayed apoptosis, and activation of signaling cascades regulating the production of NETs. This activated phenotype was confirmed experimentally by incubating healthy control neutrophils in cell-free RA SF, which was able to delay apoptosis and induce ROS production in both unprimed and TNFα primed neutrophils (p<0.05). RA SF significantly increased neutrophil migration through 3μM transwell chambers (p<0.05) and also increased production of NETs by healthy control neutrophils (p<0.001), including exposure of myeloperoxidase (MPO) and citrullinated histone-H3-positive DNA NETs. IPA analysis predicted NET production was mediated by signaling networks including AKT, RAF1, SRC, and NF-κB. Our results expand the understanding of the molecular changes that take place in the neutrophil transcriptome during migration into inflamed joints in RA, and the altered phenotype in RA SF neutrophils. Specifically, RA SF neutrophils lose their migratory properties, residing within the joint to generate signals that promote joint damage, as well as inflammation

Topics: Apoptosis; Arthritis, Rheumatoid; Chemokines; Extracellular Traps; Female; Humans; Inflammation; Joints; Male; Middle Aged; Neutrophil Activation; Neutrophils; Peroxidase; Reactive Oxygen Species; Signal Transduction; Synovial Fluid; Synovial Membrane

Allergic contact dermatitis (ACD) is a common skin disorder affecting an estimated 15-20% of the general population. The mouse model of ACD is contact hypersensitivity (CHS), which consists of two phases: induction and elicitation. Although neutrophils are required for both CHS disease phases their mechanisms of action are poorly understood. Neutrophils release myeloperoxidase (MPO) that through oxidation of biomolecules leads to cellular damage.. This study investigated mechanisms whereby MPO contributes to CHS pathogenesis.. CHS was induced in mice using oxazolone (OX) as the initiating hapten applied to the skin. After 7 days, CHS was elicited by application of OX to the ear and disease severity was measured by ear thickness and vascular permeability in the ear. The role of MPO in the two phases of CHS was determined utilizing MPO-deficient mice and a specific MPO inhibitor.. During the CHS induction phase MPO-deficiency lead to a reduction in IL-1β production in the skin and a subsequent reduction in migratory dendritic cells (DC) and effector T cells in the draining lymph node. During the elicitation phase, inhibition of MPO significantly reduced both ear swelling and vascular permeability.. MPO plays dual roles in CHS pathogenesis. In the initiation phase MPO promotes IL-1β production in the skin and activation of migratory DC that promote effector T cell priming. In the elicitation phase MPO drives vascular permeability contributing to inflammation. These results indicate that MPO it could be a potential therapeutic target for the treatment of ACD in humans.

Topics: Animals; Cell Movement; Dendritic Cells; Dermatitis, Allergic Contact; Dermatitis, Contact; Haptens; Inflammation; Interleukin-1beta; Lymph Nodes; Mice; Mice, Inbred C57BL; Neutrophils; Oxazolone; Peroxidase; Skin; T-Lymphocytes

Topics: Biomarkers; Cardiovascular Diseases; Diabetes Mellitus; Glycated Hemoglobin; Humans; Inflammation; Lipoproteins, LDL; Peroxidase; Physicians; Prediabetic State; Risk Factors; Risk Reduction Behavior

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

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

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Female; Humans; Inflammation; Peroxidase

In the current study, we explored the role of extracellular ATP (eATP) in promoting systemic inflammation during development of acute pancreatitis (AP). Release of extracellular (e)ATP was evaluated in plasma and bronchoalveolar lavage fluid (BALF) of mice with experimental acute pancreatitis (AP). Prophylactic intervention using apyrase or suramin was used to understand the role and contribution of eATP in pancreatitis-associated systemic injury. AP of varying severity was induced in C57BL/6 mice using 1-day or 2-day caerulein, caerulein + LPS and l-arginine models. eATP was measured in plasma and BALF. Mice were treated with suramin or apyrase in the caerulein and l-arginine models of AP. Plasma cytokines, lung, and pancreatic myeloperoxidase, and morphometric analysis of pancreatic and lung histology, were used to assess the severity of pancreatitis. Plasma eATP and purinergic 2 (P2) receptors in the pancreas and lungs were significantly elevated in the experimental models of AP. Blocking the effect of eATP by suramin led to reduced levels of plasma IL-6 and TNFα as well as reduced lung, and pancreatic injury. Neutralizing eATP with apyrase reduced systemic injury but did not ameliorate local injury. The results of this study support the role of eATP and P2 receptors in promoting systemic inflammation during AP. Modulating purinergic signaling during AP can be an important therapeutic strategy in controlling systemic inflammation and, thus, systemic inflammatory response syndrome during AP.

Topics: Acute Disease; Adenosine Triphosphate; Animals; Apyrase; Arginine; Bronchoalveolar Lavage Fluid; Ceruletide; Cytokines; Inflammation; Lung; Mice; Mice, Inbred C57BL; Pancreas; Pancreatitis; Peroxidase; Receptors, Purinergic; Signal Transduction; Suramin

The function of oxidatively modified low-density lipoprotein (oxLDL) in the progression of cardiovascular diseases has been extensively investigated and well-characterized with regards to the activation of multiple cellular responses in macrophages and endothelial cells. Although accumulated evidence has revealed the presence of neutrophils in vascular lesions, the effect of oxLDL on neutrophil function has not been properly investigated. In the present decade, neutrophil extracellular traps (NETs) gained immense attention not only as a primary response against pathogenic bacteria but also due to their pathological roles in tissue damage in various diseases, such as atherosclerosis and thrombosis. In this study, we investigated if oxLDL affects NET formation and if it is a risk factor for inflammatory reactions in endothelial cells. HL-60-derived neutrophils were stimulated with phorbol 12-myristate 13-acetate (PMA) for 30 min to induce NET formation, followed by incubation with 20 μg/mL native or oxidized LDL for additional 2 h. Culture media of the stimulated cells containing released NETs components were collected to evaluate NET formation by fluorometric quantitation of released DNA and detection of myeloperoxidase (MPO) by western blot analysis. NET formation of HL-60-derived neutrophils induced by PMA was significantly enhanced by additional incubation with oxLDL but not with native LDL. Treatment of HL-60-derived neutrophils with oxLDL alone in the absence of PMA did not induce NET formation. Furthermore, the culture media of HL-60-derived neutrophils after NET formation were then transferred to human aortic endothelial cell (HAECs) culture. Treatment of HAECs with the culture media containing NETs formed by HL-60-derived neutrophils increased the expression of metalloproteinase-1 protein in HAECs when HL-60-derived neutrophils were incubated with native LDL, and the expression was accelerated in the case of oxLDL. In addition, the culture media from NETs formed by HL-60-derived neutrophils caused the elongation of HAECs, which was immensely enhanced by coincubation with native LDL or oxLDL. These data suggest that oxLDL may act synergistically with neutrophils to form NETs and promote vascular endothelial inflammation.

Topics: Endothelial Cells; Extracellular Traps; HL-60 Cells; Humans; Inflammation; Lipoproteins, LDL; Peroxidase

3,4-Dihydroxyphenylethanol (DOPET) is a potent antioxidant polyphenolic compound. In this study, our objective was to investigate the underlying mechanism of the neuroprotective role of DOPET in attenuating spinal cord injury (SCI). Initially, SCI was induced by performing surgical laminectomy on the rats at T10-T12 level. Then, the neurological function-dependent locomotion was measured using Basso Beattie Bresnahan score, which declined in the SCI-induced group. Increased antioxidant levels such as superoxide dismutase, glutathione peroxidase, and glutathione along with other parameters such as increased lipid peroxidation (LPO) and myeloperoxidase (MPO) activities were all observed in the SCI group. Levels of proinflammatory cytokines such as tumor necrosis factor-α and interleukin-1β were upregulated in the serum and spinal cord tissue as observed on the immunoblot. Interestingly, protein levels of apoptotic markers such as Bax, cleaved caspase 3 and RT-PCR analysis-based mRNA level of pro-inflammatory cytokine, nuclear factor- κ activated B cells (NF-κB) were significantly upregulated in the spinal cord tissue. Nonetheless, antiapoptotic factor such as B-cell lymphoma 2 (Bcl-2) protein expression was downregulated in the same group. However, on administering 10 mg/kg of DOPET, the neuronal function was rescued, antioxidants were restored back to the normal levels, LPO and MPO activities were reduced in conjunction with downregulated levels of proinflammatory cytokines and apoptotic markers in the SCI group. These findings show that DOPET could potentially target multiple signalling pathways to combat SCI.

Topics: Animals; Antioxidants; Apoptosis Regulatory Proteins; Cytokines; Inflammation; Lipid Peroxidation; Locomotion; Male; Oxidative Stress; Peroxidase; Phenylethyl Alcohol; Rats; Rats, Sprague-Dawley; Signal Transduction; Spinal Cord Injuries

This study aimed to examine the superiority of peroxidase detection of macroscopic observations using rat wounds, and to test the external validity of the peroxidase analysis in pressure ulcers (PU) in humans.. In the animal study, rat wounds were analysed. A cross-sectional study analysed, by wound blotting, exudate samples from full-thickness PUs. Peroxidase activity was divided into two groups (ring and non-ring signals). Scores in the 'inflammation/infection' and 'necrotic tissue' components of DESIGN, a classification tool of PUs, were compared between the groups.. In the animal study, 20 rat wounds were assessed and in the clinical study, 62 samples were collected from 26 full-thickness PUs of 21 patients aged ≥ 65 years. In the animal study, five of six wounds with clinical inflammation signs showed ring signal (defined as a signal on the wound edge and no signal on the wound bed). While the tissue sections of three wounds with a ring signal showed inflammatory features, they showed no clinical signs of 'inflammation/infection'. In the clinical study, which analysed 630 ring and 32 non-ring signals, 13 samples in the ring signal group and five in the non-ring signal group had 'inflammation/infection; scores of ≥1 (p=0.016). Despite having no clinical signs, 17 samples showed the ring signal.. This study revealed the external validity of the wound blotting analysis of peroxidase and demonstrated its use to detect subclinical inflammation.

Topics: Adult; Animals; Blotting, Western; Cross-Sectional Studies; Female; Humans; Hydrogen-Ion Concentration; Inflammation; Male; Middle Aged; Peroxidase; Pressure Ulcer; Rats; Wound Healing

Background Acute respiratory distress syndrome (ARDS), which is the severest form of pulmonary injury, is the leading cause of death in critical care. At present, the mortality remains high in ARDS. Partial liquid ventilation (PLV) using perfluorocarbon (PFC) has been proven to improve gas exchange and respiratory dynamics of the lungs during ARDS. However, PLV has not been shown to reduce the mortality of ARDS. Some studies have shown that mild hypothermia therapy can reduce lung injuries in animal models of ARDS by reducing inflammatory cytokine levels in lung tissues. However, hypothermia cannot produce a lung protection effect alone, and it may have a synergistic effect with other protective measures. To explore the possible role of PLV combined with mild hypothermia in the treatment of ARDS, in this study, we used PFC liquid ventilation to induce mild hypothermia in dogs suffering from ARDS and analyzed the effects of PFC liquid ventilation-induced mild hypothermia on the levels of inflammatory factors and lung histopathology in dogs with ARDS. The experimental dogs were randomly divided into conventional mechanical ventilation (CMV), normal temperature PFC liquid ventilation (NPLV), hypothermic PFC liquid ventilation (HPLV), and mechanical ventilation (MV) groups. After induction of ARDS, the CMV group was treated with CMV for respiratory support, the HPLV group was treated with PLV-induced mild hypothermia using 15 °C PFC and maintained the rectal temperature at 34-36 °C, the NPLV group was treated with PLV using 36 °C PFC and maintained the rectal temperature at 36-38 °C. The MV group served as the control group. Analyses of the pulmonary pathology, partial pressure of oxygen in the blood, and lung wet-dry weight ratio (W/T) of each dog revealed that PLV-induced mild hypothermia significantly increased the PaO

Topics: Animals; Arteries; Blood Gas Analysis; Bronchoalveolar Lavage Fluid; Dogs; Hemodynamics; Hypothermia, Induced; Inflammation; Interleukin-6; Liquid Ventilation; Lung; Male; Partial Pressure; Peroxidase; Respiratory Distress Syndrome; Temperature; Transcription Factor RelA; Tumor Necrosis Factor-alpha

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

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

To evaluate the biomarkers related to cardiovascular risk in pre-pubertal preterm children with a birth weight of less than 1,500 g and relate them to current nutritional status, insulin resistance, and inflammation.. This is a cross-sectional, controlled study with pre-pubertal preterm children aged 5-9 years with a birth weight of less than 1500 g (Preterm group, n = 44) compared to full term children of adequate weight for gestational age (Control group, n = 30). Clinical evaluation: anthropometry and pubertal staging. Laboratory tests: total cholesterol and fractions, triglycerides, paraoxonase 1, apolipoproteins A-I and B, myeloperoxidase (MPO), high sensitivity C-reactive protein (hs-CRP), glycemia and insulin (to calculate HOMA-IR). In the preterm group, 19 (43.2%) were male, with mean birth weight and gestational age of 1157 ± 242 g and 30.0 ± 2.3 weeks, respectively. The preterm group showed lower concentrations of HDL-c (60.1 ± 10.1 vs. 69.0 ± 10.0 mg/dL; p < 0.001); higher concentrations of hs-CRP [0.55 mg/dL (0.30; 39.4) vs. 0.30 mg/dL (0.30; 10.80); p = 0.043], of MPO [21.1 ng/mL (5.7; 120.0) vs. 8.1 ng/mL (2.6; 29.6); p < 0.001] and of MPO/HDL-c ratio [0.39 (0.09; 2.07) ng/mg vs. 0.11 (0.05; 0.58)]. The MPO/HDL-c ratio was the variable that showed the best discriminatory power between the groups (AUC = 0.878; 95% CI; 0.795-0.961). MPO concentrations in the preterm group were correlated with those of hs-CRP (r = 0.390; p = 0.009), insulin (r = 0.448; p = 0.002) and HOMA-IR (r = 0.462; p = 0.002).. Prepubertal preterm children show high MPO concentrations and MPO/HDL-c ratio that are associated with inflammation and oxidative stress, which, in turn, may be associated with atherosclerosis.

Topics: Age Factors; Atherosclerosis; Biomarkers; Birth Weight; Blood Glucose; C-Reactive Protein; Case-Control Studies; Child; Child Development; Child Nutritional Physiological Phenomena; Cholesterol, HDL; Cross-Sectional Studies; Female; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Inflammation; Inflammation Mediators; Insulin; Insulin Resistance; Male; Nutritional Status; Oxidative Stress; Peroxidase; Risk Assessment; Risk Factors; Up-Regulation

Cisplatin (CP) is one of the most effective chemotherapeutics in the treatment of human cancers. However, the beneficial effects of CP are limited by the toxic effects, especially nephrotoxicity. Fluorofenidone (AKFPD) is a promising multifunctional antifibrosis pyridinone drug discovered by our group. But there is no evidence of its protective effects against acute kidney injury (AKI). Therefore, we investigated the protective effects of AKFPD on CP-induced AKI

Topics: Acute Kidney Injury; Animals; Antineoplastic Agents; Cell Line; Cisplatin; Copper Transporter 1; Gene Expression Regulation; Inflammation; Kidney; Male; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase Kinases; Organic Cation Transporter 2; Peroxidase; Pyridones; Random Allocation; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Reperfusion Injury

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

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

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

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

Aberrant innate immune response drives the pathophysiology of many diseases. Myeloperoxidase (MPO) is a highly oxidative enzyme secreted by activated myeloid pro-inflammatory immune cells such as neutrophils and macrophages, and is a key mediator of the damaging innate immune response. Current technologies for detecting MPO activity in living organisms are sparse and suffer from any combination of low specificity, low tissue penetration, or low spatial resolution. We describe a versatile imaging platform to detect MPO activity using an activatable construct conjugated to a biotin moiety (MPO-activatable biotinylated sensor, MABS) that allows monitoring the innate immune response and its modulation at different scales and settings.

Topics: Animals; Female; Fluorescence; Gold; Immunity, Innate; Inflammation; Leukocyte Count; Macrophages; Metal Nanoparticles; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophils; Oxidation-Reduction; Peroxidase; Tomography, X-Ray Computed

Hypocholesterolemia is the most frequently encountered lipid abnormality in sickle cell disease (SCD). We enrolled pediatric patients to determine the relationships between lipid profile and parameters of hemolysis, oxidative stress and chronic inflammation in SCD.. The study involved 35 pediatric SCD patients and 19 healthy controls. Patients were crisis-free and had not received transfusions for the last 3 months. Total cholesterol, triglyceride, HDL-C, LDL-C, VLDL-C, apolipoprotein A1, apolipoprotein B, LCAT, LDH, bilirubin, haptoglobin, iron, ferritin, hemin, serum amyloid A (SAA), myeloperoxidase (MPO), uric acid, ALT and GGT levels were evaluated in patients' blood.. Patients had hypocholesterolemia depicted by lower levels of total cholesterol, HDL-C, LDL-C, as well as Apolipoprotein A1 and Apolipoprotein B compared to controls. The chronic hemolysis of SCD was evident in patients by higher LDH and bilirubin and almost undetectable haptoglobin levels. Hemin levels (as a measure of oxidized heme) were significantly increased in patients with SCD. Inflammation markers, SAA and MPO, were significantly increased in the patients as well. There were negative correlations between HDL-C and LDH, and Apo A1 and SAA. Hemin was positively correlated to MPO.. Hemolysis was associated with decreased HDL -C, and Inflammation was linked to decreased apolipoprotein A1 levels in our SCD patients. Therefore, we suggest that the HDL particle is altered during the course of the disease. The altered HDL in SCD may become dysfunctional and result with a slowing down of the reverse cholesterol transport.

Topics: Adolescent; Adult; Anemia, Sickle Cell; Apolipoprotein A-I; Apolipoproteins B; Bilirubin; Biomarkers; Child; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Cholesterol, VLDL; Female; Hemolysis; Humans; Inflammation; L-Lactate Dehydrogenase; Lipids; Male; Peroxidase; Serum Amyloid A Protein; Triglycerides; Young Adult

Topics: Animals; Biomarkers; Colitis, Ulcerative; Colon; Cytokines; Diterpenes; Inflammation; Male; Oxazolone; Peroxidase; Rats, Sprague-Dawley; Receptors, Interleukin-4; Signal Transduction; STAT6 Transcription Factor; Transcription Factor RelA

Increased endothelial cell adhesion molecule (ECAM) expression, leukocyte-endothelial cell adhesive interactions (LECA), platelet-endothelial cell adhesion (PECA), mast cell activation, production of reactive oxygen species (ROS), and microvascular permeability are hallmarks of the inflammatory response. The infiltration of inflammatory phagocytes is associated with myeloperoxidase (MPO)-dependent production of hypochlorous acid, a reactive chlorinating species that targets membrane lipids to produce halogenated lipids such as 2-chlorohexadecanal (2-ClHDA) and 2-chloropalmitic acid (2-ClPA). Whether these chlorinated lipids contribute to microcirculatory dysfunction is largely unknown. Thus, the objectives of this study were to determine if chlorinated lipids exposure induces such inflammatory responses in an in vitro model employing cultured human intestinal mesenteric vascular endothelial cells (HIMVEC), and in an in vivo model examining responses in small intestinal and mesenteric postcapillary venules of naive rats. Following the addition of either 2-ClPA or 2-ClHDA to the culture medium, HIMVEC displayed increased platelet and neutrophil adherence that was associated with elevated expression of ECAMs and increased permeability. In vivo, chlorinated lipid exposure significantly increased LECA, PECA, ROS production, and albumin leakage, inflammatory events that were associated with mast cell activation and increased tissue MPO activity and expression. Our data provide proof-of-principle that 2-ClPA and 2-ClHDA induce powerful proinflammatory responses both in vitro and in vivo, suggesting the possibility that these chlorinated lipid products of the MPO/ hydrogen peroxide /chloride system may contribute to inflammation noted in neutrophil-dependent, myeloperoxidase-mediated pathologic states such as ischemia/reperfusion, hemorrhagic shock, and sepsis.

Topics: Aldehydes; Animals; Blood Platelets; Cell Adhesion; Cell Line; Endothelial Cells; Humans; Hypochlorous Acid; Inflammation; Male; Neutrophils; Peroxidase; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Sepsis; Shock, Hemorrhagic

EAFO. Flavonoid-rich fraction of

Topics: Animals; Behavior, Animal; Brain; Dose-Response Relationship, Drug; Flavonoids; Glutathione; Illness Behavior; Inflammation; Lipopolysaccharides; Liver; Male; Malondialdehyde; Mice; Nitrites; Ocimum; Oxidative Stress; Peroxidase; Plant Extracts; Plant Leaves; Tumor Necrosis Factor-alpha

Neutrophil dysfunction plays an important role in inflammation-induced tissue injury. Previously, we identified protein kinase C-δ (PKCδ) as a critical controller of neutrophil activation and trafficking but how PKCδ is regulated in inflammation has not been delineated. PKCδ activity is regulated by tyrosine phosphorylation on multiple sites. Tyrosine155 is a key regulator of apoptosis and gene expression, but its role in proinflammatory signaling is not known.. In-vitro studies - superoxide anion (O2) and neutrophil extracellular traps (NETs) were measured in bone marrow neutrophils (BMN) isolated from wild type (WT) and PKCδY155F knock-in mice (PKCδ tyrosine 155 → phenylalanine). Our novel 3D biomimetic microfluidic assay (bMFA) was used to delineate PKCδ-mediated regulation of individual steps in neutrophil adhesion and migration using WT and PKCδY155F BMN and mouse lung microvascular endothelial cells (MLMVEC). In-vivo studies - WT and PKCδY155F knock-in mice underwent sham or cecal ligation and puncture surgery and the lungs harvested 24 h post-surgery.. In vitro - PKCδY155F BMN had significantly reduced O2 and NETs release compared with WT. WT BMN, but not PKCδY155F BMN, demonstrated significant adhesion and migration across tumor necrosis factor-activated MLMVEC in bMFA. PKCδ inhibition significantly reduced WT BMN adhesion and migration under low shear and near bifurcations, but had no effect on PKCδY155F BMN. In vivo - mutation of PKCδ tyrosine 155 significantly decreased neutrophil migration into the lungs of septic mice.. PKCδ tyrosine 155 is a key phosphorylation site controlling proinflammatory signaling and neutrophil-endothelial cell interactions. These studies provide mechanistic insights into PKCδ regulation during inflammation.

Topics: Animals; Apoptosis; Bone Marrow Cells; Cell Adhesion; Endothelial Cells; Endothelium, Vascular; Female; Fibronectins; Gene Knock-In Techniques; Inflammation; Male; Mice; Mice, Transgenic; Microcirculation; Microfluidics; Neutrophil Activation; Neutrophils; Oxygen; Permeability; Peroxidase; Phenylalanine; Phosphorylation; Protein Kinase C-delta; Sepsis; Superoxides; Tyrosine

CD

Topics: Adult; CD4-Positive T-Lymphocytes; Cell Differentiation; Cells, Cultured; Glycation End Products, Advanced; Humans; Inflammation; Leukocyte Elastase; Neutrophils; Peroxidase; Th1 Cells; Th17 Cells; Transcriptional Activation

Calcitonin gene-related peptide (CGRP) has antioxidant and anti-inflammatory activities on the pathological damage of acute pancreatitis. However, its molecular mechanism on severe acute pancreatitis (SAP) remains unknown.. To evaluate the influence of CGRP-mediated p38MAPK signaling pathway in rats with SAP.. SD rats were randomly divided into Sham group, SAP group, CGRP group (SAP rats injected with CGRP), SB203580 group (rats injected with p38MAPK pathway inhibitor SB203580), and CGRP8-37 group (SAP rats injected with CGRP8-37). Serum amylase and lipase activities were determined. Histopathological observations were evaluated, and the expression of inflammatory cytokines and oxidative stress-related indexes were measured.. Compared with Sham group, SAP rats were increased in the activities of serum amylase and lipase, the pathologic assessment of pancreatic tissue, the levels of TNF-α, IL-1β, IL-6, and IL-8, the content of MDA and MPO, and the expressions of CGRP, and p-p38MAPK protein, but they were decreased in SOD activity and GSH content. The above alterations were aggravated in the CGRP8-37 group when compared with SAP group. Besides, in comparison with SAP group, rats in the CGRP and SB203580 groups presented a reduction in the activities of serum amylase and lipase, the levels of inflammatory cytokines, the content of MDA and MPO, and the expressions of p-p38MAPK protein, while showed an elevation in SOD activity and GSH content.. Pretreatment with CGRP alleviated oxidative stress and inflammatory response of SAP rats possibly by suppressing the activity of p38MAPK pathway, and thereby postponing the disease progression.

Topics: Acute Disease; Amylases; Animals; Calcitonin Gene-Related Peptide; Cytokines; Disease Progression; Enzyme Inhibitors; Imidazoles; Inflammation; Interleukin-1beta; Interleukin-6; Interleukin-8; Lipase; Malondialdehyde; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Pancreas; Pancreatitis; Peptide Fragments; Peroxidase; Pyridines; Random Allocation; Rats; Rats, Sprague-Dawley; Severity of Illness Index; Signal Transduction; Tumor Necrosis Factor-alpha

Therapeutic interventions to treat acute lung injury (ALI) remain largely limited to lung-protective strategies, as a real molecular pathophysiologically driven therapeutic intervention has yet to become available. While we have previously documented the expression of herpes virus entry mediator (HVEM) on leukocytes of septic mice and critically ill patients, its functional role in shock/sepsis-induced ALI has not yet been studied. Inasmuch, a murine model of indirect ALI (iALI) was induced by hemorrhagic shock (HEM) followed by cecal ligation and puncture (CLP), septic challenge and HVEM-siRNA or phosphate buffered saline was administrated by intratracheal instillation 2 h after hemorrhage to determine the role of HVEM in the development of experimental iALI. Indices of lung injury were measured. HVEM expression was significantly elevated in iALI mice. Compared with phosphate buffered saline treated iALI mice, HVEM knock-down by siRNA caused a reduction of cytokine/chemokine levels, myeloperoxidase activity, broncho-alveolar lavage fluid (BALF) cell count and protein concentration. HVEM-siRNA treatment reduced inflammation and attenuated pulmonary architecture destruction as well as provided an early (60 h post HEM-CLP) survival benefit in iALI mice. This ability of anti-HVEM treatment to prevent the development of iALI and provide a transient survival benefit implies that mitigating signaling through HVEM may be a novel target worth further investigation.

Topics: Acute Lung Injury; Animals; Blotting, Western; Flow Cytometry; Inflammation; Male; Mice; Mice, Inbred C57BL; Peroxidase; Receptors, Tumor Necrosis Factor, Member 14; RNA, Small Interfering; Sepsis; Virus Internalization

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

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

It has been previously verified that mesenchymal stromal cells (MSCs) have a good therapeutic effect on severe acute pancreatitis (SAP) and the potential for regeneration of damaged pancreatic tissue, but the exact molecular mechanism remains unclear. In this study, we demonstrated the therapeutic effect of bone morrow MSCs (BMSCs) on SAP, probably by targeting heme oxygenase-1 (HO-1).. Six hours after SAP induction, either phosphate-buffered saline (PBS) or BMSCs were transfused into the caudal vein of rats, zinc protoporphyrin (ZnPP) was administered intraperitoneally. Pancreatic pathological scoring, serum levels of amylase and inflammatory factors, as well as levels of reactive oxygen species (ROS), malondialdehyde (MDA) and myeloperoxidase (MPO), superoxide dismutase (SOD) and catalase (CAT) activity in the pancreas were evaluated.. Our data showed that BMSCs significantly reduce inflammation and oxidative stress, reduce apoptosis and promote angiogenesis of damaged pancreas. Moreover, BMSCs increased the level of HO-1 in the serum and pancreatic tissue in rats with SAP. In addition, the protective effect of BMSCs was partially neutralized by the HO-1 activity inhibitor ZnPP, suggesting a key role of HO-1 in the therapeutic effect of BMSCs on SAP.. BMSCs ameliorated SAP, probably by inducing expression of HO-1, which can exert anti-inflammatory and anti-oxidant effects, reduce apoptosis and promote angiogenesis.

Topics: Amylases; Animals; Apoptosis; Catalase; Heme Oxygenase (Decyclizing); Inflammation; Male; Malondialdehyde; Mesenchymal Stem Cell Transplantation; Neovascularization, Physiologic; Oxidative Stress; Pancreatitis; Peroxidase; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Superoxide Dismutase

Topics: Brain Edema; Ferric Compounds; Humans; Inflammation; Magnetic Resonance Imaging; Malaria, Cerebral; Molecular Imaging; Nanoparticles; Peroxidase

This study aimed to investigate the association between salivary levels of myeloperoxidase (MPO), neutrophil elastase (NE), soluble urokinase-type plasminogen activator receptor (suPAR), matrix metalloproteinase (MMP)-8 and tissue inhibitor of matrix metalloproteinases (TIMP)-1 and gingival inflammation development during an experimental gingivitis study.. A three-week experimental gingivitis study was conducted. Clinical recordings of dental plaque biofilm (Modified Quigley Hein Plaque Index, TQHPI) and gingival inflammation (Modified Gingival Index, MGI) were made at specific time points for each of the 42 participants. Salivary levels of MPO, NE, suPAR, MMP-8 and TIMP-1 at the same time points were measured using distinct immunoassays. For data analysis growth curve modelling was employed to account for the time-varying outcome (MGI score) and the time-varying covariates (salivary marker levels, and TQHPI score). Analyses were stratified according to the MGI-score trajectory groups previously identified as 'fast', respectively 'slow' responders.. Overall, higher MGI scores were statistically significantly positively associated with higher levels of MPO, MMP-8 and TIMP-1. Stratified analysis according to inflammation development trajectory group revealed higher levels of salivary MPO, MMP-8 and MMP-8/TIMP-1 ratio among the 'fast' responders than among 'slow' responders. None of the investigated salivary protein markers was associated with a 'slow' inflammation development response.. Salivary levels of MPO, MMP-8 and TIMP-1 were associated with the extent and severity of gingival inflammation. While the 'fast' gingival inflammation response was associated with increased levels of MPO, MMP-8 and MMP-8/TIMP-1 ratio, the 'slow' response was not associated with any of the salivary protein markers investigated in this study. Neutrophil activity seems to orchestrate a 'fast' gingival inflammatory response among participants previously primed to gingival inflammation.

Topics: Adult; Biomarkers; Dental Plaque Index; Female; Gingiva; Gingivitis; Humans; Inflammation; Male; Matrix Metalloproteinase 8; Periodontal Index; Peroxidase; Saliva; Tissue Inhibitor of Metalloproteinase-1; Young Adult

IRW (Ile-Arg-Trp), a bioactive peptide isolated from egg ovotransferrin, has been shown to exert anti-inflammatory effects. In this study, the effects of IRW on inflammatory cytokines and microbiota were explored in human umbilical vein endothelial cells (HUVECs) and a lipopolysaccharide (LPS)-induced rat model of inflammatory peritonitis. Rats were injected intraperitoneally with LPS to establish peritonitis. HUVECs were exposed to IRW for 12 h before introducing LPS. Notably, IRW exerted beneficial effects against LPS-induced peritonitis, specifically, by reducing the serum levels of tumour necrosis factor (TNF)-

Topics: Animals; Anti-Inflammatory Agents; Cell Line; Conalbumin; Cytokines; Female; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-6; Lipopolysaccharides; NF-kappa B; Peptides; Peritonitis; Peroxidase; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

Low-grade systemic inflammation is a predictor of recurrent cardiac events in patients with coronary artery disease (CAD). Plasma proteins such as matrix metalloproteinase (MMP)-9 and myeloperoxidase (MPO) have been shown to reflect basal as well as stress-induced inflammation in CAD. Measurements of MMP-9 and MPO in saliva might pose several advantages. Therefore, we investigated whether salivary levels of MMP-9 and MPO corresponded to plasma levels in patients with coronary artery disease (CAD), both at rest and after acute physical exercise.. A bicycle ergometer test was used as a model for stress-induced inflammation. Twenty-three CAD patients performed the test on two occasions 3-6 months apart. Whole unstimulated saliva was collected before, directly after and 30 min after exercise while plasma was collected before and after 30 min. MMP-9 and MPO in saliva and plasma were determined by Luminex.. MMP-9 and MPO levels were 2- to 4-fold higher in saliva than in plasma. Amongst the saliva samples, and also to a great extent amongst the plasma samples, the levels of both types of protein showed strong intercorrelations between the levels at rest and after exercise during the two visits. However, there were no (or weak) correlations between salivary and plasma MMP-9 and none between salivary and plasma MPO.. We conclude that salivary diagnostics cannot be used to assess systemic levels of MMP-9 and MPO in CAD patients, neither at rest nor after acute physical exercise.

Topics: Aged; Case-Control Studies; Coronary Artery Disease; Exercise; Female; Humans; Inflammation; Male; Matrix Metalloproteinase 9; Middle Aged; Peroxidase; Rest; Saliva

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

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

The present work provides first-time empirical and molecular interaction evidence to establish the higher biofunctionality of a therapeutic lipid, α-eleostearic acid (ESA), encapsulated in a novel and thoroughly characterized biocompatible nanoemulsion (NE) system (particle size <200 nm).. A novel methodology was employed to fabricate novel formulations of ESA. Molecular biological tools and assays were used to arrive at definite conclusions.. The proinflammatory profile was found to be significantly mitigated in the hypersensitized rats administered with the ESA-NE formulation more emphatically as compared with ESA-conventional emulsion in both in vivo and ex vivo models.. The novel ESA-NE formulation shows a lot of palpable promise for clinical applications.

Topics: Animals; Cell Cycle; Cells, Cultured; Emulsions; Flow Cytometry; Healthy Volunteers; Humans; Inflammation; Linolenic Acids; Male; Nitric Oxide; Particle Size; Peroxidase; Plant Oils; Rats

The acute respiratory distress syndrome (ARDS) is characterized by disruption of the alveolar-capillary barrier resulting in accumulation of proteinaceous edema and increased inflammatory cells in the alveolar space. We previously found that endothelial progenitor cell (EPC) exosomes prevent endothelial dysfunction and lung injury in sepsis in part due to their encapsulation of miRNA-126. However, the effects of EPC exosomes in acute lung injury (ALI) remain unknown.. To determine if EPC exosomes would have beneficial effects in ALI, intratracheal administration of lipopolysaccharide (LPS) was used to induce ALI in mice. Lung permeability, inflammation, and the role of miRNA-126 in the alveolar-epithelial barrier function were examined.. The intratracheal administration of EPC exosomes reduced lung injury following LPS-induced ALI at 24 and 48 h. Compared to placebo, intratracheal administration of EPC exosomes significantly reduced the cell number, protein concentration, and cytokines/chemokines in the bronchoalveolar lavage fluid (BALF), indicating a reduction in permeability and inflammation. Further, EPC exosomes reduced myeloperoxidase (MPO) activity, lung injury score, and pulmonary edema, demonstrating protection against lung injury. Murine fibroblast (NIH3T3) exosomes, which do not contain abundant miRNA-126, did not provide these beneficial effects. In human small airway epithelial cells (SAECs), we found that overexpression of miRNA-126-3p can target phosphoinositide-3-kinase regulatory subunit 2 (PIK3R2), while overexpression of miRNA-126-5p inhibits the inflammatory alarmin HMGB1 and permeability factor VEGFα. Interestingly, both miR-126-3p and 5p increase the expression of tight junction proteins suggesting a potential mechanism by which miRNA-126 may mitigate LPS-induced lung injury.. Our data demonstrated that human EPC exosomes are beneficial in LPS-induced ALI mice, in part through the delivery of miRNA-126 into the injured alveolus.

Topics: Acute Lung Injury; Animals; Blotting, Western; Endothelial Progenitor Cells; Exosomes; HMGB1 Protein; Inflammation; Lipopolysaccharides; Mice; MicroRNAs; Peroxidase; Phosphatidylinositol 3-Kinases; Real-Time Polymerase Chain Reaction; Severity of Illness Index; Trachea; Vascular Endothelial Growth Factor A

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

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

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

Renal ischemia-reperfusion injury (IRI) usually causes acute kidney injury. There is an urgent need to develop an effective agent to prevent renal IRI. This study aimed to examine the effect of butyrate on renal IRI in rats.. Rats were randomly assigned into 3 groups (10 rats in each group): the sham group, the IRI group, and the butyrate group. Rats were injected intravenously with 300 mg/kg of sodium butyrate in the butyrate group and with a saline solution in the sham group and IRI group 30 min before renal ischemia. After 24 h of reperfusion, renal function and histologic damage were examined. Myeloperoxidase (MPO) activity assay, in situ apoptosis examination, enzyme-linked immunosorbent assay, immunohistochemical assay, and Western blot were performed as well.. Butyrate pretreatment significantly reduced renal dysfunction and histologic damage induced by renal IRI. Butyrate pretreatment caused a significant attenuation of neutrophil infiltration, which was reflected by the reduction of renal MPO activity. Butyrate also reduced apoptotic tubular cell death and improved caspase-3 activation. The expression of TNF-α was decreased following butyrate pretreatment.. Butyrate pretreatment protects rats from renal IRI by inhibiting inflammation and apoptosis. Therefore, butyrate may be a potential therapeutic agent for preventing renal IRI.

Topics: Acute Kidney Injury; Animals; Anti-Inflammatory Agents; Apoptosis; Butyrates; Enzyme-Linked Immunosorbent Assay; Immunohistochemistry; Inflammation; Kidney; Male; Neutrophils; Peroxidase; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Tumor Necrosis Factor-alpha

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

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

Angiotensin Converting Enzyme (ACE) 2 is an important modulator of the Renin Angiotensin System (RAS) and the RAS plays a central role in renovascular hypertension. Very few studies investigated the role of components of the counterregulatory RAS axis (ACE2, Ang-(1-7) and Mas receptor) in renovascular hypertension and the results are controversial.. The aim of this study was to investigate the effects of Diminazene Aceturate (DIZE) administration on renal function and renal inflammation parameters in 2K1C hypertensive rats.. Male Wistar rats were divided into three experimental groups: sham-operated animals, 2K1C+saline and 2K1C+DIZE orally (1 mg/kg/day). At the end of the 30 days of treatment, renal function was analyzed and kidneys from all the groups were collected and processed separately for measurement of N-acetyl-beta-D-glucosaminidase (NAG) and Myeloperoxidase (MPO) activities, cytokines, chemokines and nitric oxide levels.. Oral DIZE administration for 4 weeks in hypertensive rats attenuated renal dysfunction and reduced the levels of MPO and NAG, cytokines and chemokines (IL1β, IL-6, TNF-α and MCP-1) and increased urinary nitrate/nitrite levels in 2K1C hypertensive rats.. Our findings showed that ACE2 activation may effectively improve renal alterations and inflammation induced by renovascular hypertension.

Topics: Acetylglucosaminidase; Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Cytokines; Diminazene; Enzyme Activators; Hypertension, Renovascular; Inflammation; Kidney; Male; Nitric Oxide; Peptide Fragments; Peptidyl-Dipeptidase A; Peroxidase; Rats, Wistar; Renin-Angiotensin System

An involvement of neutrophil extracellular traps (NETs) in the aortic stenosis (AS) pathogenesis is unknown.. We enrolled 50 patients, median age 66.5 years with isolated severe AS, after aortic valve replacement and 20 healthy sex/age-matched controls. Autopsy-derived aortic valves from 5 healthy donors served as controls. Valvular expression of citrullinated histone H3 (citH3), myeloperoxidase (MPO), and neutrophil elastase (NE) and macrophages (CD68) were evaluated by immunostaining. Plasma citH3 and interleukin 6 (IL-6) were also determined.. All stenotic and healthy valves expressed citH3 in the leaflets' endothelial and sub-endothelial layers at the aortic side. Amount of valvular citH3-positive cells was higher in AS patients compared with controls (53.5 [33-62]% vs. 5.7 [4.1-9.0]%, p < 0.0001) and correlated with aortic valve area (AVA; r = -0.69, p < 0.0001) and mean transvalvular gradient (r = 0.6, p < 0.0001). Double-staining revealed that in AS valves 27.2 ± 9.8% of cells were citH3/MPO- and 25.3 ± 8.9% citH3/NE-positive. Within stenotic valves, 6.4 ± 2.5% of cells showed citH3/CD68 double-positivity and were identified as macrophages. AS patients compared to controls had 83% higher plasma citH3 (p < 0.0001). In AS, plasma citH3 correlated with IL-6 (r = 0.39, p = 0.0054) levels and AVA (r = -0.45, p = 0.0009).. The presence of NETs in stenotic valves and association with AS severity suggest novel mechanisms involved in the disease progression.

Topics: Aged; Aortic Valve; Aortic Valve Stenosis; Biomarkers; Disease Progression; Echocardiography; Enzyme-Linked Immunosorbent Assay; Extracellular Traps; Female; Follow-Up Studies; Histones; Humans; Immunoturbidimetry; Inflammation; Interleukin-6; Leukocyte Elastase; Male; Middle Aged; Neutrophils; Peroxidase; Prognosis; Retrospective Studies

Dysfunction of endothelial cells of the artery wall is an early event in cardiovascular disease and atherosclerosis. The cause(s) of this dysfunction are unresolved, but accumulating evidence suggests that oxidants arising from chronic low-grade inflammation are contributory agents, with increasing data implicating myeloperoxidase (MPO, released by activated leukocytes), and the oxidants it generates (e.g. HOCl and HOSCN). As these are formed extracellularly and react rapidly with proteins, we hypothesized that MPO-mediated damage to the matrix glycoprotein fibronectin (FN) would modulate FN structure and function, and its interactions with human coronary artery endothelial cells (HCAEC). Exposure of human plasma FN to HOCl resulted in modifications to FN and its functional epitopes. A dose-dependent loss of methionine and tryptophan residues, together with increasing concentrations of methionine sulfoxide, and modification of the cell-binding fragment (CBF) and heparin-binding fragment (HBF) domains was detected with HOCl, but not HOSCN. FN modification resulted in a loss of HCAEC adhesion, impaired cell spreading and reduced cell proliferation. Exposure to HCAEC to HOCl-treated FN altered the expression of HCAEC genes associated with extracellular matrix (ECM) synthesis and adhesion. Modifications were detected on HCAEC-derived ECM pre-treated with HOCl, but not HOSCN, with a loss of antibody recognition of the CBF, HBF and extra-domain A. Co-localization of epitopes arising from MPO-generated HOCl and cell-derived FN was detected in human atherosclerotic lesions. Damage was also detected on FN extracted from lesions. These data support the hypothesis that HOCl, but not HOSCN, targets and modifies FN resulting in arterial wall endothelial cell dysfunction.

Topics: Atherosclerosis; Cells, Cultured; Endothelial Cells; Fibronectins; Humans; Inflammation; Oxidants; Oxidation-Reduction; Peroxidase

Upon consumption, dietary nitrate is reduced to nitrite in the oral cavity and to nitric oxide (

Topics: Animals; Anti-Bacterial Agents; Base Sequence; Cecum; Claudin-5; Dysbiosis; Feces; Gastric Mucosa; Gastrointestinal Microbiome; Inflammation; Male; Nitrates; Nitric Oxide Synthase Type II; Occludin; Peroxidase; Rats, Wistar; Tight Junctions; Weight Loss

Cardiorenal syndrome type 1 (CRS type 1) is characterized by a rapid worsening of cardiac function leading to acute kidney injury. In this study, we evaluate the role of lipopolysaccharide (LPS) and various inflammatory markers in the developing acute kidney injury (AKI) in acute heart failure (AHF) patients.. We enrolled 31 AHF patients and 20 CRS type 1 (the cause of AKI was presumed to be related to cardiac dysfunction) and 17 healthy volunteers without AHF, AKI or CKD, as control group (CTR). We assessed levels of LPS, proinflammatory cytokines (TNF-α, IL-6, IL-18), and oxidative stress marker (myeloperoxidase, MPO).. We observed a significant increase in LPS, TNF-α, IL-6, IL-18 and MPO levels in CRS type 1 and AHF group compared to CTR. LPS levels resulted significantly higher in CRS type 1 patients compared with AHF (118.2 pg/mL, IQR 77.8-217.6 versus 13.5 pg/mL, IQR 12.0-17.0, p = 0.008). We found a cytokines and oxidative stress dysregulation in CRS type 1 patients compared with AHF. Furthermore, we observed a strong positive significant correlation between LPS levels and IL-6 (Spearman's rho = 0.79, p < 0.001), and IL-18 (Spearman's rho = 0.77, p < 0.001) and MPO (Spearman's rho = 0.80, p < 0.001), all confirm by simple linear regression analysis.. CRS type 1 patients presented an increased level of LPS, pro-inflammatory cytokines, and MPO. Furthermore, there is a direct correlation between LPS and pro-inflammatory cytokines and stress oxidative marker. LPS may play a role in the pathophysiology of CRS type 1 inducing inflammation, oxidative stress and finally kidney damage.

Topics: Acute Disease; Acute Kidney Injury; Aged; Aged, 80 and over; Biomarkers; Cardio-Renal Syndrome; Female; Heart Failure; Humans; Inflammation; Interleukin-18; Interleukin-6; Lipopolysaccharides; Male; Oxidative Stress; Peroxidase; Prospective Studies; Tumor Necrosis Factor-alpha

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

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

Despite increasing evidence that adults with long-standing atopic dermatitis (AD) have systemic inflammation, little is known about systemic inflammation in recent-onset early pediatric AD.. To analyze blood inflammatory proteins of early pediatric AD.. Using high-throughput proteomics (proximity extension assay), we assessed 257 inflammatory and cardiovascular risk proteins in the blood of 30 children with moderate to severe AD younger than 5 years of age (within 6 months of onset) compared with age-matched pediatric control individuals and adult patients with AD.. In pediatric AD blood, T helper (Th) type 2 (CCL13, CCL22) and Th17 (peptidase inhibitor-3/elafin) markers were increased, together with markers of tissue remodeling (matrix metalloproteinases 3/9/10, urokinase receptor), endothelial activation (E-selectin), T-cell activation (IL2RA), neutrophil activation (myeloperoxidase), lipid metabolism (FABP4), and growth factors (FGF21, transforming growth factor-α). Total numbers of dysregulated proteins were smaller in pediatric AD (n = 22) than in adult AD (n = 61). Clinical severity scores were positively correlated with receptors for interleukins 33 and 36 and inversely correlated with some Th1 markers (interferon gamma, CXCL11).. Different baseline expression levels in healthy pediatric vs adult samples.. Within months of pediatric AD onset, systemic immune activation is present, with Th2/Th17 skewing but otherwise different proteomic patterns from adult AD. Future correlation of proteomic patterns with disease course, comorbidity development, and drug response may yield predictive biomarkers.

Topics: Age Factors; Biomarkers; Case-Control Studies; Chemokines; Child, Preschool; Chronic Disease; Dermatitis, Atopic; E-Selectin; Elafin; Fatty Acid-Binding Proteins; Female; Fibroblast Growth Factors; Humans; Infant; Inflammation; Interleukin-2 Receptor alpha Subunit; Male; Matrix Metalloproteinases; Peroxidase; Proteome; Receptors, Interleukin; RNA, Messenger; Severity of Illness Index; Transforming Growth Factor alpha

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

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

Oxandrolone is a synthetic oral non-aromatizable testosterone derivative. This drug has been used successfully for several decades to safely treat growth delays in various diseases including Turner's syndrome. Currently the use of oxandrolone is under clinical testing in children with burn injury; the available data indicate that the anabolic steroid increases net muscle protein balance, maintains lean body mass, and reduces intensive care unit stay. Although oxandrolone is already in clinical trials in burn patients, preclinical burn-related studies with oxandrolone - especially those that go beyond muscle-related parameters and focus on burn-associated organ dysfunction, inflammatory response and wound healing - remain to be conducted. In the current project, using a well-characterized murine model of third-degree burn, we have tested the effect of oxandrolone on indices of organ injury, clinical chemistry parameters and plasma levels of inflammatory mediators. In oxandrolone-treated mice (1mg/kg/day for up to 21 days) there was a significant amelioration of burn-induced accumulation of myeloperoxidase levels in heart and lung (but not the liver and kidney) and significantly lower degree of malon dialdehyde accumulation in the liver (but not the heart, lung and kidney). Oxandrolone-treated mice showed a significant attenuation of the burn-induced elevation in circulating alkaline aminotransferase and amylase levels, while blood urea nitrogen and creatinine levels remained unaffected, indicative of protective effects of the anabolic hormone against burn-induced hepatic and pancreatic (but not renal) functional impairment. Multiple burn-induced inflammatory mediators (TNF-α, IL-1α, IL-1β, IL-4, IL-6, IL-10, IL-12, IP-10, G-CSF, GM-CSF and interferon-γ) were significantly lower in the plasma of oxandrolone-treated animals after burn injury than in the plasma of controls subjected to burns. Finally, oxandrolone significantly accelerated burn wound healing. We conclude that oxandrolone improves organ function, modulates the systemic inflammatory response and accelerates wound healing in a murine model of burn injury.

Topics: Amylases; Anabolic Agents; Animals; Burns; Cytokines; Heart; Inflammation; Kidney; Liver; Lung; Malondialdehyde; Mice; Myocardium; Oxandrolone; Oxidative Stress; Pancreas; Peroxidase; Wound Healing

Preclinical studies have demonstrated that maternal inflammation or neonatal hyperoxia adversely affects kidney maturation. This study explored whether prenatal lipopolysaccharide (LPS) exposure can augment neonatal hyperoxia-induced kidney injury.. Pregnant Sprague-Dawley rats received intraperitoneal injections of LPS (0.5 mg/kg) in normal saline (NS) or NS on 20 and 21 days of gestation. The pups were reared in room air (RA) or 2 weeks of 85% O. The rats exposed to maternal LPS or neonatal hyperoxia exhibited significantly higher kidney injury score, lower glomerular number, higher toll-like receptor 4 (TLR4), myeloperoxidase (MPO), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) expressions, and higher MPO activity compared with the rats exposed to maternal NS and neonatal RA. The rats exposed to both maternal LPS and neonatal hyperoxia exhibited significantly lower glomerular number, higher kidney injury score, TLR4, MPO, and 8-OHdG expressions compared with the rats exposed to maternal LPS or neonatal hyperoxia.. Maternal inflammation exacerbates neonatal hyperoxia-induced kidney injury and the underlying mechanism may be related to activation of TLR4 and increased oxidative stress.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Animals, Newborn; Antibodies; Body Weight; Chorioamnionitis; Cytokines; Female; Hyperoxia; Inflammation; Kidney Diseases; Lipopolysaccharides; Maternal Exposure; Organ Size; Oxidative Stress; Oxygen; Peroxidase; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Toll-Like Receptor 4

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

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

Myeloperoxidase (MPO) is a critical proinflammatory enzyme implicated in cardiovascular, neurological, and rheumatological diseases. Emerging therapies targeting inflammation have raised interest in tracking MPO activity in patients. We describe

Topics: Animals; Female; Fluorine Radioisotopes; Humans; Inflammation; Mice; Mice, Inbred C57BL; Myocardial Infarction; Peroxidase; Positron-Emission Tomography

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

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

The bioactive phenylethanoid 3,4-dihydroxyphenylethyl alcohol glycoside (DAG) is a component isolated from Sargentodoxa cuneata. The effects of DAG on acute lung injury (ALI) are largely unknown. Here, the effects of DAG on sepsis-induced ALI were investigated, and the related mechanisms were explored. Male C57BL/6 mice were used to establish a sepsis-induced ALI model. Levels of inflammatory cytokines were determined using real-time quantitative reverse transcription PCRs (qRT-PCR) and enzyme-linked immunosorbent assays (ELISAs). Pathological changes in the lung tissues were evaluated using haematoxylin and eosin (HE) staining. Mouse survival was quantified, and macrophage polarization was analyzed using flow cytometry. Our results showed that, in septic mice, pretreatment with DAG significantly improved survival, reduced histological damage in the lung, and suppressed the inflammatory response by inhibiting the activation of the NF-κB, STAT3, and p38 MAPK signaling pathways. Moreover, DAG treatment reduced the percentage of M1 macrophages in the bronchoalveolar lavage fluid (BALF) and spleen. In addition, DAG treatment decreased the production of pro-inflammatory cytokines and suppressed the activation of the NF-κB, STAT3, and p38 MAPK signaling pathways in LPS-induced MH-S cells. DAG treatment also reduced the relative abundances of M1 macrophages and M1 macrophage markers by suppressing the activation of the Notch1 signaling pathway. Thus, our results provided new insights for the development of drugs to treat ALI.

Topics: Acute Lung Injury; Animals; Capillary Permeability; Cecum; Cell Polarity; Cytokines; Glycosides; Inflammation; Inflammation Mediators; Ligation; Lipopolysaccharides; Lung; Macrophages; Male; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; Neutrophil Infiltration; NF-kappa B; Peroxidase; Phenotype; Punctures; Sepsis; STAT3 Transcription Factor; Survival Analysis

Though the cross-induction of either acute kidney (AKI) injury to ischemic stroke (IS) or IS to AKI might not be encountered in the early stages of cerebrorenal syndrome (CRS), both pathologies coexist in late stages. Therefore, we firstly established a late stage CRS rat model by simultaneous induction of both diseases, and further, cerebro and reno-protective activities of human platelet-rich plasma (hPRP), a blood-derived tissue engineering biomaterial, were tested in this pathology. hPRP was administrated via left common carotid artery and abdominal aorta 2 h post-sham procedure in Sprague-Dawley rats. Circulatory inflammatory markers (TNF-α/MPO/IL-6/Ly6G/CD11b/c), histopathologic cerebro and renal changes and oxidative stress were determined. Inflammation, infarct size, brain-associated inflammatory/DNA and mitochondrial damage and oxidative-stress with reduced neurons and neurological function were manifested in CRS group compared to other groups. CRS group also demonstrated declined renal function, accelerated renal collagen deposition, fibrosis and compromised glomerular podocyte components (podocin/ZO-1/fibronectin/synaptopodin). However, hPRP simultaneously suppressed all the inflammatory, cerebral and renal pathologic characteristics. hPRP also inhibited the expression of brain-associated inflammatory/DNA/mitochondrial damage and oxidative-stress biomarkers. These findings imply that hPRP may effectively exert cerebro- and renoprotective activities in late stage CRS through anti-oxidative, anti-inflammatory, anti-DNA and anti-mitochochondrial damaging activities.

Topics: Acute Kidney Injury; Animals; Biocompatible Materials; Blotting, Western; Immunohistochemistry; Inflammation; Interleukin-6; Kidney; Magnetic Resonance Imaging; Male; Oculocerebrorenal Syndrome; Oxidative Stress; Peroxidase; Platelet-Rich Plasma; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Tumor Necrosis Factor-alpha

Background Curcumin is extensively used as a therapeutic intervention for treating several ailments. The antioxidant curcumin has an anti-inflammatory and chelating property with arsenic to exhibit a strong therapeutic effect on reproductive organs. This study was undertaken to describe the protective effect of noninvasive administration of curcumin against sodium-arsenite-mediated uterine hazards in female Wistar rats. Methods Twenty-four female Wistar rats were randomly divided into four groups. The treatment was continued for 8 days and given orally sodium arsenite (10 mg/kg body weight) in combination with curcumin (20 mg/kg body weight). Results Our evaluation revealed that 8 days of sodium arsenite (10 mg/kg body weight) treatment reduced the activities of the uterine enzymatic antioxidants superoxide dismutase, catalase, and peroxidase. Blood levels of vitamin B12 and folic acid decreased followed by an increased serum lactate dehydrogenase, homocysteine level, and hepatic metallothionein-1 in arsenic-treated rats. Necrosis of uterine tissue along with the disruption of ovarian steroidogenesis was marked in arsenic-treated rats with an upregulation of uterine NF-κB and IL-6 along with a raised level of serum TNF-α. Oral administration of curcumin (20 mg/kg body weight/day) in arsenic-treated rats significantly reinstated these alterations of the antioxidant system followed by an improvement of ovarian steroidogenesis and the circulating level of B12 and folate along with the downregulation of serum homocysteine, metallothionein-1, and cytokines. Conclusions The findings of this study clearly and strongly elucidated that arsenic-induced oxidative stress in uterus is linked to an alteration of inflammation-signaling biomarkers and these have been protected through the co-administration of curcumin due to its anti-inflammatory, free radical scavenging, and antioxidant activity by the possible regulation of an S-adenosine methionine pool.

Topics: Animals; Antioxidants; Arsenic; Arsenites; Catalase; Curcumin; Cytokines; Female; Glutathione; Glutathione Peroxidase; Inflammation; Metallothionein; NF-kappa B; Oxidative Stress; Peroxidase; Rats; Rats, Wistar; Sodium Compounds; Superoxide Dismutase; Uterus

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

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

Here, we evaluated the possible protective effects of oleuropein, the major phenolic constituent in virgin olive oil against glycerol-induced acute kidney injury (AKI) in rats.. Twenty-eight Sprague Dawley rats were allocated equally into four groups as follows: control group, oleuropein group (50 mg/kg body weight), AKI group and the oleuropein + AKI group. AKI was induced by injecting 50% glycerol (10 ml/kg body weight) intramuscularly.. Glycerol injection increased the kidney relative weight as well as rhabdomyolysis (RM)- and AKI-related index levels, including the levels of creatine kinase, lactate dehydrogenase, creatinine, urea, and Kim-1 expression. Additionally, alteration in oxidative conditions in renal tissue was recorded, as confirmed by the elevated malondialdehyde and nitric oxide levels and the decreased glutathione content. Concomitantly, the protein and mRNA expression levels of antioxidant enzymes were suppressed. Moreover, Nfe2l2 and Hmox1 mRNA expression was also downregulated. Glycerol triggered inflammatory reactions in renal tissue, as evidenced by the increased pro-inflammatory cytokines and Ccl2 protein and mRNA expression, whereas myeloperoxidase activity was increased. Furthermore, glycerol injection enhanced apoptotic events in renal tissue by increasing the expression of the pro-apoptotic proteins and decreasing that of anti-apoptotic. However, oleuropein administration reversed the molecular, biochemical, and histological alterations resulting from glycerol injection.. Our data suggest that oleuropein has potential as an alternative therapy to prevent or minimize RM incidence and subsequent development of AKI, possibly due to its potent anti-stress, anti-inflammatory, and anti-apoptotic effects.

Topics: Acute Kidney Injury; Animals; Antioxidants; Apoptosis; Cell Adhesion Molecules; Creatine Kinase; Creatinine; Glutathione; Glycerol; Inflammation; Iridoid Glucosides; Iridoids; Kidney; Male; Malondialdehyde; Nitric Oxide; Oxidation-Reduction; Oxidative Stress; Peroxidase; Rats; Rats, Sprague-Dawley; Rhabdomyolysis

Hypochlorite (HOCl), a strong oxidant and antimicrobial agent, has been proposed to be associated with hemostatic abnormalities during inflammatory response. However, its complex impact on hemostasis is not completely understood. In this report we studied the effect of clinically relevant (micromolar) HOCl concentrations on thrombus formation under flow, kinetics of platelet-fibrin clot formation, its architecture, retraction, and lysis. We found that HOCl (up to 500 µM) did not affect kinetics of coagulation measured in whole blood. HOCl (500-1000 µM) markedly diminished thrombus formation under flow. Clot retraction rate was reduced by HOCl dose-dependently (50-500 µM). HOCl (125-500 µM) inhibited fibrinolysis in whole blood and in platelet-depleted plasma, dose-dependently. Activity of plasmin was reduced by HOCl at concentrations started from 500 µM. HOCl (up to 500 µM) did not reduce plasminogen binding to fibrin under flow. HOCl (125-500 µM) modulated architecture of fibrin- and platelet-fibrin clots towards structures made of thin and densely packed fibers. Exposure of pure fibrinogen to HOCl (10-1000 µM) resulted in formation of dityrosine and was associated with altered fibrin structure derived from such modified fibrinogen. HOCl-altered fibrin net structure was not related with modulation of platelet procoagulant response, thrombin generation, and factor XIII activity. We conclude that, in human blood, clinically relevant HOCl concentrations may inhibit thrombus formation under flow, clot retraction and fibrinolysis. Fibrinolysis and clot retraction seem to be the most sensitive to HOCl-evoked inhibition. HOCl-modified fibrinogen and altered clot structure associated with it are likely to be primary sources of attenuated fibrinolysis.

Topics: Blood Coagulation; Blood Platelets; Clot Retraction; Factor XIII; Fibrin; Fibrinogen; Fibrinolysis; Hemostasis; Humans; Hypochlorous Acid; Inflammation; Peroxidase; Thrombin; Thrombosis

Chronic inflammation and impaired sleep increase the risk for cardiovascular disease. Menopausal women may be particularly at risk as a result of impaired sleep. The objective of the current investigation was to assess the relationship between poor sleep and C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and myeloperoxidase (MPO) in healthy non- and postmenopausal women and men.. A fasting blood draw was obtained from 122 healthy men and women (31 were postmenopausal). Higher scores on the Pittsburgh Sleep Quality Index (PSQI) were used to define poor sleep. Given the sample size and healthy nature of the sample, hierarchical linear regression analyses were performed on a composite inflammatory score involving CRP, IL-6, and TNF-α. Sex/menopausal group and PSQI were entered as predictors, and the interaction of the group by PSQI was entered stepwise. Analyses on MPO were performed separately.. Sleep quality was associated with higher inflammatory activity (β = 0.272, P = 0.003), which remained significant (P = 0.046) after controlling for age, waist circumference, exercise times per week, and depressive symptoms. While in the same direction, sleep quality was not significantly associated with MPO. Dichotomizing sleep quality led to similar results.. Impaired sleep quality is independently associated with greater inflammation in healthy adult men and women. Despite an overall less favorable metabolic and inflammatory profile in postmenopausal women, impaired sleep did not emerge as differentially related to inflammatory activity in this group.

Topics: Adult; Aging; Biomarkers; C-Reactive Protein; Female; Humans; Inflammation; Interleukin-6; Male; Middle Aged; Peroxidase; Postmenopause; Premenopause; Sleep Wake Disorders; Tumor Necrosis Factor-alpha

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

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

The aims of this study were to evaluate if the use of copper oxide wire particles, isolated or in association with closantel, in lambs infected with Haemonchus contortus enhances the anthelmintic efficacy of closantel, as well as to evaluate the effects of treatment in hepatic energy metabolism, inflammatory markers and hematological and biochemical tests. The lambs were randomly divided into five groups (6 animals each), as follows: uninfected animals (Control); animals infected with H. contortus (HC); infected and treated with closantel (HC + CL); infected and treated with copper oxide wire particles (HC + Cu); and infected and treated with closantel plus copper oxide wire particles (HC + CL + Cu). The animals of infected groups were infected orally with H. contortus (5,000 L3 -larvae) and on day 14 post infection (p.i) the treatments were initiated. The egg per gram of feces (EPG), butyrylcholinesterase (BuChE), myeloperoxidase (MPO), adenylate kinase (AK) and pyruvate kinase (PK) activities and hematological and biochemical tests were evaluated. Treatments with copper oxide (isolated and associated) were able to reduce the EPG count on days 28, 35, 42 and 49 p.i when compared to HC group, while closantel was able to reduce EPG only from day 35 p.i. Moreover, treatment with closantel (isolated or associated) was able to prevent the inhibition of hepatic AK and PK activities caused by H. contortus infection, which may contribute to efficient intracellular energetic communication in order to maintain the balance between cellular ATP consumption and production. Butyrylcholinesterase and MPO activities were higher in infected lambs compared to uninfected, while treated groups showed lower enzymatic activity compared to the group HC. The use of all therapeutic protocols was able to reduce the EPG count. Based on these evidences, the use of copper oxide plus closantel may be considered an alternative to treat lambs infected by H. contortus.

Topics: Abomasum; Adenylate Kinase; Administration, Oral; Animals; Anthelmintics; Blood Chemical Analysis; Butyrylcholinesterase; Capsules; Copper; Energy Metabolism; Erythrocyte Count; Feces; Haemonchiasis; Hematocrit; Hemoglobins; Inflammation; Liver; Male; Parasite Egg Count; Peroxidase; Pyruvate Kinase; Random Allocation; Salicylanilides; Sheep; Sheep Diseases

Topics: Case-Control Studies; Eosinophil Cationic Protein; Eosinophils; Humans; Inflammation; Nasal Mucosa; Neutrophils; Peroxidase; Rhinitis, Allergic; Rhinosporidiosis; Sinusitis

Cyanogenic glycosides are found in a diverse group of plants and are metabolized into thiocyanate by the intestines and liver. Conversion of plant derived thiocyanates into cyanide and isocyanic acid occurs by the activity of neutrophil-derived enzyme myeloperoxidase. Therefore, increased intake of cyanogenic glycoside rich plant based diet may lead to increased isocyanic acid induced protein carbamylation in chronic inflammatory states (increased myeloperoxidase activity). As there is a close relationship between non-enzymatic post-translational modification and protein function, carbamylation induced structural changes also affect the functions of proteins. Carbamylation induced structural alterations of proteins have recently drawn a great attention in the current literature, especially regarding the alterations of proteins with long half-life such as type I collagen, elastin, α-crystallin. We hypothesize that a plant-based natural diet, rich in cyanogenic glycosides, may have unintended consequences on native protein structure/function in individuals with chronic inflammatory diseases such as chronic kidney and rheumatological diseases because of the higher rate of transformation of plant derived thiocyanates into isocyanic acid by the increased activity of neutrophil-derived enzyme myeloperoxidase. Regulation of myeloperoxidase activity or moderation of cyanogenic glycoside rich diet might be important in the prevention/modulation of dangerous protein carbamylation process, especially in this patient group.

Topics: Chronic Disease; Collagen; Cyanates; Cyanides; Diet; Elastin; Glycosides; Humans; Inflammation; Intestines; Liver; Models, Theoretical; Neutrophils; Peroxidase; Protein Carbamylation; Proteins; Risk; Up-Regulation

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

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

We investigated the skeletal muscle adaptation to l-arginine supplementation prior to a single session of resistance exercise (RE) during the early phase of muscle repair. Wistar rats were randomly assigned into non-exercised (Control), RE plus vehicle (RE); RE plus l-arginine (RE+L-arg) and RE plus aminoguanidine (RE+AG) groups. Animals received four doses of either vehicle (0.9% NaCl), l-arg (1 g/b.w.), or AG (iNOS inhibitor) (50 mg/b.w.). The animals performed a single RE session until the concentric failure (ladder climbing; 80% overload) and the skeletal muscles were harvested at 0, 8, 24, and 48 hours post-RE. The RE resulted in increased neutrophil infiltrate (24 hours post-RE) (3621 vs 11852; P<.0001) associated with enhanced TNF-α (819.49 vs 357.02; P<.005) and IL-6 (3.84 vs 1.08; P<.0001). Prior, l-arginine supplementation attenuates neutrophil infiltration (5622; P<.0001), and also TNF-α (506.01; P<.05) and IL-6 (2.51, P<.05) levels. AG pretreatment mediated an inhibition of iNOS levels similar to levels found in RE group. RE animals displayed increased of atrogin-1 (1.9 fold) and MuRF-1 (3.2 fold) mRNA levels, reversed by l-arg supplementation [atrogin-1 (0.6 fold; P<.001); MuRF-1 (0.8-fold; P<.001)] at 24 hours post-RE. MyoD up-regulated levels were restricted to l-arg treated animals at 24 hours (2.8 vs 1.5 fold; P<.005) and 48 hours post-RE (2.4 vs 1.1 fold; P<.001). AG pretreatment reversed these processes at 24 hours [atrogin-1 (2.1 fold; P<.0001); MuRF-1 (2.5 fold; P<.0001); MyoD (1.4 fold)]. l-arginine supplementation seems to attenuate the resolution of RE-induced muscle inflammation and up-regulates MyoD expression during the early phase of muscle repair.

Topics: Adaptation, Physiological; Animals; Arginine; Guanidines; Inflammation; Interleukin-6; Male; Muscle Proteins; Muscle, Skeletal; Nitric Oxide Synthase Type II; Peroxidase; Physical Conditioning, Animal; Rats, Wistar; SKP Cullin F-Box Protein Ligases; Tripartite Motif Proteins; Tumor Necrosis Factor-alpha; Ubiquitin-Protein Ligases

During sepsis, systemic inflammation is observed and is associated with multiple organ failure. Activation of NF-κB is crucial for inducing inflammation, which is controlled by degradation of inhibitor molecules (IκB). The ubiquitination proteasome pathway is responsible for the regulation of protein turnover. In this study, we hypothesized that administration of 4[4-(5-nitro-furan-2-ylmethylene)-3, -dioxo-pyrazolidin-1-yl]-benzoic acid ethyl ester (PYR-41), an inhibitor of ubiquitination, could reduce inflammation and organ injury in septic mice. PYR-41 prevented the reduction of IκB protein levels and inhibited release of tumor necrosis factor (TNF)-α in mouse macrophage RAW264.7 cells at 4 h after lipopolysaccharide stimulation dose-dependently. Male C57BL/6 mice were subjected to cecal ligation and puncture (CLP) to induce sepsis. PYR-41 (5 mg/kg) or dimethyl sulfoxide in saline (vehicle) was injected intravenously immediately after CLP. At 20 h after CLP, PYR-41 treatment significantly decreased serum levels of proinflammatory cytokines (TNF-α, interleukin [IL]-1β, and IL-6) and organ injury markers (aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase). PYR-41 significantly improved microscopic structure, and reduced myeloperoxidase activity, number of apoptotic cells and caspase-3 degradation in the lungs of septic mice. The reduced protein levels of IκB in the lungs after CLP were restored by PYR-41 treatment. PYR-41 inhibited the expression of cytokines (IL-1β and IL-6), chemokines (keratinocyte-derived chemokine and macrophage inflammatory protein 2), and inflammatory mediators (cyclooxygenase-2 and inducible nitric oxide synthase) in the lungs of septic mice. Importantly, PYR-41 significantly increased 10-day survival in septic mice from 42% to 83%. Therefore, targeting ubiquitination by PYR-41 to inhibit NF-κB activation may represent a potential strategy of sepsis therapeutics.

Topics: Animals; Benzoates; Blotting, Western; Furans; In Situ Nick-End Labeling; Inflammation; Lipopolysaccharides; Lung Injury; Male; Mice; Mice, Inbred C57BL; Peroxidase; Pyrazoles; RAW 264.7 Cells; Sepsis

In present study, two hydrolyzed residue polysaccharides (RPS) of enzymatic-RPS (ERPS) and acidic-RPS (ARPS) were successfully obtained from the residue of Lentinula edodes, and the anti-inflammatory as well as antioxidative effects on lipopolysaccharide-induced (LPS-induced) lung injured mice were investigated. The results demonstrated that ERPS showed superior lung protective effects by ameliorating the lung wet-to-dry weight (W/D) ratio, reducing the TNF-α, IL-6, and IL-1β levels in BALF, lowing the pulmonary MPO activity, decreasing the serum C3 and hs-CPR contents, as well as improving the antioxidant status by enhancing pulmonary enzyme activities (SOD, GSH-Px, CAT, and T-AOC) and eliminating the lipid peroxidation (MDA and LPO), respectively. These conclusions indicated that both RPS and its hydrolysates (ARPS and ERPS) might be suitable for functional foods and a potentially effective candidate medicine for the treatment of lung injury.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Bronchoalveolar Lavage Fluid; Catalase; Complement C3; Edema; Fungal Polysaccharides; Gene Expression; Glutathione Peroxidase; Inflammation; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; Lung; Lung Injury; Male; Malondialdehyde; Mice; Oxidative Stress; Peroxidase; Shiitake Mushrooms; Superoxide Dismutase; Tumor Necrosis Factor-alpha

We investigated the effect of repeated remote ischaemic post-conditioning (RIPoC) on the organ distribution of the intramyocardially injected MSCs in rat myocardial ischemia model. Myocardial ischemia of adult female Sprague-Dawley rats was induced by 30-min. obstruction of the left anterior descending coronary artery. Repeated RIPoC was induced after ischemia with three cycles of 5-min. occlusion and reperfusion of the limb with the frequency of half a day, 1 or 2 days, respectively. Compared with that by single RIPoC, repeated RIPoC transiently reduced oxidative stress, lipid peroxidation and inflammation in ischaemic myocardium; the gene expression of stromal cell-derived factor-1 alpha (SDF-1α) was consistently induced by repeated RIPoC procedures. A total of 4 × 10

Topics: Animals; Cell Shape; Chemokine CXCL12; Electrocardiography; Female; Gene Expression Regulation; Heart Function Tests; Inflammation; Ischemic Postconditioning; Lipid Peroxidation; Malondialdehyde; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Oxidative Stress; Peroxidase; Rats, Sprague-Dawley; Superoxide Dismutase

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

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

Calprotectin promotes the release of inflammatory mediators (e.g., monocyte chemoattractant protein-1 [MCP-1] and myeloperoxidase [MPO]) during the innate immune response as a mechanism to augment leukocyte chemotaxis and phagocytosis. Although plasma calprotectin is elevated with traditional continuous moderate-intensity exercise (CME) as an indicator of the inflammatory response, high-intensity interval exercise (HIIE) has been shown to attenuate systemic inflammation while providing similar improvements in cardiovascular health. Therefore, the purpose of this study was to compare plasma levels of calprotectin, MCP-1, and MPO between acute HIIE vs. CME.. Nine healthy males (24.67±3.27yrs) were recruited to participate in HIIE and CME on a cycle ergometer. HIIE consisted of 10 repeated 60s of cycling at 90% max watts (W. Acute HIIE elicited a lower elevation in calprotectin and MPO compared to CME. An increase in MCP-1 was observed across time in both exercise protocols. Furthermore, our analyses did not reveal any significant correlation in percent change (baseline to immediately following exercise) among calprotectin, MCP1, and MPO in neither HIIE nor CME. However, a significant positive correlation was observed in the overall release of calprotectin and MPO across all four time points in both HIIE and CME. Conclusions Our findings indicate that acute HIIE may potentially diminish the systemic release of inflammatory mediators (calprotectin and MPO) compared to CME.

Topics: Adult; Chemokine CCL2; Enzyme-Linked Immunosorbent Assay; Exercise; Exercise Therapy; Humans; Inflammation; Leukocyte L1 Antigen Complex; Male; Peroxidase; Random Allocation; Time Factors; Young Adult

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

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

Topics: Animals; Brain; Brain Chemistry; Cerebral Cortex; Chemokine CXCL1; Chorioamnionitis; Female; Fetus; Inflammation; Lipopolysaccharides; Magnetic Resonance Imaging; Peroxidase; Placenta; Pregnancy; Rats; Rats, Sprague-Dawley; Receptors, Interleukin-8B; RNA, Messenger; Signal Transduction

Rotula aquatica belongs to the family Boraginaceae, and is reported to contain baunerol, steroids and alkaloids. In Ayurveda, R. aquatica has been used for the treatment of various diseases such as diabetes, treatment of piles, venereal disease, and cancer. The current study aims to investigate the anti-inflammatory effect of methanolic extract of R. aquatica (MERA) in RAW 264.7 cells. The cytotoxicity of MERA was analyzed by MTT assay. The total cyclooxygenase (COX) activity, 5-lipoxygenase (5-LOX) activity, myeloperoxidase activity, inducible nitric oxide synthase activity, nitrate level and reactive oxygen species production were studied in LPS-stimulated RAW 264.7 cells. The gene level expression of cyclooxygenase-2 (COX-2), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) were also evaluated in this study. The MERA did not show any cytotoxicity at different concentrations (6.25-100 µg/ml). MERA (100 μg/ml) inhibited total COX and 5-LOX activity at 50.53 and 62.03%, respectively, besides significantly (p < 0.05) diminished nitrate and ROS generation, when compared with LPS control. Moreover, MERA down-regulated the mRNA expressions of inflammatory marker genes like TNF-α, IL-6, and COX-2 against LPS stimulation. Our results demonstrate that MERA is able to attenuate inflammatory response, possibly via ROS and NO suppression, inhibiting the production of arachidonic acid metabolites and modulation of proinflammatory mediators and cytokines release.

Topics: Animals; Anti-Inflammatory Agents; Arachidonate 5-Lipoxygenase; Boraginaceae; Cell Line; Cytokines; Inflammation; Inflammation Mediators; Interleukin-6; Lipopolysaccharides; Macrophages; Mice; Nitric Oxide; Nitric Oxide Synthase Type II; Peroxidase; Plant Extracts; RAW 264.7 Cells; Reactive Oxygen Species; Tumor Necrosis Factor-alpha

Feeding small European sea bass, Dicentrarchus labrax, for 6 weeks with Tenebrio molitor larval meal showed significant anti-inflammatory responses (ceruloplasmin, myeloperoxidase and nitric oxide). Serum bacteriolytic activity against a Gram negative bacterium was not significantly affected by dietary Tenebrio, while both lysozyme antibacterial activity and serum trypsin inhibition usually linked to the anti-parasite activity of the fish, were significantly enhanced. The latter may be due to the similarities in the composition of the exoskeleton of parasites and insects that may therefore act as an immunostimulant potentially increasing the anti-parasitic activity. The addition of exogenous proteases significantly decreased both trypsin-inhibition and serum bacteriolytic activity probably through direct inhibition of the proteins responsible for these immune functions. Further investigation involving bacterial or parasitic challenges will be necessary to assess if the effects of dietary mealworm meal on the immune system observed in the present study are translated into an improved resistance to diseases.

Topics: Animals; Anti-Inflammatory Agents; Bass; Ceruloplasmin; Diet; Fish Proteins; Immune System; Immunity, Innate; Inflammation; Insecta; Muramidase; Nitric Oxide; Peroxidase; Tenebrio; Trypsin

A previously healthy 58-year-old man was admitted for muscle pain and weakness [manual muscle testing (MMT) of 4/4 for upper and lower limbs]. We detected elevated levels of inflammatory makers and PR3-anti-neutrophil cytoplasmic antibody (ANCA). Subsequently, the muscle weakness rapidly progressed to an MMT of 2 for all limbs. Magnetic resonance imaging indicated muscle edema, and the creatine kinase (CK) level increased to 29,998 U/L. Methylprednisolone (mPSL) and cyclophosphamide pulse therapy improved the patient symptoms. MMT recovered to 4 for all limbs. A muscle biopsy showed degenerated muscle fibers surrounded by neutrophil-predominant infiltration. In addition, lamina elastic breakdown and fibrinoid necrosis of arterioles were observed. A final diagnosis of microscopic polyangiitis (MPA) limited to the muscles was made.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Asian People; Biomarkers; Cyclophosphamide; Humans; Inflammation; Lower Extremity; Male; Microscopic Polyangiitis; Middle Aged; Muscle Weakness; Myeloblastin; Peroxidase; Prednisolone; Treatment Outcome; Upper Extremity

Intestinal mucositis (IM) is a common side effect of irinotecan-based chemotherapy. The involvement of inflammatory mediators, such as TNF-α, IL1-β, IL-18 and IL-33, has been demonstrated. However, the role of adaptive immune system cells, whose activation is partially regulated by these cytokines, is yet unknown. Thus, we investigated the role of regulatory T cells (Tregs) in irinotecan-induced IM. C57BL/6 mice were injected with saline or irinotecan (75mgkg

Topics: Animals; Camptothecin; Cyclophosphamide; Cytokines; Diarrhea; Ileum; Inflammation; Intestinal Mucosa; Irinotecan; Mice; Mice, Inbred C57BL; Mucositis; Neutrophil Infiltration; Peroxidase; T-Lymphocytes, Regulatory; Th17 Cells

Toxoplasma gondii (T. gondii) is the causative agent of toxoplasmosis, common zoonosis among vertebrates and high incidence worldwide. During the infection, the parasite needs to transpose the intestinal barrier to spread throughout the body, which may be a trigger for an inflammatory reaction. This work evaluated the inflammatory alterations of early T. gondii infection in peripheral blood cells, in the mesenteric microcirculation, and small intestinal tissue by measurement of MPO (myeloperoxidase) activity and NO (nitric oxide) level in rats. Animals were randomly assigned into control group (CG) that received saline orally and groups infected with 5,000 oocysts for 6 (G6), 12 (G12), 24 (G24), 48 (G48) and 72 hours (G72). Blood samples were collected for total and differential leukocyte count. Intravital microscopy was performed in the mesentery to evaluate rolling and adhesion of leukocytes. After euthanasia, 0.5cm of the duodenum, jejunum and ileum were collected for the determination of MPO activity, NO level and PCR to identify the parasite DNA and also the mesentery were collected to perform immunohistochemistry on frozen sections to quantify adhesion molecules ICAM-1, PECAM-1 and P-Selectin. The parasite DNA was identified in all infected groups and there was an increase in leukocytes in the peripheral blood and in expression of ICAM-1 and PECAM-1 in G6 and G12, however, the expression of P-selectin was reduced in G12. Leukocytes are in rolling process during the first 12 hours and they are adhered at 24 hours post-infection. The activity of MPO increased in the duodenum at 12 hours, and NO increased in the jejunum in G72 and ileum in G24, G48 and G72. Our study demonstrated that T. gondii initiates the infection precociously (at 6 hours) leading to a systemic activation of innate immune response resulting in mild inflammation in a less susceptible experimental model.

Topics: Acute Disease; Animals; Immunocompetence; Inflammation; Intercellular Adhesion Molecule-1; Intestines; Nitric Oxide; Peroxidase; Rats; Real-Time Polymerase Chain Reaction; Toxoplasma; Toxoplasmosis, Animal

BACKGROUND Diosgenin, a phytosteroid sapogenin, has anti-inflammatory properties shown to reduce myocardial ischemia-reperfusion injury (MIRI). However, the specific mechanism by which this is achieved is not clear. This study investigated the protective effects of diosgenin on myocardial ischemia/reperfusion (I/R) and the potential anti-inflammatory mechanisms. MATERIAL AND METHODS Healthy adult male SD rats, body weight (b.w.) 250-280 g, were used to model ischemia-reperfusion injury (IRI) and were administered diosgenin (50 mg/kg and 100 mg/kg b.w.) intragastrically for 4 consecutive weeks before surgery. The left anterior descending artery (LAD) was ligated to induce myocardial ischemia for 30 min and reperfusion for 30 min, 60 min, and 120 min while relevant indicators were detected. RESULTS Both 50 mg and 100 mg diosgenin oral administration increased left ventricular developed pressure (LVDP) and maximum changing rate of ventricular pressure (±dp/dtmax), decreased left ventricular end-diastolic pressure (LVEDP), and myocardial enzyme markers. TTC staining suggested that diosgenin reduced myocardial infarct size in the rat model. Pathological results showed that myocardial ischemia and inflammation were alleviated by diosgenin. In addition, the increased expression of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) in serum, and myeloperoxidase (MPO) in myocardium were significantly suppressed by diosgenin administration. Diosgenin further inhibited the phosphorylation of transcription factor NF-κB and modulated the expression of downstream inflammatory cytokines by regulating the activation of p38-MAPK and JNK pathways. CONCLUSIONS Results demonstrate diosgenin plays an anti-inflammatory role in the protection of MIRI through regulation of p38-MAPK and JNK pathways and phosphorylation of NF-κB.

Topics: Animals; Cardiotonic Agents; Diosgenin; Heart Function Tests; Inflammation; Interleukin-1beta; Male; MAP Kinase Signaling System; Myocardial Reperfusion Injury; Myocardium; NF-kappa B; Peroxidase; Phosphorylation; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

Oxidative stress and inflammation are associated with endothelial injury and coronary artery disease. Inflammatory factors that promote oxidative damage include endothelin-1 (ET-1), myeloperoxidase (MPO), and C-reactive protein (CRP). Current guidelines recommend the use of statins in patients with risk of atherosclerotic cardiovascular disease (ASCVD).. To assess the impact of atorvastatin on plasma inflammatory and oxidant biomarkers in patients with moderate to very high risk of ASCVD.. Two hundred ten patients presented to the cardiology clinic were included and stratified into low, moderate, high, and very high risk of ASCVD. Moderate- (20 mg/d) to high-intensity (40 mg/d) atorvastatin was prescribed. Plasma levels of lipids, ET-1, CRP, MPO, total nitrite, lipid peroxides (thiobarbituric acid reactive substances [TBARS]), and superoxide dismutase (SOD) activities were measured at baseline and 12 weeks after treatment.. Relative to low-risk patients, baseline plasma inflammatory markers of CRP, MPO, ET-1, and nitrite were higher in patients with very high risk of ASCVD, whereas plasma SOD was lower (all P < .05). Use of high and moderate atorvastatin therapy significantly reduced low-density lipoprotein and total cholesterol levels, as well as plasma levels of CRP, MPO, nitrite, and TBARS, and increased plasma SOD activity in patients with moderate to very high risk of ASCVD, independent of lipid-lowering effects.. Key markers of oxidative stress/inflammation such as CRP, ET-1, total nitrite, and MPO are associated with an increased risk of ASCVD. Moderate- and high-intensity atorvastatin use reduces plasma oxidative stress and inflammation regardless of ASCVD risk and independent of its lipid-lowering effect.

Topics: Adult; Aged; Atherosclerosis; Atorvastatin; C-Reactive Protein; Dose-Response Relationship, Drug; Endothelin-1; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Lipids; Male; Middle Aged; Oxidants; Oxidative Stress; Peroxidase; Prospective Studies; Risk Factors; Superoxide Dismutase

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

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

Atherosclerosis is characterised by the infiltration of macrophages at sites of inflammation within the vessel wall and the release of myeloperoxidase (MPO), which forms hypochlorous acid (HOCl) and hypothiocyanous acid (HOSCN). HOCl is a damaging oxidant implicated in the development of atherosclerosis. Preferential formation of HOSCN occurs under conditions where thiocyanate ions are elevated, as is the case in smokers. HOSCN reacts selectively with thiols, which can result in more enzyme inactivation and damage than HOCl at susceptible sites, which may contribute to atherosclerosis in smokers. In this study, we show that exposure of macrophages to HOSCN results in a time- and dose-dependent increase in the mRNA expression and release of pro-inflammatory cytokines and chemokines, including monocyte chemotactic protein 1, tumour necrosis factor alpha, and interleukins 6, 8 and 1β. At high oxidant concentrations (>200 μM), a significant loss of cellular thiols and increased cell death is observed. HOSCN-induced cytokine/chemokine expression and cell death were decreased on pharmacological inhibition of nuclear factor kappa B. These data highlight a pathway by which HOSCN could promote inflammation and the development of atherosclerosis, in the presence of supra-physiological levels of the precursor thiocyanate, which are achievable by cigarette smoking.

Topics: Atherosclerosis; Cell Differentiation; Cell Line; Cell Survival; Chemokines; Cytokines; Humans; Inflammation; Inflammation Mediators; Macrophages; NF-kappa B; Peroxidase; Smoking; Sulfhydryl Compounds; Tetradecanoylphorbol Acetate; Thiocyanates; Up-Regulation

Poor child gut health, resulting from a lack of access to an improved toilet or clean water, has been proposed as a biological mechanism underlying child stunting and oral vaccine failure. Characteristics related to household sanitation, water use, and hygiene were measured among a birth cohort of 270 children from peri-urban Iquitos Peru. These children had monthly stool samples and urine samples at four time points and serum samples at (2-4) time points analyzed for biomarkers related to intestinal inflammation and permeability. We found that less storage of fecal matter near the household along with a reliable water connection were associated with reduced inflammation, most prominently the fecal biomarker myeloperoxidase (MPO) (no sanitation facility compared with those with an onsite toilet had -0.43 log MPO, 95% confidence interval [CI]: -0.74, -0.13; and households with an intermittent connection versus those with a continuous supply had +0.36 log MPO, 95% CI: 0.08, 0.63). These results provide preliminary evidence for the hypothesis that children less than 24 months of age living in unsanitary conditions will have elevated gut inflammation.

Topics: Bathroom Equipment; Biomarkers; Child, Preschool; Cohort Studies; Environment; Feces; Gastrointestinal Tract; Growth Disorders; Humans; Hygiene; Infant; Inflammation; Intestinal Diseases; Longitudinal Studies; Peroxidase; Peru; Sanitation; Socioeconomic Factors; Urine; Water

Topics: Animals; Animals, Genetically Modified; Aorta; Calpain; Cell Adhesion; Cell Adhesion Molecules; Cell Culture Techniques; Endothelial Cells; Inflammation; Leukocytes; Mice; Peroxidase; Protein Phosphatase 2; Signal Transduction; Up-Regulation; Vascular Diseases

To evaluate the analgesic effect of Glucantime (antimoniate N-methylglucamine) in Leishmania amazonensis infection and complete Freund's adjuvant (CFA), chronic paw inflammation model, in BALB/c mice.. Two models of chronic inflammatory pain in BALB/c mice paw were used: infection with L. amazonensis and CFA stimulation. Both animals models received daily treatment with Glucantime (10 mg/kg, i.p.) and during the treatment was measured the mechanical hyperalgesia with electronic version of von Frey filaments. After the treatment, the paw skin sample was collected for analysis of myeloperoxidase (MPO) and N-acetyl-β-glucosaminidase (NAG) activity, and IL-1β, TNF-α, IL-6, IFN-γ and IL-10 cytokines production by ELISA.. Leishmania amazonensis-induced chronic inflammation with significant increase in mechanical hyperalgesia, MPO and NAG activity, and IL-1β, TNF-α and IL-6 production in the paw skin. Glucantime (10 mg/kg, i.p.) inhibited L. amazonensis-induced mechanical hyperalgesia and IL-1β and IL-6 cytokines productions. In chronic inflammatory model induced by CFA, Glucantime treatment during 7 days inhibited CFA-induced mechanical hyperalgesia, MPO and NAG activity, and IL-1β, TNF-α, IL-6 and IFN-γ production as well as increased IL-10 production.. Our data demonstrated that Glucantime reduced the chronic inflammatory pain induced by L. amazonensis and CFA stimuli by inhibiting the hyperalgesic cytokines production.

Topics: Acetylglucosaminidase; Animals; Chronic Pain; Cytokines; Freund's Adjuvant; Inflammation; Leishmaniasis, Cutaneous; Male; Meglumine; Meglumine Antimoniate; Mice; Organometallic Compounds; Peroxidase; Skin

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

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

Exosomes isolated from plasma of patients with sepsis may induce vascular apoptosis and myocardial dysfunction by mechanisms related to inflammation and oxidative stress. Despite previous studies demonstrating that these vesicles contain genetic material related to cellular communication, their molecular cargo during sepsis is relatively unknown. In this study, we evaluated the presence of microRNAs (miRNAs) and messenger RNAs (mRNAs) related to inflammatory response and redox metabolism in exosomes of patients with septic shock.. Blood samples were collected from 24 patients with septic shock at ICU admission and after 7 days of treatment. Twelve healthy volunteers were used as control subjects. Exosomes were isolated by ultracentrifugation, and their miRNA and mRNA content was evaluated by qRT-PCR array.. As compared with healthy volunteers, exosomes from patients with sepsis had significant changes in 65 exosomal miRNAs. Twenty-eight miRNAs were differentially expressed, both at enrollment and after 7 days, with similar kinetics (18 miRNAs upregulated and 10 downregulated). At enrollment, 35 differentially expressed miRNAs clustered patients with sepsis according to survival. The pathways enriched by the miRNAs of patients with sepsis compared with control subjects were related mostly to inflammatory response. The comparison of miRNAs from patients with sepsis according to hospital survival demonstrated pathways related mostly to cell cycle regulation. At enrollment, sepsis was associated with significant increases in the expression of mRNAs related to redox metabolism (myeloperoxidase, 64-fold; PRDX3, 2.6-fold; SOD2, 2.2-fold) and redox-responsive genes (FOXM1, 21-fold; SELS, 16-fold; GLRX2, 3.4-fold). The expression of myeloperoxidase mRNA remained elevated after 7 days (65-fold).. Exosomes from patients with septic shock convey miRNAs and mRNAs related to pathogenic pathways, including inflammatory response, oxidative stress, and cell cycle regulation. Exosomes may represent a novel mechanism for intercellular communication during sepsis.

Topics: Adult; Aged; Brazil; Exosomes; Female; Forkhead Box Protein M1; Glutaredoxins; Humans; Inflammation; Intensive Care Units; Male; Membrane Proteins; MicroRNAs; Middle Aged; Oxidative Stress; Patient Outcome Assessment; Peroxidase; Peroxiredoxin III; Prospective Studies; RNA, Messenger; Selenoproteins; Shock, Septic; Superoxide Dismutase

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

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

Sepsis affects millions of people worldwide and is associated with acute kidney injury (AKI). Innate and adaptive immune cells have been shown to play an important role in AKI through release of various inflammatory mediators which include reactive oxidant species (ROS). Acetate, a short chain fatty acid produced by gut bacteria has anti-inflammatory properties and has also been shown to modulate oxidative stress in different immune cells. Effects of acetate have been shown to be both GPR43 dependent and independent in different cells/tissues. However, the role of acetate on T cell NADPH oxidase (NOX2)/ROS signaling remains unexplored during sepsis-induced AKI. Therefore, the current study investigated the effect of acetate on sepsis-induced AKI parameters and T cell oxidant-antioxidant balance. Our results show that acetate ameliorates sepsis-induced AKI as reflected by a decrease in serum, creatinine/blood urea nitrogen and renal myeloperoxidase activity/lipid peroxides and restoration of kidney tubular structure. Moreover, acetate administration was associated with correction of oxidant-antioxidant imbalance in T cells during sepsis-induced AKI. Acetate produced its inhibitory effects on NOX2/ROS signaling via attenuation of histone deacetylase activity in T cells which was induced during AKI. Overall, the data suggest that acetate might be beneficial during sepsis-induced AKI by restoration of oxidant-antioxidant balance in T cells.

Topics: Acetates; Acute Kidney Injury; Animals; Blood Urea Nitrogen; Cells, Cultured; Creatinine; Gastrointestinal Microbiome; Histone Deacetylases; Humans; Inflammation; Kidney; Male; Mice; Mice, Inbred BALB C; NADPH Oxidases; Oxidative Stress; Peroxidase; Reactive Oxygen Species; Sepsis; Signal Transduction; T-Lymphocytes

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

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

Acute lung injury (ALI) is a critical illness syndrome with high morbidity and mortality in patients. Inflammation has been known to be involved in the development of ALI. The purpose of this study was to investigate the effect of puerarin on lipopolysaccharide (LPS)-induced ALI in mice. The pro-inflammatory cytokines TNF-α, IL-6 and IL-1β were determined by ELISA. Western blot analysis was used for detecting the expression of NF-κB, IκBα, and LXRα. And myeloperoxidase (MPO) activity, lung wet/dry (W/D) ratio, and histopathological examination were also detected in lung tissues. The results showed that puerarin significantly inhibited LPS-stimulated MPO activity in lung tissues. Meanwhile, puerarin attenuated lung histopathological changes and lung wet/dry (W/D) ratio. We also found that the expression of pro-inflammatory cytokines, TNF-α, IL-6 and IL-1β were inhibited by puerarin. Puerarin also inhibited LPS-induced TNF-α in RAW264.7 cells and IL-8 in A549 cells. From the results of western blotting, puerarin significantly suppressed LPS-stimulated NF-κB activation. And the expression of LXRα was dose-dependently increased by treatment of puerarin. The inhibition of puerarin on TNF-α production in RAW264.7 cells and IL-8 production in A549 cells were blocked by LXRα inhibitor geranylgeranyl pyrophosphate (GGPP). These results suggested that puerarin attenuated ALI by activating LXRα, which subsequently inhibited LPS-induced inflammatory response.

Topics: A549 Cells; Acute Lung Injury; Animals; Cytokines; Humans; Inflammation; Interleukin-1beta; Interleukin-6; Interleukin-8; Isoflavones; Lipopolysaccharides; Liver X Receptors; Lung; Mice; Mice, Inbred BALB C; NF-kappa B; NF-KappaB Inhibitor alpha; Peroxidase; Polyisoprenyl Phosphates; RAW 264.7 Cells; Tumor Necrosis Factor-alpha

Myeloperoxidase (MPO) is an oxidant-producing enzyme that can also regulate cellular functions via its nonenzymatic effects. Mature active MPO isolated from normal human neutrophils is a 145 kDa homodimer, which consists of 2 identical protomers, connected by a single disulfide bond. By binding to CD11b/CD18 integrin, dimeric MPO induces neutrophil activation and adhesion augmenting leukocyte accumulation at sites of inflammation. This study was performed to compare the potency of dimeric and monomeric MPO to elicit selected neutrophil responses. Monomeric MPO (hemi-MPO) was obtained by treating the dimeric MPO by reductive alkylation. Analysis of the crucial signal transducer, intracellular Ca

Topics: Calcium Signaling; CD11b Antigen; CD18 Antigens; Cell Adhesion; Humans; Inflammation; Neutrophil Activation; Neutrophils; Peroxidase; Protein Multimerization

Oxidation of native low-density lipoproteins (LDLs-nat) plays an important role in the development of atherosclerosis. A major player in LDL-nat oxidation is myeloperoxidase (MPO), a heme enzyme present in azurophil granules of neutrophils and monocytes. MPO produces oxidized LDLs called Mox-LDLs, which cause a pro-inflammatory response in human microvascular endothelial cells (HMEC), monocyte/macrophage activation and formation of foam cells. Resolvin D1 (RvD1) is a compound derived from the metabolism of the polyunsaturated fatty acid DHA, which promotes resolution of inflammation at the ng/ml level.. In the present study, we used liquid chromatography-mass spectrometry (LC-MS/MS) to investigate the synthesis of RvD1 and its precursors - 17(S)-hydroxy docosahexaenoic acid (17S-HDHA) and docosahexaenoic acid (DHA) - by HMEC, in the presence of several concentrations of Mox-LDLs, copper-oxidized-LDLs (Ox-LDLs), and native LDLs or in mouse plasma. The LC-MS/MS method has been validated and applied to cell supernatants and plasma to measure production of RvD1 and its precursors in several conditions.. Mox-LDLs played a significant role in the synthesis of RvD1 and 17S-HDHA from DHA compared to Ox-LDLs. Moreover, Mox-LDLs and LDLs-nat acted in synergy to produce RvD1. In addition, different correlations were found between RvD1 and M1 macrophages, age of mice or Cl-Tyr/Tyr ratio.. These results suggest that although Mox-LDLs are known to be pro-inflammatory and deleterious in the context of atherosclerosis, they are also able to induce a pro-resolution effect by induction of RvD1 from HMEC. Finally, our data also suggest that HMEC can produce RvD1 on their own.

Topics: Animals; Atherosclerosis; Calibration; Cell Line; Chromatography, Liquid; Copper; Docosahexaenoic Acids; Endothelial Cells; Humans; Inflammation; Limit of Detection; Lipids; Lipoproteins, LDL; Macrophages; Mass Spectrometry; Mice; Mice, Inbred C57BL; Oxygen; Peroxidase; Reactive Oxygen Species; RNA, Small Interfering

Myeloperoxidase (MPO) impairing endothelial functions. We investigated whether increasing concentration of myeloperoxidase (MPO) and inflammatory markers induce progression and incident acute coronary syndrome (ACS) in stable coronary artery disease (SCAD) patients. Therefore, the concentration of MPO, lipids, lipoproteins (apo(apolipoprotein) AI, apoB, lipoprotein associated phospholipase A2 (LpPLA2) level), inflammatory markers (high sensitivity C-reactive protein (hsCRP), tumor necrosis factor-α (TNF-α), interleukine-6 (IL-6) concentration) were examined.. This study concerned 67 SCAD patients divided into groups: all patients, patients with MPO < 200 ng/ml, MPO 200-300 ng/ml, MPO > 300 ng/ml concentration and 15 controls. ApoAI, apoB and hsCRP levels were examined using the immunonephelometric method, and MPO, LpPLA2, IL-6, TNF-α concentration was performed by using Quantikine ELISA kit R&D Systems.. In the all patients, and in group with MPO 200-300 ng/ml TC, LDL-C, nonHDL-C, LpPLA2 concentration and TC/HDL-C, LDL-C/HDL-C ratios were insignificant, and significantly higher concentration of TG, apoB, MPO, inflammatory markers and TG/HDL-C, MPO/apoAI, MPO/HDL-C ratios but HDL-C, apoAI level and HDL-C/apoAI ratio were significantly reduced. In the group of patients with MPO < 200 ng/ml, level of TC, LDL-C, nonHDL-C, apoAI, apoAII, LpPLA2 and MPO and LDL-C/HDL-C ratio were in-significant, HDL-C was decreased but apoB, TG, inflammatory markers, apoB/apoAI, TG/HDL-C, MPO/apoAI, MPO/HDL-C ratio were significantly increased. In the group of patients with MPO > 300 ng/ml concentration of TC, LDL-C, nonHDL-C, apoAII, LpPLA2 and LDL-C/HDL-C ratios were not significant, but HDL-C and apoAI concentrations were significantly decreased. The concentrations of TG, apoB, MPO and inflammatory markers and TG/HDL-C, MPO/apoAI, MPO/HDL-C ratios were significantly increased compared to the controls. The apoAI concentration was significantly decreased and the concentration of MPO and hsCRP as well as MPO/apoAI and MPO/HDL-C ratios were significantly higher as compared to the group of patients with MPO < 200 ng/ml. Spearman's correlation test showed a positive correlation between MPO concentration and MPO/apoAI and MPO/HDL-C ratios in all patients and MPO < 200 ng/ml, MPO 200-300 ng/ml. The patients with MPO > 300 ng/ml showed a positive correlation between the concentration of MPO and the level of hsCRP and IL-6, and a negative correlation between MPO/apoAI ratio and the concentration of HDL-C, apoAI and apoAII.. The results suggest that moderate dyslipidemia and dyslipoproteinemia deepening of inflammation, and inflammation slowly induce increase MPO concentration which decrease apoAI and HDL-C level and disturb HDLs function. The increasing MPO level and MPO/HDL-C, MPO/apoAI ratios can differentiate the SCAD patients at the risk of acute coronary syndrome (ACAD) and stroke.

Topics: Acute Coronary Syndrome; Aged; Apolipoprotein A-I; Apolipoprotein B-100; Biomarkers; Coronary Artery Disease; Female; Humans; Inflammation; Interleukin-6; Lipids; Male; Middle Aged; Peroxidase; Phospholipases A2; Tumor Necrosis Factor-alpha

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

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

Mastitis is inflammation of a breast (or udder). Angiopoietin-like protein 2 (ANGPTL2) has been found as a key inflammatory mediator in mastitis. Purpose of this research was to investigate the mechanisms about repressing effect of kaempferol on mastitis.. Forty mice were randomly divided into 4 groups (n=10): C57BL/6J control mice, untreated murine mastitis, 10mg/kg kaempferol treated murine mastitis (ip), and 30mg/kg kaempferol treated murine mastitis (ip). Primary cultured mouse mammary epithelial cells (MMEC) were indiscriminately divided into seven groups including control group, 10mmol/L vehicle of kaempferol group, 10μmol/L kaempferol treated group, 20μg/mL LPS treated group, 1μmol/L kaempferol plus LPS treated group, 3μmol/L kaempferol plus LPS treated group, and 10μmol/L kaempferol plus LPS treated group.. In murine mastitis, kaempferol (10 or 30mg/kg) treatment prevented mastitis development, decreased myeloperoxidase (MPO) production, interleukin (IL)-6 level, tumour necrosis factor-α (TNF-α) concentration, and ANGPTL2 expression. In MMEC, kaempferol (1, 3 or 10μM) reduced MPO production, TNF-α concentration, IL-6 level, and ANGPTL2 expression.. The results in present study show that kaempferol modulates the expression of ANGPTL2 to lessen the mastitis in mice.

Topics: Angiopoietin-Like Protein 2; Angiopoietin-like Proteins; Animals; Epithelial Cells; Female; Inflammation; Interleukin-6; Kaempferols; Mastitis; Mice; Mice, Inbred C57BL; Peroxidase; Tumor Necrosis Factor-alpha

Although cisplatin is a potent anticancer drug, it instigates oxidative and pro-inflammatory reactions that pose significant and distressing clinical symptoms. Therefore, this study investigated the effects of vitamin C and (or) l-carnitine on cisplatin-induced gastric mucosa damage in rat. The rats were allocated into 6 groups (n = 5). The control group received distilled water, while the treatment groups received cisplatin alone (CIP), or cisplatin with vitamin C, l-carnitine, or their combination. Cisplatin caused disruption of the gastric mucosa histoarchitecture and altered the mucus barrier function. Moreover, the stomach tissue of the CIP-treated group showed increased levels of oxidative stress markers (malondialdehyde and H

Topics: Animals; Antioxidants; Ascorbic Acid; Biomarkers; Body Weight; Carnitine; Cell Count; Cisplatin; Cytokines; Feeding Behavior; Gastric Mucosa; Hydrogen Peroxide; Inflammation; Inflammation Mediators; Male; Malondialdehyde; Mucus; Nitric Oxide Synthase; Oxidants; Peroxidase; Rats, Wistar

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

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

The number of white blood cell (WBC) in semen is an important indicator of genital tract inflammation in male infertility. The peroxidase assay is the recommended reference method for seminal WBC counting. However, it is time-consuming and may cause relatively heavy workload in daily routine. Meanwhile, the main component in the reagent of peroxidase test is harmful to human and the environment. In this study, we evaluated the analytical performance of the Sysmex UF-1000i that is a urine flow cytometer as a screening tool for genital tract infection in male infertility patients through the counting of seminal WBC. We examined 143 semen samples and compared the results of UF-1000i and manual microscopy. The intra-assay variability, stability and linearity studies were performed. The intravariability (CV %) of seminal WBC count by Sysmex UF-1000i was 2.34%-9.65%. The method of UF-1000i displayed a good agreement with the reference assay of manual microscopy, and the r value for correlation of seminal WBC count between UF-1000i and manual microscopy was over 0.999 (p < 0.001). The Sysmex UF-1000i is capable of producing reliable seminal WBC count consistent with that obtained by manual microscopy. It is a suitable alternative to the manual microscopy, thus reduces the workload.

Topics: Adult; Enzyme Assays; Genital Diseases, Male; Humans; Infertility, Male; Inflammation; Leukocyte Count; Male; Mass Screening; Microscopy; Middle Aged; Peroxidase; Semen; Semen Analysis; Workload

Tumor progression locus 2 (TPL2), a serine/threonine protein kinase, is a major inflammatory mediator in immune cells. The predominant inflammatory actions of TPL2 depend on the activation of mitogen-activated protein kinases (MAPK) and the upregulated production of the cytokines tumor necrosis factor alpha (TNF-α) and interleukin 1β (IL-1β) in macrophages and dendritic cells in response to lipopolysaccharide (LPS). Significant increases in TNF-α, IL-6, IL-β, and IL-8 levels in patients with

Topics: Animals; Blotting, Western; Cecum; Clostridium Infections; Colon; Cytokines; Disease Susceptibility; Humans; Inflammation; MAP Kinase Kinase Kinases; Mice, Inbred C57BL; Mice, Knockout; Peroxidase; Proto-Oncogene Proteins; Signal Transduction

Growth differentiation factor‑15 (GDF‑15) is a transforming growth factor (TGF)‑β superfamily member with a poorly characterized biological activity, speculated to be implicated in several diseases. The present study aimed to determine whether GDF‑15 participates in sepsis‑induced acute liver injury in mice. Lipopolysaccharide (LPS) and D‑galactosamine (D‑GalN) were administered to mice to induce acute liver injury. Survival of mice, histological changes in liver tissue, and levels of inflammatory biomarkers in serum and liver tissue were evaluated following treatment with GDF‑15. The underlying mechanism was investigated by western blotting, ELISA, flow cytometry, and reverse transcription‑quantitative polymerase chain reaction using Kupffer cells. The results demonstrated that GDF‑15 prevented LPS/D‑GalN‑induced death, increase in inflammatory cell infiltration and serum alanine aminotransferase and aspartate aminotransferase activities. In addition, GDF‑15 treatment reduced the production of hepatic malondialdehyde and myeloperoxidase, and attenuated the increase of interleukin (IL)‑6, tumor necrosis factor (TNF)‑α, and IL‑1β expression in serum and liver tissue, accompanied by inducible nitric oxide synthase (iNOS) inactivation in the liver. Similar changes in the expression of inflammatory cytokines, IL‑6, TNF‑α and IL‑1β, and iNOS activation were observed in the Kupffer cells. Further mechanistic experiments revealed that GDF‑15 effectively protected against LPS‑induced nuclear factor (NF)‑κB pathway activation by regulating TGFβ‑activated kinase 1 (TAK1) phosphorylation in Kupffer cells. In conclusion, GDF‑15 reduced the activation of pro‑inflammatory factors, and prevented LPS‑induced liver injury, most likely by disrupting TAK1 phosphorylation, and consequently inhibiting the activation of the NF‑κB pathway in the liver.

Topics: Animals; Cytokines; Enzyme Activation; Galactosamine; Growth Differentiation Factor 15; Inflammation; Inflammation Mediators; Kupffer Cells; Lipopolysaccharides; Liver; Male; Malondialdehyde; MAP Kinase Kinase Kinases; Mice, Inbred C57BL; NF-kappa B; Nitric Oxide Synthase Type II; Peroxidase; Phosphorylation; Protective Agents

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

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

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by cellular infiltration into the joints and cartilage destruction. Neutrophils play a crucial role in the pathogenesis of RA. Triptolide (TP) is a bioactive compound derived from Tripterygium wilfordii Hook F, which has been used in folk medicine as a treatment for a variety of inflammatory disorders, including RA, for many centuries. Previous studies have shown that TP possesses anti-arthritic activity. However, the anti-arthritic mechanism of TP remains to be fully defined. In the present study, we used the adjuvant-induced arthritis (AA) murine model of RA to investigate the impact of TP on RA and neutrophil function. TP alleviated AA by reducing neutrophil recruitment and suppressing the expression of interleukin-6 and tumour necrosis factor-α in vivo. TP also suppressed the expression of pro-inflammatory cytokines in neutrophils, promoted neutrophil apoptosis and inhibited the migration, NETosis and autophagy of neutrophils in vitro. Based on our findings, TP effectively ameliorates RA by down-regulating neutrophil inflammatory functions, indicating that TP represents a potential therapeutic agent for RA.

Topics: Animals; Apoptosis; Arthritis, Experimental; Arthritis, Rheumatoid; Autophagy; Chronic Disease; Cytokines; Diterpenes; Epoxy Compounds; Extracellular Traps; Inflammation; Leukocyte Elastase; Lipopolysaccharides; Male; Mice, Inbred C57BL; Neutrophil Infiltration; Neutrophils; Peroxidase; Phenanthrenes

Carbon nanotubes are widely used in the area of biomedicine, and the binding of protein to carbon nanotubes are believed to play an important role in the potential cytotoxicity of nanomaterials. In this work, we investigated the effects of human fibrinogen-surface coatings on the biodegradation and cytotoxicity of carboxylated single-walled carbon nanotubes (SWCNTs). It was found that the electrostatic and π-π stacking interactions might be the crucial factors in stabilizing the binding of fibrinogen with SWCNTs by both theoretical and experimental approaches. Although naked SWCNTs could induce significant toxicity to macrophages, coating these nanomaterials with fibrinogen could greatly attenuate their toxicity. On the other hand, although SWCNTs and fibrinogen-preincubated SWCNTs were resistant to biodegradation in resting macrophages, both naked and fibrinogen-coated SWCNTs could be effectively and similarly degraded through myeloperoxidase (MPO) and peroxynitrite (ONOO

Topics: Adsorption; Biocompatible Materials; Cell Line; Fibrinogen; Humans; Inflammation; Macrophages; Microscopy, Atomic Force; Nanotubes, Carbon; Oxidation-Reduction; Peroxidase; Peroxynitrous Acid; Protein Binding

Nutrient deficiencies limit the growth and turnover of intestinal mucosa, but studies assessing whether specific nutrients protect against or improve environmental enteric dysfunction (EED) are scarce. We aimed to investigate associations between nutrient intake and EED assessed by lactulose:mannitol (L:M) ratio, anti-1-antitrypsin, myeloperoxidase (MPO), and neopterin (NEO) among children 9-24 months in Bhaktapur, Nepal.. Among 231 included children, nutrient intake was assessed monthly by 24 h recalls, and 3-month usual intake was estimated using Multiple Source Method. Associations between nutrient intake and L:M ratio (measured at 15 months) were assessed using multiple linear regression, while associations between nutrient intake and fecal markers (measured quarterly) were assessed using Generalized Estimating Equations (GEE) models.. We found that associations between nutrient intake from complementary food and L:M ratio, alpha-1-antitrypsin (AAT), MPO and NEO were generally negative but weak. The only significant associations between nutrient intake (potassium, magnesium, phosphorous, folate, and vitamin C) and markers for intestinal inflammation were found for MPO.. Negative but weak associations between nutrient intake and markers of intestinal inflammation were found. Significant associations between several nutrients and MPO might merit further investigation.

Topics: alpha 1-Antitrypsin; Biomarkers; Breast Feeding; Child Nutrition Sciences; Child, Preschool; Cohort Studies; Diet; Energy Intake; Feces; Female; Humans; Infant; Inflammation; Intestinal Diseases; Intestinal Mucosa; Lactulose; Male; Mannitol; Neopterin; Nepal; Nutrients; Peroxidase; Regression Analysis

Myeloperoxidase (MPO) is a leukocyte-derived redox enzyme that has been linked to oxidative stress and damage in many inflammatory states, including cardiovascular disease. We have discovered aminopyridines that are potent mechanism-based inhibitors of MPO, with significant selectivity over the closely related thyroid peroxidase. 1-((6-Aminopyridin-3-yl)methyl)-3-(4-bromophenyl)urea (Aminopyridine 2) inhibited MPO in human plasma and blocked MPO-dependent vasomotor dysfunction ex vivo in rat aortic rings. Aminopyridine 2 also showed high oral bioavailability and inhibited MPO activity in vivo in a mouse model of peritonitis. Aminopyridine 2 could effectively be administered as a food admixture, making it an important tool for assessing the relative importance of MPO in preclinical models of chronic inflammatory disease.

Topics: Aminopyridines; Animals; Aorta; Biological Availability; Enzyme Inhibitors; Humans; Inflammation; Male; Mice; Mice, Inbred C57BL; Peroxidase; Rats; Rats, Sprague-Dawley

Beverages containing Trichilia catigua are commonly employed in folk medicine. T. catigua bark extracts possess antioxidant, anti-inflammatory, and bactericidal properties. These properties suggest T. catigua bark extracts as a potential treatment for inflammatory bowel diseases (IBD). Using the 2,4,6-trinitrobenzenesulphonic acid (TNBS)-induced model of colitis in rats we evaluated the effect of an ethyl-acetate fraction (EAF) of T. catigua (200 mg/kg) administered by daily oral gavage or intrarectally at different time points after TNBS challenge. TNBS treatment evoked severe colonic inflammation after 24 h that persisted for 7 days, characterized by weight loss, high levels of myeloperoxidase activity, histological and macroscopic damage, and elevated index of oxidative stress in the blood. T. catigua EAF treatment prevented the oxidative stress within 24 h and enhanced tissue recovery observed at day 7, returning histological and macroscopic damage levels to that of the control group. TNBS treatment led to loss of myenteric neurons after 28 days. T. catigua EAF was unable to prevent the neuronal loss. Oral delivery of T. catigua EAF was more effective than intrarectal administration of the extract. In conclusion, T. catigua EAF treatment normalized oxidative stress parameters in blood and reduced the degree of acute inflammation in TNBS colitis.

Topics: Acetates; Administration, Oral; Animals; Biomarkers; Body Weight; Colitis; Colon; Inflammation; Male; Meliaceae; Myenteric Plexus; Neurons; Oxidative Stress; Peroxidase; Plant Extracts; Rats, Wistar; Trinitrobenzenesulfonic Acid; Wound Healing

To determine whether a cyclooxygenase (COX)-2 selective nonsteroidal anti-inflammatory drug (NSAID) would reduce gastric ulceration and gastrointestinal (GI) inflammation compared with a non-COX selective NSAID.. Randomized block design.. Twenty-five healthy adult horses.. Horses were randomly assigned to receive placebo (n = 5), phenylbutazone (n = 10), or firocoxib (n = 10) administered daily for 10 days. Gastroscopy was performed on days 0 and 10, and both squamous and glandular ulcers were scored according to established scoring criteria. Fecal samples were collected on days 0, 10, and 20 to test for fecal myeloperoxidase (MPO) concentration by enzyme-linked immunosorbent assay.. Both classes of NSAID induced GI injury as determined by gastric ulceration scores and fecal MPO. Glandular gastric ulceration scores and fecal MPO concentrations were higher in horses treated with phenylbutazone at day 10 (P < .001 and P = .0018, respectively). Increases in fecal MPO were significantly decreased 10 days following cessation of treatment for firocoxib but remained greater than baseline for the phenylbutazone group.. Although both classes of NSAID induced gastric ulceration, the COX-2 selective NSAID firocoxib induced less severe glandular ulceration. Although there were increases in fecal MPO in both groups after 10 days of treatment, this increase was significant only in horses receiving the nonselective COX inhibitor phenylbutazone.. These findings suggest that both classes of NSAID induce GI injury in horses; however, at the dosages used in this study, the COX-2 selective NSAID firocoxib resulted in less severe injury.

Topics: 4-Butyrolactone; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase 2 Inhibitors; Feces; Gastrointestinal Diseases; Horse Diseases; Horses; Inflammation; Peroxidase; Phenylbutazone; Random Allocation; Stomach Ulcer; Sulfones

Uric acid is the final product of purine metabolism in humans and is considered to be quantitatively the main antioxidant in plasma. In vitro studies showed that the oxidation of uric acid by peroxidases, in presence of superoxide, generates urate free radical and urate hydroperoxide. Urate hydroperoxide is a strong oxidant and might be a relevant intermediate in inflammatory conditions. However, the identification of urate hydroperoxide in cells and biological samples has been a challenge due to its high reactivity. By using mass spectrometry, we undoubtedly demonstrated the formation of urate hydroperoxide and its corresponding alcohol, hydroxyisourate during the respiratory burst in peripheral blood neutrophils and in human leukemic cells differentiated in neutrophils (dHL-60). The respiratory burst was induced by phorbol myristate acetate (PMA) and greatly increased oxygen consumption and superoxide production. Both oxygen consumption and superoxide production were further augmented by incubation with uric acid. Conversely, uric acid significantly decreased the levels of HOCl, probably because of the competition with chloride by the catalysis of myeloperoxidase. In spite of the decrease in HOCl, the overall oxidative status, measured by GSH/GSSG ratio, was augmented in the presence of uric acid. In summary, the present results support the formation of urate hydroperoxide, a novel oxidant in neutrophils oxidative burst. Urate hydroperoxide is a strong oxidant and alters the redox balance toward a pro-oxidative environment. The production of urate hydroperoxide in inflammatory conditions could explain, at least in part, the harmful effect associated to uric acid.

Topics: Catalysis; Cell Line, Tumor; Free Radicals; Humans; Inflammation; Mass Spectrometry; Neutrophils; Oxidation-Reduction; Peroxidase; Peroxides; Reactive Oxygen Species; Superoxides; Uric Acid

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

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

Resveratrol is a natural polyphenol found mainly on red grapes and in red wine, pointed as an important anti-inflammatory/immunomodulatory molecule. However, its bioavailability problems have limited its use encouraging the search for new alternatives agents. Thus, in this study, we synthetize 12 resveratrol analogues (6 imines, 1 thioimine and 5 hydrazones) and investigated its cytotoxicity, antioxidant activity and in vitro anti-inflammatory/immunomodulatory properties. The most promising compounds were also evaluated in vivo. The results showed that imines presented less cytotoxicity, were more effective than resveratrol on DPPH scavenger and exhibited an anti-inflammatory profile. Among them, the imines with a radical in the para position, on the ring B, not engaged in an intramolecular hydrogen-interaction, showed more prominent anti-inflammatory activity modulating, in vivo, the edema formation, the inflammatory infiltration and cytokine levels. An immunomodulatory activity also was observed in these molecules. Thus, our results suggest that imines with these characteristics presents potential to control inflammatory disorders.

Topics: Adjuvants, Immunologic; Animals; Anti-Inflammatory Agents; Antioxidants; Biological Availability; Biphenyl Compounds; Cell Proliferation; Cytokines; Down-Regulation; Imines; Inflammation; Inflammation Mediators; Lymphocytes; Major Histocompatibility Complex; Mice; Mice, Inbred C57BL; Peroxidase; Picrates; RAW 264.7 Cells; Resveratrol

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

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

Oxidative stress during sepsis pathogenesis remains the most-important factor creating imbalance and dysregulation in immune-cell function, usually observed following initial infection. Hydrogen peroxide (H

Topics: Albumins; Animals; Brain; Cognitive Dysfunction; Endotoxemia; Gene Expression Regulation; Humans; Hydrogen Peroxide; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Lipopolysaccharides; Macrophages; Manganese Compounds; Mice; Nanocomposites; Oxidative Stress; Oxides; Peroxidase; Peroxides; Reactive Oxygen Species; Signal Transduction; Tumor Necrosis Factor-alpha

In 93 preterm infants ≤32 weeks of gestational age and 12 control infants, epithelial lining fluid disaturated-phosphatidylcholine, surfactant protein A and B, albumin, and myeloperoxidase activity were assessed after intubation and before exogenous surfactant administration. We found that disaturated-phosphatidylcholine, surfactant protein B, and myeloperoxidase were significantly higher in preterms with chorioamnionitis.

Topics: Albumins; Chorioamnionitis; Epithelium; Female; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Inflammation; Peroxidase; Phosphatidylcholines; Pregnancy; Prospective Studies; Pulmonary Surfactant-Associated Protein A; Pulmonary Surfactants; Respiratory Distress Syndrome, Newborn; Surface-Active Agents; Trachea

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

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

Ca2+-sensing receptor (CaSR) represents a potential therapeutic target for inflammatory bowel diseases and strongly prefers aromatic amino acid ligands. We investigated the regulatory effects of dietary supplementation with aromatic amino acids - tryptophan, phenylalanine and tyrosine (TPT) - on the CaSR signalling pathway and intestinal inflammatory response. The in vivo study was conducted with weanling piglets using a 2 × 2 factorial arrangement in a randomised complete block design. Piglets were fed a basal diet or a basal diet supplemented with TPT and with or without inflammatory challenge. The in vitro study was performed in porcine intestinal epithelial cell line to investigate the effects of TPT on inflammatory response using NPS-2143 to inhibit CaSR. Dietary supplementation of TPT alleviated histopathological injury and decreased myeloperoxidase activity in intestine challenged with lipopolysaccharide. Dietary supplementation of TPT decreased serum concentration of pro-inflammatory cytokines (IL-1β, IL-6, IL-8, IL-12, granulocyte-macrophage colony-stimulating factor, TNF-α), as well as the mRNA abundances of pro-inflammatory cytokines in intestine but enhanced anti-inflammatory cytokines IL-4 and transforming growth factor-β mRNA levels compared with pigs fed control diet and infected by lipopolysaccharide. Supplementation of TPT increased CaSR and phospholipase Cβ2 protein levels, but decreased inhibitor of NF-κB kinase α/β and inhibitor of NF-κB (IκB) protein levels in the lipopolysaccharide-challenged piglets. When the CaSR signalling pathway was blocked by NPS-2143, supplementation of TPT decreased the CaSR protein level, but enhanced phosphorylated NF-κB and IκB levels in IPEC-J2 cells. To conclude, supplementation of aromatic amino acids alleviated intestinal inflammation as mediated through the CaSR signalling pathway.

Topics: Amino Acids, Aromatic; Animals; Colon; Cytokines; Diet; Dietary Supplements; Epithelial Cells; Female; I-kappa B Kinase; Inflammation; Intestines; Jejunum; Lipopolysaccharides; NF-kappa B; Peroxidase; Phenylalanine; Phosphorylation; Random Allocation; Receptors, Calcium-Sensing; RNA, Messenger; Signal Transduction; Sus scrofa; Swine; Tryptophan; Tumor Necrosis Factor-alpha; Tyrosine

The effects of fructo-oligosaccharides (FOS) on gut-barrier function are still controversial in human and animal studies. Diet conditions would be a major factor for the controversy in animal studies. We fed rats a semi-purified (SP) or a non-purified diet (NP) with or without FOS (60 g/kg diet) for 9 (experiment 1) or 10 d (experiment 2). We assessed microbial fermentation, gut permeability, and inflammatory responses in the cecum (experiment 1), and mucus layer in the cecum, intestinal transit time and microbiota composition (experiment 2). FOS supplementation induced a very acidic fermentation due to the accumulation of lactate and succinate in SP, while short-chain fatty acids were major products in NP. Gut permeability estimated by urinary chromium-EDTA excretion, bacterial translocation into mesenteric lymph nodes, myeloperoxidase activity, and expressions of the inflammatory cytokine genes in the cecal mucosa were greater in SP+FOS than in SP, but these alterations were not observed between NP and NP+FOS (experiment 1). FOS supplementation destroyed the mucus layer on the epithelial surface in SP, but not in NP. Intestinal transit time was 3-fold longer in SP+FOS than in SP, but this was not the case between NP and NP+FOS. Lower species richness of cecal microbiota was manifest solely in SP+FOS (experiment 2). These factors suggest that impact of FOS on gut permeability and inflammatory responses in the cecal mucosa quite differs between SP and NP. Increased gut permeability in SP+FOS could be evoked by the disruption of the mucus layer due to stasis of the very acidic luminal contents.

Topics: Animal Feed; Animals; Bacterial Translocation; Cecum; Chromium; Cytokines; Diet; Digestion; Edetic Acid; Fatty Acids, Volatile; Fermentation; Fructose; Gastrointestinal Microbiome; Gastrointestinal Transit; Inflammation; Intestinal Mucosa; Lactic Acid; Male; Oligosaccharides; Permeability; Peroxidase; Prebiotics; Rats, Wistar; Succinic Acid

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

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

Sinapis Semen is derived from the dried mature seeds of Sinapis alba L. or Brassica juncea (L.) Czern. et Coss. Traditionally, the seeds from S. alba are called "White Sinapis Semen" while those from B. juncea are called "Yellow Sinapis Semen".. The present study aimed to compare the chemical composition and the anti-inflammatory effects of 50% aqueous ethanol extracts of the White Sinapis Semen (EWSS) and Yellow Sinapis Semen (EYSS) using both acute (12-O-tetradecanoylphorbol-acetate (TPA)- and arachidonic acid (AA)-induced mouse ear edema) and chronic (multiple applications of croton oil (CO)) inflammatory models.. The anti-inflammatory effects of EWSS and EYSS were determined by measuring the ear thickness and myeloperoxidase (MPO) activity. The anti-inflammatory mechanism was explored by measuring the protein and mRNA levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6 in the ear of the TPA-treated mice.. The results showed that both EWSS and EYSS significantly decreased the ear thickness in both the TPA- and AA-induced acute models, as well as in the CO-induced chronic model. In addition, EWSS and EYSS could markedly inhibit the MPO activity in the ears of TPA-, AA- or CO-treated mice. Moreover, EWSS and EYSS also remarkably inhibited the protein and mRNA levels of TNF-α and IL-6 in the ears of TPA-treated mice. Comparatively, EWSS exerted more potent anti-inflammatory effect than that of EYSS.. Our results revealed that both EWSS and EYSS are effective anti-inflammatory agents against acute and chronic inflammatory processes, and EWSS possess more potent anti-inflammatory effect than EYSS. The anti-inflammatory effect of the two herbs may be mediated, at least in part, by suppressing the mRNA expression of a panel of inflammatory mediators including TNF-α, IL-6 and IL-1β.

Topics: Animals; Anti-Inflammatory Agents; Arachidonic Acid; China; Edema; Inflammation; Interleukin-1beta; Interleukin-6; Male; Mice; Mice, Inbred BALB C; Mustard Plant; Peroxidase; Plant Extracts; Seeds; Sinapis; Tetradecanoylphorbol Acetate; Tumor Necrosis Factor-alpha

Cardiovascular morbidity and mortality of premenopausal women are significantly lower compared to men of similar age. However, this protective effect evidently decreases after the onset of menopause. We hypothesized that physical exercise could be a potential therapeutic strategy to improve inflammatory processes and cardiovascular antioxidant homeostasis, which can be affected by the loss of estrogen and the adverse environmental factors, such as overnutrition. Ovariectomized (OVX, n= 40) and sham-operated (SO, n= 40) female Wistar rats were randomized to exercising (R) and non-exercising (NR) groups. Feeding parameters were chosen to make a standard chow (CTRL) or a high triglyceride diet (HT) for 12 weeks. Aortic and cardiac heme oxygenase (HO) activity and HO-1 concentrations significantly decreased in all of the NR OVX and SO HT groups. However, the 12-week physical exercise was found to improve HO-1 values. Plasma IL-6 concentrations were higher in the NR OVX animals and rats fed HT diet compared to SO CTRL rats. TNF-α concentrations were significantly higher in the NR OVX groups. 12 weeks of exercise significantly reduced the concentrations of both TNF-α and IL-6 compared to the NR counterparts. The activity of myeloperoxidase enzyme (MPO) was significantly increased as a result of OVX and HT diet, however voluntary wheel-running exercise restored the elevated values. Our results show that estrogen deficiency and HT diet caused a significant decrease in the activity and concentration of HO enzyme, as well as the concentrations of TNF-α, IL-6, and the activity of MPO. However, 12 weeks of voluntary wheel-running exercise is a potential non-pharmacological therapy to ameliorate these disturbances, which determine the life expectancy of postmenopausal women.

Topics: Animals; Aorta; Body Weight; Cardiovascular Diseases; Diet, High-Fat; Estrogens; Female; Heme Oxygenase (Decyclizing); Inflammation; Interleukin-6; Myocardium; Ovariectomy; Peroxidase; Physical Conditioning, Animal; Random Allocation; Rats, Wistar; Risk Factors; Triglycerides; Tumor Necrosis Factor-alpha

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

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

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

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

Body fatness is a risk factor for colorectal cancer, and promotes an inflammatory environment. Indeed, inflammation in normal colorectal mucosa may be a factor linking body fatness to colorectal carcinogenesis. In this study, we evaluated myeloperoxidase (MPO)-positive cells infiltration of normal colorectal mucosa as a marker of cancer-promoting inflammation in overweight and obese subjects. One hundred and three subjects with normal colonoscopy entered the study. Waist circumference (WC) and body mass index (BMI) were measured, and MPO-positive cells on histological sections of biopsies of normal colorectal mucosa were counted under a light microscope. The occurrence of adenomas was then evaluated on follow-up colonoscopies. Mean MPO-positive cell count (±s.e.m.) was higher in subject with a WC equal or above the obesity cutoff values according to gender (2.63±0.20 vs 2.06±0.18, P=0.03), and in subjects with BMI equal or above 25 kg m

Topics: Adenoma; Antigens, Differentiation, Myelomonocytic; Biomarkers, Tumor; Body Mass Index; Colonoscopy; Colorectal Neoplasms; Early Detection of Cancer; Female; Follow-Up Studies; Humans; Immunoenzyme Techniques; Inflammation; Intestinal Mucosa; Italy; Male; Middle Aged; Odds Ratio; Overweight; Peroxidase; Risk Factors; Waist Circumference

Topics: Amnion; Animals; Cell Movement; Cell Proliferation; Cells, Cultured; Cytokines; Epithelial Cells; Humans; Inflammation; Lipoxins; Lung; Macrophages; Mice, Inbred C57BL; Neutrophils; Peroxidase; Phagocytosis

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

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

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

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

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Cyclooxygenase 1; Cyclooxygenase 2 Inhibitors; Cytokines; Dinoprostone; Indomethacin; Inflammation; Leukocyte Count; Male; Mice; NG-Nitroarginine Methyl Ester; Nitrates; Nitric Oxide; Nitric Oxide Synthase Type II; Nitrites; Peroxidase; Pleurisy; Pyrazoles; Tetrazoles; Up-Regulation

Neutrophil extracellular traps (NETs) are extracellular DNA filaments formed during neutrophil activation. This process, called netosis, was originally associated with neutrophil antibacterial properties. However, several lines of evidence now suggest a major role for netosis in thrombosis, autoimmune diseases, and cancer. We demonstrate here that highly purified human blood monocytes are also capable of extracellular trap (ET) release in response to several stimuli. Monocyte ETs display a morphology analogous to NETs and are associated with myeloperoxidase (MPO), lactoferrin (LF), citrullinated histones, and elastase. Monocyte ET release depends on oxidative burst but not on MPO activity, in contrast to neutrophils. Moreover, we demonstrate procoagulant activity for monocyte ETs, a feature that could be relevant to monocyte thrombogenic properties. This new cellular mechanism is likely to have implications in the multiple pathologic contexts where monocytes are implicated, such as inflammatory disorders, infection, or thrombosis.

Topics: Extracellular Traps; Histones; Humans; Infections; Inflammation; Lactoferrin; Monocytes; Pancreatic Elastase; Peroxidase; Thrombosis

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

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

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

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

Salvianolic acid B (SAB) is one the major phytocomponents of Radix Salvia miltiorrhiza and exhibit numerous health promoting properties. The objective of the current study was to examine whether SAB exerts a renoprotective effect by attenuating oxidative stress and inflammatory response through activating phosphatidylinositol 3-kinase/serine-threonine kinase B (PI3K/Akt) signaling pathway in a renal ischemic reperfusion rat model. Forty Sprague-Dawley male rats (250-300 g) were obtained and split into four groups with ten rats in each group. The right kidney of all rats was removed (nephrectomy). The rats of the Control group received only saline (occlusion) and served as a sham control group, whereas rats subjected to ischemic reperfusion (IR) insult by clamping the left renal artery served as a postitive control group. The other 2 groups of rats were pretreated with SAB (20 and 40 mg·kg-1·day-1) for 7 days prior IR induction and served as treatment groups (SAB 20+IR; SAB 40+IR). Renal markers creatinine (Cr) and blood urea nitrogen (BUN) were significantly lower in the groups that received SAB. Pretreatment with SAB appears to attenuate oxidative stress by suppressing the production of lipid peroxidation products like malondialdehyde as well as elevating antioxidant activity. The concentration of inflammatory markers and neutrophil infiltration (myeloperoxidase) were significantly decreased. Meanwhile, PI3K protein expression and pAkt/Akt ratio were significantly upregulated upon supplementation with SAB, indicating its renoprotective activity. Taken together, these results indicate that SAB can therapeutically alleviate oxidative stress and inflammatory process via modulating PI3K/Akt signaling pathway and probably ameliorate renal function and thus act as a renoprotective agent.

Topics: Animals; Benzofurans; Blood Urea Nitrogen; Creatinine; Drugs, Chinese Herbal; Inflammation; Kidney; Lipid Peroxidation; Male; Oxidative Stress; Peroxidase; Phosphatidylinositol 3-Kinases; Protective Agents; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Reperfusion Injury; Signal Transduction

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

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

Topics: Animals; Colitis; Cytokines; Electroacupuncture; Gene Expression Regulation; Inflammation; Male; Peroxidase; Rats; Rats, Sprague-Dawley; Time Factors; Trinitrobenzenesulfonic Acid; Vagus Nerve Stimulation

Bao-Xin-Tang (BXT) is a traditional Chinese medicinal formula used for the treatment of coronary heart disease and known to have favorable therapeutic benefits. The current study was designed to determine whether BXT has a cardioprotective role for acute myocardial infarction. The underlying mechanisms were also explored.. The Sprague-Dawley rat model of acute myocardial infarction was established by occluding the left anterior descending branch of the coronary artery. After a 3-h ischemic period, we determined the myocardial infarction size, inflammatory components, and antioxidant activities.. The data showed that BXT could reduce the infarction size and lower the levels of C-reactive protein, interleukin-6, and myeloperoxidase, and increase the activities of superoxide dismutase and the anti-inflammatory cytokine, interleukin-10. These results indicate that administration of BXT, following acute myocardial infarction, could reduce infarct size.. The effects of BXT may be related to its anti-inflammatory and anti-oxidative properties.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents; Antioxidants; C-Reactive Protein; Cardiotonic Agents; Coronary Vessels; Drugs, Chinese Herbal; Infarction; Inflammation; Interleukin-10; Interleukin-6; Male; Myocardial Infarction; Myocardium; Oxidative Stress; Peroxidase; Phytotherapy; Rats, Sprague-Dawley; Superoxide Dismutase

To investigate whether modulating GSK-3β could attenuate myocardial ischemia reperfusion injury (MIRI) induced acute lung injury (ALI) and analyze the underlying mechanism.. Male SD rats were subjected to MIRI with or without myocardial ischemic post-conditioning in the presence or absence of GSK-3β inhibitor. GSK-3β inhibitor was injected peritoneally 10min before MIRI. Lung W/D weight ratio, MPO, PMNs, histopathological changes, TUNEL, Bax, Bcl-2, IL-6, IL-8, IL-10, GSK-3β, and caspase-3 were evaluated in the lung tissues of all rats.. After MIRI, lung injury was significantly increased manifested as significant morphological changes and increased leukocytes in the interstitial capillaries, Lung W/D ratio, MPO, and PMN in BALF, which was associated with enhanced inflammation evidenced by increased expressions of IL-6, IL-8 and reduced expression of IL-10. MIRI significantly increased cell apoptosis in the lung as increased levels of apoptotosis, Bax, cleaved caspase-3, and reduced expression of Bcl-2 was observed, which was concomitant with reduced p-GSK-3β. All these changes were reversed/prevented by ischemic post-conditioning, while these beneficial effects of ischemic post-conditioning were abolished by GSK-3β inhibition.. Myocardial ischemia reperfusion injury induces acute lung injury by induction of inflammation and cell apoptosis. Ischemic post-conditioning protects the lung from ALI following MIRI by increasing p-GSK-3β.

Topics: Acute Lung Injury; Animals; Apoptosis; bcl-2-Associated X Protein; Caspase 3; Down-Regulation; Enzyme Activation; Glycogen Synthase Kinase 3 beta; In Situ Nick-End Labeling; Inflammation; Interleukins; Ischemic Postconditioning; Male; Models, Animal; Myocardial Infarction; Myocardial Reperfusion Injury; Neutrophils; Peroxidase; Protective Agents; Proto-Oncogene Proteins c-bcl-2; Random Allocation; Rats, Sprague-Dawley

Topics: Biomarkers; Body Height; Carrier Proteins; Child, Preschool; Environment; Environmental Exposure; Feces; Female; Growth Disorders; Humans; Infant; Infections; Inflammation; Intestinal Diseases; Intestinal Mucosa; Intestines; Male; Malnutrition; Models, Biological; Neopterin; Nutritional Status; Permeability; Peroxidase; Peru

This study investigated the potential anti-inflammatory effect of hesperidin against carrageenan induced pleurisy in rat model.. Twenty-four adult female Wistar rats (350 - 450g) were grouped as follows: Group I: rats were administered saline solution only (Normal control group); Group II: rats were administered saline solution (NaCl 0.9%) orally and injected with carrageenan (Inflammation control group); Group III: rats were administered hesperidin only (Hesperidin group); Group IV: rats were administered hesperidin orally and intrapleurally injected with 2% carrageenan (Inflammation treated with hesperidin group). The exudate volume, total leukocyte count, reactive oxygen species (ROS), myeloperoxidase (MPO),δ-aminolevulinate dehydratase (δ-ALA-D), catalase (CAT), superoxide dismutase (SOD), activities as well as non-protein thiol group (NPSH) and thiobarbituric acid reactive substances (TBARS) levels were determined.. Pretreatment with hesperidin at a dose of 80 mg/kg orally per day for 21 days, minimized the increase in pleural exudate volume and leucocyte count and modulated the activities of MPO, SOD and CAT, as well as the levels of ROS, NPSH and TBARS in carrageenan-induced rats.. Our results suggest that hesperidin can elicit its anti-inflammatory action by blocking exudate and leukocyte influx into pleural cavity, inhibiting MPO activity and preventing oxidative damage.

Topics: Animals; Anti-Inflammatory Agents; Catalase; Glutathione; Hesperidin; Inflammation; Liver; Oxidative Stress; Peroxidase; Pleurisy; Porphobilinogen Synthase; Rats; Rats, Wistar; Reactive Oxygen Species; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances

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

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

Simultaneous, sensitive and quantitative detection of biomarkers in infectious disease is crucial for guiding antimicrobial treatment and predicting prognosis. This work reported an ultrasensitive and quantitative microfluidic immunoassay combined with the streptavidin-biotin-peroxidase (SA-B-HRP) nanocomplex-signal amplification system (MIS) to detect two inflammatory biomarkers, procalcitonin (PCT, for discriminating bacterial infections from nonbacterial infections) and interleukin-6 (IL-6, for monitoring the kinetics of infectious disease) simultaneously. The amplification system was based on the one step self-assembly of SA and B-HRP to form the SA-B-HRP nanocomplex, which effectively amplified the chemiluminescent signals. The linear ranges for PCT and IL-6 detections by MIS were 250-1.28 × 10

Topics: Biomarkers; Biotin; Humans; Immunoassay; Inflammation; Microfluidic Analytical Techniques; Peroxidase; Peroxidases; Streptavidin

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

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

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

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

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

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

The purpose of the present study was to assess the effect of astaxanthin (ASX) treatment on the acute lung injury (ALI) induced by cecal ligation and puncture (CLP) in mice. Mice were randomly allocated into the following groups: (1) the saline control group, in which mice were given saline before sham operation; (2) the ASX control group, in which mice received ASX before sham operation; (3) the ALI group, in which mice were given saline before CLP operation; and (4) the ALI+ASX group, in which mice received ASX before CLP operation. ASX was dissolved in olive oil and administrated by oral gavage for 14days consecutively before the CLP or sham operation. In experiment 1, Kaplan-Meier survival analysis was conducted for 72h after CLP. In experiment 2, blood, bronchoalveolar lavage fluid (BALF) and lung tissues were collected at 24h after the CLP or sham operation to determine the severity of lung injury. The results showed that ASX treatment could significantly decrease the CLP-induced mortality rate in mice. Meanwhile, ASX treatment significantly attenuated CLP-induced lung histopathological injury, inflammatory infiltration, total protein and albumin concentration, and total cell and neutrophil counts in the BALF. Furthermore, ASX treatment alleviated oxidative/nitrative stress, inflammation levels and pulmonary apoptosis in lung tissues. In addition, ASX treatment markedly down-regulated the expression of inducible nitric oxide synthase (i-NOS), nitrotyrosine (NT) and nuclear factor-kappa B (NF-Κb) P65 in the lung tissues compared with that in the ALI group. Astaxanthin treatment had markedly protective effect against ALI in mice, and the potential mechanism is associated with its ability to inhibit the inflammatory response, oxidative/nitrative stress, and pulmonary apoptosis, as well as down-regulate NF-κB P65 expression.

Topics: Acute Lung Injury; Animals; Apoptosis; Bronchoalveolar Lavage Fluid; Cecum; Cytokines; Down-Regulation; Inflammation; Ligation; Lung; Malondialdehyde; Mice, Inbred C57BL; Nitrosative Stress; Organ Size; Oxidative Stress; Peroxidase; Punctures; Reactive Oxygen Species; Transcription Factor RelA; Xanthophylls

Gastric ulcer is a common gastrointestinal disorder with increasing incidence and prevalence attributed to loss of balance between aggressive and protective factors. Nobiletin (NOB), a major component of polymethoxyflavones in citrus fruits, has a broad spectrum of health beneficial properties including anti-inflammatory and anti-tumor activities. Although NOB was originally shown to possess anti-inflammatory activity, its effects on gastric ulcer were rarely explored previously.. The aim of the present study was to investigate the anti-ulcerogenic activity of NOB on ethanol-induced gastric ulcer in mice and to elucidate the underlying mechanisms.. Seventy-two male Kunming mice administered with absolute ethanol (0.2 ml/animal) were pretreated with NOB (5, 10 or 20 mg/kg), cimetidine (100 mg/kg), or vehicles by intragastric administration in different experimental groups for three days, and animals were euthanized 3 h after ethanol ingestion. Gross and microscopic lesions, immunological and biochemical parameters were taken into consideration.. The results showed that ethanol induced gastric injury, increased malondialdehyde (MDA) levels, decreased glutathione (GSH) content, superoxide dismutase (SOD) activity, and prostaglandin E. These findings suggest that the gastroprotective activity is attribute to the improvement of antioxidant activities, the stimulation of PGE

Topics: Animals; Anti-Inflammatory Agents; Anti-Ulcer Agents; Antioxidants; Cytokines; Dinoprostone; Ethanol; Flavones; Gastric Mucosa; Glutathione; Inflammation; Interleukin-6; Male; Malondialdehyde; Mice; Oxidative Stress; Peroxidase; Protective Agents; Stomach Ulcer; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Neutrophil-derived myeloperoxidase (MPO) is recognized as a major source of oxidative stress at the airway surface of a cystic fibrosis (CF) lung where, despite limited evidence, the antioxidant glutathione is widely considered to be low. The aims of this study were to establish whether oxidative stress or glutathione status are associated with bronchiectasis and whether glutathione deficiency is inherently linked to CF or a consequence of oxidative stress. MPO was measured by ELISA in 577 bronchoalveolar lavage samples from 205 clinically-phenotyped infants and children with CF and 58 children without CF (ages 0.2-6.92 years). Reduced glutathione (GSH), oxidized glutathione species (GSSG; glutathione attached to proteins, GSSP; glutathione sulfonamide, GSA) and allantoin, an oxidation product of uric acid, were measured by mass spectrometry. The odds of having bronchiectasis were associated with MPO and GSSP. GSH was low in children with CF irrespective of oxidation. Oxidized glutathione species were significantly elevated in CF children with pulmonary infections compared to uninfected CF children. In non-CF children, infections had no effect on glutathione levels. An inadequate antioxidant response to neutrophil-mediated oxidative stress during infections exists in CF due to an inherent glutathione deficiency. Effective delivery of glutathione and inhibition of MPO may slow the development of bronchiectasis.

Topics: Age of Onset; Allantoin; Bronchiectasis; Bronchoalveolar Lavage Fluid; Case-Control Studies; Child; Child, Preschool; Cystic Fibrosis; Female; Glutathione; Glutathione Disulfide; Humans; Infant; Inflammation; Lung; Male; Neutrophils; Oxidation-Reduction; Oxidative Stress; Peroxidase; Sulfones

Cathelicidins are the largest family of antimicrobial peptides. C-BF, which is short for Cathelicidin-Bungarus Fasciatus, was isolated from snake venom. C-BF was found to be the most potential substitutes for antibiotics. In this study, we analyzed the effects of cathelicidin-derived peptide C-BF, on lipopolysaccharide (LPS)-induced intestinal damage in weaned piglets, to evaluate the therapeutic effect of C-BF on infectious disease of piglets. Twenty-four piglets were randomly assigned into four groups: control, C-BF, LPS, and C-BF+LPS. The LPS and C-BF+LPS groups were intraperitoneally injected with LPS at fixed timepoints, while the control and C-BF groups were injected with equal volumes of saline. The C-BF and C-BF+LPS groups were then intraperitoneally injected with antimicrobial peptide C-BF, while the control and LPS groups were injected with equal volumes of saline. All piglets were observed for 15days and then sacrificed for analysis. The results showed that C-BF significantly improved the growth performance of weaned piglets compared with LPS-treated animals (P<0.05), and that C-BF could ameliorate the structural and developmental damage to the small intestine caused by LPS treatment. Further, the level of apoptosis in the LPS group was significantly higher than in the other three groups (P<0.05), as was the invasion of inflammatory cells into the intestinal mucosa of the jejunum (P<0.05), leading to increased secretion of pro-inflammatory cytokines. In conclusion, the study indicates that C-BF treatment may be a potential therapy for LPS/pathogen-induced intestinal injury in piglets.

Topics: Animals; Antimicrobial Cationic Peptides; Apoptosis; Cathelicidins; Enzyme-Linked Immunosorbent Assay; Inflammation; Intestines; Jejunum; Lipopolysaccharides; Microscopy, Electron, Scanning; Peroxidase; Reptiles; Swine

Previous investigations have shown that inflammation induces changes in lipid and lipoprotein metabolism, and increased expression of angiopoietin-like protein 3 (ANGPTL3) contributes to the development of dyslipidemia. Here we investigated whether there is a correlation between increased ANGPTL3 expression and dyslipidemia in mastitis mice. Thirty mice were divided into two groups: control group and Staphylococcus aureus (S. aureus)-induced mastitis mice group. Changes in the levels of blood lipids [total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C)]; activity of myeloperoxidase (MPO); concentrations of plasma inflammation biomarkers [interferon-γ (IFNγ), tumor necrosis factor α (TNFα), and interleukin-1α (IL-1α)]; concentration of plasma ANGPTL3 protein; lipoprotein lipase (LPL) activities in postheparin plasma; expressions of hepatic N-acetylgalactosaminyltransferase 2 (GALNT2), hepatic ANGPTL3 and adipose LPL were determined. The major results indicated specific pathological mammary tissue changes, elevated MPO activity, reduced GALNT2 mRNA expression, elevated ANGPTL3 mRNA and protein expression and reduced LPL mRNA and protein expression. In plasma samples the S.aureus infused mice displayed elevated ANGPTL3 protein concentration, TG, TC and LDL-C levels, and reduced postheparin LPL activities and HDL-C level. The data suggests that ANGPTL3 is part of the machinery causing dyslipidemia majorily via LPL inhibition in mastitis mice.

Topics: Angiopoietin-Like Protein 3; Angiopoietin-like Proteins; Animals; Cholesterol, HDL; Cholesterol, LDL; Dyslipidemias; Female; Humans; Inflammation; Lipoprotein Lipase; Mastitis; Mice; N-Acetylgalactosaminyltransferases; Peroxidase; Polypeptide N-acetylgalactosaminyltransferase; Staphylococcus aureus; Triglycerides

Complexation with cyclodextrins (CDs) is a technique that has been extensively used to increase the aqueous solubility of oils and improve their stability. In addition, this technique has been used to convert oils into solid materials. This work aims to develop inclusion complexes of

Topics: Animals; Anti-Inflammatory Agents; Carrageenan; Crystallography, X-Ray; Cyclodextrins; Drug Compounding; Fabaceae; Gene Expression Regulation; Inflammation; Mice; Nitrites; Peroxidase; Plant Extracts; Solubility

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

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

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

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

This study investigated the changes of circulating histones following radiofrequency ablation (RFA) in lung cancer patients and their impact on systemic inflammation.. Serial blood samples were obtained from a total of 65 primary and metastatic lung cancer patients undergoing RFA at 2 time points: pre-RFA and post-RFA within 48 h. Circulating histones, myeloperoxidase (MPO), and multiple inflammatory cytokines were measured. Moreover, the patient's sera were incubated overnight with human monocytic U937 cells in the presence or absence of anti-histone antibody, and cytokine production was evaluated.. Compared to pre-RFA, there was a significant increase in circulating histones within 48 h after RFA, along with an elevation of MPO and several canonical inflammatory cytokines. Circulating histones were correlated with these inflammatory markers. Notably, compared to the sera obtained before RFA, the patients' post-RFA sera significantly stimulated cytokine production in the supernatant of U937 cells, which could be prevented by anti-histone antibody, thereby confirming a cause-effect relationship between circulating histones and systemic inflammation.. This study showed that circulating histones may serve as a marker indicating RFA-related systemic inflammation as well as represent a therapeutic target for resolution of inflammation.

Topics: Adult; Aged; Biomarkers, Tumor; Catheter Ablation; Cell Line, Tumor; Cytokines; Female; Histones; Humans; Inflammation; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Peroxidase

Peripheral inflammatory stimuli may activate a brain neuroinflammatory processes with consequences in brain function. The present study investigated if anthocyanins (ANT) consumption was able to prevent the memory loss, the neuronal damage, and the neuroinflammatory processes triggered by the intraperitoneal lipopolysaccharide (LPS) administration. C57BL6 male mice were treated with ANT (30-100 mg/kg by gavage). With a single dose or during 10 days, before be challenged with LPS (250 μg/kg intraperitoneally single administration), a classical inductor of inflammation. The data obtained showed that ANT was able to confer protection against the memory impairment after 10 days of ANT treatment (100 mg/kg). This phytonutrient also prevented the hypothermia episode induced by LPS. Moreover, ANT prevented the increase in protein carbonyl, NOx, and MDA levels in the hippocampus and cerebral cortex (4 and 24 h) in animal challenged with LPS. ANT showed a protective effect on the increase in the pro-inflammatory cytokines content, especially Interleukin (IL)-1β, tumoral necrosis factor-α and on the reduction of IL-10 induced by LPS. ANT 100 mg/kg prevented the infiltration of peripheral immune cells in the hippocampus at 24 h post-LPS administration. In parallel, LPS increased the activity of myeloperoxidase in cortex and hippocampus, and ANT prevented this effect, also reducing microglia (Iba-1) and astrocyte (GFAP) immunoreactivity. Thus, our data support that ANT are a promising therapeutic component against brain disorders associated with process of neuroinflammation. Graphical Abstract ᅟ.

Topics: Animals; Anthocyanins; Cerebral Cortex; Hippocampus; Hypothermia, Induced; Inflammation; Inflammation Mediators; Lipopolysaccharides; Male; Memory Disorders; Mice, Inbred C57BL; Models, Biological; Neuroglia; Neurons; Neuroprotective Agents; Oxidative Stress; Peroxidase; Sodium-Potassium-Exchanging ATPase

Many microbial and plant-derived metabolites contribute to the production of inflammatory mediators and the expression of pro-inflammatory molecules. Ophiobolin A (OPA) is a fungal secondary metabolite produced by Bipolaris species. The aim of our study was to examine the acute effects of this compound on inflammatory processes. Male Wistar rats were treated with 5% ethanol, 0.01 mg/kg OPA, 0.1 mg/kg OPA and 1.0 mg/kg OPA per os. After 24 h of the administrations, inflammatory mediators such as interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-α) and myeloperoxidase (MPO) enzyme as well as heme oxygenase (HO) activity were measured in both plasma and cardiac tissue, along with serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). We found that OPA caused a significant elevation in the concentrations of IL-6 and TNF-α, increased MPO activity and decreased HO enzyme activity in the plasma. While OPA induces inflammation in the plasma, it did not change the level of inflammatory mediators in the cardiac tissue and the concentrations of serum ALT and AST. Our findings indicate that rapid release of inflammatory mediators by OPA promotes systemic inflammation. However, this acute OPA treatment does not show toxic effects on the cardiac tissue and the concentrations of liver enzymes.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Heart Ventricles; Heme Oxygenase (Decyclizing); Inflammation; Interleukin-6; Male; Peroxidase; Rats, Wistar; Sesterterpenes; Tumor Necrosis Factor-alpha

Hospitalization with bronchiolitis is linked to the development of early childhood chronic wheeze and asthma. Viral etiology and severity of inflammation are potential contributing factors. Previously we observed reduced airway neutrophil infiltration in breastfed bronchiolitic infants, with a corresponding reduction in disease severity. This study aimed to examine whether respiratory viral etiology and co-infection alters the pattern of neutrophil influx, and the inflammatory mediator profile, resulting in epithelial damage in bronchiolitis.. Nasopharyngeal aspirates (NPAs) collected from hospitalized infants were assessed for viruses, soluble protein, cellular infiltrate, interleukin (IL)-6, -8, and myeloperoxidase (MPO).. NPAs were collected from 228 bronchiolitic and 14 non-bronchiolitic infants. In the bronchiolitic cohort, human rhinovirus was most prevalent (38%), followed by respiratory syncytial virus (36%), adenovirus (10%), and human metapneumovirus (6%), with 25% positive for viral co-infections and 25% negative for all screened viruses. Viral-induced bronchiolitis was associated with increased cellular infiltrate and protein, above control, and virus-negative infants (P < 0.05). Cellular infiltrate correlated to IL-6, -8, and MPO (r = 0.331, 0.669, and 0.661; P < 0.01). Protein, IL-6, -8, and MPO differed significantly between viral groups; however, the majority of marker values for all groups fall within an overlapping, indistinguishable range, precluding their use as biomarkers of viral etiology. No significant difference was found between single and viral co-infections for any parameter.. Bronchiolitic infants presenting with a detectable respiratory virus during hospitalization demonstrated elevated markers of airway tissue inflammation and injury. In this cohort, viral etiology did not discernibly modulate chemokine-mediated neutrophil infiltration and activation. Pediatr Pulmonol. 2017;52:238-246. © 2016 Wiley Periodicals, Inc.

Topics: Adenoviridae; Adenoviridae Infections; Breast Feeding; Bronchiolitis; Bronchiolitis, Viral; Coinfection; Female; Humans; Immunoassay; Infant; Inflammation; Interleukin-6; Interleukin-8; Male; Metapneumovirus; Nasopharynx; Neutrophil Infiltration; Neutrophils; Paramyxoviridae Infections; Peroxidase; Picornaviridae Infections; Polymerase Chain Reaction; Respiratory Sounds; Respiratory Syncytial Virus Infections; Respiratory Syncytial Viruses; Rhinovirus; Severity of Illness Index

Acute inflammation is a normal response of tissue to an injury. During this process, inflammatory mediators are produced and metabolic alterations occur. Adipose tissue is metabolically activated, and upon food consumption, it disrupts the inflammatory response. However, little is known about the acute inflammatory response in joints that results from diet-induced adipose tissue remodeling. The objective of this study was to determine whether alterations in adipose tissue mass arising from food consumption modify the inflammatory response of antigen-induced joint inflammation in mice.. Male BALB/c mice were fed a chow diet, a highly refined carbohydrate-containing (HC) diet for 8 wk. They were then immunized and, after 2 wk, received a knee injection of methylated bovine serum albumin (mBSA). They were sacrificed at 6, 24, and 48 h after injection. The effect of the cafeteria diet for 8 wk, which also increases adipose tissue, or conjugated linoleic acid (CLA) supplementation for 4 wk, a model of lipodystrophy, was evaluated 24 h after knee challenge with mBSA.. Cellular influx, predominantly neutrophils, in synovial fluid was attenuated in the HC diet group, as were levels of myeloperoxidase and IL-1β in periarticular tissue and histopathological analysis. These responses were associated with reduced adiponectin and increased leptin in serum, which was pronounced in mice fed the HC diet. Cafeteria diet and CLA supplementation induced a profile similar to that seen with the HC diet in terms of inflammation, disease response, and metabolic alteration. Interestingly, after the injection of mBSA, the area of adipocytes in the infrapatellar fat pad increased in mice fed with chow diet similar to those fed the HC and cafeteria diet.. We demonstrated that attenuation of joint response induced by diet was independent of adipose tissue remodeling but could be associated with metabolic alterations.

Topics: Adipocytes; Adiponectin; Adipose Tissue; Adiposity; Animals; Arthritis; Diet; Dietary Carbohydrates; Dietary Fats; Dietary Supplements; Inflammation; Interleukin-1beta; Knee Joint; Leptin; Linoleic Acids, Conjugated; Lipid Metabolism; Lipodystrophy; Male; Metabolome; Mice, Inbred BALB C; Neutrophils; Obesity; Peroxidase; Serum Albumin, Bovine

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

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

Sepsis remains a common clinical problem with significant mortality. Activation of the Kupffer cells during sepsis is associated with systemic inflammatory response and multiple organ failure. Kupffer cell activation also leads to structural changes in the liver sinusoidal endothelial cells (LSECs) during endotoxemia. However, these effects remain to be elucidated in caecal-ligation and puncture (CLP)-induced polymicrobial sepsis. To investigate the role of Kupffer cells on LSECs fenestrae and inflammation during CLP-induced sepsis, sepsis was induced by CLP and mice were treated with gadolinium chloride (GdCl3) before CLP-induced sepsis, to inactivate Kupffer cells. Mice were sacrificed after 8 h. Blood, liver, and lung tissues were collected and processed to measure LSECs fenestration, myeloperoxidase (MPO) activity, alanine transaminase (ALT) and aspartate aminotransferase (AST) activity, histological examination, and various cytokines/chemokines levels. LSECs fenestrae was studied using scanning electron micrographs of the LSECs. Strikingly, CLP mice treated with GdCl3 were protected against liver injury as evidenced by decreased LSECs defenestration and damage, MPO, ALT and AST activities, liver tissue damage, and inflammatory cytokines TNF-α, IL-6 and IL-1β, and chemokines MCP-1 and MIP-2α. However, CLP mice treated with GdCl3 had no protection against increased lung MPO activity, tissue damage, inflammatory cytokines, and chemokines. Treatment with GdCl3 also had no effect on the systemic inflammatory response as shown by no change in the circulatory inflammatory cytokines and chemokines following CLP-induced sepsis. Collectively, these data suggest that inactivation of Kupffer cells by GdCl3 protects the liver but had no effect on lung injury or inflammation and systemic inflammatory response following CLP-induced sepsis.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Chemokine CCL2; Chemokine CXCL2; Enzyme-Linked Immunosorbent Assay; Gadolinium; Inflammation; Interleukin-1beta; Interleukin-6; Kupffer Cells; Liver; Lung; Lung Injury; Male; Mice; Mice, Inbred C57BL; Microscopy, Electron, Scanning; Peroxidase; Sepsis; Tumor Necrosis Factor-alpha

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

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

In this study, we assessed the oxidative damage occurring in plasma proteins when human blood was exposed to inflammatory concentrations of hypochlorous acid (HOCl). We used specific thiol labelling and Western blot analyses to determine protein thiol oxidation, as well as analytical gel filtration HPLC coupled to fluorescence detection to explore formation of high molecular weight (HMW) protein aggregates. Thiol-containing proteins oxidized by HOCl were identified by redox proteomics. Mass spectrometry (MS) analysis was performed to elucidate the protein composition of HMW aggregates. α1-antitrypsin, transthyretin, and haptoglobin showed thiol oxidation at HOCl concentrations higher than those causing complete oxidation of albumin. At the highest HOCl concentrations, formation of carbonylated and di-tyrosine cross-linked HMW protein aggregates also occurred. MS analysis identified fibrinogen, complement C3 and apolipoprotein A-I as components of HMW protein aggregates. These results could be relevant for human diseases characterized by inflammatory conditions in which myeloperoxidase and HOCl are involved.. In this study we evaluated the oxidative damage occurring on plasma proteins when reconstituted human blood was exposed to inflammatory concentrations of hypochlorous acid (HOCl). Pathophysiological concentrations of HOCl are able to induce different modifications on plasma proteins such as carbonylation, sulfhydryl oxidation and formation of high molecular weight (HMW) protein aggregates characterized by di-tyrosine fluorescence. There are two relevant aspects emerging from this paper. The first one consists on identifying low abundant proteins undergoing sulfhydryl oxidation by biotin-maleimide derivatization followed by MALDI-TOF mass spectrometry. This approach suggests three low-abundant proteins undergoing HOCl-induced oxidation: transthyretin, α1-antitrypsin, and haptoglobin. In addition, we analysed HMW protein aggregates forming after HOCl exposure. These aggregates are characterized by carbonylation, intra- and/or intermolecular di-tyrosine bridges. After their isolation from SDS-PAGE gel electrophoresis, using electrospray tandem mass spectrometry coupled to reversed-phase nanoscale capillary liquid chromatography, we identified some protein constituents of these HMW aggregates such as α, β, γ fibrinogen chains, apolipoprotein A-I and complement C3. In particular, our work highlights how fibrinogen is an important constituent of HOCl-induced HMW protein aggregates validating the mass spectrometry result with additional experiments. Further investigations are required in order to evaluate the possibility to use carbonylated and di-Tyr cross-linked HMW protein aggregates as (early) biomarkers for disease progression in inflammatory conditions in which myeloperoxidase and HOCl are involved.

Topics: Apolipoprotein A-I; Biomarkers; Blood Proteins; Blood Specimen Collection; Complement C3; Fibrinogen; Humans; Hypochlorous Acid; Inflammation; Mass Spectrometry; Oxidation-Reduction; Oxidative Stress; Peroxidase; Protein Aggregates; Sulfhydryl Compounds; Tyrosine

Synovitis is a key factor in joint disease pathophysiology, which affects a greater proportion of women than men. P2X7 receptor activation contributes to arthritis, but whether it plays a role in articular inflammatory pain in a sex-dependent manner is unknown. We investigated whether the P2X7 receptor blockade in the knee joint of male and female rats reduces the articular hyperalgesia and inflammation induced by a carrageenan knee joint synovitis model. Articular hyperalgesia was quantified using the rat knee joint incapacitation test and the knee joint inflammation, characterized by the concentration of cytokines tumor necrosis factor-α, interleukin-1β, interleukin-6, and cytokine-induced neutrophil chemoattractant-1, and by neutrophil migration, was quantified using enzyme-linked immunosorbent assay and by myeloperoxidase enzyme activity measurement, respectively. P2X7 receptor blockade by the articular coadministration of selective P2X7 receptor antagonist A740003 with carrageenan significantly reduced articular hyperalgesia, pro-inflammatory cytokine concentrations, and myeloperoxidase activity induced by carrageenan injection into the knee joint of male and estrus female rats. However, a lower dose of P2X7 receptor antagonist was sufficient to significantly induce the antihyperalgesic and anti-inflammatory effects in estrus female but not in male rats. These results suggest that P2X7 receptor activation by endogenous adenosine 5'-triphosphate is essential to articular hyperalgesia and inflammation development in the knee joint of male and female rats. However, female rats are more responsive than male rats to the antihyperalgesic and anti-inflammatory effects induced by P2X7 receptor blockade.. P2X7 receptors could be promising therapeutic targets in the treatment of knee joint disease symptoms, especially in women, who are more affected than men by these conditions.

Topics: Acetamides; Animals; Carrageenan; Dose-Response Relationship, Drug; Estrus; Female; Gait Disorders, Neurologic; Hyperalgesia; Inflammation; Injections, Intra-Articular; Interleukin-6; Knee Joint; Male; Neutrophils; Peroxidase; Purinergic P2X Receptor Antagonists; Quinolines; Rats; Rats, Wistar; Synovitis; Tumor Necrosis Factor-alpha

This study aimed to investigate the feasibility of producing semisolid formulations based on nanocapsule suspensions containing the association of the coenzyme Q10 and vitamin E acetate by adding gellan gum (2%) to the suspensions. Furthermore, we studied their application as an alternative for the treatment of inflammation induced by ultraviolet B (UVB) radiation. For this, an animal model of injury induced by UVB-radiation was employed. All semisolids presented pH close to 5.5, drug content above 95% and mean diameter on the nanometric range, after redispersion in water. Besides, the semisolids presented non-Newtonian flow with pseudoplastic behavior and suitable spreadability factor values. The results also showed that the semisolid containing coenzyme Q10-loaded nanocapsules with higher vitamin E acetate concentration reduced in 73±8% the UVB radiation-induced ear edema. Moreover, all formulations tested were able to reduce inflammation parameters evaluated through MPO activity and histological procedure on injured tissue and the semisolids containing the nanoencapsulated coenzyme Q10 reduced oxidative parameters assessment through the non-protein thiols levels and lipid peroxidation. This way, the semisolids based on nanocapsules may be considered a promising approach for the treatment and prevention of skin inflammation diseases.

Topics: Acetylglucosaminidase; Administration, Cutaneous; Animals; Edema; Hydrogen-Ion Concentration; Inflammation; Leukocytes; Light; Lipid Peroxidation; Mice; Nanocapsules; Nanostructures; Oxidative Stress; Particle Size; Peroxidase; Polysaccharides; Polysaccharides, Bacterial; Radiation Injuries; Rheology; Skin; Sulfhydryl Compounds; Sunburn; Tocopherols; Ubiquinone; Ultraviolet Rays

To use biomarkers to gain insight into and gauge the residual (post-treatment) level of inflammation in two groups of intensively treated patients with severe chronic pain.. Three study groups were analyzed, and included: (i) patients (n = 90) with chronic intractable pain (CIP), (ii) patients (n = 26) with chronic pain and MRI-documented arachnoiditis (ARC) and (iii) normal subjects without a diagnosis of chronic pain (n = 86). We determined and compared the serum concentrations of Alpha-1 Antitrypsin (A1AT), Myeloperoxidase (MPO) and soluble Tumor Necrosis Factor receptor type 2 (sTNFR2) in each of the patient populations studied.. Patients treated for ARC or CIP had higher serum levels of A1AT and MPO than normal untreated subjects without a diagnosis of chronic pain. ARC patients had an A1AT mean serum concentration of 167.9 ± 41.9 mg/dL as compared to 148.9 ± 35.2 mg/dL for normal subjects (p = 0.023). CIP patients had the highest mean serum A1AT level 183.6 ± 39.2 mg/dL with p values of <0.0001 or 0.08 when compared to normal subjects or ARC patients respectively. ARC patients had an MPO mean serum concentration of 344.6 ± 227.9 ng/mL as compared to 188.2 ± 107.5 ng/mL for normal subjects (p = < 0.0001). CIP patients had a similar mean serum MPO level of 352.3 ± 164 ng/mL with p values of <0.0001 or 0.85 when compared to normal subjects or ARC patients respectively. In addition, we noted a difference in the pattern of MPO expression in patients with ARC in that 34% had levels of MPO at normal or below and 31% had levels 2-fold or greater than normal.. This data supports the concept that in centralized pain, sites of neuroinflammation elaborate MPO and other inflammatory factors which may not be completely cleared from the system despite extensive and complex treatment regimens.

Topics: Adult; Aged; alpha 1-Antitrypsin; Analgesics; Arachnoiditis; Biomarkers; Female; Humans; Inflammation; Male; Middle Aged; Pain, Intractable; Peroxidase; Tumor Necrosis Factor-alpha

Growth and development shortfalls that are disproportionately prevalent in children living in poor environmental conditions are postulated to result, at least in part, from abnormal gut function. Using data from The Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) longitudinal cohort study, we examine biomarkers of gut inflammation and permeability in relation to environmental exposures and feeding practices. Trends in the concentrations of three biomarkers, myeloperoxidase (MPO), neopterin (NEO), and α-1-antitrypsin (AAT), are described from fecal samples collected during the first 2 years of each child's life. A total of 22,846 stool samples were processed during the longitudinal sampling of 2,076 children 0-24 months of age. Linear mixed models were constructed to examine the relationship between biomarker concentrations and recent food intake, symptoms of illness, concurrent enteropathogen infection, and socioeconomic status. Average concentrations of MPO, NEO, and AAT were considerably higher than published references for healthy adults. The concentration of each biomarker tended to decrease over the first 2 years of life and was highly variable between samples from each individual child. Both MPO and AAT were significantly elevated by recent breast milk intake. All three biomarkers were associated with pathogen presence, although the strength and direction varied by pathogen. The interpretation of biomarker concentrations is subject to the context of their collection. Herein, we identify that common factors (age, breast milk, and enteric infection) influence the concentration of these biomarkers. Within the context of low- and middle-income communities, we observe concentrations that indicate gut abnormalities, but more appropriate reference standards are needed.

Topics: alpha 1-Antitrypsin; Bangladesh; Biomarkers; Brazil; Cell Membrane Permeability; Child, Preschool; Cohort Studies; Feces; Female; Follow-Up Studies; Gastrointestinal Microbiome; Humans; India; Infant; Inflammation; Linear Models; Longitudinal Studies; Male; Neopterin; Nepal; Pakistan; Peroxidase; Peru; Socioeconomic Factors; South Africa; Tanzania

To improve understanding of the preclinical stage of colonic inflammation by exploring the existence of a link between early inflammatory changes in the colonic mucosa and the systemic redox balance.. Clinical characteristics, a fasting blood draw, and mucosal biopsies from the right, left, and sigmoid-rectum colonic tracts collected from 28 healthy individuals (14/14 males/females) who underwent colonoscopy. Myeloperoxidase (MPO) positive cells infiltrating colonic mucosa specimens were assessed by immunohistochemistry, and patients divided into high or low MPO expressing cells/optical field groups (MPO. The study is the first demonstrating a connection between systemic redox balance and MPO expression in the colonic mucosa, according to the colonic tract and patient gender. Further research evaluating the MPO expression in the human colon and its relationship with pathological conditions could benefit from these results.

Topics: Antioxidants; Colon; Colonoscopy; Female; Healthy Volunteers; Humans; Immunohistochemistry; Inflammation; Intestinal Mucosa; Male; Oxidation-Reduction; Oxidative Stress; Peroxidase

Warfarin (WF) is an anticoagulant which also affects physiological processes other than hemostasis. Our previous investigations showed the effect of WF which gained access to the organism via skin on resting peripheral blood granulocytes. Based on these data, the aim of the present study was to examine whether WF could modulate the inflammatory processes as well. To this aim the effect of WF on the inflammatory response induced by subcutaneous sponge implantation in rats was examined.. Warfarin-soaked polyvinyl sponges (WF-sponges) were implanted subcutaneously and cell infiltration into sponges, the levels of nitric oxide (NO) and inflammatory cytokines tumor necrosis factor (TNF) and interleukin-6 (IL-6) production by sponge cells were measured as parameters of inflammation. T cell infiltration and cytokine interferon-γ (IFN-γ), interleukin-17 (IL-17) and interleukin-10 (IL-10) were measured at day 7 post implantation.. Warfarin exerted both stimulatory and suppressive effects depending on the parameter examined. Flow cytometry of cells recovered from sponges showed higher numbers of granulocytes (HIS48. Warfarin affects some of the parameters of inflammatory reaction induced by subcutaneous polyvinyl sponge implantation. Differential (both stimulatory as well as inhibitory) effects of WF on inflammatory response to sponge implants might affect the course and/or duration of this reaction.

Topics: Animals; Anticoagulants; Cell Survival; Cytokines; Inflammation; Leukocyte Count; Male; Nitric Oxide; Peroxidase; Polyvinyls; Rats; Skin; Warfarin

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

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

Histone deacetylase inhibitors (HDACI) are members of a family of epigenetic modifying agents with broad anti-inflammatory properties. These anti-inflammatory properties may have important therapeutic implications in acute respiratory distress syndrome (ARDS). However, administration of HDACI may create an immunosuppressive environment conducive to bacterial growth. Accordingly, the aim of the current study is to investigate the effect of HDACI valproic acid (VPA) on host inflammatory response and bacterial burden in a murine model of Escherichia coli pneumonia-induced ARDS.. ARDS was induced in male C57BL6 mice (n = 24) by endotracheal instillation of 3 × 10 E. coli. VPA (250 mg/kg) was administered 30 minutes after E. coli instillation in the intervention group. Blood samples were collected at 3 and 6 hours, and animals were sacrificed at 6 hours. Bronchoalveolar lavage (BAL) was performed, and tissue specimens were harvested. Cytokine levels were measured in blood and BAL, and so was transalveolar protein transit. Cell counts and colony forming units were quantified in BAL fluid.. VPA reduced neutrophil influx into the lungs and local tissue destruction through decreased myeloperoxidase activity. It also ameliorated the pulmonary and systemic inflammatory response. This led to greater bacterial proliferation in the pulmonary parenchyma.. Administration of VPA in a clinically relevant bacterial model of murine ARDS mitigates the host inflammatory response, essentially preventing ARDS, but creates an immunosuppressive environment that favors bacterial overgrowth.

Topics: Animals; Bronchoalveolar Lavage Fluid; Cytokines; Enzyme-Linked Immunosorbent Assay; Escherichia coli; Inflammation; Male; Mice; Mice, Inbred C57BL; Peroxidase; Pneumonia, Bacterial; Respiratory Distress Syndrome; Valproic Acid

Ulcerative colitis (UC) is an inflammatory bowel disease with significant morbidity. Cardamonin is a natural chalcone derivative with considerable anti-inflammatory activity. Herein, the potential protective effect of cardamonin against UC was tested in a rat model.. Rats were given 10 or 30mg/kg/day of cardamonin orally for 14days before induction of UC. On the 14th day of treatment, UC was induced by intrarectal instillation of 2ml 3% acetic acid. Twenty four h after acetic acid instillation, rats were sacrificed and colons were analyzed by macroscopic and histopathological examination. Colon lipid peroxidation was examined by biochemical evaluation of malondialdehyde (MDA). Myeloperoxidase (MPO), iNOS, NF-κB, TNFα levels were measured by ELISA. Moreover, caspase-3 and COX-2 were assessed by immunohistochemical analysis.. Cardamonin at 10 and 30mg/kg decreased the disease activity index and macroscopic damage index scores, and significantly reduced histopathological deterioration. Additionally, cardamonin reduced levels of MPO, iNOS, NF-κB, TNFα and MDA (p<0.05). Immunohistochemistry revealed down-regulation of COX-2 and caspase-3 in groups treated with cardamonin.. Cardamonin has a protective effect against acetic acid-induced colitis. This effect may be due to reducing inflammation, oxidative stress and apoptosis.

Topics: Acetic Acid; Animals; Anti-Inflammatory Agents; Caspase 3; Chalcones; Colitis, Ulcerative; Colon; Cyclooxygenase 2; Inflammation; Lipid Peroxidation; Male; Malondialdehyde; NF-kappa B; Nitric Oxide Synthase Type II; Peroxidase; Protective Agents; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

The gastrointestinal alterations associated with the consumption of an obesogenic diet, such as inflammation, permeability impairment and oxidative stress, have been poorly explored in both diet-induced obesity (DIO) and genetic obesity. The aim of the present study was to examine the impact of an obesogenic diet on the gut health status of DIO rats in comparison with the Zucker (fa/fa) rat leptin receptor-deficient model of genetic obesity over time. For this purpose, female Wistar rats (n 48) were administered a standard or a cafeteria diet (CAF diet) for 12, 14·5 or 17 weeks and were compared with fa/fa Zucker rats fed a standard diet for 10 weeks. Morphometric variables, plasma biochemical parameters, myeloperoxidase (MPO) activity and reactive oxygen species (ROS) levels in the ileum were assessed, as well as the expressions of proinflammatory genes (TNF-α and inducible nitric oxide synthase (iNOS)) and intestinal permeability genes (zonula occludens-1, claudin-1 and occludin). Both the nutritional model and the genetic obesity model showed increased body weight and metabolic alterations at the final time point. An increase in intestinal ROS production and MPO activity was observed in the gastrointestinal tracts of rats fed a CAF diet but not in the genetic obesity model. TNF-α was overexpressed in the ileum of both CAF diet and fa/fa groups, and ileal inflammation was associated with the degree of obesity and metabolic alterations. Interestingly, the 17-week CAF group and the fa/fa rats exhibited alterations in the expressions of permeability genes. Relevantly, in the hyperlipidic refined sugar diet model of obesity, the responses to chronic energy overload led to time-dependent increases in gut inflammation and oxidative stress.

Topics: Animals; Claudin-1; Diet; Feeding Behavior; Female; Ileum; Inflammation; Obesity; Occludin; Oxidative Stress; Peroxidase; Rats, Wistar; Rats, Zucker; Reactive Oxygen Species; Receptors, Leptin; Tumor Necrosis Factor-alpha; Weight Gain; Zonula Occludens-1 Protein

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arterial Pressure; Cyclooxygenase 2; Epoprostenol; Gene Expression Regulation, Enzymologic; Heart Rate; Hypotension; I-kappa B Proteins; Inflammation; Lipopolysaccharides; Male; Nitric Oxide; Nitric Oxide Synthase Type II; Peroxidase; Peroxynitrous Acid; Rats; Rats, Wistar; Ribosomal Protein S6; Signal Transduction; TOR Serine-Threonine Kinases; Transcription Factor RelA; Tumor Necrosis Factor-alpha; Tyrosine

Several studies have reported that polyphenols may exert beneficial effects on inflammatory bowel disease. This study aimed to evaluate the effects of preventive consumption of polyphenol-rich red grape pomace extracts (GPEs) on dextran sulfate sodium (DSS)-induced colitis in rats. Rats were fed for 21 days with a semi-synthetic diet enriched with a GPE (Alicante-S, Alicante-P or Pinot-S) and colitis was induced by DSS administration in drinking water (40 g L(-1) ) during the last 7 days of experimentation.. GPEs attenuated clinical signs and colon shortening and Alicante GPEs limited histological lesions induced by DSS. GPEs curbed the increase in myeloperoxidase activity and modulated antioxidant enzyme activities. Moreover, GPEs prevented the DSS-induced increase in pro-inflammatory cytokine levels and the up-regulation of various genes implicated in colitis such as intercellular adhesion molecule 1 (ICAM-1) and matrix metalloproteinase 9 (MMP-9).. These results suggest that polyphenol-rich red GPEs could provide prevention against colon inflammation.

Topics: Animals; Antioxidants; Colitis; Colon; Cytokines; Dextran Sulfate; Fruit; Inflammation; Intercellular Adhesion Molecule-1; Male; Matrix Metalloproteinase 9; Oxidative Stress; Peroxidase; Plant Extracts; Polyphenols; Rats; Rats, Wistar; Up-Regulation; Vitis

Our study aimed to evaluate whether obesity induced by cafeteria diet changes the neutrophil effector/inflammatory function and whether treatment with green tea extract (GT) can improve neutrophil function.. Male Wistar rats were treated with GT by gavage (12 weeks/5 days/week; 500 mg/kg of body weight), and obesity was induced by cafeteria diet (8 weeks). Neutrophils were obtained from the peritoneal cavity (injection of oyster glycogen). The following analyses were performed: phagocytic capacity, chemotaxis, myeloperoxidase activity (MPO), hypochlorous acid (HOCl), superoxide anion (O 2 (·-) ), hydrogen peroxide (H2O2), IL-1β, IL-6 and TNFα, mRNA levels of inflammatory genes, calcium mobilisation, activities of antioxidant enzymes, hexokinase and G6PDH.. Neutrophils from obese rats showed a significant decrease in migration capacity, H2O2 and HOCl production, MPO activity and O 2 (·-) production. Phagocytosis and CD11b mRNA levels were increased, while inflammatory cytokines release remained unmodified. mRNA levels of TLR4 and IκK were enhanced. Treatment of obese rats with GT increased neutrophil migration, MPO activity, H2O2, HOCl and O 2 (·-) production, whereas TNF-α and IL-6 were decreased (versus obese). Similar reductions in TLR4, IκK and CD11b mRNA were observed. Catalase and hexokinase were increased by obesity, while SOD and G6PDH were decreased. Treatment with GT reduced catalase and increased the GSH/GSSG ratio.. In response to a cafeteria diet, we found a decreased chemotaxis, H2O2 release, MPO activity and HOCl production. We also showed a significant immunomodulatory effect of GT on the obese condition recovering some of these factors such H2O2 and HOCl production, also reducing the levels of inflammatory cytokines.

Topics: Animals; Antioxidants; Catalase; CD11b Antigen; Glucosephosphate Dehydrogenase; Hexokinase; Hydrogen Peroxide; Hypochlorous Acid; Inflammation; Interleukin-1beta; Interleukin-6; Male; Neutrophils; Obesity; Peroxidase; Phagocytosis; Plant Extracts; Polyphenols; Rats; Rats, Wistar; RNA, Messenger; Superoxides; Tea; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Myeloperoxidase (MPO)-generated halogenating molecules, such as hypochlorous acid and hypobromous acid (HOBr), in inflammatory regions are postulated to contribute to disease progression. In this study, we showed that ergothioneine (EGT), derived from an edible mushroom, inhibited MPO activity as well as the formation of 8-bromo-2'-deoxyguanosine in vitro. The HOBr scavenging effect of EGT is higher than those of ascorbic acid and glutathione. We initially observed that the administration of Coprinus comatus, an edible mushroom containing a high amount of EGT, inhibited the UV-B-induced inflammatory responses and DNA halogenation, suggesting that EGT is a promising anti-inflammatory agent from mushrooms.

Topics: Agaricales; Animals; Anti-Inflammatory Agents; Ascorbic Acid; Bromates; Deoxyguanosine; DNA; Ergothioneine; Glutathione; Halogenation; Hypochlorous Acid; Inflammation; Male; Mice; Mice, Hairless; Peroxidase; Ultraviolet Rays

The aim of the study was to investigate the possible anti-inflammatory and antioxidant effects of BAY 73-6691 on neutrophils from SCA patients. This study included 35 patients with a molecular diagnosis of SCA, whose neutrophils were isolated and treated with BAY 73-6691 at the concentrations 100, 10, 1.0 and 0.1 μg/mL. LDH release and MTT assays were performed to verify cell viability. To evaluate oxidative stress, the following parameters were determined by spectrophotometric assays: NO and malondialdehyde (MDA) levels and activity of catalase, superoxide dismutase (SOD) and glutathione peroxidase (GPx). As inflammatory markers, myeloperoxidase (MPO) levels were evaluated by colorimetric assay and TNF-α by enzyme immunoassay. The results showed that neutrophils from SCA patients not treated with hydroxyurea (HU) had significantly lower NO levels and catalase and SOD activity, as well as significantly higher MDA, MPO and TNF-α levels when compared with neutrophils from SCA patients treated with HU and neutrophils from control group. Treatment of SCA neutrophils with BAY 73-6691 resulted in 94%, 200% and 168% increase in NOx levels, SOD and catalase activity, respectively. In addition, there was a reduction of approximately 46% and 45% in TNF-α and MPO levels, respectively. In SCAHU neutrophils, there was a 30% and 44% increase in NOx levels and SOD activity, respectively, and a 28% and 37% decrease in TNF-α and MPO levels, respectively. However, these effects were observed at cytotoxic doses only. The results of this study are original and demonstrate that inhibition of phosphodiesterase-9 in neutrophils from SCA patients with BAY 73-6691 was able to increase the NO bioavailability and attenuate oxidative stress and inflammation in neutrophils from patients not treated with HU.

Topics: Adult; Anemia, Sickle Cell; Biomarkers; Cell Survival; Female; Humans; Inflammation; Male; Neutrophils; Nitric Oxide; Oxidative Stress; Peroxidase; Phosphodiesterase Inhibitors; Pyrazoles; Pyrimidines; Tumor Necrosis Factor-alpha

Sepsis progression is linked with the imbalance between reactive oxygen species and antioxidant enzymes. Thus, the aim of this study was to evaluate the effect of alpha-lipoic acid (ALA), a powerful antioxidant, in organs of rats submitted to sepsis. Male Wistar rats were subjected to sepsis by cecal ligation puncture (CLP) and treated with ALA or vehicle. After CLP (12 and 24 h), the myeloperoxidase (MPO) activity, protein and lipid oxidative damage, and antioxidant enzymes in the liver, kidney, heart, and lung were evaluated. ALA was effective in reducing MPO activity, lipid peroxidation in the liver, and protein carbonylation only in the kidney in 12 h after CLP. In 12 h, SOD activity increased in the kidney and CAT activity in the liver and kidney with ALA treatment. Thus, ALA was able to reduce the inflammation and oxidative stress in the liver and kidney after sepsis in rats.

Topics: Animals; Antioxidants; Catalase; Cecum; Inflammation; Kidney; Lipid Peroxidation; Liver; Lung; Male; Myocardium; Neutrophil Infiltration; Oxidative Stress; Peroxidase; Protein Carbonylation; Rats; Rats, Wistar; Reactive Oxygen Species; Sepsis; Superoxide Dismutase; Thioctic Acid

Inflammation-associated oxidative stress contributes to hepatic ischemia/reperfusion injury (IRI). Detrimental inflammatory event cascades largely depend on activated Kupffer cells (KCs) and neutrophils, as well as proinflammatory cytokines, including tumor necrosis factor α (TNF-α) and interleukin (IL) 18. The aim of our study was to evaluate the effects of IL 18 binding protein (IL 18Bp) in hepatic IRI of mice. Thirty C57BL/6 mice were allocated into 3 groups: sham operation, ischemia/reperfusion (I/R), and I/R with intravenous administration of IL 18Bp. Hepatic ischemia was induced for 30 minutes by Pringle's maneuver. After 120 minutes of reperfusion, mice were euthanized, and the liver and blood samples were collected for histological, immunohistochemical, molecular, and biochemical analyses. I/R injury induced the typical liver pathology and upregulated IL-18 expression in the liver of mice. Binding of IL 18 with IL 18Bp significantly reduced the histopathological indices of I/R liver injury and KC apoptosis. The I/R-induced increase of TNF-α, malondialdehyde, aspartate aminotransferase, and alanine aminotransferase levels was prevented in statistically significant levels because of the pretreatment with IL 18Bp. Likewise, blocking of IL 18 ablated the I/R-associated elevation of nuclear factor kappa B, c-Jun, myeloperoxidase, and IL 32 and the up-regulation of neutrophils and T-helper lymphocytes. Administration of IL 18Bp protects the mice liver from I/R injury by intervening in critical inflammation-associated pathways and KC apoptosis.

Topics: Alanine Transaminase; Animals; Apoptosis; Aspartate Aminotransferases; Cytokines; DNA Primers; Gene Expression Regulation; Immunohistochemistry; Inflammation; Intercellular Signaling Peptides and Proteins; Interleukin-18; Liver; Liver Diseases; Liver Transplantation; Male; Malondialdehyde; Mice; Mice, Inbred C57BL; Models, Animal; Neutrophils; Oxidative Stress; Peroxidase; Reperfusion Injury; Signal Transduction; Tumor Necrosis Factor-alpha; Up-Regulation

The objectives of this study were to assess the effects of hyaluronic acid (HY), multi-walled carbon nanotubes (MWCNT), and MWCNT functionalized with HY (HY-MWCNT) on the resolution of neutrophilic inflammation in the pleural cavity of LPS-challenged mice and to assess the influence of these materials in the inflammatory process of bone repair of tooth sockets of rats.. C57Bl/6 mice were intra-pleurally injected with HY, MWCNT, HY-MWCNT, phosphate-buffered saline (PBS), or LPS. The animals were euthanized after 8 and 24 h, and cells were harvested for total and differential cell counting. The tooth sockets of Wistar rats were filled with HY, MWCNT, HY-MWCNT, or blood clot (control). After 1, 3, and 7 days, histological and morphometric analyses evaluated the number of cell nuclei and blood vessels, and bone trabeculae formation in the sockets. Myeloperoxidase (MPO) activity quantified neutrophil accumulation in the sockets.. HY, MWCNT, and HY-MWCNT increased neutrophilic recruitment at 8 h and reduced the inflammatory process at 24 h in the pleural cavity. Histological and morphometric analyses and MPO activity showed no significant differences in the recruitment of inflammatory cells in the tooth sockets. HY increased the number of blood vessels, and HY and HY-MWCNT increased bone trabeculae formation at 7 days of tooth extraction.. HY, MWCNT, and HY-MWCNT resolved the neutrophilic inflammation in the pleural cavity of the mice. However, these materials did not modulate the inflammatory process in the early stages of bone repair of the tooth sockets, thereby excluding this action as a possible mechanism by which these biomaterials accelerate bone repair.. HY-MWCNT is capable of accelerating bone repair/regeneration without affecting the inflammatory phase during the bone healing process.

Topics: Animals; Cell Movement; Hyaluronic Acid; Inflammation; Leukocytes; Male; Mice; Mice, Inbred C57BL; Nanotubes, Carbon; Peroxidase; Rats; Rats, Wistar; Regenerative Medicine; Tooth Socket; Wound Healing

We tested our hypothesis that Myc-interacting zinc finger protein 1 (MIZ1), a cell cycle regulator, suppressed inflammation, and therefore, represented a useful prognostic marker in patients with acute necrotizing pancreatitis (ANP) complicated by acute lung injury.. Sprague-Dawley rats were randomly divided into control and ANP groups at different time points. The MIZ1 protein expression was measured by Western blot and ELISA, and confirmed using immunohistochemistry. The severity of pancreatic and lung injury was evaluated by the injury score and wet/dry weight ratio. The severity of disease was evaluated by serum C-reactive protein (CRP). The MPO activity of lung tissue amylase levels and the degree of inflammation were evaluated by serum tumor necrosis factor (TNF)-α and interleukin (IL)-6 expression. The risk due to multiple factors was investigated by relationship analysis.. The serum levels of CRP, amylase, TNF-α, and IL-6 were gradually increased at 6, 24, and 48 h in ANP when compared with the control rats. The MIZ1 expressions were greatly decreased in ANP rats, especially at 24 h. Statistical analysis showed that there were time-dependent differences in ANP rats when compared with control rats (6 vs. 24 or 48 h, P < 0.01). MIZ1 showed close negative correlation with the degree of pancreatic and lung injury, serum amylase, CRP, TNF-α, and IL-6 (P < 0.01, respectively).. The decreasing MIZ1 expression was closely correlated with inflammatory response, and development of ANP. Decreasing MIZ1 levels indicate a risk for ANP.

Topics: Acute Lung Injury; Amylases; Animals; Blotting, Western; C-Reactive Protein; Disease Models, Animal; DNA-Binding Proteins; Enzyme-Linked Immunosorbent Assay; Immunohistochemistry; Inflammation; Interleukin-6; Lung; Nuclear Proteins; Pancreas; Pancreatitis, Acute Necrotizing; Peroxidase; Protein Inhibitors of Activated STAT; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Severity of Illness Index; Tumor Necrosis Factor-alpha; Ubiquitin-Protein Ligases

The aim of the current study was to investigate the time course of the expression of growth differentiation factor‑15 (GDF‑15) in rat ischemic myocardium with increasing durations of reperfusion, and to elucidate its physiopathological role in the no‑reflow phenomenon. Wistar rats were randomly divided into ischemia reperfusion (I/R) and sham groups, and myocardial I/R was established by ligation of the left anterior descending coronary artery for 1 h followed by reperfusion for 2, 4, 6, 12, 24 h and 7 days whilst rats in the sham group were subjected to a sham operation. The expression levels of GDF‑15 and ICAM‑1 were measured, in addition to myeloperoxidase (MPO) activity. The myocardial anatomical no‑reflow and infarction areas were assessed. The area at risk was not significantly different following various periods of reperfusion, while the infarct area and no‑reflow area were significantly greater following 6 h of reperfusion (P<0.05). The mRNA and protein expression levels of GDF‑15 were increased during the onset and development of no‑reflow, and peaked following 24 h of reperfusion. MPO activity was reduced with increasing reperfusion duration, while ICAM‑1 levels were increased. Hematoxylin and eosin staining demonstrated that myocardial neutrophil infiltration was significantly increased by I/R injury, in particular following 2, 4 and 6 h of reperfusion. GDF‑15 expression levels were negatively correlated with MPO activity (r=‑0.55, P<0.001), and the MPO activity was negatively correlated with the area of no‑reflow (r=‑0.46, P<0.01). By contrast, GDF‑15 was significantly positively correlated with ICAM‑1 levels (r=0.52, P<0.01), which additionally were demonstrated to be significantly positively associated with the size of the no‑reflow area (r=0.39, P<0.05). The current study demonstrated the time course effect of reperfusion on the expression of GDF‑15 in the myocardial I/R rat model, with the shorter reperfusion times (6 h) resulting in significant no‑reflow in ischemic myocardium. GDF‑15 may protect the I/R myocardium from no‑reflow by inhibiting the inflammatory‑like response, which involves neutrophil infiltration and transendothelial migration.

Topics: Animals; Benzothiazoles; Cardiotonic Agents; Enzyme-Linked Immunosorbent Assay; Growth Differentiation Factor 15; Inflammation; Intercellular Adhesion Molecule-1; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Neutrophil Infiltration; No-Reflow Phenomenon; Peroxidase; Rats, Wistar; RNA, Messenger; Thiazoles; Time Factors

Citral is an active compound of lemongrass oil which has been reported to have anti-inflammatory effects. In this study, we investigated the effects of citral on lipopolysaccharide (LPS)-induced inflammatory response in a rat model of peritonitis and human umbilical vein endothelial cells (HUVECs). LPS was intraperitoneally injected into rats to establish a peritonitis model. The HUVECs were treated with citral for 12 h before exposure to LPS. The levels of TNF-α and IL-8 were measured using ELISA. Western blotting was used to detect the expression of VCAM-1, ICAM-1, NF-κB, and PPAR-γ. The results showed that citral had a protective effect against LPS-induced peritonitis. Citral decreased the levels of WBCs and inflammatory cytokines TNF-α and IL-6. Citral also inhibited LPS-induced myeloperoxidase (MPO) activity in the peritoneal tissue. Treatment of HUVECs with citral significantly inhibited TNF-α and IL-8 expression induced by LPS. LPS-induced VCAM-1 and ICAM-1 expression were also suppressed by citral. Meanwhile, we found that citral inhibited LPS-induced NF-κB activation in HUVECs. Furthermore, we found that citral activated PPAR-γ and the anti-inflammatory effects of citral can be reversed by PPAR-γ antagonist GW9662. In conclusion, citral inhibits LPS-induced inflammatory response via activating PPAR-γ which attenuates NF-κB activation and inflammatory mediator production.

Topics: Acyclic Monoterpenes; Anilides; Animals; Anti-Inflammatory Agents; Cell Adhesion; Enzyme Activation; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; Leukocyte Count; Lipopolysaccharides; Monoterpenes; Neutrophils; NF-kappa B; Peritonitis; Peroxidase; Plant Oils; PPAR gamma; Rats; Terpenes; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

Acute pancreatitis is an inflammatory condition that may lead to multisystemic organ failure with considerable mortality. Recently, resolvin D1 (RvD1) as an endogenous anti-inflammatory lipid mediator has been confirmed to protect against many inflammatory diseases. This study was designed to investigate the effects of RvD1 in acute pancreatitis and associated lung injury. Acute pancreatitis varying from mild to severe was induced by cerulein or cerulein combined with LPS, respectively. Mice were pretreated with RvD1 at a dose of 300 ng/mouse 30 min before the first injection of cerulein. Severity of AP was assessed by biochemical markers and histology. Serum cytokines and myeloperoxidase (MPO) levels in pancreas and lung were determined for assessing the extent of inflammatory response. NF-κB activation was determined by Western blotting. The injection of cerulein or cerulein combined with LPS resulted in local injury in the pancreas and corresponding systemic inflammatory changes with pronounced severity in the cerulein and LPS group. Pretreated RvD1 significantly reduced the degree of amylase, lipase, TNF-α, and IL-6 serum levels; the MPO activities in the pancreas and the lungs; the pancreatic NF-κB activation; and the severity of pancreatic injury and associated lung injury, especially in the severe acute pancreatitis model. These results suggest that RvD1 is capable of improving injury of pancreas and lung and exerting anti-inflammatory effects through the inhibition of NF-κB activation in experimental acute pancreatitis, with more notable protective effect in severe acute pancreatitis. These findings indicate that RvD1 may constitute a novel therapeutic strategy in the management of severe acute pancreatitis.

Topics: Animals; Anti-Inflammatory Agents; Ceruletide; Disease Models, Animal; Docosahexaenoic Acids; Gastrointestinal Agents; Inflammation; Interleukin-6; Lung; Lung Injury; Mice; Mice, Inbred C57BL; NF-kappa B; Pancreas; Pancreatitis, Acute Necrotizing; Peroxidase; Protective Agents; Signal Transduction

Atherosclerosis (AS) is the primary pathological result of obesity. Vulnerable AS plaques cause fatal clinical end points such as myocardial infarction and stroke. To prevent this, improvements in early diagnosis and treatment are essential. Because vulnerable AS plaques are frequently nonstenotic, they are preclinically undetectable using conventional imaging. Levels of blood lipids, C-reactive protein, and interleukin-6 are increased, but are insufficient to indicate the process of critical perpetuation before the end points present. More specific biomarkers (e.g. troponin, copetin, natriuretic peptides, growth differentiation factor-15, or soluble ST2) indicate the acute coronary syndrome or cardiac insufficiency, but not a critical destabilization of AS lesions in coronary or carotid arteries. Thus, valuable time (months to years) that could be used to treat the patient is wasted. An improved management of this dilemma may involve better detection of variations in degrees of immune inflammation in plaques by using new biomarkers in blood and/or within the lesion (molecular imaging). Macrophage and T-cell polarization, and innate and adaptive immune responses (e.g. Toll-like receptors) are involved in this critical process. New biomarkers in these mechanisms include pentraxin 3, calprotectins S100A8/S100A9, myeloperoxidase, adiponectin, interleukins, and chemokines. These proteins may also be candidates for molecular imaging using nuclear (magnetic resonance) imaging tools. Nevertheless, the main challenge remains: which asymptomatic individual should be screened? At which time interval? Intense interdisciplinary research in laboratory medicine (biomarkers), nanomedicine (nanoparticle development), and radiology (molecular imaging) will hopefully address these questions.

Topics: Adiponectin; Atherosclerosis; Biomarkers; C-Reactive Protein; Cholesterol; Cytokines; Humans; Inflammation; Inflammation Mediators; Leukocyte L1 Antigen Complex; Myocardial Infarction; Peroxidase; Risk Factors; Serum Amyloid P-Component; Stroke

This study aimed to investigate the protective effects of apigenin against paraquat (PQ)-induced acute lung injury (ALI) in mice. Male Kunming mice were randomly divided into five groups: group 1 (control), group 2 (PQ), group 3 (PQ + apigenin 25 mg/kg), group 4 (PQ + apigenin 50 mg/kg), and group 5 (PQ + apigenin 100 mg/kg). The PQ + apigenin group received apigenin by gavage daily for consecutive 7 days, respectively, while the mice in control and PQ groups were given an equivalent volume of saline. We detected the lung wet/dry weight ratios and the histopathology of the lung. The levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), malondialdehyde (MDA), myeloperoxidase (MPO), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) were determined using enzyme-linked immunosorbent assay (ELISA) kits. The activity of nuclear factor (NF)-κB was also determined. The results indicated that apigenin administration decreased biochemical parameters of inflammation and oxidative stress, and improved oxygenation and lung edema in a dose-dependent manner. These protective effects of apigenin were associated with inhibition of NF-κB. In conclusion, apigenin reduces PQ-induced ALI by inhibition of inflammation and oxidative stress.

Topics: Acute Lung Injury; Animals; Apigenin; Glutathione Peroxidase; Inflammation; Interleukin-6; Lung; Male; Malondialdehyde; Mice; NF-kappa B; Oxidative Stress; Paraquat; Peroxidase; Random Allocation; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Neutrophil extracellular traps (NETs) are a combination of DNA fibers and granular proteins, such as neutrophil elastase (NE). NETs are released in the extracellular space in response to different stimuli. Carrageenan is a sulfated polysaccharide extracted from Chondrus crispus, a marine algae, used for decades in research for its potential to induce inflammation in different animal models. In this study, we show for the first time that carrageenan injection can induce NET release in a mouse model of acute peritonitis. Carrageenan induced NET release by viable neutrophils with NE and myeloperoxidase (MPO) expressed on DNA fibers. Furthermore, although this polysaccharide was able to stimulate reactive oxygen species (ROS) generation by peritoneal neutrophils, NADPH oxidase derived ROS were dispensable for NET formation by carrageenan. In conclusion, our results show that carrageenan-induced inflammation in the peritoneum of mice can induce NET formation in an ROS-independent manner. These results may add important information to the field of inflammation and potentially lead to novel anti-inflammatory agents targeting the production of NETs.

Topics: Animals; Carrageenan; Disease Models, Animal; DNA; Extracellular Traps; Inflammation; Leukocyte Elastase; Mice; Mice, Inbred BALB C; NADPH Oxidases; Neutrophils; Peritonitis; Peroxidase; Reactive Oxygen Species

Inflammation of the colon in patients with ulcerative colitis (UC) causes pain and altered motility, at least in part through the damage of the myenteric neurons (MNs). Thus, it is important to evaluate new drugs for UC treatment that could also protect myenteric neurons efficiently. As a well-known neural protective and anti-inflammatory agent, melatonin could protect neurons from damage through the activation of the nuclear factor erythroid 2-related factor 2 and antioxidant responsive element (Nrf2-ARE) signaling pathway. Therefore, we investigated the potential protective effect of melatonin against MN damage during colitis induced by 2,4-dinitrobenzene sulfonic acid (DNBS) in rats. Colitis was induced by intracolonic (i.c.) instillation of DNBS and treated with melatonin at a dose of 2.5 mg/kg for 4 days. The damage of MN in the left colon was immunohistochemically evaluated in different groups. Ulcerations and inflammation in the colon were semiquantitatively observed. Myeloperoxidase (MPO), superoxide dismutase (SOD), and malondialdehyde (MDA) levels were detected to evaluate the inflammatory and oxidative stress status. The protein and mRNA expressions of Nrf2 and heme oxygenase-1 (HO-1) in the colon were detected by Western blot and quantitative polymerase chain reaction (qPCR), respectively. Melatonin partially prevented the loss of MN and alleviated the inflammation and oxidative stress induced by DNBS. In addition, melatonin markedly increased the Nrf2 and HO-1 level in the colitis. These results indicate that melatonin protects MN from damage by reducing inflammation and oxidative stress, effects that are partly mediated by the Nrf2-ARE pathway.

Topics: Animals; Colitis; Colon; Dinitrofluorobenzene; Disease Models, Animal; Heme Oxygenase-1; Inflammation; Malondialdehyde; Melatonin; Neurons; Oxidative Stress; Peroxidase; Protective Agents; Rats; Superoxide Dismutase

Metallothioneins (MTs) are a family of low molecular-weight and cysteine-rich metalloproteins that regulate metal metabolism and protect cells from oxygen free radicals. Recent studies suggested that MTs have some anti-inflammatory effects. However, the role of MTs in post-burn inflammation remains unclear. This study is designed to investigate the role of MTs in post-burn inflammation in a mouse burn model. MT-I/II null (-/-) and C57BL/6 wild-type (WT) mice were randomly divided into sham burn, burn, Zn treated, and Zn-MT-2 treated groups. The inflammatory cytokines levels were measured by enzyme-linked immunosorbent assay (ELISA). Myeloperoxidase (MPO) activity was determined by spectrophotometry. In in vitro study, exogenous MT-2 was added to macrophages that were stimulated with burn serum in the presence or absence of a p38 MAPK inhibitor SB203580. The IL-6 and TNF-α messenger RNA (mRNA) expression were detected by quantitative real-time polymerase chain reaction. The levels of p38 expression were determined by Western blot. Burn induced increased inflammatory cytokines such as interleukin (IL)-1β, IL-6, tumor necrosis factors-α, and macrophage chemoattractant protein-1 production in burn wound and serum. The MPO activities in the lung and heart were also increased after burn. These effects were significantly more prominent in MT (-/-) mice than in WT mice. Furthermore, these effects were inhibited by administration of exogenous MT-2 to both WT and MT (-/-) mice. Exogenous MT-2 inhibited the p38 expression and abrogated the increase of IL-6 and TNF-α mRNA expression from macrophages that were stimulated with burn serum. The effect of MT-2 was not further strengthened in the presence of SB203580. MTs may have a protective role against post-burn inflammation and inflammatory organ damage, at least partly through inhibiting the p38 MAPK signaling.

Topics: Animals; Burns; Chemokine CCL2; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Imidazoles; Inflammation; Interleukin-1beta; Interleukin-6; Macrophages; Male; MAP Kinase Signaling System; Metallothionein; Mice; Mice, Inbred C57BL; Mice, Knockout; p38 Mitogen-Activated Protein Kinases; Peroxidase; Pyridines; Real-Time Polymerase Chain Reaction; RNA, Messenger; Tumor Necrosis Factor-alpha

The aim of the study was to investigate the ameliorative effects of curcumin on fibrinogen like protein-2 (fgl-2), some oxido-inflammatory and apoptotic markers in rat-induced acute pancreatitis (AP). Seventy-five albino rats were divided into control group, l-arginine (l-Arg)-induced AP group, curcumin pre-treated group before AP induction, curcumin post-treated group after AP induction, and curcumin injected group only. AP group showed severe necrotizing pancreatitis confirmed by histopathological changes and elevations in serum amylase and lipase activities, levels of epithelial neutrophil-activating peptide 78, tissue content of protein carbonyls, levels of tumor necrosis factor α, and caspase-3 as well as myeloperoxidase activity. Significant elevation in pancreatic fgl-2 mRNA expression was detected in AP group. Improvement of all parameters was detected with increase of caspase-3 in both curcumin-treated groups that confirmed curcumin ameliorative effects against AP through induction of apoptosis and inhibition of micro-thrombosis, inflammation, and oxidative stress.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Arginine; Caspase 3; Curcumin; Disease Models, Animal; Fibrinogen; Gene Expression Regulation; Inflammation; Injections, Intraperitoneal; Male; Oxidative Stress; Pancreatitis, Acute Necrotizing; Peroxidase; Protein Carbonylation; Rats; Rats, Sprague-Dawley; RNA, Messenger; Tumor Necrosis Factor-alpha

Most patients with cerebral malaria (CM) sustain cerebral microvascular sequestration of Plasmodium falciparum-infected red blood cells (iRBCs). Although many young children are infected with P. falciparum, CM remains a rare outcome; thus, we hypothesized that specific host conditions facilitate iRBC cerebral sequestration. To identify these host factors, we compared the peripheral whole-blood transcriptomes of Malawian children with iRBC cerebral sequestration, identified as malarial-retinopathy-positive CM (Ret+CM), to the transcriptomes of children with CM and no cerebral iRBC sequestration, defined as malarial-retinopathy-negative CM (Ret-CM). Ret+CM was associated with upregulation of 103 gene set pathways, including cytokine, blood coagulation, and extracellular matrix (ECM) pathways (P < 0.01; false-discovery rate [FDR] of <0.05). Neutrophil transcripts were the most highly upregulated individual transcripts in Ret+CM patients. Activated neutrophils can modulate diverse host processes, including the ECM, inflammation, and platelet biology to potentially facilitate parasite sequestration. Therefore, we compared plasma neutrophil proteins and neutrophil chemotaxis between Ret+CM and Ret-CM patients. Plasma levels of human neutrophil elastase, myeloperoxidase, and proteinase 3, but not lactoferrin or lipocalin, were elevated in Ret+CM patients, and neutrophil chemotaxis was impaired, possibly related to increased plasma heme. Neutrophils were rarely seen in CM brain microvasculature autopsy samples, and no neutrophil extracellular traps were found, suggesting that a putative neutrophil effect on endothelial cell biology results from neutrophil soluble factors rather than direct neutrophil cellular tissue effects. Meanwhile, children with Ret-CM had lower levels of inflammation, higher levels of alpha interferon, and upregulation of Toll-like receptor pathways and other host transcriptional pathways, which may represent responses that do not favor cerebral iRBC sequestration.. There were approximately 198 million cases of malaria worldwide in 2013, with an estimated 584,000 deaths occurring mostly in sub-Saharan African children. CM is a severe and rare form of Plasmodium falciparum infection and is associated with high rates of mortality and neurological morbidity, despite antimalarial treatment. A greater understanding of the pathophysiology of CM would allow the development of adjunctive therapies to improve clinical outcomes. A hallmark of CM is cerebral microvasculature sequestration of P. falciparum-infected red blood cells (iRBCs), which results in vasculopathy in some patients. Our data provide a global analysis of the host pathways associated with CM and newly identify an association of activated neutrophils with brain iRBC sequestration. Products of activated neutrophils could alter endothelial cell receptors and coagulation to facilitate iRBC adherence. Future studies can now examine the role of neutrophils in CM pathogenesis to improve health outcomes.

Topics: Brain; Cell Adhesion; Child; Child, Preschool; Endothelial Cells; Erythrocytes; Female; Gene Expression Profiling; Humans; Inflammation; Leukocyte Elastase; Malaria, Cerebral; Malawi; Male; Metabolic Networks and Pathways; Myeloblastin; Neutrophil Activation; Neutrophils; Peroxidase; Plasmodium falciparum

Myeloperoxidase (MPO) released at sites of inflammation catalyzes the formation of the oxidants hypochlorous acid (HOCl) and hypothiocyanous acid (HOSCN) from H2O2 and halide and pseudo-halide ions. HOCl, a major oxidant produced under physiological conditions reacts rapidly with many biological molecules, and is strongly linked with tissue damage during inflammatory disease. The role of HOSCN in disease is less clear, though it can initiate cellular damage by pathways involving the selective oxidation of thiol-containing proteins. Utilizing a thiol-specific proteomic approach, we explored the cellular targets of HOSCN in macrophages (J774A.1). We report that multiple thiol-containing proteins involved in metabolism and glycolysis; fructose bisphosphate aldolase, triosephosphate isomerase, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and creatine kinase, together with a number of chaperone, antioxidant and structural proteins, were modified in a reversible manner in macrophages treated with HOSCN. The modification of the metabolic enzymes was associated with a decrease in basal glycolysis, glycolytic reserve, glycolytic capacity and lactate release, which was only partly reversible on further incubation in the absence of HOSCN. Inhibition of glycolysis preceded cell death and was seen in cells exposed to low concentrations (≤25µM) of HOSCN. The ability of HOSCN to inhibit glycolysis and perturb energy production is likely to contribute to the cell death seen in macrophages on further incubation after the initial treatment period, which may be relevant for the propagation of inflammatory disease in smokers, who have elevated plasma levels of the HOSCN precursor, thiocyanate.

Topics: Atherosclerosis; Cell Death; Cell Line; Glutathione; Glycolysis; Humans; Hydrogen Peroxide; Inflammation; Macrophages; Oxidants; Peroxidase; Protein Processing, Post-Translational; Proteomics; Sulfhydryl Compounds; Thiocyanates

Neutrophil myeloperoxidase content is determined by the Advia 2120 hematology system by staining characteristics. Changes in myeloperoxidase staining are shown by location of neutrophils on Advia peroxidase dot plots and as myeloperoxidase index (MPXI). Significant changes in MPXI have been reported during severe inflammation in horses, dogs, and people but conclusions were inconsistent.. Infusion of endotoxin was used to initiate an inflammatory stimulus under controlled conditions and over a longer time period than in previous studies to document kinetics of changes in neutrophil numbers, morphology, and myeloperoxidase staining. Identification of consistent time-related changes may allow better interpretation of changes in neutrophil characteristics during inflammation.. Five Standardbred trotting horses received an intravenous infusion over a 6-hour period with Escherichia coli endotoxin. Neutrophil count, MPXI, neutrophil characteristics in Advia 2120 Perox dot plots and neutrophil morphology in blood smears were monitored with repeated sampling for up to 10 days.. Endotoxin infusion immediately caused severe neutropenia which converted to neutrophilia 14 hours after start of endotoxin infusion. Neutrophilia was still present 78 hours after start of infusion. Large "giant" neutrophils first appeared in blood smears and Advia Perox dot plots after 36-48 hours. A marked and consistent decrease in MPXI was seen in all horses 6 days (150 hours) after endotoxin exposure.. Endotoxemia caused prominent, time-related changes in equine neutrophil characteristics including emergence of giant neutrophils and markedly decreased MPXI several days after endotoxin infusion.

Topics: Animals; Endotoxemia; Endotoxins; Horse Diseases; Horses; Inflammation; Neutropenia; Neutrophils; Peroxidase

The aim of this study is to evaluate the protective effects of chrysophanol (CH) against paraquat (PQ)-induced pulmonary injury. Fifty BALB/C mice were randomized into five groups: (1) control, (2) PQ, (3) PQ + dexamethasone (Dex, 2 mg/kg), (4) PQ + CH (10 mg/kg), and (5) PQ + CH (20 mg/kg). A single dose of PQ (50 mg/kg, i.p.) was intraperitoneally given to induce acute lung injury. Then mice were treated with CH (10 and 20 mg/kg/day, orally) for 7 days. At the end of the experiment, animals were euthanized and then bronchoalveolar lavage fluid (BALF) and lung tissues were collected for histological observation, biochemical analysis, and Western blot analysis. Malondialdehyde (MDA), myeloperoxidase (MPO), superoxide dismutase (SOD), interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α (TNF-α) levels in BALF were determined. The levels of SOD and MDA in the lung were also detected. The peroxisome proliferator-activated receptor (PPAR)-γ and nuclear factor-kappaB (NF-κB) pathway proteins in the lung were determined by Western blot. Histological examination indicated that CH attenuated lung inflammation caused by PQ. Biochemical results showed that CH treatment significantly reduced the levels of MDA, MPO, and inflammatory cytokines and increased the level of SOD, compared to those in the PQ group. Meanwhile, Western Blot results revealed that CH increased PPAR-γ expression and inhibited NF-κB pathway activation after PQ challenge. These findings suggested the potential therapeutic effects of CH which is derived from a natural product on PQ-induced pulmonary injury.

Topics: Acute Lung Injury; Animals; Anthraquinones; Bronchoalveolar Lavage Fluid; Dexamethasone; Herbicides; Inflammation; Interleukin-1beta; Interleukin-6; Lung; Malondialdehyde; Mice, Inbred BALB C; NF-kappa B; Paraquat; Peroxidase; PPAR gamma; Pulmonary Edema; Random Allocation; Superoxide Dismutase; Tumor Necrosis Factor-alpha

AGEs are a heterogeneous group of molecules formed from the nonenzymatic reaction of reducing sugars with free amino groups of proteins, lipids, and/or nucleic acids. AGEs have been shown to play a role in various conditions including cardiovascular disease and diabetes. In this study, we hypothesized that AGEs play a role in the "multiple hit hypothesis" of nonalcoholic fatty liver disease (NAFLD) and contribute to the pathogenesis of hepatosteatosis. We measured the effects of various mouse chows containing high or low AGE in the presence of high or low fat content on mouse weight and epididymal fat pads. We also measured the effects of these chows on the inflammatory response by measuring cytokine levels and myeloperoxidase activity levels on liver supernatants. We observed significant differences in weight gain and epididymal fat pad weights in the high AGE-high fat (HAGE-HF) versus the other groups. Leptin, TNF-α, IL-6, and myeloperoxidase (MPO) levels were significantly higher in the HAGE-HF group. We conclude that a diet containing high AGEs in the presence of high fat induces weight gain and hepatosteatosis in CD-1 mice. This may represent a model to study the role of AGEs in the pathogenesis of hepatosteatosis and steatohepatitis.

Topics: Adipose Tissue; Animals; Diet, High-Fat; Fatty Liver; Glycation End Products, Advanced; Humans; Inflammation; Interleukin-6; Leptin; Liver; Mice; Non-alcoholic Fatty Liver Disease; Obesity; Oxidation-Reduction; Peroxidase; Tumor Necrosis Factor-alpha; Weight Gain

The purpose of this study was to assess the protective effect of senegenin on acute lung injury (ALI) in rats induced by sepsis. Rat ALI model was reproduced by cecal ligation and puncture (CLP). All rats were randomly divided into five groups: group 1 (control), group 2 (CLP), group 3 (CLP + senegenin 15 mg/kg), group 4 (CLP + senegenin 30 mg/kg), and group 5 (CLP + senegenin 60 mg/kg). CLP + senegenin groups received senegenin by gavage daily for consecutive 5 days, respectively, while the mice in control and CLP groups were given an equivalent volume of saline. We detected the lung wet/dry weight ratios and the histopathology of the lung. The levels of lung tissue myeloperoxidase (MPO), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) were determined. Meanwhile, the nuclear factor-kappa B (NF-κB) activation, tumor necrosis factor-alpha (TNF-α), and interleukin-1β (IL-1β) levels were studied. The results demonstrated that senegenin treatment significantly attenuated CLP-induced lung injury, including reduction of lung wet/dry weight ratio, protein leak, infiltration of leukocytes, and MPO activity. In addition, senegenin markedly decreased MDA content and increased SOD activity and GSH level. Serum levels of TNF-α and IL-1β were also decreased by senegenin administration. Furthermore, senegenin administration inhibited the nuclear translocation of NF-κB in the lungs. These findings indicate that senegenin exerts protective effects on CLP-induced septic rats. Senegenin may be a potential therapeutic agent against sepsis.

Topics: Active Transport, Cell Nucleus; Acute Lung Injury; Animals; Anti-Inflammatory Agents; Antioxidants; Cecum; Drugs, Chinese Herbal; Enzyme Activation; Glutathione; Inflammation; Interleukin-1beta; Lung; Male; Malondialdehyde; NF-kappa B; Oxidative Stress; Peroxidase; Random Allocation; Rats; Rats, Sprague-Dawley; Sepsis; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Hydrogen sulphide is an endogenous inflammatory mediator produced by cystathionine-γ-lyase (CSE) in macrophages. To determine the role of H2S and macrophages in sepsis, we used small interference RNA (siRNA) to target the CSE gene and investigated its effect in a mouse model of sepsis. Cecal ligation puncture (CLP)-induced sepsis is characterized by increased levels of myeloperoxidase (MPO) activity, morphological changes in liver and pro-inflammatory cytokines and chemokines in the liver and lung. SiRNA treatment attenuated inflammation in the liver and lungs of mice following CLP-induced sepsis. Liver MPO activity increased in CLP-induced sepsis and treatment with siRNA significantly reduced this. Similarly, lung MPO activity increased following induction of sepsis with CLP while siRNA treatment significantly reduced MPO activity. Liver and lung cytokine and chemokine levels in CLP-induced sepsis reduced following treatment with siRNA. These findings show a crucial pro-inflammatory role for H2S synthesized by CSE in macrophages in sepsis and suggest CSE gene silencing with siRNA as a potential therapeutic approach for this condition.

Topics: Animals; Cystathionine gamma-Lyase; Disease Models, Animal; Gene Silencing; Humans; Hydrogen Sulfide; Inflammation; Macrophages; Mice; Monocytes; Peroxidase; Punctures; Sepsis

Green tea-derived polyphenol (-)-epigallocatechin-3-gallate (EGCG) has been extensively studied for its antioxidant and anti-inflammatory properties in models of inflammatory bowel disease, yet the underlying molecular mechanism is not completely understood. Herein, we demonstrate that EGCG can potently inhibit the proinflammatory enzyme myeloperoxidase in vitro in a dose-dependent manner over a range of physiologic temperatures and pH values. The ability of EGCG to mediate its inhibitory activity is counter-regulated by the presence of iron and lipocalin 2. Spectral analysis indicated that EGCG prevents the peroxidase-catalyzed reaction by reverting the reactive peroxidase heme (compound I:oxoiron) back to its native inactive ferric state, possibly via the exchange of electrons. Further, administration of EGCG to dextran sodium sulfate-induced colitic mice significantly reduced the colonic myeloperoxidase activity and alleviated proinflammatory mediators associated with gut inflammation. However, the efficacy of EGCG against gut inflammation is diminished when orally coadministered with iron. These findings indicate that the ability of EGCG to inhibit myeloperoxidase activity is one of the mechanisms by which it exerts mucoprotective effects and that counter-regulatory factors such as dietary iron and luminal lipocalin 2 should be taken into consideration for optimizing clinical management strategies for inflammatory bowel disease with the use of EGCG treatment.

Topics: Acute-Phase Proteins; Animals; Antioxidants; Catechin; Dextran Sulfate; Disease Models, Animal; Humans; Inflammation; Iron, Dietary; Lipocalin-2; Lipocalins; Mice, Inbred C57BL; Oncogene Proteins; Peroxidase; Proto-Oncogene Proteins; Tea

In this work a diclofenac acid nanosuspension formulation was produced as a novel approach for the treatment of skin inflammation. Drug nanocrystals, prepared by the wet media milling technique and stabilized using Poloxamer 188, were characterized by different techniques: scanning electron microscopy, differential scanning calorimetry, X-ray powder diffractometry, Fourier transform infrared spectroscopy and photon correlation spectroscopy. The ability of nanocrystals to improve dermal drug bioavailability was investigated ex vivo by using Franz diffusion vertical cells and mouse skin, in comparison with both diclofenac acid coarse suspensions and a commercial formulation. The topical anti-inflammatory activity of the drug nanosuspension was assessed in vivo by testing its effect compared to common inflammatory endpoints: i.e. the inhibition of chemically induced oedema and leucocyte infiltration (reflected in myeloperoxidase activity). Following the milling procedure, diclofenac nanocrystals exhibited a mean diameter of approximately 279nm, a low polydispersity index (∼0.17) and maintained the same polymorphic form of the starting bulk powder. When the drug nanosuspension was applied on the mouse skin it produced a higher accumulation of diclofenac in the skin compared to both the coarse suspensions and the commercial formulation, as demonstrated by ex vivo transdermal delivery experiments. Moreover, the nanosuspension provided an in vivo oedema inhibition of 50%, which was not statistically different from the commercial formulation. On the contrary, the nanosuspension showed a higher inhibition of myeloperoxidase activity in the damaged tissue (86%) than the commercial formulation (16%).

Topics: Administration, Cutaneous; Animals; Anti-Inflammatory Agents, Non-Steroidal; Biological Availability; Biological Transport; Diclofenac; Edema; Inflammation; Male; Mice; Nanoparticles; Neutrophil Infiltration; Particle Size; Permeability; Peroxidase; Poloxamer; Skin; Solubility; Suspensions

Rheumatoid arthritis (RA)--a widespread chronic inflammatory disease in industrialized countries--is characterized by a persistent and progressive joint destruction. The chronic pro-inflammatory state results from a mutual activation of the innate and the adaptive immune system, while the exact pathogenesis mechanism is still under discussion. New data suggest a role of the innate immune system and especially polymorphonuclear granulocytes (PMNs, neutrophils) not only during onset and the destructive phase of RA but also at the chronification of the disease. Thereby the enzymatic activity of myeloperoxidase (MPO), a peroxidase strongly abundant in neutrophils, may be important: While its peroxidase activity is known to contribute to cartilage destruction at later stages of RA the almost MPO-specific oxidant hypochlorous acid (HOCl) is also discussed for certain anti-inflammatory effects. In this study we used pristane-induced arthritis (PIA) in Dark Agouti rats as a model for the chronic course of RA in man. We were able to shown that a specific detection of the HOCl-producing MPO activity provides a sensitive new marker to evaluate the actual systemic inflammatory status which is only partially detectable by the evaluation of clinical symptoms (joint swelling and redness measurements). Moreover, we evaluated the long-term pharmacological effect of the well-known anti-inflammatory flavonoid epigallocatechin gallate (EGCG). Thereby only upon early and continuous oral application of this polyphenol the arthritic symptoms were considerably diminished both in the acute and in the chronic phase of the disease. The obtained results were comparable to the treatment control (application of methotrexate, MTX). As revealed by stopped-flow kinetic measurements, EGCG may regenerate the HOCl-production of MPO which is known to be impaired at chronic inflammatory diseases like RA. It can be speculated that this MPO activity-promoting effect of EGCG may contribute to the pharmacological mode of action of this polyphenol.

Topics: Animals; Arthritis; Biomarkers; Catechin; Chronic Disease; Female; Inflammation; Methotrexate; Orosomucoid; Peroxidase; Rats; Terpenes

Intravenous tranexamic acid (TXA) is an effective adjunct after hemorrhagic shock (HS) because of its antifibrinolytic properties. TXA is also a serine protease inhibitor, and recent laboratory data demonstrated that intraluminal TXA into the small bowel inhibited digestive proteases and protected the gut. A Disintegrin And Metalloproteinase 17 (ADAM-17) and tumor necrosis factor α (TNF-α) are effective sheddases of intestinal syndecan-1, which when shed, exposes the underlying intestinal epithelium to digestive proteases and subsequent systemic insult. We therefore hypothesized that intraluminal TXA as a serine protease inhibitor would reduce intestinal sheddases and syndecan-1 shedding, mitigating gut and distant organ (lung) damage.. Mice underwent 90 minutes of HS to a mean arterial pressure of 35 ± 5 mm Hg followed by the intraluminal administration of TXA or vehicle. After 3 hours, the small intestine, lung, and blood were collected for analysis.. Intraluminal TXA significantly reduced gut and lung histopathologic injury and inflammation compared with HS alone. Gut, lung, and systemic ADAM-17 and TNF-α were significantly increased by HS but lessened by TXA. In addition, gut and lung syndecan-1 immunostaining were preserved and systemic shedding lessened after TXA. TXA reduced ADAM-17 and TNF-α, but not syndecan-1, in TXA-sham animals compared with sham vehicles.. Results of the present study demonstrate a beneficial effect of intraluminal TXA in the gut and lung after experimental HS in part because of the inhibition of the syndecan-1 shedding by ADAM-17 and TNF-α. Further studies are needed to determine if orally administered TXA could provide similar intestinal protection and thus be of potential benefit to patients with survivable hemorrhage at risk for organ injury. This is particularly relevant in patients or soldiers who may not have access to timely medical care.

Topics: ADAM17 Protein; Animals; Enzyme-Linked Immunosorbent Assay; Inflammation; Intestinal Mucosa; Intestine, Small; Lung Injury; Male; Mice; Mice, Inbred C57BL; Peroxidase; Shock, Hemorrhagic; Syndecan-1; Tranexamic Acid; Tumor Necrosis Factor-alpha

Eimeria spp. multiply within the intestinal tract causing severe inflammatory responses. Chitosan (CS), meanwhile, has been shown to exhibit anti-inflammatory activities in different experimental models. Here, we investigated the effect of CS on the outcome of inflammation caused by Eimeria papillata in the mouse intestine. Investigations were undertaken into the oocyst output in feces and developmental stages and goblet cells in intestinal tissue. Assays for lipid peroxidation, nitric oxide (NO), and myeloperoxidase (MPO) were also performed. T cells in intestinal tissue were counted using immunohistochemistry while total IgA in serum or intestinal wash was assayed using ELISA. In addition, mRNA expression of tumor necrosis factor alpha (TNF-α), transforming growth factor β (TGF-β), interleukin (IL)-10, and IL-4 were detected using real-time PCR. The data indicated a reduction in both oocyst output and in the number of parasite developmental stages following CS treatment, while the goblet cell hypoplasia in infected mice was also inhibited. CS decreased lipid peroxidation, NO, and MPO but did not alter the T cell count or IgA levels in comparison to the infected group. The expression of TNF-α and TGF-β decreased but IL-10 and IL-4 increased after CS treatment in comparison to the non-treated infected group. In conclusion, CS showed anti-inflammatory and protective effects against E. papillata infection.

Topics: Animals; Anti-Inflammatory Agents; Chitosan; Coccidiosis; Coccidiostats; Cytokines; Eimeria; Feces; Goblet Cells; Inflammation; Intestines; Lipid Peroxidation; Male; Mice; Nitric Oxide; Peroxidase

To investigate the potential effects of pretreatment with allopurinol on renal ischemia/reperfusion injury (IRI) in a rat model.. Twenty four rats were subjected to right kidney uninephrectomy were randomly distributed into the following three groups (n=8): Group A (sham-operated group); Group B (ischemic group) with 30 min of renal ischemia after surgery; and Group C (allopurinol + ischemia group) pretreated with allopurinol at 50 mg/kg for 14 days. At 72 h after renal reperfusion, the kidney was harvested to assess inflammation and apoptosis.. Pretreatment with allopurinol significantly improved renal functional and histological grade scores following I/R injury (p<0.05). Compared with Group B, the expression levels of caspase-3 and Bax were markedly reduced in Group C, meanwhile, whereas expression of bcl-2 was clearly increased (p<0.05). A newly described marker of inflammation, High Mobility Group Box 1(HMGB1), showed reduced expression in Group C (p<0.05).. Pretreatment with allopurinol had a protective effect on kidney ischemia/reperfusion injury, which might be related to the inhibition of HMGB1 expression.

Topics: Allopurinol; Animals; Apoptosis; Blood Urea Nitrogen; Disease Models, Animal; HMGB1 Protein; Inflammation; Ischemic Preconditioning; Kidney; Male; Peroxidase; Protective Agents; Random Allocation; Rats, Sprague-Dawley; Reperfusion Injury; Superoxide Dismutase

PepT1 transports dietary and bacterial peptides in the gut. We hypothesized that cysteinyl-glycine would ameliorate the inflammatory effect of a bacterial peptide, formyl-methionyl-leucyl-phenylalanine (fMLP), in both sow-fed and parenterally-fed piglets.. An intestinal perfusion experiment was performed in piglets (N = 12) that were sow-reared or provided with parenteral nutrition (PN) for 4 d. In each piglet, five segments of isolated intestine were perfused with five treatments including cysteine and glycine, cysteinyl-glycine, fMLP, free cysteine and glycine with fMLP, or cysteinyl-glycine with fMLP. Mucosal cytokine responses and intestinal morphology was assessed in each gut segment.. PN piglets had lower mucosal IL-10 by approximately 20% (P < 0.01). Cysteinyl-glycine lowered TNF-α response to fMLP in PN-fed animals and IFN-γ response to fMLP in both groups (P < 0.05). The free cysteine and glycine treatment reduced TNF-α in sow-fed animals (P < 0.05). fMLP affected villus height in parenterally (P < 0.05), but not sow-fed animals.. Parenteral feeding conferred a susceptibility to mucosal damage by fMLP. The dipeptide was more effective at attenuating the inflammatory response to a bacterial peptide than free amino acids. This may be due to competitive inhibition of fMLP transport or a greater efficiency of transport of dipeptides.

Topics: Animals; Cysteine; Cytokines; Dipeptides; Disease Models, Animal; Genetic Predisposition to Disease; Glycine; Inflammation; Interleukin-10; Intestinal Mucosa; Mannitol; Mucous Membrane; N-Formylmethionine Leucyl-Phenylalanine; Parenteral Nutrition; Perfusion; Peroxidase; Random Allocation; Swine; Time Factors

Reactive oxygen species (ROS) protect the host against a large number of pathogenic microorganisms. ROS have different effects on parasites of the genus Leishmania: some parasites are susceptible to their action, while others seem to be resistant. The role of ROS in L. amazonensis infection in vivo has not been addressed to date.. In this study, C57BL/6 wild-type mice (WT) and mice genetically deficient in ROS production by phagocytes (gp91(phox-/-)) were infected with metacyclic promastigotes of L. amazonensis to address the effect of ROS in parasite control. Inflammatory cytokines, parasite loads and myeloperoxidase (MPO) activity were evaluated. In parallel, in vitro infection of peritoneal macrophages was assessed to determine parasite killing, cytokine, NO and ROS production.. In vitro results show induction of ROS production by infected peritoneal macrophages, but no effect in parasite killing. Also, ROS do not seem to be important to parasite killing in vivo, but they control lesion sizes at early stages of infection. IFN-γ, TNF-α and IL-10 production did not differ among mouse strains. Myeloperoxidase assay showed augmented neutrophils influx 6 h and 72 h post - infection in gp91(phox-/-) mice, indicating a larger inflammatory response in gp91(phox-/-) even at early time points. At later time points, neutrophil numbers in lesions correlated with lesion size: larger lesions in gp91(phox-/-) at earlier times of infection corresponded to larger neutrophil infiltrates, while larger lesions in WT mice at the later points of infection also displayed larger numbers of neutrophils.. ROS do not seem to be important in L. amazonensis killing, but they regulate the inflammatory response probably by controlling neutrophils numbers in lesions.

Topics: Animals; Cytokines; Disease Models, Animal; Inflammation; Leishmania mexicana; Leishmaniasis; Mice; Mice, Inbred C57BL; Parasite Load; Peroxidase; Reactive Oxygen Species

This study tested the hypothesis that preactivated and disaggregated shape-changed platelet (PreD-SCP) therapy attenuates lung injury from acute respiratory distress syndrome (ARDS) induced by 100% oxygen inhalation and complicated by sepsis through peritoneal administration of 1.5 mg/kg lipopolysaccharide (LPS).. Adult male Sprague-Dawley rats, weighing 325 to 350 g, were randomized into group 1 (normal controls [NC]), group 2 (NC + PreD-SCP [3.0 × 10, intravenous administration]), group 3 (ARDS-LPS), and group 4 (ARDS-LPS + PreD-SCP), and sacrificed by 72 h after ARDS induction.. The lung injury score was significantly higher in group 3 than that in other groups, and significantly higher in group 4 than that in groups 1 and 2, whereas the numbers of alveolar sacs and oxygen saturation (%) showed a reversed pattern compared with that of lung injury score among the four groups (all P < 0.0001) without significant difference between groups 1 and 2. The expressions of proinflammatory cells (CD11+, CD14+, CD68+) and proteins (tumor necrosis factor [TNF]-α, nuclear factor [NF]-κB, interleukin [IL]-1ββ, matrix metalloproteinase [MMP]-9, inducible nitric oxide synthase, intercellular adhesion molecule-1) exhibited a pattern identical to the lung injury score. Circulating levels of white blood cell, IL-6, TNF-α, myeloperoxidase and CCL5, and pulmonary protein expressions of oxidative stress (NOX-1/NOX-2, oxidized protein), apoptotic (Bax, cleaved caspase 3/poly (ADP-ribose) polymerase), fibrotic (Smad3, transforming growth factor [TGF]-β), and DNA damage (γ-H2AX) biomarkers showed an identical pattern, whereas protein expressions of antifibrotic (Smad1/5, bone morphogenetic protein [BMP]-2) and anti-inflammatory (Bcl-2) biomarkers demonstrated an opposite pattern compared with the proinflammatory indices among the four groups (all P < 0.001).. PreD-SCP therapy effectively improved lung injury in ARDS complicated by sepsis.

Topics: Animals; Blood Platelets; Chemokine CCL5; Inflammation; Interleukin-1beta; Interleukin-6; Male; NF-kappa B; Peroxidase; Rats; Rats, Sprague-Dawley; Respiratory Distress Syndrome; Sepsis; Tumor Necrosis Factor-alpha

A controlled human exposure study was conducted to investigate the impact of inhalational exposures to wood smoke PM2.5 on measured concentrations of airway and systemic inflammatory biomarkers.. Mimicking wildland firefighter activities, 10 participants were exposed to three doses of wood smoke PM2.5 (filtered-air, 250 μg/m, and 500 μg/m) while exercising on a treadmill. Exhaled breath condensate (EBC) and blood plasma samples were obtained pre-, immediately post-, and 1-hour postexposure. 8-isoprostane, pH, and myeloperoxidase were measured in EBC, while H2O2, surfactant protein D, and pentraxin-3 (PTX3) were measured in both EBC and plasma.. Only pH, 8-isoprostane, and PTX3 displayed significant changes when comparing pre- and postexposures.. Markers of inflammation and oxidative stress, including PTX3, pH, and 8-isoprostane in EBC and/or plasma, are sensitive to wood smoke inhalation, with further investigations warranted.

Topics: Biomarkers; Breath Tests; C-Reactive Protein; Dinoprost; Firefighters; Fires; Humans; Hydrogen Peroxide; Hydrogen-Ion Concentration; Inflammation; Inhalation Exposure; Male; Oxidative Stress; Particulate Matter; Peroxidase; Pulmonary Surfactant-Associated Protein D; Serum Amyloid P-Component; Smoke; Wood

N-acylethanolamines (NAEs) comprise a family of bioactive lipid molecules present in animal and plant tissues, with N-palmitoylethanolamine (PEA) having received much attention owing to its anti-inflammatory, analgesic and neuroprotective activities. 2-Pentadecyl-2-oxazoline (PEA-OXA), the oxazoline of PEA, reportedly modulates activity of N-acylethanolamine-hydrolyzing acid amidase (NAAA), which catabolizes PEA. Because PEA is produced on demand and exerts pleiotropic effects on non-neuronal cells implicated in neuroinflammation, modulating the specific amidases for NAEs (NAAA in particular) could be a way to preserve PEA role in maintaining cellular homeostasis through its rapid on-demand synthesis and equally rapid degradation. This study provides the first description of PEA-OXA in both green and roasted coffee beans and Moka infusions, and its synthesis. In an established model of carrageenan (CAR)-induced rat paw inflammation, PEA-OXA was orally active in limiting histological damage and thermal hyperalgesia 6h after CAR intraplantar injection in the right hindpaw and the accumulation of infiltrating inflammatory cells. PEA-OXA appeared to be more potent compared to ultramicronized PEA given orally at the same dose (10mg/kg). PEA-OXA markedly reduced also the increase in hindpaw myeloperoxidase activity, an index of polymorphonuclear cell accumulation in inflammatory tissues. NAAA modulators like PEA-OXA may serve to maximize availability of NAEs (e.g. PEA) while providing for recycling of the NAE components for further resynthesis.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Carrageenan; Coffee; Disease Models, Animal; Hyperalgesia; Inflammation; Male; Oxazoles; Peroxidase; Rats; Rats, Sprague-Dawley

Tumor necrosis factor (TNF) receptor-associated factor 5 (TRAF5) is a key mediator of TNF receptor superfamily members and is important in both T helper (Th) cell immunity and the regulation of multiple signaling pathways. To clarify TRAF5's influence on inflammatory bowel diseases (IBDs), we investigated TRAF5 deficiency's effect on dextran sulfate sodium- (DSS-) induced colitis. Colitis was induced in TRAF5 knockout (KO) mice and their wild-type (WT) littermates by administering 3% DSS orally for 7 days. The mice were then sacrificed, and their colons were removed. Our data suggested that KO mice were more susceptible to DSS-induced colitis. TRAF5 deficiency significantly enhanced IFN-γ, IL-4, and IL-17a mRNA and protein levels in the colons of DSS-fed mice, and the mRNA expression of T-bet and GATA-3 was also markedly elevated. However, ROR-α and ROR-γt mRNA levels did not differ between DSS-induced KO and WT mice. Flow cytometry showed increased frequencies of Th2 and IFN-γ/IL-17a-coproducing CD4(+) T cells in the colons of DSS-induced KO mice. Additionally, TRAF5 deficiency significantly enhanced the activation of NF-κB in CD4(+) T cells after DSS administration. These results indicated that TRAF5 deficiency significantly aggravated DSS-induced colitis, most likely by regulating Th cell-mediated inflammation.

Topics: Animals; Blotting, Western; CD4-Positive T-Lymphocytes; Colitis; Dextran Sulfate; Disease Models, Animal; Electrophoresis, Polyacrylamide Gel; Female; Flow Cytometry; Inflammation; Interleukin-17; Male; Mice; Mice, Knockout; Peroxidase; Real-Time Polymerase Chain Reaction; RNA, Messenger; T-Lymphocytes, Helper-Inducer; TNF Receptor-Associated Factor 5

To determine changes in blood granulocyte counts and in plasma myeloperoxidase (MPO) and elastase (ELT) concentrations in surgical colic cases, and to determine the relationship between these changes and the surgical procedure performed, occurrence of postoperative ileus, and final outcome.. Prospective clinical study conducted over a 12-month period.. University teaching hospital.. Fifty-three horses undergoing emergency laparotomy and surviving at least 12 hours postoperatively.. Blood samples were taken before surgery, during surgery, at the recovery from anesthesia, and then serially until the 150th hour after the first blood sampling. Granulocyte counts were performed by an automated cell hematology analyzer. Specific ELISAs were performed for the MPO and ELT measurements. Mixed models were used to compare the time-trends of the 3 parameters.. Taking all horses together, the time-trends of MPO and ELT were not significantly different from each other, but they were significantly different from the granulocyte time-trend. The type of surgical procedure did not influence the time-trends of the 3 parameters. Significant changes in the granulocyte time-trends were associated with postoperative ileus and outcome. Significant changes in the MPO time-trends were associated with outcome. The ELT time-trends were not influenced by ileus or outcome.. Granulocyte counts and MPO change over time and are related to the severity of the inflammatory reaction in surgical colic cases. These time-trends may allow evaluation of treatment efficacy in an effort to modulate excessive granulocyte activation and degranulation.

Topics: Animals; Colic; Female; Granulocytes; Horse Diseases; Horses; Inflammation; Laparotomy; Leukocyte Elastase; Male; Peroxidase; Postoperative Complications; Prospective Studies; Severity of Illness Index; Time Factors; Treatment Outcome

Myeloperoxidase (MPO) activity contributes to arterial inflammation, vascular dysfunction and disease, including atherosclerosis. Current assessment of MPO activity in biological systems in vivo utilizes 3-chlorotyrosine (3-Cl-Tyr) as a biomarker of hypochlorous acid (HOCl) and other chlorinating species. However, 3-Cl-Tyr is formed in low yield and is subject to further metabolism. Recently, we reported a method to selectively assess MPO-activity in vivo by measuring the conversion of hydroethidine to 2-chloroethidium (2-Cl-E(+)) by liquid chromatography with tandem mass spectrometry (LC-MS/MS) (J. Biol. Chem., 289, 2014, pp. 5580-5595). The hydroethidine-based method has greater sensitivity for MPO activity than measurement of 3-Cl-Tyr. The current methods paper provides a detailed protocol to determine in vivo and ex vivo MPO activity in arteries from mouse models of vascular inflammation and disease by utilizing the conversion of hydroethidine to 2-Cl-E(+). Procedures for the synthesis of standards, preparation of tissue homogenates and the generation of 2-Cl-E(+) are also provided in detail, as are the conditions for LC-MS/MS detection of 2-Cl-E(+).

Topics: Animals; Biomarkers; Chromatography, Liquid; Disease Models, Animal; Halogenation; Humans; Hydrogen Peroxide; Hypochlorous Acid; Inflammation; Mice; Oxidation-Reduction; Peroxidase; Phenanthridines; Tandem Mass Spectrometry; Tyrosine; Vascular Diseases

Necrosis amplifies inflammation and plays important roles in acute respiratory distress syndrome (ARDS). Necroptosis is a newly identified programmed necrosis that is mediated by receptor interacting protein 3 (RIP3). However, the potential involvement and impact of necroptosis in lipopolysaccharide (LPS)-induced ARDS remains unknown. We therefore explored the role and mechanism of RIP3-mediated necroptosis in LPS-induced ARDS. Mice were instilled with increasing doses of LPS intratracheally to induce different degrees of ARDS. Lung tissues were harvested for histological and TUNEL staining and western blot for RIP3, p-RIP3, X-linked inhibitor of apoptosis protein (XIAP), mixed lineage kinase domain-like protein (MLKL), total and cleaved caspases-3/8. Then, wild-type and RIP3 knock-out mice were induced ARDS with 30 mg/kg LPS. Pulmonary cellular necrosis was labeled by the propidium Iodide (PI) staining. Levels of TNF-a, Interleukin (IL)-1β, IL-6, IL-1α, IL-10 and HMGB1, tissue myeloperoxidase (MPO) activity, neutrophil counts and total protein concentration were measured. Results showed that in high dose LPS (30mg/kg and 40mg/kg) -induced severe ARDS, RIP3 protein was increased significantly, accompanied by increases of p-RIP3 and MLKL, while in low dose LPS (10mg/kg and 20mg/kg) -induced mild ARDS, apoptosis was remarkably increased. In LPS-induced severe ARDS, RIP3 knock-out alleviated the hypothermia symptom, increased survival rate and ameliorated the lung tissue injury RIP3 depletion also attenuated LPS-induced increase in IL-1α/β, IL-6 and HMGB1 release, decreased tissue MPO activity, and reduced neutrophil influx and total protein concentration in BALF in severe ARDS. Further, RIP3 depletion reduced the necrotic cells in the lung and decreased the expression of MLKL, but had no impact on cleaved caspase-3 in LPS-induced ARDS. It is concluded that RIP3-mediated necroptosis is a major mechanism of enhanced inflammation and lung tissue injury in high dose LPS- induced severe ARDS in mice.

Topics: Animals; Apoptosis; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Inflammation; Inhibitor of Apoptosis Proteins; Lipopolysaccharides; Lung; Lung Injury; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Necrosis; Neutrophils; Peroxidase; Receptor-Interacting Protein Serine-Threonine Kinases; Respiratory Distress Syndrome

According to literature, the inflammatory response and platelets are associated with coronary heart disease mortality. In this study, we examine if similar relationships exist after acute cerebral infarctions.. Between 2005 and 2007, individuals (n = 61) hospitalized with acute stroke were investigated 2.1 ± .3 (SD) days after hospital admission. After 9.3 ± .7 (SD) years, 29 patients (age 79 ± 8 [SD]; 12 women) had died. They were compared with survivors (age 69 ± 9 [SD]; 9 women) with respect to inflammatory parameters and platelet features such as activity and reactivity.. Inflammation and platelets at the acute event do not forecast long-term survival of stroke sufferers.

Topics: Aged; Aged, 80 and over; Blood Platelets; C-Reactive Protein; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Humans; Inflammation; Male; Middle Aged; Neutrophils; Peroxidase; Retrospective Studies; Stroke

Simple, objective and inexpensive tools for the assessment of mucosal inflammation in ulcerative colitis (UC) are highly desirable. The aim of this study was to evaluate a broad spectrum of activity markers comparing two sampling methods: fecal samples and the mucosal patch technique.. Twenty patients with active UC and 14 healthy controls were characterized by means of clinical indices and endoscopy together with histology and immunohistochemistry on colorectal sections. Neutrophil myeloperoxidase (MPO), calprotectin, eosinophil cationic protein (ECP), eosinophil protein X (EPX/EDN) and IL-1β were analyzed in fecal samples and rectal fluid collected by the patch technique. Nitric oxide (NO) was analyzed in rectal gas samples. Expression of activity markers on colorectal neutrophils and eosinophils were analyzed by flow cytometry.. All fecal and patch markers were increased in UC patients compared with healthy controls. Fecal markers and the level of neutrophil activation correlated to disease activity, whereas patch markers did not. The best markers in terms of discriminative power were fecal MPO and IL-1β. Fecal marker levels were related to sigmoidal histology scores and to neutrophil number and activation. Patch markers were related to rectal inflammation only.. The levels of inflammation markers in feces and patch fluid distinctly reflected active inflammation in UC. The degree of disease activity was however best assessed by fecal markers, particularly MPO and IL-1β. Fecal markers reflect colorectal inflammation both macroscopically and on a cellular level, and may be useful for the evaluation of subclinical inflammation. The applicability of patch markers is restricted to rectal inflammation.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Colitis, Ulcerative; Colonoscopy; Eosinophil Cationic Protein; Eosinophil-Derived Neurotoxin; Feces; Female; Flow Cytometry; Humans; Immunohistochemistry; Inflammation; Interleukin-1beta; Leukocyte L1 Antigen Complex; Male; Middle Aged; Mucous Membrane; Neutrophils; Peroxidase; Young Adult

Ginkgolides are the major bioactive components of Ginkgo biloba extracts, however, the exact constituents of Ginkgolides contributing to their pharmacological effects remain unknown. Herein, we have determined the anti-inflammatory effects of Ginkgolide B (GB) and Ginkgolides mixture (GM) at equivalent dosages against lipopolysaccharide (LPS)-induced inflammation. RAW 264.7 cell culture model and mouse model of LPS-induced lung injury were used to evaluate in vitro and in vivo effects of GB and GM, respectively. In RAW 264.7 cells, GB and GM at equivalent dosages exhibit an identical capacity to attenuate LPS-induced inducible nitric oxide synthase mRNA and protein expression and subsequent NO production. Likewise, GB and GM possess almost the same potency in attenuating LPS-induced expression and activation of nuclear factor kappa B (p65) and subsequent increases in tumor necrosis factor-α mRNA levels. In LPS-induced pulmonary injury, GB and GM at the equivalent dosages have equal efficiency in attenuating the accumulation of inflammatory cells, including neutrophils, lymphocytes, and macrophages, and in improving the histological damage of lungs. Moreover, GB and GM at equivalent dosages decrease the exudation of plasma protein to the same degree, whereas GM is superior to GB in alleviating myeloperoxidase activities. Finally, though GB and GM at equivalent dosages appear to reduce LPS-induced IL-1β mRNA and protein levels and IL-10 protein levels to the same degree, GM is more potent than GB to attenuate the IL-10 mRNA levels. Taken together, this study demonstrates that GB functions as the determinant constituent of Ginkgolides in alleviating LPS-induced lung injury.

Topics: Animals; Bronchoalveolar Lavage Fluid; Female; Ginkgolides; Inflammation; Interleukin-10; Interleukin-1beta; Lactones; Lipopolysaccharides; Lung; Lung Injury; Mice; Mice, Inbred ICR; NF-kappa B; Nitric Oxide; Peroxidase; RAW 264.7 Cells; Signal Transduction

To evaluate the effects of an intraperitoneal solution of methylene blue (MB), lidocaine and pentoxyphylline (PTX) on intestinal ischemic and reperfusion injury.. Superior mesenteric artery was isolated and clamped in 36 adult male Sprague Dawley rats. After 60 minutes, clamp was removed and a group received intraperitoneally UNITO solution (PTX 25mg/kg + lidocaine 5mg/kg + MB 2mg/kg), while the other group was treated with warm 0.9% NaCl solution. Rats were euthanized 45 min after drug administration. Lung and bowel were collected for histological evaluation (using Park's score) and determination of myeloperoxidase (MPO) and malondialdehyde (MDA) levels.. Control samples showed lymphoplasmocytic infiltrate and crypt necrosis of villi. MPO and MDA measurements shown no differences between treated and control groups.. The combination of lidocaine, methylene blue and pentoxyphylline administered intraperitoneally at the studied dose, did not decreased histological lesion scores and biochemical markers levels in intestinal ischemia/reperfusion injury.

Topics: Animals; Anti-Inflammatory Agents; Drug Combinations; Drug Synergism; Inflammation; Infusions, Parenteral; Intestines; Lidocaine; Lung; Male; Malondialdehyde; Methylene Blue; Models, Animal; Pentoxifylline; Peroxidase; Random Allocation; Rats, Sprague-Dawley; Reperfusion Injury; Statistics, Nonparametric

Statins possess a wide variety of pleiotropic properties that are independent of their lipid-lowering abilities such as attenuating inflammation, oxidative stress, coagulation, platelet aggregation and stimulating bone formation. The aim of the study is to evaluate the effect of statins on clinical periodontal parameters and gingival crevicular fluid (GCF) levels of IL-1β, IL-10, and myeloperoxidase (MPO) in inflammatory periodontal diseases. Seventy-nine subjects with hyperlipidemia and 48 systemically healthy controls (C) were included. Hyperlipidemic patients were either given a diet (HD) or prescribed statin (HS). Patients were classified into three subgroups as those who were periodontally healthy (h), who had gingivitis (g), or who had chronic periodontitis (p). Blood samples were collected for the measurement of lipid profiles. Plaque index (PI), gingival index (GI), probing pocket depth (PD), clinical attachment level (CAL), and percentage of bleeding on probing (BOP) were recorded. Gingival crevicular fluid levels of IL-1β, IL-10, and MPO were measured in order to determine the anti-inflammatory and antioxidant effects of statins. Probing depth values of the HSp group were significantly lower than those of the Cp group. Percentage of BOP of the HSg group was significantly lower than those of the HDg and Cg groups. While the IL-1β level of the HSp group was significantly lower than that of the HDp group, IL-10 levels of the HSg group were significantly higher than those of the HDg group. MPO levels were significantly lower in the HSg group when compared to those in the HDg and Cg groups. Statin use decreased the IL-1β and MPO levels and enhanced IL-10 in GCF. It can be suggested that statins may attenuate periodontal inflammation and progression of periodontal inflammation.

Topics: Case-Control Studies; Chronic Periodontitis; Cohort Studies; Gingival Crevicular Fluid; Gingivitis; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Inflammation; Interleukin-10; Interleukin-1beta; Periodontium; Peroxidase

Caryocar coriaceum Wittm. (Pequi) is found in southern Ceará, where the fruit is used as food and in folk medicine as an anti-inflammatory, and to promote healing. However, little is known about the effects of repeated administration of its oil on the biochemical parameters of the blood. This work aimed to evaluate the effects Caryocar coriaceum fixed oil (OFCC); on the lipid profiles of healthy mice, on dyslipidemia induced by tyloxapol, and to study its anti-inflammatory effect both in vivo and in vitro. The results revealed significant reduction in total serum cholesterol and triglycerides, and an increase in HDL-C. The paw edema (induced by carrageenan) and myeloperoxidase (MPO), in polymorphonuclear culture cells, was reduced at all dose levels. Results demonstrated that Caryocar coriaceum's fix oil present anti-inflammatory activity and, for the first time describe the hypolipidemic effects, supporting its traditional use and suggest that present a potential cardioprotective effect.

Topics: Animals; Anti-Inflammatory Agents; Biomarkers; Carrageenan; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Dyslipidemias; Ericales; Fruit; Humans; Hypolipidemic Agents; Inflammation; Lipids; Neutrophils; Peroxidase; Phytotherapy; Plant Extracts; Plant Oils; Plants, Medicinal; Polyethylene Glycols; Rats, Wistar; Time Factors

Alpinetin, a composition of Alpinia katsumadai Hayata, has been reported to have a number of biological properties, such as antibacterial, antitumor and other important therapeutic activities. However, the effect of alpinetin on inflammatory bowel disease (IBD) has not yet been reported. The purpose of this study was to investigate the anti-inflammatory effect and mechanism of alpinetin on dextran sulfate sodium (DSS)-induced colitis in mice. In vivo, DSS-induced mice colitis model was established by giving mice drinking water containing 5% (w/v) DSS for 7 days. Alpinetin (25, 50 and 100 mg/kg) were administered once a day by intraperitoneal injection 3 days before DSS treatment. In vitro, phorbol myristate acetate (PMA)-differentiated monocytic THP-1 macrophages were treated with alpinetin and stimulated by lipopolysaccharide (LPS). The results showed that alpinetin significantly attenuated diarrhea, colonic shortening, histological injury, myeloperoxidase (MPO) activity and the expressions of tumor necrosis factor (TNF-α) and interleukin (IL-1β) production in mice. In vitro, alpinetin markedly inhibited LPS-induced TNF-α and IL-1β production, as well as Toll-like receptor 4 (TLR4) mediated nuclear transcription factor-kappaB (NF-κB) and NOD-like receptor protein 3 (NLRP3) inflammasome activation. In conclusion, this study demonstrated that alpinetin had protective effects on DSS-induced colitis and may be a promising therapeutic reagent for colitis treatment.

Topics: Animals; Cell Survival; Colitis; Dextran Sulfate; Female; Flavanones; Humans; Inflammasomes; Inflammation; Injections, Intraperitoneal; Interleukin-1beta; Lipopolysaccharides; Macrophages; Mice; Mice, Inbred BALB C; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Peroxidase; Signal Transduction; Tetradecanoylphorbol Acetate; THP-1 Cells; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Epidemiological studies have shown adverse effects of ambient air pollutants on health with inflammation and oxidative stress playing an important role. We examine the association between blood biomarkers of inflammation and coagulation and physical attributes of particulate matter which are not routinely measured such as particle length or surface area concentration and apparent density of PM.. Between 3/2007 and 12/2008 187 non-smoking individuals with type 2 diabetes mellitus (T2D) or impaired glucose tolerance (IGT) were examined within the framework of the KORA Study in Augsburg, Germany. In addition, we selected 87 participants with a potential genetic predisposition on detoxifying and inflammatory pathways. This was defined by the null polymorphism for glutathione S-transferase M1 in combination with a certain single nucleotide polymorphism on the C-reactive protein (CRP) gene (rs1205) or the fibrinogen gene (rs1800790). Participants had blood drawn up to seven different times, resulting in 1765 blood samples. Air pollutants were collected at a central measurement station and individual 24-h averages calculated. Associations between air pollutants and high sensitivity CRP, myeloperoxidase (MPO), interleukin (IL)-6 and fibrinogen were analysed using additive mixed models.. For the panel with genetic susceptibility, increases were seen for CRP and MPO with most attributes, specifically particle length and active surface concentration. The %change of geometric mean and 95% confidence intervals for the 5-day average exposure for CRP and MPO were 34.6% [21.8;48.8] and 8.3% [3.2;13.6] per interquartile range increase of particle length concentration and 29.8% [15.9;45.3] and 10.4 [4.4;16.7] for active surface area. Results for the panel of T2D and IGT and the other blood biomarkers were less conclusive.. Particle length concentration and active surface concentration showed strong positive associations with blood biomarkers reflecting inflammation. These air pollution metrics might reflect harmful aerosol properties better than particulate mass or number concentration. They might therefore be important for epidemiological studies.

Topics: Aged; Air Pollutants; Blood Coagulation; C-Reactive Protein; Diabetes Mellitus, Type 2; Female; Fibrinogen; Glucose Intolerance; Glutathione Transferase; Humans; Inflammation; Interleukin-6; Male; Middle Aged; Particulate Matter; Peroxidase; Polymorphism, Single Nucleotide

Evidence from several epidemiological and experimental studies points to a beneficial role of dietary polyphenols in inflammatory bowel disease. In this study, we investigate the protective effect of dietary supplementation with various amounts of a polyphenol-rich grape pomace extract (GPE) on the development of dextran sulfate sodium (DSS)-induced colitis in rats. Rats were fed 21 days on a semisynthetic diet enriched with GPE (0.1%, 0.5%, and 1%), and acute colitis was induced by DSS (40 g/L in the drinking water) administration during the last 7 days. The low GPE content in the diet (0.1%) attenuated clinical signs and colon shortening and limited DSS-induced histological lesions. GPE 0.1% also attenuated the DSS-induced increase in myeloperoxidase activity and improved superoxide dismutase activity. Higher amounts of GPE in the diet induced only weak and nonsignificant protective effects. These results suggest that consumption of a low amount of polyphenol-rich GPE helps protect against colitis development.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Colitis; Dextran Sulfate; Dietary Supplements; Fruit; Inflammation; Inflammatory Bowel Diseases; Male; Peroxidase; Phytotherapy; Plant Extracts; Polyphenols; Rats, Wistar; Superoxide Dismutase; Vitis

Cooking may impair meat protein digestibility. When undigested proteins are fermented by the colon microbiota, they can generate compounds that potentially are harmful to the mucosa.. This study addressed the effects of typical cooking processes and the amount of bovine meat intake on the quantity of undigested proteins entering the colon, as well as their effects on the intestinal mucosa.. Male Wistar rats (n = 88) aged 8 wk were fed 11 different diets containing protein as 20% of energy. In 10 diets, bovine meat proteins represented 5% [low-meat diet (LMD)] or 15% [high-meat diet (HMD)] of energy, with the rest as total milk proteins. Meat was raw or cooked according to 4 processes (boiled, barbecued, grilled, or roasted). A meat-free diet contained only milk proteins. After 3 wk, rats ingested a (15)N-labeled meat meal and were killed 6 h later after receiving a (13)C-valine injection. Meat protein digestibility was determined from (15)N enrichments in intestinal contents. Cecal short- and branched-chain fatty acids and hydrogen sulfide were measured. Intestinal tissues were used for the assessment of protein synthesis rates, inflammation, and histopathology.. Meat protein digestibility was lower in rats fed boiled meat (94.5% ± 0.281%) than in the other 4 groups (97.5% ± 0.0581%, P < 0.001). Cecal and colonic bacterial metabolites, inflammation indicators, and protein synthesis rates were not affected by cooking processes. The meat protein amount had a significant effect on cecal protein synthesis rates (LMD > HMD) and on myeloperoxidase activity in the proximal colon (HMD > LMD), but not on other outcomes. The ingestion of bovine meat, whatever the cooking process and the intake amount, resulted in discrete histologic modifications of the colon (epithelium abrasion, excessive mucus secretion, and inflammation).. Boiling bovine meat at a high temperature (100°C) for a long time (3 h) moderately lowered protein digestibility compared with raw meat and other cooking processes, but did not affect cecal bacterial metabolites related to protein fermentation. The daily ingestion of raw or cooked bovine meat had no marked effect on intestinal tissues, despite some slight histologic modifications on distal colon.

Topics: Animals; Cattle; Cecum; Colon; Cooking; Diet; Dietary Proteins; Digestion; Fatty Acids, Volatile; Feeding Behavior; Fermentation; Inflammation; Intestinal Mucosa; Male; Peroxidase; Protein Biosynthesis; Rats, Wistar; Red Meat

Proprotein convertase subtilisin/kexin type 9 (PCSK9) targets lipoprotein receptors for degradation, thereby reducing hepatic lipid clearance. PCSK9 inhibition reduces mortality in septic mice, presumably through increased hepatic clearance of pathogen lipids due to increased lipoprotein receptor concentrations. However, PCSK9 overexpression in vivo has not been studied in sepsis. Therefore, this study aimed to evaluate the effects of differential PCSK9 expression on systemic infection, inflammation, and coagulation in sepsis.. Wild-type, PCSK9 knockout (KO), and transgenic (Tg) mice that overexpress PCSK9 were subjected to sham surgery or cecal ligation and puncture (CLP). Bacterial loads were measured in lungs, peritoneal cavity fluid, and blood. Organ pathology was assessed in lungs, liver, and kidneys. Lung myeloperoxidase activity, and plasma concentrations of alanine aminotransferase (ALT), creatinine, cell-free DNA (cfDNA), protein C, thrombin-antithrombin (TAT) complexes, interleukin (IL)-6, and IL-10 were also measured 6 h postoperatively. Morbidity was assessed for 16 h following CLP.. Overexpression of PCSK9 in mice increased liver and kidney pathology, plasma IL-6, ALT, and TAT concentrations during sepsis, whereas PCSK9 KO mice exhibited reduced bacterial loads, lung and liver pathology, myeloperoxidase activity, plasma IL-10, and cfDNA during CLP-induced sepsis. All septic mice had reduced plasma levels of protein C, but the protein C ratio relative to normal was significantly decreased in PCSK9 Tg mice. Dyspnea, cyanosis, and overall grimace scores were greatest in septic mice overexpressing PCSK9, whereas PCSK9 KO mice retained core body temperature during sepsis.. These findings demonstrate that PCSK9 deficiency confers protection against systemic bacterial dissemination, organ pathology, and tissue inflammation, particularly in the lungs and liver, while PCSK9 overexpression exacerbates multi-organ pathology as well as the hypercoagulable and pro-inflammatory states in early sepsis.

Topics: Alanine Transaminase; Animals; Blood Coagulation; Disease Models, Animal; Female; Inflammation; Interleukin-10; Interleukin-6; Kidney; Liver; Lung; Male; Mice; Mice, Knockout; Peroxidase; Proprotein Convertase 9; Protein C; Sepsis

The aim was to measure concentrations of four neutrophil-derived proteins in meconium as biomarkers describing prenatal environment.. Calprotectin, lactoferrin, myeloperoxidase and PMN-elastase concentrations were measured using ELISA kits in serial meconium portions (n = 81) from 20 healthy neonates.. The highest concentration was for calprotectin (286.5 ± 214.6 µg/g) with a positive correlation (r = 0.75, p < 0.0001) with myeloperoxidase (1.81 ± 1.72 µg/g). For PMN-elastase (1.70 ± 2.69 µg/g) a negative correlation was observed with calprotectin and myeloperoxidase (r = -0.51, p < 0.0001; r = -0.60, p < 0.0001, respectively). Concentration of lactoferrin (45.07 ± 78.53 µg/g) correlated only with that of myeloperoxidese (r = 0.36, p = 0.0009).. Calprotectin, lactoferrin, myeloperoxidase and PMN-elastase concentrations in meconium are interrelated. These proteins may serve as objective biomarkers describing and/or assessing the intrauterine environment.

Topics: Adult; Biomarkers; Birth Weight; Enzyme-Linked Immunosorbent Assay; Female; Gestational Age; Humans; Infant, Newborn; Inflammation; Lactoferrin; Leukocyte Elastase; Leukocyte L1 Antigen Complex; Male; Meconium; Neutrophils; Peroxidase

Ursolic acid (UA; 3b-hydroxy-12-urs-12-en-28-oic acid), a natural pentacyclic triterpenoid carboxylic acid, has been known to possess potent anti-inflammatory, antioxidant, and antinociceptive effects in various animal models. Therefore, this study was designed to investigate the antihyperalgesic, anti-inflammatory, and antioxidant effects of UA at 5, 10, and 20 mg/kg of doses via per os (p.o.) route for 14 days in chronic constriction injury (CCI)-induced neuropathic pain in rats. Pain behavior in rats was evaluated before and after UA administration via mechanical and heat hyperalgesia. CCI caused significant increase in levels of pro-inflammatory cytokines and oxido-nitrosative stress. In addition, significant increase in myeloperoxidase, malondialdehyde, protein carbonyl, nitric oxide (NO), and total oxidant status (TOS) levels in sciatic nerve and spinal cord concomitant with mechanical and heat hyperalgesia is also noted for CCI-induced neuropathic pain. Administration of UA significantly reduced the increased levels of pro-inflammatory cytokines and TOS. Further, reduced glutathione is also restored by UA. UA also showed in vitro NO and superoxide radical scavenging activity. UA has a potential in attenuating neuropathic pain behavior in CCI model which may possibly be attributed to its anti-inflammatory and antioxidant properties.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Constriction; Cytokines; Disease Models, Animal; Hyperalgesia; Inflammation; Male; Malondialdehyde; Neuralgia; Nitric Oxide; Oxidative Stress; Peroxidase; Protein Carbonylation; Rats; Sciatic Nerve; Spinal Cord; Superoxides; Triterpenes; Ursolic Acid

The tripeptide-copper complex glycyl-l-histidyl-l-lysine-Cu (II) (GHK-Cu) is involved in wound healing and tissue remodeling. Although GHK-Cu exhibits anti-aging and tissue renewing properties, its roles in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) are still unknown. Therefore, we examined the effects of GHK-Cu in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages in vitro and ALI in mice in vivo. GHK-Cu treatment reduced reactive oxygen species (ROS) production, increased superoxide dismutase (SOD) activity while decreased TNF-α and IL-6 production through the suppression of NF-κB p65 and p38 MAPK signaling in vitro and in vivo model of ALI. Moreover, GHK-Cu attenuated LPS-induced lung histological alterations, suppressed the infiltration of inflammatory cells into the lung parenchyma in LPS-induced ALI in mice. Taken together, these findings demonstrate that GHK-Cu possesses a protective effect in LPS-induced ALI by inhibiting excessive inflammatory responses; accordingly it may represent a novel therapeutic approach for ALI/ARDS.

Topics: Acute Lung Injury; Animals; Antioxidants; Cell Proliferation; Immune System; Inflammation; Lipopolysaccharides; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Oligopeptides; p38 Mitogen-Activated Protein Kinases; Permeability; Peroxidase; RAW 264.7 Cells; Reactive Oxygen Species; Respiratory Distress Syndrome; Superoxide Dismutase; Transcription Factor RelA

Excess catecholamine levels are suggested to be cardiotoxic and to underlie stress-induced heart failure. The cardiotoxic effects of norepinephrine and epinephrine are well recognized. However, although cardiac and circulating dopamine levels are also increased in stress cardiomyopathy patients, knowledge regarding putative toxic effects of excess dopamine levels on cardiomyocytes is scarce. We now studied the effects of elevated dopamine levels in H9c2 cardiomyoblasts. H9c2 cells were cultured and treated with dopamine (200 μM) for 6, 24, and 48 h. Subsequently, the effects on lipid accumulation, cell viability, flippase activity, reactive oxygen species (ROS) production, subcellular NADPH oxidase (NOX) protein expression, and ATP/ADP and GTP/GDP levels were analyzed. Dopamine did not result in cytotoxic effects after 6 h. However, after 24 and 48 h dopamine treatment induced a significant increase in lipid accumulation, nitrotyrosine levels, indicative of ROS production, and cell death. In addition, dopamine significantly reduced flippase activity and ATP/GTP levels, coinciding with phosphatidylserine exposure on the outer plasma membrane. Furthermore, dopamine induced a transient increase in cytoplasmic and (peri)nucleus NOX1 and NOX4 expression after 24 h that subsided after 48 h. Moreover, while dopamine induced a similar transient increase in cytoplasmic NOX2 and p47

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Animals; Caspase 3; Cell Line; Cell Membrane; Cell Survival; Dopamine; Dopamine Agents; Flow Cytometry; Guanosine Diphosphate; Guanosine Triphosphate; Hydrogen-Ion Concentration; Inflammation; Lipid Metabolism; Microscopy, Electron; Microscopy, Fluorescence; Myoblasts, Cardiac; NADH, NADPH Oxidoreductases; NADPH Oxidase 1; NADPH Oxidase 4; NADPH Oxidases; Nuclear Proteins; Oxidative Stress; Peroxidase; Rats; Reactive Oxygen Species; Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins; Tyrosine

Capsicum baccatum is the most consumed red pepper species in Brazil. Our previous studies demonstrated the anti-inflammatory properties of its crude extract, whose activity is yet to be fully characterized. Herein, we examined the anti-inflammatory in vivo effects of enriched extracts obtained through bioguided fractionation as dichloromethane (DCM), butanol (BUT), and residual aqueous (RAq) extracts and its influence on inflammatory mediators produced by macrophages in vitro. We demonstrated that all C. baccatum extracts presented anti-inflammatory activity in vivo. In addition, we showed that BUT and RAq were more effective in inhibiting the neutrophil migration induced by carrageenan (Cg) to peritoneal cavity and both extracts inhibited paw edema induced by Cg, prostaglandin E2, and histamine in mice. Furthermore, the pretreatment with C. baccatum extracts significantly reduced the levels of myeloperoxidase (MPO) in the paw tissues of mice compared with the carrageenan group. Once again, RAq and BUT caused the greatest reduction in MPO levels. Moreover, it was demonstrated for the first time that C. baccatum inhibited the nitric oxide and tumor necrosis factor-alpha production by lipopolysaccharide/interferon gamma (IFN-γ)-stimulated macrophages. These anti-inflammatory effects seem to be at least, in part, independent of capsaicin. Hence, red pepper has bioactive compounds and might be used to develop food-derived extracts to treat related inflammatory diseases.

Topics: Animals; Anti-Inflammatory Agents; Capsicum; Carrageenan; Edema; Fruit; Inflammation; Inflammation Mediators; Interferon-gamma; Lipopolysaccharides; Macrophages; Male; Mice; Mice, Inbred BALB C; Neutrophil Infiltration; Nitric Oxide; Peroxidase; Phytotherapy; Plant Extracts; RAW 264.7 Cells; Tumor Necrosis Factor-alpha

The present study was designed to investigate the gastroprotective effect of xanthones 7-preniljacareubin (PJB), 1,3,5,6-tetrahydroxy xanthone (THX), 3-demethyl-2-geranyl-4-prenylbellidypholine (DGP) and 1,5,8-trihydroxy-4', 5'-dimethyl-2H-pyrane (2,3:3,2)-4-(3-methylbut-2-enyl) xanthone (TDP) isolated of branches from G. achachairu. Their structures were identified through the spectroscopic analysis in comparison with previously reported data. The xanthones were tested at dose of 10 mg/kg against ethanol 60%/HCl 0.3 N-induced gastric ulcer in female swiss mice. The xanthones PJB, THX, DGP and TDP exhibit gastroprotective effect after intraperitoneal treatment, but only the first two displayed anti-ulcer activity after oral administration. Both PJB and THX augmented the antioxidative capacity of tissue by an increase in glutathione levels, as well as were able to prevent an increase in myeloperoxidase activity and tumor necrosis factor level. On the other hand, only THX showed an in vitro free radical scavenger activity, and only PJB avoided mucus depletion on gastric mucosa, which was not associated with an increase in mucin production at glandular level. In addition, PJB and THX inhibited the in vitro H(+)K(+)-ATPase activity at similar range as omeprazole. Together, these results demonstrate the anti-ulcer efficacy of xanthones isolated from G. achachairu, which can contribute for future directions in the development of effective strategies to improve gastric diseases.

Topics: Animals; Anti-Ulcer Agents; Antioxidants; Biphenyl Compounds; Carbon-13 Magnetic Resonance Spectroscopy; Female; Free Radical Scavengers; Garcinia; Gastric Mucosa; Glutathione; H(+)-K(+)-Exchanging ATPase; Immunohistochemistry; Inflammation; Mice; Mucins; Peroxidase; Picrates; Protective Agents; Proton Magnetic Resonance Spectroscopy; Stomach Ulcer; Tumor Necrosis Factor-alpha; Xanthones

Blood neutrophils perform an essential host-defense function by directly migrating to bacterial invasion sites to kill bacteria. The mechanisms mediating the transition from the migratory to bactericidal phenotype remain elusive. Here, we demonstrate that TRPM2, a trp superfamily member, senses neutrophil-generated reactive oxygen species and restrains neutrophil migration. The inhibitory function of oxidant sensing by TRPM2 requires the oxidation of Cys549, which then induces TRMP2 binding to formyl peptide receptor 1 (FPR1) and subsequent FPR1 internalization and signaling inhibition. The oxidant sensing-induced termination of neutrophil migration at the site of infection permits a smooth transition to the subsequent microbial killing phase.

Topics: Animals; Cell Movement; HL-60 Cells; Humans; Inflammation; Lung; Mice; Neutrophils; Oxidants; Peroxidase; Reactive Oxygen Species; Receptors, Formyl Peptide; TRPM Cation Channels

LL202, a newly-synthesized flavonoid derivative, has been reported to inhibit inflammatory-induced angiogenesis. However, the exact role of LL202 in inflammation along with its mechanism has not been explored. In this study, we investigated the anti-inflammatory effect of LL202 on intestinal inflammation by establishing dextran sulfate sodium (DSS)-induced experimental colitis. LL202 attenuated DSS-induced body weight loss, colon length shortening and colonic pathological damage. The inflammatory cells infiltration, myeloperoxidase (MPO) and inducible nitric oxide synthase (iNOS) activities were decreased by LL202 in a dose-dependent manner. LL202 reduced the production of pro-inflammatory cytokines in serum and colon of DSS-induced mice as well. Mechanically, LL202 could decrease the expression and nuclear translation of AP-1 to protect against DSS-induced colitis. In lipopolysaccharide (LPS)-induced THP-1 cells, LL202 markedly decreased the secretion, mRNA level and protein expression of IL-1β, IL-6 and TNF-α via inhibiting ERK/JNK/p38 MAPK pathways and the nuclear translocation of AP-1. Furthermore, these findings were confirmed in LPS-induced bone marrow derived macrophages (BMDM). In conclusion, our study demonstrated that LL202 could exert its anti-inflammatory effect via inhibiting MAPK/AP-1 signaling, which suggested that LL202 might be a potential effective drug for the treatment of inflammatory bowel diseases.

Topics: Active Transport, Cell Nucleus; Animals; CD11b Antigen; Colitis; Cytokines; Dextran Sulfate; Female; Flavonoids; Gene Expression Regulation; Humans; Inflammation; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; Nitric Oxide Synthase Type II; Peroxidase; RNA, Messenger; Signal Transduction; THP-1 Cells; Transcription Factor AP-1; Tumor Necrosis Factor-alpha

HDL-cholesterol concentration is a reliable negative risk factor for acute cerebral infarction (ACI). Beyond quantitative aspects, our aim was to determine whether lipoprotein profiles and HDL functionality were altered at the acute phase of ischemic stroke.. Blood was taken from ACI patients within 4.5 h of symptom onset. Lipoproteins were separated by electrophoresis for determination of particle size. HDLs were isolated from plasma of patients (n = 10) and controls (n = 10) by ultracentrifugation. The relative amounts of paraoxonase 1 (PON1), α1antitrypsin (AAT) and myeloperoxidase (MPO) were determined by Western blot. HDL functional assays were performed on human-brain endothelial cells stimulated with TNFα.. Stroke patients had higher proportion of large HDL particles relative to controls (37.8 ± 11.8 vs. 28.4 ± 6.6, p = 0.04). HDLs from patients contained significantly less ApoA1 (1.63 ± 0.42 vs. 2.54 ± 0.71 mg/mL, p = 0.0026) and PON1 (4598 ± 1921 vs. 6598 ± 1127 AU, p = 0.01) than those from controls, whereas MPO and AAT were more abundant in HDLs isolated from ACI patients (respectively 3657 ± 1457 vs. 2012 ± 1234 and 3347 ± 917 vs. 2472 ± 470 AU, p = 0.014 and p = 0.015). HDLs reduced the expression of VCAM1, MCP1 and MMP3 mRNA induced by TNFα in blood-brain barrier endothelial cells. HDLs from patients were less effective in inhibiting TNFα-induced transcription of these genes (respectively 38.6 vs. 55.6% for VCAM1, p = 0.047, 44 vs. 48.1% for MCP1, p = 0.015 and 70 vs. 74% for MMP3, p = 0.024).. ACI may be associated with a modified distribution of HDL particles (increased proportion of large particles) and HDL-binding proteins, resulting in an inappropriate protection of endothelial cells under ischemic conditions.

Topics: Adult; Aged; Aged, 80 and over; alpha 1-Antitrypsin; Apolipoprotein A-I; Aryldialkylphosphatase; Brain Infarction; Brain Ischemia; Case-Control Studies; Electrophoresis; Endothelium, Vascular; Female; Humans; Inflammation; Lipoproteins, HDL; Male; Middle Aged; Particle Size; Peroxidase; RNA, Messenger; Stroke; Tumor Necrosis Factor-alpha

Positive reaction of the bronchi to distilled water inhalation in asthmatics is associated with significant stimulation of the respiratory epithelium desquamation against the background of increased content of eosinophilic and neutrophilic leukocytes in induced sputum, predomination of eosinophil and neutrophil cytolysis, and lower activity of myeloperoxidase in leukocyte granules (in comparison with the parameter in patients with a negative response to bronchostimulation). Enhanced cytolysis and destruction of leukocytes and high myeloperoxidase concentration in the extracellular space are essential for the development of bronchial hyperresponsiveness to hypoosmotic stimulus in asthma.

Topics: Adult; Asthma; Bronchi; Bronchial Hyperreactivity; Eosinophils; Female; Humans; Inflammation; Macrophages; Male; Neutrophils; Peroxidase; Young Adult

Short-term cigarette smoke (CS) exposure does not cause emphysema; however, some pathogenesis hallmarks are maintained, such as oxidative stress and inflammation. This study aimed to test the efficacy of eucalyptol against short-term CS exposure in mice. C57BL/6 mice were exposed to 12 cigarettes per day for 5 days (CS group). The control group was exposed to sham smoking. Three groups of mice exposed to CS were treated to different concentrations of eucalyptol (1, 3, 10 mg/mL) via inhalation (15 min/daily) for 5 days (CS + 1 mg, CS+3 mg and CS+10 mg groups). CS group and control one were sham treated by using vehicle. The anti-inflammatory and antioxidant effects of eucalyptol were assessed 24 h after the last CS exposure by determining cell counts, measuring cytokine production and performing western blotting, biochemical and histological analyses. Eucalyptol at 3 mg/mL and 10 mg/mL concentrations reduced total leukocyte numbers compared to the CS group (p < 0.001), while macrophage numbers were reduced at all concentrations (p < 0.001). Myeloperoxidase, used as neutrophil marker, was reduced at 3 mg/mL (p < 0.01) and 10 mg/mL (p < 0.05) concentrations. Eucalyptol reduced cytokine levels (IL-1β, IL-6 and KC) at 3 mg/mL and 10 mg/mL concentrations (p < 0.01) compared to the CS group. The exception was TNF-α, with a reduction only at 10 mg/mL of eucalyptol compared to the CS group (p < 0.001). Additionally, eucalyptol decreased the NF-kappa B p65 subunit at 3 mg/mL and 10 mg/mL compared to the CS group (p < 0.01). Regarding oxidative stress, eucalyptol reduced reactive oxygen species, superoxide dismutase, catalase and malondialdehyde, mainly at 3 mg/mL and 10 mg/mL concentrations compared to the CS group (at least p < 0.05), parallel to reduced glutathione levels at the same concentrations (p < 0.001). Furthermore, treatment with eucalyptol attenuated CS-induced histopathological alterations. Collectively, these results indicate that eucalyptol acts through a mechanism involving decreased oxidative stress, inflammation and the NF-kappa B p65 subunit against CS-induced acute lung inflammation. Thus, eucalyptol may be a potential agent in the treatment of pulmonary inflammation caused by CS in humans.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Cyclohexanols; Disease Models, Animal; Dose-Response Relationship, Drug; Eucalyptol; Inflammation; Macrophages; Male; Mice; Mice, Inbred C57BL; Monoterpenes; Neutrophils; Oxidative Stress; Peroxidase; Pneumonia; Reactive Oxygen Species; Smoke; Smoking; Transcription Factor RelA; Tumor Necrosis Factor-alpha

Duchenne Muscular Dystrophy (DMD) is a fatal skeletal muscle wasting disease presenting with excessive myofibre necrosis and increased inflammation and oxidative stress. In the mdx mouse model of DMD, homeostasis of the amino acid taurine is altered, and taurine administration drastically decreases muscle necrosis, dystropathology, inflammation and protein thiol oxidation. Since the severe pathology of the Golden Retriever Muscular Dystrophy (GRMD) dog model more closely resembles the human DMD condition, we aimed to assess the generation of oxidants by inflammatory cells and taurine metabolism in this species. In muscles of 8 month GRMD dogs there was an increase in the content of neutrophils and macrophages, and an associated increase in elevated myeloperoxidase, a protein secreted by neutrophils that catalyses production of the highly reactive hypochlorous acid (HOCl). There was also increased chlorination of tyrosines, a marker of HOCl generation, increased thiol oxidation of many proteins and irreversible oxidative protein damage. Taurine, which functions as an antioxidant by trapping HOCl, was reduced in GRMD plasma; however taurine was increased in GRMD muscle tissue, potentially due to increased muscle taurine transport and synthesis. These data indicate a role for HOCl generated by neutrophils in the severe dystropathology of GRMD dogs, which may be exacerbated by decreased availability of taurine in the blood. These novel data support continued research into the precise roles of oxidative stress and taurine in DMD and emphasise the value of the GRMD dogs as a suitable pre-clinical model for testing taurine as a therapeutic intervention for DMD boys.

Topics: Animals; Biomarkers; Disease Models, Animal; Dogs; Inflammation; Macrophages; Male; Muscle Proteins; Muscle, Skeletal; Muscular Dystrophy, Duchenne; Neutrophils; Oxidation-Reduction; Oxidative Stress; Peroxidase; Tyrosine

No Abstract Available.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; C-Reactive Protein; Fibrinogen; Heart Diseases; Humans; Inflammation; Lipoproteins; Peroxidase

Evidence shows that sunscreens undergo degradation processes induced by UV irradiation forming free radicals, which reduces skin protection. In this regard, the biological effects of three commercial sunscreen formulations upon UVB irradiation in the skin were investigated. The three formulations had in common the presence of benzophenone-3 added with octyl methoxycinnamate or octyl salycilate or both, which are regular UV filters in sunscreens. The results show that formulations F1 and F2 presented partial degradation upon UVB irradiation. Formulations F1 and F2 presented higher skin penetration profiles than F3. None of the formulations avoided UVB irradiation-induced GSH depletion, but inhibited reduction of SOD activity, suggesting the tested formulations did not present as a major mechanism inhibiting all UVB irradiation-triggered oxidative stress pathways. The formulations avoided the increase of myeloperoxidase activity and cytokine production (IL-1β and TNF-α), but with different levels of protection in relation to the IL-1β release. Concluding, UVB irradiation can reduce the stability of sunscreens, which in turn, present the undesirable properties of reaching viable skin. Additionally, the same SPF does not mean that different sunscreens will present the same biological effects as SPF is solely based on a skin erythema response. This found opens up perspectives to consider additional studies to reach highly safe sunscreens.

Topics: Animals; Drug Compounding; Drug Stability; Female; Glutathione; Inflammation; Interleukin-1beta; Male; Mice; Oxidative Stress; Peroxidase; Skin; Sun Protection Factor; Sunscreening Agents; Superoxide Dismutase; Tumor Necrosis Factor-alpha; Ultraviolet Rays

Topics: Anemia, Iron-Deficiency; Bilirubin; Heme Oxygenase-1; Humans; Infant; Inflammation; Macrophages; Male; Oxidative Stress; Peroxidase

BackgroundIntestinal mucositis is a major concern related with cancer therapy. It is well established that overproduction of reactive oxygen species and inflammatory mediators plays vital role in the pathogenesis of mucositis. The aim of the study was to investigate the modulatory effect of vitamin E (vit. E) on 5-fluorouracil (5-FU)-induced intestinal mucositis by targeting oxidative stress and inflammatory markers in rats. MethodsRats were randomly divided into four groups of six animals each. All four-group animals received normal standard diet and water throughout the experimental period which last up to 10 days. Rats were gavaged with vit. E (300 mg/kg b. wt.) daily for 10 days (day 1-10) and were given intraperitoneal injection of 5-FU (150 mg/kg b. wt.) or saline (control) on day 8 to induce mucositis. Results We found that vit. E supplementation ameliorated 5-FU-induced lipid peroxidation, myeloperoxidase activity, activation of nuclear factor κB, expression of cyclooxygenase-2, inducible nitric oxide synthase and mucin depletion. Vit. E administration also attenuated 5-FU-induced histological anomalies such as neutrophil infiltration, loss of cellular integrity, villus and crypt deformities. ConclusionsFindings of the study suggest that vit. E inhibits 5-FU-induced mucositis via modulation of oxidative stress, activation of redox sensitive transcription factor and its downstream targets.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Biomarkers; Cyclooxygenase 2; Fluorouracil; Inflammation; Intestinal Mucosa; Intestine, Small; Lipid Peroxidation; Male; Mucins; Mucositis; NF-kappa B; Nitric Oxide Synthase Type II; Oxidative Stress; Peroxidase; Random Allocation; Rats, Sprague-Dawley; Vitamin E

Hecogenin is a steroidal sapogenin plays important role in treatment of variety of inflammatory diseases. We have investigated the anti-inflammatory effects of Hecogenin (50 µg/animal) (HG), Fluticasone (50 µg/animal) (FC) and Hecogenin+Fluticasone (HG+FC) combination (25 µg/animal, each) on various inflammatory models. The anti-inflammatory effect of HG, FC and HG+FC combination was studied on % inhibition of dry weight of granuloma tissue, Δ ear weight, myeloperoxidase assay, serum pro-inflammatory cytokines, colon weight to length ratio, macroscopic lesions, adhesion score, diarrhoea score and histopathological analysis of ear and colon tissue on Cotton pellets induced granuloma in rats, Croton oil induced ear edema in mice and TNBS induced granuloma in rats. Topical administration of HG and its combination with FC showed significant decrease (p<0.001) in the % inhibition of dry weight of granuloma tissue, Δ ear weight, myeloperoxidase level, serum pro-inflammatory cytokines levels, colon weigh to length ratio as compared with Cotton pellets treated with acetone groups and Croton oil treated animals. Further histopathological analysis of ear tissue showed significant decrease in dermal thickness and epidermal hyperplasia and colon tissue showed reduction of edema, infiltration of inflammatory cells and normalization of crypt structure compared to DC animals. Thus, the findings of present study suggest the possible role of HG in the treatment of inflammation by reducing the dose of FC in combination with HG.

Topics: Animals; Anti-Inflammatory Agents; Body Weight; Colon; Cytokines; Disease Models, Animal; Fluticasone; Inflammation; Mice; Peroxidase; Rats; Rats, Wistar; Sapogenins

Prior investigations showed that increased levels of cyclic AMP down-regulate lung inflammatory changes, stimulating the interest in phosphodiesterase (PDE)4 as therapeutic target. Here, we described the synthesis, pharmacological profile and docking properties of a novel sulfonamide series (5 and 6a-k) designed as PDE4 inhibitors. Compounds were screened for their selectivity against the four isoforms of human PDE4 using an IMAP fluorescence polarized protocol. The effect on allergen- or LPS-induced lung inflammation and airway hyper-reactivity (AHR) was studied in A/J mice, while the xylazine/ketamine-induced anesthesia test was employed as a behavioral correlate of emesis in rodents. As compared to rolipram, the most promising screened compound, 6a (LASSBio-448) presented a better inhibitory index concerning PDE4D/PDE4A or PDE4D/PDE4B. Accordingly, docking analyses of the putative interactions of LASSBio-448 revealed similar poses in the active site of PDE4A and PDE4C, but slight unlike orientations in PDE4B and PDE4D. LASSBio-448 (100 mg/kg, oral), 1 h before provocation, inhibited allergen-induced eosinophil accumulation in BAL fluid and lung tissue samples. Under an interventional approach, LASSBio-448 reversed ongoing lung eosinophilic infiltration, mucus exacerbation, peribronchiolar fibrosis and AHR by allergen provocation, in a mechanism clearly associated with blockade of pro-inflammatory mediators such as IL-4, IL-5, IL-13 and eotaxin-2. LASSBio-448 (2.5 and 10 mg/kg) also prevented inflammation and AHR induced by LPS. Finally, the sulfonamide derivative was shown to be less pro-emetic than rolipram and cilomilast in the assay employed. These findings suggest that LASSBio-448 is a new PDE4 inhibitor with marked potential to prevent and reverse pivotal pathological features of diseases characterized by lung inflammation, such as asthma.

Topics: Animals; Catalytic Domain; Cyclic AMP; Cyclic Nucleotide Phosphodiesterases, Type 4; Eosinophil Peroxidase; Guinea Pigs; Humans; Inflammation; Lung; Male; Mice; Molecular Docking Simulation; Muscle Contraction; Muscle, Smooth; Peroxidase; Phosphodiesterase 4 Inhibitors; Protein Isoforms; Respiratory Hypersensitivity; Sulfonamides; Trachea

Complementary or alternative medicine is of great interest for the treatment of inflammatory bowel disease, with the aim of ameliorating the side effects of the drugs commonly used or improving their efficacy. In this study, we evaluated the ability of goat whey to prevent intestinal inflammation in the experimental model of acetic acid-induced rats and compared it to sulfasalazine. Pretreatment with goat whey (1, 2, and 4g/kg) and sulfasalazine (250mg/kg) on colitic rats improved colonic inflammatory markers, including myeloperoxidase activity, leukotriene B

Topics: Acetic Acid; Animals; Colitis; Colon; Goats; Humans; Inflammation; Peroxidase; Rats; Rats, Wistar; Trinitrobenzenesulfonic Acid; Whey

In the blood of children (n=16) with large thermal skin burns (> 20% of total body surface), luminol-dependent chemiluminescence (CL) of neutrophils stimulated with phorbol-12-myristate-13-acetate (PMA) and myeloperoxidase (MPO) activity in neutrophils and plasma were assayed in the early period (1-7 post-burn days). PMA-stimulated neutrophils in thermally injured patients produced higher CL than those in a reference group of healthy children (n=24), p<0.01. MPO activity was elevated in neutrophils and plasma in 40% and 57% of patients' blood samples, respectively. The albumin fraction isolated from plasma of burned patients enhanced the PMA-stimulated CL response of blood samples from healthy volunteer. Our results suggest that the acute inflammatory response induced by thermal injury involves activation of neutrophils and is accompanied by MPO release into the plasma. MPO-mediated modification of serum albumin induces its capacity to prime neutrophils and thus to enhance further inflammatory reaction.. U deteĭ (n=16) c termicheskimi ozhogami kozhi ploshchad'iu bolee 20% poverkhnosti tela v ranniĭ period (1-7 sutki) posle travmy izmeriali liuminol-zavisimuiu khemiliuminestsentsiiu (KhL) neĭtrofilov krovi, stimulirovannykh forbol-12-miristat-13-atsetatom (FMA), aktivnost' mieloperoksidazy (MPO) v neĭtrofilakh i plazme krovi. Uroven' KhL stimulirovannykh neĭtrofilov byl vyshe u patsientov, chem u zdorovykh deteĭ iz gruppy sravneniia (r<0,01). V 40% obraztsov krovi patsientov obnaruzhena povyshennaia aktivnost' MPO v neĭtrofilakh, a v 57% obraztsov – aktivnost' MPO v plazme. Al'buminovaia fraktsiia plazmy obozhzhennykh usilivala KhL otvet krovi zdorovykh donorov na FMA. Poluchennye dannye svidetel'stvuiut o tom, chto ostraia vospalitel'naia reaktsiia v otvet na termicheskiĭ ozhog privodit k aktivatsii neĭtrofilov i soprovozhdaetsia vysvobozhdeniem MPO v plazmu krovi. Modifikatsiia belkov plazmy krovi, v pervuiu ochered' al'bumina, s uchastiem MPO mozhet stimulirovat' aktivatsiiu neĭtrofilov i provotsirovat' dal'neĭshee razvitie vospalitel'noĭ reaktsii organizma v otvet na travmu.

Topics: Burns; Child; Child, Preschool; Female; Humans; Inflammation; Male; Neutrophils; Peroxidase; Serum Albumin

Intestinal mucositis is an inflammatory process occurring in the intestinal mucosa and is a common side effect of irinotecan hydrochloride (CPT-11) based anticancer regimens. The transient receptor potential cation channel, subfamily A, member 1 (TRPA1) receptor is highly expressed in the intestinal mucosa and has the ability to identify cell damage signaling indicates its possible association with intestinal mucositis. Carvacrol is an agonist of the TRPA1 receptor and has anti-inflammatory properties. Thus, the aim of the present study was to verify the supposed anti-inflammatory and protective action of carvacrol via TRPA1 activation against intestinal mucositis induced by CPT-11 in mice. Briefly, mice were treated with either DMSO 2% or CPT-11 (75 mg/kg, per 4 days, i.p.) or the carvacrol (25, 75 or 150 mg/kg, per 8 days, i.p.) before CPT-11. In other group, the animals were pretreated with HC-030031, a TRPA1 antagonist, 30 min before treatment with carvacrol. On day 7, animal survival and bacteremia were assessed, and following euthanasia, samples of the jejunum were obtained for morphometric analysis and measurement of antioxidant and pro-inflammatory markers. Carvacrol was found to exert an anti-inflammatory action against CPT-11-induced intestinal mucositis through strong interactions with TRPA1 receptors; reduction in the production or release or both of pro-inflammatory cytokines (TNF-α, IL-1β, and KC); and decrease in other indicators of inflammation (MPO, NF-κB, COX-2) and oxidative stress (GSH, MDA, and NOx levels). It also contributed to the restoration of the tissue architecture of the villi and crypts in the small intestine, and improved clinical parameters such as survival, body mass variation, leukogram, and blood bacterial count. Thus, TRPA1 could be a target for future therapeutic approaches in the treatment of intestinal mucositis.

Topics: Animals; Antioxidants; Body Weight; Camptothecin; Cyclooxygenase 2; Cymenes; Female; Immunohistochemistry; Inflammation; Intestines; Irinotecan; Leukocyte Count; Mice; Molecular Docking Simulation; Monoterpenes; Mucositis; NF-kappa B; Oxidative Stress; Peroxidase; Survival Analysis; Transient Receptor Potential Channels; TRPA1 Cation Channel

The aim of this study was to evaluate the effect of Pogostemon cablin essential oil (PEO) on leukocyte behavior in the inflammatory response.. PEO was analyzed using Gas Chromatography/Mass Spectrometry (GC/SM) and Nuclear Magnetic Resonance Spectroscopy (NMR) methods and showed predominance of patchoulol (38.50%), α-bulnesene (20.37%), α-guaiene (12.31%), seychellene (8.33%) and α-patchoulene (4.91%). PEO at concentrations of 1, 3, 10, 30, 60 and 90μg/ml reduced the in vitro neutrophil chemotaxis toward fMLP, and at concentrations of 3 and 10μg/ml, increased the phagocytic activity of neutrophils. Topical application of PEO in high concentrations promoted an increase of ear edema and myeloperoxidase (MPO) activity. However, the oral treatment with 100, 200 and 300mg/kg reduced leukocyte recruitment, nitric oxide (NO) production, and rolling and adherent leukocyte number in the microcirculation.. PEO affects the leukocyte behavior, and the mechanism proposed of PEO seems to be, at least in part, involving the participation of NO and pro-inflammatory cytokines.

Topics: Acute Disease; Administration, Topical; Animals; Cell Adhesion; Cell Survival; Chemotaxis; Edema; Exudates and Transudates; Gas Chromatography-Mass Spectrometry; Inflammation; Leukocyte Count; Leukocyte Rolling; Leukocytes; Male; Mice; Nitric Oxide; Peritonitis; Peroxidase; Phagocytosis; Pogostemon; Sesquiterpenes; Zymosan

Since the severe corneal ulceration of mouse cornea is known to occur with inflammation. As one of imperative matrix metalloproteinase, the potential roles of matrix metalloproteins 9 (MMP9) in corneal ulceration and keratitis are still unveiled caused by fungal invasion. In this study, Candida albicans (CA) inoculated wild-type KM mice cornea was used as a model pathogen in corneal inflammation.  CA invasion significantly stimulated the expression of collagen IV and MMP9 detected by RT-PCR, Real-time PCR and Immunofluorescent staining in mouse cornea as soon as 6 hours post infection, and relatively decreased at 1 day post infection. For examining the role of MMP9 in fungal keratitis, the mice corneas were subconjunctivally injected MMP9 antibody or recombinant MMP9 protein 6 hours prior to CA inoculation, using rabbit IgG as control. Subconjunctival injection of recombinant MMP9 protein prior to CA inoculation enhanced, whereas MMP9 antibody attenuated corneal ulceration and inflammation, examining basement membrane, fungal load, myeloperoxidase (MPO) and proinflammatory cytokines including Macrophage inflammatory protein 2 (MIP2), Interleukin-1β (IL-1β) and Tumor necrosis factor-α (TNF-α). Inhibition of MMP9 could potentially attenuate Candida albicans induced inflammation in mouse cornea.

Topics: Animals; Antibodies; Candida albicans; Chemokine CXCL2; Collagen Type IV; Cornea; Enzyme-Linked Immunosorbent Assay; Inflammation; Interleukin-1beta; Matrix Metalloproteinase 9; Mice; Mice, Inbred BALB C; Microscopy, Fluorescence; Peroxidase; Real-Time Polymerase Chain Reaction; Recombinant Proteins; Tumor Necrosis Factor-alpha

Dental implants form the mainstay of dental treatment involving rehabilitation of missing teeth. One of the major concerns for the clinicians doing dental implants is the postsurgical failure of dental implants. Success of dental implants is dependent upon the skills of the surgeon and the amount and quality of the bone remaining at the edentulous area where dental implant has to be placed. Myeloperoxidase (MPO) and nitrites are few of the enzymes and molecules which are said to be altered in inflammation. However, their exact role in the inflammatory processes around natural tooth and dental implant is still unclear. Hence we comparatively evaluated the levels of MPO and nitrites in the areas around the dental implants and natural teeth.. The present study comprises 42 patients who underwent prosthetic rehabilitation by dental implants from 2011 to 2014. Depth of probing value (DP), score of plaque index (SPI), gingival index (GI), and index of gingival bleeding time (GBT) were evaluated for the assessment of the periimplant soft tissue changes. Assessment of inflammation around the dental implant surface and around natural tooth was done based on the readings of these parameters. For the measurement of the MPO levels, spectrophotometric MPO assay was used. All the results were analyzed by Statistical Package for the Social Sciences (SPSS) software.. The mean plaque index values were 1.56 and 0.97 in periodontitis cases of natural teeth and inflamed cases of dental implants respectively. While comparing mean plaque index, mean probing depth, and mean gingival bleeding index in between the two groups, significant difference was obtained. Mean MPO concentration in periodontitis and gingivitis cases in natural teeth were 0.683 and 0.875 U/μL, while in inflamed dental implant cases, the mean value was 0.622 U/μL. While comparing the total MPO levels, total nitrite levels, and total nitrite concentration in between two study groups, significant difference was obtained. On comparing the healthy and periodontitis cases in natural teeth, significant difference was obtained.. In the inflammatory processes occurring around dental implant and natural teeth, MPO and NO make some amount of significant contribution.. The present study enforces on the role of MPO and nitrite as diagnostic and prognostic marker.

Topics: Biomarkers; Dental Implantation, Endosseous; Dental Implants; Dental Plaque Index; Dental Restoration Failure; Gingiva; Gingival Crevicular Fluid; Gingival Hemorrhage; Gingivitis; Humans; Inflammation; Mouth, Edentulous; Nitrites; Periodontal Index; Periodontal Pocket; Periodontitis; Peroxidase; Tooth

Monocytes are key players in atherosclerotic. Human monocytes display a considerable heterogeneity and at least three subsets can be distinguished. While the role of monocyte subset heterogeneity has already been well investigated in coronary artery disease (CAD), the knowledge about monocytes and their heterogeneity in peripheral artery occlusive disease (PAOD) still is limited. Therefore, we aimed to investigate monocyte subset heterogeneity in patients with PAOD. Peripheral blood was obtained from 143 patients suffering from PAOD (Rutherford stage I to VI) and three monocyte subsets were identified by flow cytometry: CD14

Topics: Adult; Aged; Aged, 80 and over; Atherosclerosis; Body Mass Index; Female; Flow Cytometry; GPI-Linked Proteins; Humans; Inflammation; Lipopolysaccharide Receptors; Male; Membrane Glycoproteins; Middle Aged; Monocytes; Peripheral Arterial Disease; Peroxidase; Phenotype; Prospective Studies; Receptors, IgG

We hypothesized that treatment with quercetin could result in improved hemodynamics, lung inflammatory parameters and mortality in a rat model of hemorrhagic shock.. Rats were anesthetized (80 mg/kg ketamine plus 8 mg/kg xylazine i.p.). The protocol included laparotomy for 15 min (trauma), hemorrhagic shock (blood withdrawal to reduce the mean arterial pressure to 35 mmHg) for 75 min and resuscitation by re-infusion of all the shed blood plus lactate Ringer for 90 min. Intravenous quercetin (50 mg/kg) or vehicle were administered during resuscitation.. There was a trend for increased survival 84.6% (11/13) in the treated group vs. the shock group 68.4% (13/19,. Quercetin partially prevented the changes in blood pressure and lung injury in shock associated to hemorrhage and reperfusion.

Topics: Animals; Arterial Pressure; Biomarkers; Edema; Hemodynamics; Inflammation; Interleukin-6; Isotonic Solutions; Male; Peroxidase; Pulmonary Edema; Quercetin; Rats; Rats, Wistar; Reperfusion; Resuscitation; Ringer's Lactate; Shock, Hemorrhagic; Shock, Traumatic

Acute lung injury (ALI) is associated with high mortality and uncontrolled inflammation plays a critical role in ALI. TREM-1 is an amplifier of inflammatory response, and is involved in the pathogenesis of many infectious diseases. NLRP3 inflammasome is a member of NLRs family that contributes to ALI. However, the effect of TREM-1 on NLRP3 inflammasome and ALI is still unknown. This study aimed to determine the effect of TREM-1 modulation on LPS-induced ALI and activation of the NLRP3 inflammasome. We showed that LR12, a TREM-1 antagonist peptide, significantly improved survival of mice after lethal doses of LPS. LR12 also attenuated inflammation and lung tissue damage by reducing histopathologic changes, infiltration of the macrophage and neutrophil into the lung, and production of the pro-inflammatory cytokine, and oxidative stress. LR12 decreased expression of the NLRP3, pro-caspase-1 and pro-IL-1β, and inhibited priming of the NLRP3 inflammasome by inhibiting NF-κB. LR12 also reduced the expression of NLRP3 and caspase-1 p10 protein, and secretion of the IL-1β, inhibited activation of the NLRP3 inflammasome by decreasing ROS. For the first time, these data show that TREM-1 aggravates inflammation in ALI by activating NLRP3 inflammasome, and blocking TREM-1 may be a potential therapeutic approach for ALI.

Topics: Acute Lung Injury; Animals; Bronchoalveolar Lavage Fluid; Cytokines; Inflammasomes; Inflammation; Interleukin-10; Interleukin-1beta; Lipopolysaccharides; Lung; Macrophages; Malondialdehyde; Mice; Mice, Inbred C57BL; Myeloid Cells; Neutrophils; NLR Family, Pyrin Domain-Containing 3 Protein; Oxidative Stress; Peroxidase; Reactive Oxygen Species; Superoxide Dismutase; Triggering Receptor Expressed on Myeloid Cells-1

Macrophage metalloelastase-12 (MMP-12), a protein of the matrix metalloproteinase family, is involved in the breakdown of extracellular matrix in normal physiological processes as well as in disease processes. MMP-12 is almost exclusively produced by macrophages and is associated with inflammatory disorders. Giving the fact that inflammation negatively influences ejaculate parameters, we investigated a possible presence and correlation of MMP-12 in seminal plasma with parameters of the ejaculate, especially in leucocytospermic ejaculates. Forty-two patients who presented for semen analysis were assigned into four groups depending on the result of semen analysis according to the WHO guidelines 2010: normozoospermia (n = 11), OAT (n = 10), azoospermia (n = 10) and leucocytospermia (>1 mio. peroxidase-positive cells per ml) (n = 11). MMP-12 was detected by ELISA and was measurable in nearly all seminal plasma samples. Generally, MMP-12 concentrations were significantly higher in leucocytospermic samples than in nonleucocytospermic ones (P = 0.001). The MMP-12 levels between the latter nonleucocytospermic groups did not differ. Moreover, MMP-12 levels correlated with the presence of peroxidase-positive leucocytes. No correlation with CD 14 positive monocytes/macrophages was detected. In this study, we demonstrate that MMP-12 is present in seminal plasma and is correlated with inflammatory conditions in human semen and therefore may serve as predictor of ongoing inflammatory processes.

Topics: Adult; Biomarkers; Genital Diseases, Male; Humans; Inflammation; Leukocytes; Lipopolysaccharide Receptors; Macrophages; Male; Matrix Metalloproteinase 12; Peroxidase; Predictive Value of Tests; Semen; Semen Analysis

The actions of hydrogen sulfide in human physiology have been extensively studied and, although it is an essential mediator of many biological functions, the underlying molecular mechanisms of its actions are ill-defined. To elucidate the roles of sulfide in inflammation, we have investigated its interactions with human myeloperoxidase (MPO), a major contributor to inflammatory oxidative stress.. The interactions of sulfide and MPO were investigated using electron paramagnetic resonance, electronic circular dichroism, UV-vis and stopped-flow spectroscopies.. We found favourable reactions between sulfide and the native-ferric enzyme as well as the MPO redox intermediates, ferrous MPO, compound I and compound II. Sulfide was a potent reversible inhibitor of MPO enzymic activity with an IC50 of 1 µM. In addition, the measured second-order rate constants for the reactions of sulfide with compound I [k = (1.1 ± 0.06) × 10(6)  M(-1)  s(-1)] and compound II [k = (2.0 ± 0.03) × 10(5)  M(-1)  s(-1)] suggest that sulfide is a potential substrate for MPO in vivo.. Endogenous levels of sulfide are likely to inhibit the activity of circulating and endothelium-bound MPO. The fully reversible inhibition suggests a mediatory role of sulfide on the oxidant-producing function of the enzyme. Furthermore, the efficient HOCl oxidation of sulfide to give polysulfides (recently recognized as important components of sulfide biology) together with MPO-catalysed sulfide oxidation and the lack of interaction between MPO and sulfide oxidation products, predict a modulatory role of MPO in sulfide signalling.

Topics: Animals; Circular Dichroism; Electron Spin Resonance Spectroscopy; Humans; Hydrogen Sulfide; Inflammation; Inhibitory Concentration 50; Male; Oxidation-Reduction; Oxidative Stress; Peroxidase; Rats, Wistar; Signal Transduction

Pseudomonas aeruginosa, the major pathogen involved in lethal infections in cystic fibrosis (CF) population, is able to cause permanent chronic infections that can persist over the years. This ability to chronic colonize CF airways is related to a series of adaptive bacterial changes involving the immunostimulant lipopolysaccharide (LPS) molecule. The structure of LPSs isolated from several P. aeruginosa strains showed conserved features that can undergo chemical changes during the establishment of the chronic infection. In the present paper, we report the elucidation of the structure and the biological activity of the R-LPS (lipooligosaccharide, LOS) isolated from the persistent CF isolate P. aeruginosa strain RP73, in order to give further insights in the adaptation mechanism of the pathogen in the CF environment. The complete structural analysis of P. aeruginosa RP73 LOS was achieved by chemical analyses, NMR spectroscopy and MALDI MS spectrometry, while the assessment of the biological activity was attained testing the in vivo pro-inflammatory capacity of the isolated LOS molecule. While a typical CF LPS is able to trigger a high immune response and production of pro-inflammatory molecules, this P. aeruginosa RP73 LOS showed to possess a low pro-inflammatory capacity. This was possible due to a singular chemical structure possessing an under-acylated lipid A very similar to the LPS of P. aeruginosa found in chronic lung diseases such as bronchiectstasis.

Topics: Acylation; Animals; Carbon-13 Magnetic Resonance Spectroscopy; Cystic Fibrosis; Inflammation; Lipid A; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Neutrophil Infiltration; Peroxidase; Proton Magnetic Resonance Spectroscopy; Pseudomonas aeruginosa; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

Cisplatin is a platinum-based chemotherapy drug. However, its chemotherapeutic use is restricted by serious side effects, especially nephrotoxicity. Inflammatory mechanisms have a significant role in the pathogenesis of cisplatin-induced nephrotoxicity. Thalidomide is an immunomodulatory and anti-inflammatory agent and is used for the treatment of various inflammatory diseases. The purpose of this study was to investigate the potential nephroprotective effect of thalidomide in a mouse model of cisplatin-induced nephrotoxicity. Nephrotoxicity was induced in mice by a single injection of cisplatin (15 mg/kg, i.p.) and treated with thalidomide (50 and 100 mg/kg/day, orally) for 4 days, beginning 24 h prior to the cisplatin injection. Renal toxicity induced by cisplatin was demonstrated by increasing plasma levels of creatinine and blood urea nitrogen (BUN). Cisplatin increased the renal production of the proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and transforming growth factor (TGF)-β1. In addition, kidney levels of malondialdehyde (MDA), myeloperoxidase (MPO), and nitric oxide (NO) were increased by cisplatin. Biochemical results showed that thalidomide reduced cisplatin-induced increase in plasma creatinine and BUN. Thalidomide treatment also significantly reduced tissue levels of the proinflammatory cytokines, MDA, MPO, and NO and increased anti-inflammatory cytokine IL-10. Furthermore, histological examination indicated that thalidomide ameliorated renal damage caused by cisplatin. These data suggest that thalidomide attenuates cisplatin-induced nephrotoxicity possibly by inhibition of inflammatory reactions. Taken together, our findings indicate that thalidomide might be a valuable candidate for the prevention of nephrotoxicity in patients receiving cisplatin.

Topics: Acute Kidney Injury; Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Blood Urea Nitrogen; Cisplatin; Creatinine; Immunosuppressive Agents; Inflammation; Interleukin-10; Interleukin-1beta; Interleukin-6; Male; Malondialdehyde; Mice; Models, Animal; Nephritis; Nitric Oxide; Peroxidase; Random Allocation; Thalidomide; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

Punicalagin, a bioactive ellagitannin isolated from pomegranate, has been reported to have anti-inflammatory property. In the present study, we analyzed the role of punicalagin against acute respiratory distress syndrome (ARDS) induced by lipopolysaccharide (LPS) in mice. Male BALB/c mice with ARDS, induced by intranasal instillation of LPS, were treated with punicalagin 1 h prior to LPS exposure. The effects of punicalagin on pro-inflammatory cytokines, myeloperoxidase activity, nuclear factor kappa B (NF-κB) activation, and the histopathological changes were evaluated. The results showed that punicalagin treatment attenuated LPS-induced lung edema, elevating TNF-α, IL-6, and IL-1β levels in the bronchoalveolar lavage fluid (BALF). Meanwhile, punicalagin significantly inhibited LPS-induced increases in the macrophage and neutrophil infiltration of lung tissues and myeloperoxidase activity. Furthermore, punicalagin inhibits Toll-like receptor 4 (TLR4) expression and NF-κB activation induced by LPS. In conclusion, this is the first study to demonstrate that punicalagin protects against LPS-induced ARDS in mice. The underlying mechanisms may include inhibition of TLR4-mediated NF-κB signaling pathways.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; Enzyme Activation; Hydrolyzable Tannins; Inflammation; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; Lung; Macrophages; Male; Mice; Mice, Inbred BALB C; Neutrophil Infiltration; Neutrophils; NF-kappa B; Peroxidase; Pulmonary Edema; Random Allocation; Respiratory Distress Syndrome; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Most researchers agree that there are multiple factors influencing the development of recurrent depressive disorder (rDD). Previous studies have found that myeloperoxidase (MPO) may be a key inflammatory enzyme involved in this disorder. The purpose of this study was to determine the mRNA and protein levels of MPO in patients with rDD and to define the relationship between serum MPO levels and cognitive performance.. The study comprised 236 subjects: patients with rDD (n=131) and healthy subjects (n=105, HS). Assessment of cognitive function was based on performance on the Trail Making Test, the Stroop Test, the Verbal Fluency Test (VFT) and the Auditory-Verbal Learning Test (AVLT).. MPO gene expression at mRNA level and at protein level was significantly higher in the rDD group when compared to the HS (p<0.01). There were no significant correlations for each group separately, but in the entire group, statistically significant correlations occurred between both mRNA and protein levels and following test: TMT part A and part B (positive correlations), part RCNb and part NCWd of the Stroop Test (positive correlation), the Verbal Fluency Test (negative correlation) and the AVLT (negative correlation).. Our study provides evidence that the MPO enzyme coding gene and MPO expression are important for the regulation of cognitive functioning.

Topics: Cognition; Depression; Depressive Disorder; Female; Humans; Inflammation; Male; Peroxidase

Gestational genitourinary infections are associated with lifelong disabilities, but it is unknown if neonatal inflammation is involved.. Mothers of 914 infants born before 28th gestation week reported cervical/vaginal infection (CVI), and/or urine/bladder/kidney infection (UTI), or neither. Inflammation proteins measured in baby's blood on postnatal days 1, 7, and 14 were considered elevated if in the top quartile for gestational age. Logistic regression models adjusting for potential confounders assessed odds ratios.. Compared to mothers with neither UTI/CVI, those with CVI were more likely to have infants with elevated CRP, SAA, MPO, IL-1β, IL-6, IL-6R, TNF-α, RANTES, ICAM-3, E-selectin, and VEGF-R2 on day 1; those with UTI were more likely to have infants with elevated MPO, IL-6R, TNF-R1, TNF-R2, and RANTES on day 7. Placental anaerobes and genital mycoplasma were more common in pregnancies with CVI.. Gestational UTI/CVI should be targeted for preventing systemic inflammation in the very preterm newborn.

Topics: Adult; Antigens, CD; C-Reactive Protein; Cell Adhesion Molecules; Cytokines; E-Selectin; Female; Female Urogenital Diseases; Gestational Age; Humans; Infant, Extremely Premature; Infant, Newborn; Inflammation; Male; Peroxidase; Pregnancy; Receptors, Cell Surface; Young Adult

Obstructive sleep apnea (OSA) is characterized by recurrent respiratory disorders associated with increased cardiovascular morbidity and mortality. The increment of systemic inflammation in OSA has been considered as the major pathogenic mechanism leading to cardiovascular diseases. There is limited and conflicting information in the literature investigating myeloperoxidase (MPO) activity and soluble tumor necrosis factor receptor-1 (sTNF-R1) levels in OSA patients. The aim of our study is to assess the clinical utility of plasma MPO activity and sTNF-R1 levels as risk markers for systemic inflammation and development of cardiovascular diseases in OSA patients.. 59 OSA patients diagnosed with polysomnograhpy for Apnea-Hypopnea index (AHI), and 26 healthy volunteers enrolled into the study. Plasma MPO activity was measured using a spectrophotometric method. An enzyme-linked immunosorbent assay (ELISA) method was used to detect plasma sTNF-R1 levels.. Plasma MPO activity and sTNF-R1 levels were significantly higher (43.2 ± 21.65 vs. 30.44 ± 8.05 p = .0046; 2.379 ± 1.2 vs. 1.086 ± 0.86 p < .0001, respectively) in the total OSA patients compared to the control group. There was a significant weak correlation between MPO activity and disease severity indicator AHI (p = .03 r = .27).. Elevated plasma MPO activity and sTNF-R1 levels in the OSA patients indicate increased systemic inflammation and oxidative stress which might contribute to the higher incidence of cardiovascular diseases. Therefore, we recommend measurement of plasma MPO activity and sTNF-R1 levels in the OSA patients as potential risk predictors for cardiovascular diseases.

Topics: Adult; Aged; Biomarkers; Cardiovascular Diseases; Female; Humans; Inflammation; Male; Middle Aged; Oxidative Stress; Peroxidase; Receptors, Tumor Necrosis Factor, Type I; Severity of Illness Index; Sleep Apnea, Obstructive

Urera aurantiaca Wedd. (Urticaceae) is a medicinal plant commonly used in traditional medicine to relieve pain in inflammatory processes. In the present study, the in vivo anti-inflammatory and antinociceptive effects of U. aurantiaca methanolic extract and its possible mechanisms of action were investigated. The extract showed anti-inflammatory activity in the ear edema in mice test (34.3% inhibition), myeloperoxidase (MPO) activity was markedly reduced in animals administered with the extract: within 49.6% and 68.5%. In the histological analysis, intense dermal edema and intense cellular infiltration of inflammatory cells were markedly reduced in the ear tissue of the animals treated with the extract. In the carrageenan-induced hind paw edema in rats assay the extract provoked a significant inhibition of the inflammation (45.5%, 5 h after the treatment) and the MPO activity was markedly reduced (maximum inhibition 71.7%), The extract also exhibited significant and dose-dependent inhibitory effect on the increased vascular permeability induced by acetic acid. The extract presented antioxidant activity in both 2,2-diphenyl-1-picrylhydrazyl and 2,2'-azinobis 3-ethylbenzothiazoline 6-sulfonic acid tests and its total phenol content was 35.4 ± 0.06 mg GAE/g of extract. Also, the extract produced significant inhibition on nociception induced by acetic acid (ED50 : 8.7 mg/kg, i.p.) administered intraperitoneally and orally. Naloxone significantly prevented this activity.

Topics: Acetic Acid; Analgesics; Animals; Anti-Inflammatory Agents; Carrageenan; Edema; Female; Free Radical Scavengers; Inflammation; Male; Mice; Pain; Peroxidase; Phytotherapy; Plant Components, Aerial; Plant Extracts; Plants, Medicinal; Rats; Rats, Sprague-Dawley; Urticaceae

This study evaluates the inhibitory effect of IPO against ischemia reperfusion (I/R) induced lung injury in rats.. Anesthetized and mechanically ventilated adult Sprague-Dawley rats were randomly assigned to one of the following groups (n=12 each): the sham operated control group, the ischemia-reperfusion (IR) group (30min of left-lung ischemia and 24h of reperfusion), the IPO group (three successive cycles of 30-s reperfusion per 30-s occlusion before restoring full perfusion), and the dexamethasone plus IPO group (rats were injected with dexamethasone (3mg/kg·day(-1)) 10min prior to the experiment and the rest of the procedures were the same as the IPO group). Lung injury was assessed by wet-to-dry lung weight ratio and tissue apoptosis and biochemical changes.. Lung ischemia-reperfusion increased lung MDA production, serum proinflammatory cytokine count, and MPO activity and reduced antioxidant enzyme activities (all p<0.05 I/R versus sham), accompanied with a compensatory increase in caspase-3, bax, Fas, FasL proteins and a decrease in Bcl-2 protein. Plasma levels of TNF-α, IL-6, and IL-1β were increased in the I/R group (all p<0.05 versus sham). IPO attenuated or prevented all the above changes. Treatment with dexamethasone enhanced all the protective effects of postconditioning.. Postconditioning obviously inhibits I/R induced lung injury by its antioxidant, anti-inflammatory and anti-apoptosis activities.

Topics: Animals; Antioxidants; Apoptosis; bcl-2-Associated X Protein; Caspase 3; Dexamethasone; Fas Ligand Protein; fas Receptor; Free Radical Scavengers; Inflammation; Interleukin-1beta; Interleukin-6; Ischemic Postconditioning; Lung; Male; Malondialdehyde; Peroxidase; Rats; Rats, Sprague-Dawley; Rats, Wistar; Reperfusion Injury; Tumor Necrosis Factor-alpha

Alveolar macrophages (AMs) undergo increased apoptosis during sepsis-induced acute respiratory distress syndrome (ARDS). Ghrelin exhibits an antiapoptotic effect in several cell types and protects against sepsis-induced ARDS in rats; however, the molecular mechanisms underlying this antiapoptotic effect remain poorly understood. In this study, we first examined the antiapoptotic effect of ghrelin on lipopolysaccharide (LPS)-stimulated AMs in vitro. In AMs, GH secretagogue receptor-1a (GHSR-1a), the ghrelin receptor, was expressed, and treatment of AMs with ghrelin markedly reduced LPS-induced apoptosis, mitochondrial transmembrane potential decrease, and cytochrome c release. These effects of ghrelin were mediated by GHSR-1a because a GHSR-1a-targeting small interfering RNA abolished the antiapoptotic action of ghrelin. LPS treatment activated the c-Jun N-terminal kinase (JNK) signaling pathway but inhibited the Wnt/β-catenin pathway. Interestingly, combined LPS-ghrelin treatment reduced JNK activation and increased Wnt/β-catenin activation. Furthermore, like ghrelin treatment, the addition of the JNK inhibitor SP600125 or the glycogen synthase kinase-3β inhibitor SB216763 rescued AMs from apoptosis. We also demonstrated that ghrelin altered the balance of Bcl-2-family proteins and inhibited caspase-3 activity. Next, we investigated whether ghrelin protected against septic ARDS in vivo. Sepsis was induced in male rats by performing cecal ligation and puncture; administration of ghrelin reduced sepsis-induced AMs apoptosis, pulmonary injury, protein concentrations in the bronchoalveolar lavage fluid, the lung neutrophil infiltration, and wet to dry weight ratio. However, administration of a specific ghrelin-receptor antagonist, [D-Lys-3]-GH-releasing peptide-6, abolished the beneficial effects of ghrelin. Collectively our results suggest that ghrelin exerts an antiapoptotic effect on AMs at least partly by inhibiting JNK and activating the Wnt/β-catenin pathway and thereby helps alleviate septic ARDS in rats.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; beta Catenin; Cell Line; Cell Survival; Ghrelin; Inflammation; JNK Mitogen-Activated Protein Kinases; Lipopolysaccharides; Lung Diseases; Macrophages, Alveolar; Male; Peroxidase; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Receptors, Ghrelin; RNA Interference; Signal Transduction; Wnt Proteins

Ischemic preconditioning (IPC) has been demonstrated to provide a neuroprotection against brain damage produced by focal cerebral ischemia. However, it is elusive whether ischemic preconditioning attenuates ischemic brain damage through modulating phosphatidylinositol 3-kinase/Akt (PI3K/Akt) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway. In the present study, we first explored the best scheme of repetitive ischemic preconditioning (RIPC) to protect rat brain against ischemic damage and then further investigated the underlying mechanisms in RIPC's neuroprotection. Adult male Sprague-Dawley rats underwent ischemic preconditioning or (and) middle cerebral artery occlusion (MCAO). LY294002 or (and) PD98059 were injected intracerebroventricularly to selectively inhibit the activation of PI3K/Akt or ERK1/2. Neurological deficit scores, cerebral infarct volume, and morphological characteristic were detected at corresponding time after cerebral ischemia. The enzymatic activity of myeloperoxidase (MPO) was measured 24 h after cerebral ischemia. Expressions of p-Akt, t-Akt, p-ERK1/2, t-ERK1/2, nuclear factor-kappa B (NF-κB) p65, and cyclooxygenase-2 (COX-2) in ischemic brain were determined by Western blot. The release of tumor necrosis factor-α (TNF-α) in blood was examined by ELISA. In the various schemes of RIPC, IPC2 × 5 min causes less neuronal damage in the cortex and subcortex of ischemic brain and provides an obvious alleviation of cerebral infarction and neurological deficit after lethal ischemia. IPC2 × 5 min significantly reduces cerebral infarct volume, neurological deficit scores, and MPO activity; all of which were diminished by LY294002 or (and) PD98059. IPC2 × 5 min significantly upregulates the expressions of p-Akt and p-ERK1/2, which were inhibited by LY294002 or (and) PD98059. IPC2 × 5 min significantly downregulates the expressions of NF-κB p65 and COX-2 and attenuates the release of TNF-α; all of which were abolished by LY294002 or (and) PD98059. IPC2 × 5 min is the best scheme of RIPC to protect rat brain against cerebral ischemia. IPC2 × 5 min attenuates brain damage in rats subjected to lethal ischemia, and this neuroprotection is associated with inhibition of neuroinflammation through modulating PI3K/Akt and ERK1/2 signaling pathway.

Topics: Animals; Cyclooxygenase 2; Infarction, Middle Cerebral Artery; Inflammation; Ischemic Preconditioning; Male; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; NF-kappa B; Peroxidase; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley

Phosphoserine-containing peptides have been shown to exert antioxidative stress effects, by lowering lipid peroxidation, increasing intracellular glutathione, and increasing the expression of antioxidant enzymes in human intestinal epithelial cells. However, the role of phosphoserine residues in antioxidative stress activity, and their mechanism of action, remains unknown.. The antioxidative stress activity of phosphoserine and phosphoserine peptides was examined using an in vitro model of hydrogen peroxide (H2 O2 )-induced oxidative stress in Caco-2 cells. Phosphoserine dimers (2PS) reduced IL-8 secretion in H2 O2 -treated Caco-2 cells, and reduced H2 O2 -induced expression of genes involved in inflammation and generation of reactive oxygen species (ROS), including chemokine (C-C motif) ligand 5 (CCL5), lactoperoxidase (LPO), myeloperoxidase (MPO), neutrophil cytosolic factor 1/2 (NCF1/2), and nitric oxide synthase 2A (NOS2), and upregulated metallothionein 3 (MT3), peroxiredoxin 3 (PRDX3), and surfactant, pulmonary-associated protein D (SFTPD), which are involved in protection against oxidative stress and activation of the Nrf2 signaling pathway. At the protein level, 2PS reduced H2 O2 -induced phosphorylation of the ERK1/2 and JNK MAPKs, and increased Nrf2 expression. Moreover, the ability of 2PS to reduce H2 O2 -induced IL-8 secretion, a marker of inflammation and oxidative stress, was abrogated in Nrf2 knockdown cells.. These results suggest that 2PS reduce H2 O2 -induced oxidative stress via the Nrf2 signaling pathway, and reveal a potential mechanism for the antioxidative stress activity of phosphoserine-containing peptides.

Topics: Antioxidants; Caco-2 Cells; Chemokine CCL5; Humans; Hydrogen Peroxide; Inflammation; Interleukin-8; Lactoperoxidase; Lipid Peroxidation; Metallothionein 3; NADPH Oxidases; Nerve Tissue Proteins; NF-E2-Related Factor 2; Nitric Oxide Synthase Type II; Oxidative Stress; Peroxidase; Peroxiredoxin III; Phosphorylation; Phosphoserine; Polymers; Reactive Oxygen Species; Signal Transduction; Up-Regulation

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

It has been previously reported that Toll‑like receptor 4 (TLR4)/NF‑κB signaling mediates early inflammation during myocardial ischemia and reperfusion. It has additionally been suggested that resveratrol produces cardioprotective and anti‑inflammatory effects. The aim of the present study was to investigate whether resveratrol could modulate TLR4/NF‑κB signaling, reduce neutrophil accumulation and TNF‑α induction in an ischemia/reperfusion injured rat heart model. Rats were randomly exposed to a sham operation, myocardial ischemia and reperfusion (MI/R), MI/R + resveratrol or MI/R + resveratrol + L‑NAME. The data showed that following MI/R, the expression of myocardial TLR4 and NF‑κB increased significantly in the area of induced ischemia. As compared with MI/R, resveratrol significantly attenuated the expression of TLR4 and NF‑κB and reduced the levels of myeloperoxidase, serum and myocardial TNF‑α production, myocardial infarct size and myocardial apoptosis induced by MI/R. All the effects of resveratrol were abolished upon application of L‑NAME, a nitric oxide (NO) synthase inhibitor. These data provide evidence that resveratrol inhibits TLR4/NF‑κB signaling in the rat heart subjected to MI/R, and the anti‑inflammatory effect of resveratrol is associated with NO production.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Disease Models, Animal; Down-Regulation; Heart; Inflammation; Male; Myocardial Reperfusion Injury; Myocardium; Neutrophils; NF-kappa B; NG-Nitroarginine Methyl Ester; Nitric Oxide; Peroxidase; Rats; Rats, Sprague-Dawley; Resveratrol; Signal Transduction; Stilbenes; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Dextran sodium sulphate (DSS)-induced colitis is a widely used model for inflammatory bowel disease. However, various factors including nutrition may affect the development of this colitis. This study aimed to compare and characterize the impact of purified and non-purified basal diets on the development of DSS-induced colitis in the rat.. Wistar rats were fed a non-purified or a semi-synthetic purified diet for 21 days. Colitis was then induced in half of the rats by administration of DSS in drinking water (4% w/v) during the last 7 days of experimentation. At the end of the experimental period, colon sections were taken for histopathological examination, determination of various markers of inflammation (myeloperoxidase: MPO, cytokines) and oxidative stress (superoxide dismutase: SOD, catalase: CAT, glutathione peroxidase: GPx and glutathione reductase: GRed activities), and evaluation of the expression of various genes implicated in this disorder.. DSS ingestion induced a more marked colitis in animals receiving the purified diet, as reflected by higher histological score and increased MPO activity. A significant decrease in SOD and CAT activities was also observed in rats fed the purified diet. Also, in these animals, administration of DSS induced a significant increase in interleukin (IL)-1α, IL-1β and IL-6. In addition, various genes implicated in inflammation were over-expressed after ingestion of DSS by rats fed the purified diet.. These results show that a purified diet promotes the onset of a more severe induced colitis than a non-purified one, highlighting the influence of basal diet in colitis development.

Topics: Animals; Antioxidants; Body Weight; Catalase; Colitis; Colon; Cytokines; Dextran Sulfate; Diet; Disease Models, Animal; Energy Intake; Glutathione Peroxidase; Glutathione Reductase; Inflammation; Interleukin-1alpha; Interleukin-1beta; Interleukin-6; Male; Oxidative Stress; Peroxidase; Rats; Rats, Wistar; Superoxide Dismutase; Up-Regulation

ADAMTS13 is a plasma metalloproteinase that cleaves large multimeric forms of von Willebrand factor (VWF) to smaller, less adhesive forms. ADAMTS13 activity is reduced in systemic inflammatory syndromes, but the cause is unknown. Here, we examined whether neutrophil-derived oxidants can regulate ADAMTS13 activity. We exposed ADAMTS13 to hypochlorous acid (HOCl), produced by a myeloperoxidase-H2O2-Cl(-) system, and determined its residual proteolytic activity using both a VWF A2 peptide substrate and multimeric plasma VWF. Treatment with 25 nm myeloperoxidase plus 50 μm H2O2 reduced ADAMTS13 activity by >85%. Using mass spectrometry, we demonstrated that Met(249), Met(331), and Met(496) in important functional domains of ADAMTS13 were oxidized to methionine sulfoxide in an HOCl concentration-dependent manner. The loss of enzyme activity correlated with the extent of oxidation of these residues. These Met residues were also oxidized in ADAMTS13 exposed to activated human neutrophils, accompanied by reduced enzyme activity. ADAMTS13 treated with either neutrophil elastase or plasmin was inhibited to a lesser extent, especially in the presence of plasma. These observations suggest that oxidation could be an important mechanism for ADAMTS13 inactivation during inflammation and contribute to the prothrombotic tendency associated with inflammation.

Topics: ADAM Proteins; ADAMTS13 Protein; Chromatography, Liquid; Fibrinolysin; Gene Expression Regulation, Enzymologic; Humans; Hydrogen Peroxide; Hypochlorous Acid; Inflammation; Leukocyte Elastase; Mass Spectrometry; Methionine; Neutrophils; Oxidants; Oxygen; Peroxidase; Protein Structure, Tertiary; Thrombosis; von Willebrand Factor

Acute inflammation and angiogenesis are persistent features of several pathological conditions induced by biological agents leading to the resolution of local and systemic events. Glycoproteins derived from the protozoan Trypanosoma cruzi are suggested to mediate angiogenesis induced by inflammatory cells with still undescribed mechanisms. In this study, we investigated the effects of total antigen from trypomastigote forms of T. cruzi (Y strain), inoculated in sponges 24h after implantation in mice, on angiogenesis, inflammatory cell pattern and endogenous production of inflammatory and angiogenic mediators on days 1, 4, 7 and 14 post-implant. There was an increase in hemoglobin content and in the number of blood vessels associated with T. cruzi antigen stimuli on the 14th day, assessed by the hemoglobin of the implants and by morphometric analysis. However, these antigens were not able to increase type I collagen content on the 14th day. Parasite antigens also induced high production of vascular endothelial growth factor (VEGF) and inflammatory mediators TNF-alpha, CCL2 and CCL5 on the 7th day in sponges when compared to the unstimulated group. Neutrophils and macrophages were determined by measuring myeloperoxidase (MPO) and N-acetyl-β-d-glucosaminidase (NAG) enzyme activities, respectively. Only NAG was increased after stimulation with antigens, starting from day 4 and peaking at day 7. Together, these data showed that antigens from the Y strain of T. cruzi are able to promote inflammatory neovascularization probably induced by macrophage-induced angiogenic mediators in T. cruzi antigen-stimulated sponges in Swiss mice.

Topics: Acetylglucosaminidase; Angiogenic Proteins; Animals; Antigens, Protozoan; Biomarkers; Disease Models, Animal; Female; Inflammation; Inflammation Mediators; Macrophages; Mice; Neovascularization, Pathologic; Neutrophil Infiltration; Neutrophils; Peroxidase; Surgical Sponges; Time Factors; Trypanosoma cruzi

Abdominal sepsis is associated with significant changes in systemic inflammation and coagulation. The purpose of the present study was to examine the role of peripheral blood monocytes for systemic coagulation, including thrombin generation and consumption of coagulation factors. Abdominal sepsis was induced by cecal ligation and puncture (CLP) in C57BL/6 mice. Plasma and lung levels of IL-6 and C-X-C motif (CXC) chemokines [chemokine CXC ligand (CXCL)1, CXCL2, and CXCL5], pulmonary activity of myeloperoxidase, thrombin generation, and coagulation factors were determined 6 h after CLP induction. Administration of clodronate liposomes decreased circulating levels of monocytes by 96%. Time to peak thrombin formation was increased and peak and total thrombin generation was decreased in plasma from CLP animals. Monocyte depletion decreased time to peak formation of thrombin and increased peak and total generation of thrombin in septic animals. In addition, monocyte depletion decreased the CLP-induced increase in the levels of thrombin-antithrombin complexes in plasma. Depletion of monocytes increased plasma levels of prothrombin, factor V, factor X, and protein C in septic mice. Moreover, depletion of monocytes decreased CLP-induced levels of IL-6 and CXC chemokines in the plasma and lung by >59% and 20%, respectively. CLP-induced myeloperoxidase activity in the lung was attenuated by 44% in animals depleted of monocytes. Taken together, our findings show, for the first time, that peripheral blood monocytes regulate systemic coagulation. The results of our study improve our understanding of the pathophysiology of sepsis and encourage further attempts to target innate immune cell functions in abdominal sepsis.

Topics: Animals; Blood Coagulation; Blood Coagulation Factors; Chemokines, CXC; Inflammation; Interleukin-6; Lung; Male; Mice; Mice, Inbred C57BL; Monocytes; Peroxidase; Sepsis; Thrombin

Some oligosaccharides have immunoregulatory and anti-inflammatory functions in the intestine. This study investigated the immunoregulatory effect of lactosucrose (LS) on 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitic rats. Alkaline phosphatase activity was increased but myeloperoxidase activity was decreased in the LS-TNBS group, as compared with the TNBS group (colitis rats without receiving LS). LS supplementation stimulated IL-4 and IL-10 production, while up-regulating CD86 expression in dendritic cells. LS supplementation reduced the ratio of CD80/CD86 and the ratio of IFN-γ/IL-4 compared to the TNBS group. Moreover, IFN-γ was significantly correlated with CD80 (r = 0.764, p < 0.01), whereas IL-4 was significantly correlated with CD86 (r = 0.489, p < 0.05). These results indicated that LS attenuated colitis by promoting the production of Th2-type cytokines and rebalancing the ratio of Th1/Th2 and that enhanced IL-4 production is correlated with enhanced CD86 expression in the gut. Therefore, LS is a functional food for patients with inflammatory bowel disease.

Topics: Alkaline Phosphatase; Animals; Anti-Inflammatory Agents, Non-Steroidal; B7-1 Antigen; B7-2 Antigen; Colitis; Colon; Dendritic Cells; Female; Gene Expression Regulation; Inflammation; Interferon-gamma; Interleukin-10; Interleukin-4; Intestinal Mucosa; Peroxidase; Rats; Rats, Sprague-Dawley; Severity of Illness Index; Th1-Th2 Balance; Trinitrobenzenesulfonic Acid; Trisaccharides

Evidence associates polyphenol-rich foods to reduction of low-grade inflammation and mortality for cardiovascular disease, the mechanisms underlying such effects being still unclear. Consumption of a fatty meal by healthy volunteers induces rapid and reversible low-grade inflammation. The aim of the present study was to evaluate the effect of orange juice on cellular modifications induced by a fatty meal.. 18 apparently healthy subjects consumed a fatty meal, during which they drunk orange juice, either blond or red, or water, according to a randomized cross-over design. Two hours after the end of the fatty meal, both white blood cell (WBC) and platelet counts significantly increased (12.5 and 5%, respectively), while mean platelet volume decreased and a 25% release of myeloperoxidase (MPO) from polymorphonuclear leukocyte occurred. Both juices significantly prevented WBC increase and MPO degranulation, in respect to control. Triglycerides significantly increased (42%) after the fatty meal, but at a lower extent when red orange juice was consumed with the meal (20%), in respect to blond orange juice or control. This effect was statistically significant in the subgroup of 8 subjects with hypertriglyceridemia. Vascular stiffness (augmentation index), measured by Endo-PAT2000, significantly decreased after the meal only in conjunction with red orange juice.. In healthy subjects the concomitant intake of orange juice may prevent the low-grade inflammatory reaction induced by a fatty meal, at cellular and possibly at vascular function levels. The relative role of different polyphenols on the observed effects of orange juices remains to be established.

Topics: Adult; Beverages; Cardiovascular Diseases; Citrus sinensis; Female; Healthy Volunteers; Humans; Inflammation; Male; Meals; Peroxidase; Postprandial Period; Risk Factors; Triglycerides

Left ventricular (LV) remodeling, which includes ventricular dilatation and increased interstitial fibrosis after myocardial infarction (MI), is the critical process underlying the progression to heart failure. Therefore, a novel approach for preventing LV remodeling after MI is highly desirable. Yuzu is a citrus plant originating in East Asia, and has a number of cardioprotective properties such as hesperidin. However, no study has proved whether yuzu can prevent LV remodeling. The aim of this study was to determine the effects of yuzu on heart failure (HF) and its potential impact on the LV remodeling process after MI. Our in vivo study using the permanent left anterior descending coronary artery (LAD) occlusion model demonstrate that one week pre-treatment with yuzu or its major metabolite hesperidin before LAD occlusion significantly attenuated cardiac dysfunction, myocyte apoptosis and inflammation. Not only yuzu but also hesperidin inhibited caspase-3 activity, myeloperoxidase expression, α-smooth muscle actin expression, and matrix metalloproteinase-2 activity in a permanent LAD occlusion rat model. To our knowledge, our findings provide the first evidence that yuzu and hesperidin prevent MI-induced ventricular dysfunction and structural remodeling of myocardium.

Topics: Animals; Apoptosis; Blotting, Western; Citrus; Coronary Occlusion; Echocardiography; Enzyme Activation; Hesperidin; Immunohistochemistry; Inflammation; Male; Matrix Metalloproteinase 2; Myocardial Infarction; Myocardium; Peroxidase; Phytotherapy; Plant Extracts; Rats, Sprague-Dawley; Ventricular Remodeling

The objective of this work was use of silybin nanoparticles in treatment of ulcerative colitis (UC). Eudragit RL PO nanoparticles loaded with silybin were produced using solvent-evaporation emulsification technique. Then, they were coated by Eudragit FS30D. Drug release was studied in different physiological environments. Colitis was induced by 4% of acetic acid in rats which received freeze-dried nanoparticles of silybin (75 mg/kg/day), dexamethasone (1 mg/kg/day), blank nanoparticles and normal saline orally for 5 days. Then macroscopic, histopathological evaluation and biochemical analysis, including myeloperoxidase (MPO) activity, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels in colon tissues were determined using enzyme-linked immunosorbent assay (ELISA) kits. Macroscopic and histopathological scores were improved by the optimised nanoparticles. The optimised nanoparticles had a particle size of 109 ± 6 nm, zeta potential of 15.4 ± 2 mV, loading efficiency of 98.3 ± 12% and release efficiency of 40.8 ± 5.5% at 24 h. TNF-α, IL-6 and MPO activity were reduced significantly by nanoparticles compared to control group (p < 0.05).

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Colitis; Colon; Dexamethasone; Drug Carriers; Freeze Drying; Inflammation; Interleukin-6; Male; Nanoparticles; Peroxidase; Polymethacrylic Acids; Rats, Wistar; Silybin; Silybum marianum; Silymarin; Tumor Necrosis Factor-alpha

Lactobacillus acidophilus is widely used for gastrointestinal disorders, but its role in inflammatory conditions like in chemotherapy-induced mucositis is unclear. Here, we report the effect of L. acidophilus on 5-fluorouracil-induced (5-FU) intestinal mucositis in mice.. Mice weighing 25-30 g (n = 8) were separated into three groups, saline, 5-FU, and 5-FU + L. acidophilus (5-FU-La) (16 × 10(9) CFU/kg). In the 5-FU-La group, L. acidophilus was administered concomitantly with 5-FU on the first day and alone for two additional days. Three days after the last administration of L. acidophilus, the animals were euthanized and the jejunum and ileum were removed for histopathological assessment and for evaluation of levels of myeloperoxidase activity, sulfhydryl groups, nitrite, and cytokines (TNF-α, IL-1β, CXCL-1, and IL-10). In addition, we investigated gastric emptying using spectrophotometry after feeding a 1.5-ml test meal by gavage and euthanasia. Data were submitted to ANOVA and Bonferroni's test, with the level of significance at p < 0.05.. Intestinal mucositis induced by 5-FU significantly (p < 0.05) reduced the villus height-crypt depth ratio and GSH concentration and increased myeloperoxidase activity and the nitrite concentrations compared with the control group. Furthermore, 5-FU significantly (p < 0.05) increased cytokine (TNF-α, IL-1β, and CXCL-1) concentrations and decreased IL-10 concentrations compared with the control group. 5-FU also significantly (p < 0.05) delayed gastric emptying and gastrointestinal transit compared with the control group. All of these changes were significantly (p < 0.05) reversed by treatment with L. acidophilus.. Lactobacillus acidophilus improves the inflammatory and functional aspects of intestinal mucositis induced by 5-FU.

Topics: Animals; Antimetabolites, Antineoplastic; Cytokines; Fluorouracil; Gastric Emptying; Gastrointestinal Motility; Gastrointestinal Transit; Inflammation; Intestinal Mucosa; Lactobacillus acidophilus; Male; Mice; Mucositis; Peroxidase; Probiotics

With the rapid developments in the medical applications of carbon nanomaterials such as carbon nanohorns (CNHs), carbon nanotubes, and graphene based nanomaterials, understanding the long-term fate, health impact, excretion, and degradation of these materials has become crucial. Herein, the in vitro biodegradation of CNHs was determined using a non-cellular enzymatic oxidation method and two types of macrophage cell lines. Approximately 60% of the CNHs was degraded within 24 h in a phosphate buffer solution containing myeloperoxidase. Furthermore, approximately 30% of the CNHs was degraded by both RAW 264.7 and THP-1 macrophage cells within 9 days. Inflammation markers such as pro-inflammatory cytokines interleukin 6 and tumor necrosis factor α were not induced by exposure to CNHs. However, reactive oxygen species were generated by the macrophage cells after uptake of CNHs, suggesting that these species were actively involved in the degradation of the nanomaterials rather than in an inflammatory pathway induction.

Topics: Animals; Cell Line, Tumor; Humans; Hydrogen Peroxide; Inflammation; Interleukin-6; Macrophages; Mice; Microscopy, Electron, Transmission; Monocytes; Nanotechnology; Nanotubes, Carbon; Oxygen; Peroxidase; RAW 264.7 Cells; Reactive Oxygen Species; Tumor Necrosis Factor-alpha

Liver ischemia-reperfusion injury (IRI) is a major cause of morbidity and mortality after resection surgery, liver transplantation, and hemorrhagic and septic shock. Mir-155 is upregulated by a broad range of inflammatory mediators, and it has been demonstrated to be involved in both innate and adaptive immune responses. However, the role of mir-155 in liver IRI has never been investigated. In this study, mir-155 deficiency protected mice from liver IRI, as shown by lower serum alanine aminotransferase (ALT) levels and Suzuki scores. Mir-155 deficiency results in the development of M2 macrophages, which respond to IR-induced innate immune stimulation by producing a regulatory inflammatory response with higher level of IL-10, but lower levels of TNF-α, IL-6, and IL-12p40. Mir-155 deficiency suppresses IL-17 expression, which contributes to the liver IRI development. In our further in vitro study, the results show that the Th17 differentiation is inhibited by SOCS1 overexpression and the promoted M2 macrophage development induced by mir-155 deficiency is abolished by SOCS1 knockdown. In conclusion, mir-155 deficiency attenuates liver IRI through upregulation of SOCS1, and this was associated with promoted M2 macrophage and inhibited Th17 differentiation.

Topics: Adaptive Immunity; Alanine Transaminase; Animals; CD4-Positive T-Lymphocytes; Cell Differentiation; Cell Separation; Disease Models, Animal; Flow Cytometry; Immunity, Innate; Inflammation; Interleukin-10; Interleukin-12 Subunit p40; Interleukin-6; Kupffer Cells; Liver; Liver Transplantation; Macrophages; Male; Mice; Mice, Inbred C57BL; MicroRNAs; Peroxidase; Reperfusion Injury; Suppressor of Cytokine Signaling 1 Protein; Suppressor of Cytokine Signaling Proteins; Th17 Cells; Tumor Necrosis Factor-alpha; Up-Regulation

This study evaluated the potential anti-inflammatory effects of natural phthalides, isolated from Ligusticum porteri, and of semi-synthetic phthalides. Anti-inflammatory activity was investigated in two mouse models; one with ear edema, induced with 12-O-tetradecanoylphorbol-13-acetate, and the other with paw edema, induced with carrageenan. The effect on the RAW 264.7 stimulated with lipopolysaccharide cells was evaluated and after application of 12-O-tetradecanoylphorbol-13-acetate, the activity of myeloperoxidase was assessed to serve as an index of leukocytes infiltration together with the histological evaluations. We also assessed the inhibition of cyclooxygenases 1 and 2 in vitro. Our results demonstrated that administration of semi-synthetic phthalides significantly inhibited the ear edema induced by 12-O-tetradecanoylphorbol-13-acetate, and reduced the paw edema caused by carrageenan. The anti-inflammatory activity of phthalides could, in part, be explained by the reduction in myeloperoxidase activity and the infiltration of leukocytes. The semi-synthetic phthalides also inhibited the production of oxide nitric in RAW cells.

Topics: Animals; Anti-Inflammatory Agents; Benzofurans; Biological Products; Carrageenan; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Edema; Inflammation; Male; Mice; Nitric Oxide Synthase; Nitrites; Peroxidase; RAW 264.7 Cells; Skin; Tetradecanoylphorbol Acetate

High mobility group box 1 (HMGB1) is a systemic inflammation‑associated cytokine mediator. The aim of the present study was to examine the effect of the downregulation of HMGB1 in a lipopolysaccharide (LPS)‑induced mouse model of acute lung injury (ALI). It was identified that serum levels of tumor necrosis factor‑α and interleukin‑1β, lung myeloperoxidase activity and malondialdehyde content, as well as lung wet/dry weight ratios were all increased following LPS challenge. However, LPS‑mediated increases in these parameters were significantly downregulated in HMGB1 small interfering (si)RNA‑treated mice versus the negative control siRNA‑treated mice. In addition, the administration of HMGB1 siRNA in LPS‑treated mice resulted in a decreased DNA binding activity of nuclear factor‑κB (NF‑κB) in the lung. It was demonstrated that downregulation of HMGB1 decreases inflammation and the severity of sepsis associated with ALI, possibly via inhibiting the NF‑κB DNA‑binding activity. The present data support HMGB1 as a contributor to the pathogenesis of LPS‑induced sepsis and ALI.

Topics: Acute Lung Injury; Animals; DNA; Down-Regulation; Electrophoretic Mobility Shift Assay; Enzyme-Linked Immunosorbent Assay; HMGB1 Protein; Inflammation; Interleukin-1beta; Lipopolysaccharides; Lung; Malondialdehyde; Mice; Mice, Inbred C57BL; NF-kappa B; Peroxidase; Protein Binding; RNA Interference; RNA, Small Interfering; Severity of Illness Index; Tumor Necrosis Factor-alpha

Endoplasmic reticulum stress (ER stress) has been increasingly recognized as an important mechanism in various liver diseases. However, its intrinsic physiological role in acute liver failure (ALF) remains largely undetermined. This study aimed to examine how ER stress orchestrates glycogen synthase kinase 3β (GSK3β) and inflammation to affect ALF. In a murine ALF model induced by D-galactosamine (D-GalN) and lipopolysaccharide (LPS), 4-phenylbutyric acid (4-PBA) is to be administered to relieve ER stress. The lethality rate, liver damage, cytokine expression, and the activity of GSK3β were evaluated. How to regulate LPS-induced inflammation and TNF-α-induced hepatocyte apoptosis by ER stress was investigated in vitro. In vivo, ER stress was triggered in the liver with the progression of mice ALF model. ER stress was essential for the development of ALF because ER stress inhibition by 4-PBA ameliorated the liver damage through decreasing liver inflammation and hepatocyte apoptosis. 4-PBA also decreased GSK3β activity in the livers of ALF mice. In vitro, ER stress induced by tunicamycin synergistically increased LPS-triggered pro-inflammatory cytokine induction and promoted the activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathway in bone marrow-derived macrophages; moreover, tunicamycin also cooperated with TNF-α to increase hepatocyte apoptosis. ER stress promoted LPS-triggered inflammation depending on GSK3β activation because inhibition of GSK3β by SB216763, the specific inhibitor of GSK3β, resulted in downregulation of pro-inflammatory genes. ER stress contributes to liver inflammation and hepatotoxicity in ALF, particularly by regulating GSK3β, and is therefore a potential therapeutic target for ALF.

Topics: Alanine Transaminase; Animals; Anti-Inflammatory Agents; Apoptosis; Aspartate Aminotransferases; Endoplasmic Reticulum Stress; Galactosamine; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hepatocytes; Indoles; Inflammation; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; Liver; Liver Failure, Acute; Macrophages; Male; Maleimides; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; Neutrophil Infiltration; NF-kappa B; Peroxidase; Phenylbutyrates; Tumor Necrosis Factor-alpha; Tunicamycin

Obesity alters endocrine and metabolic functions of adipose tissue and has been recognized as a chronic inflammatory disease, which in turn may contribute to the development of insulin resistance, type 2 diabetes, obesity-associated vasculopathy and cardiovascular disease. The pathogenesis of obesity involves many regulatory pathways including transcriptional regulatory networks, including microRNAs.. A total of 83 patients were included in the study. Patients were recruited from a cardiology outpatient clinic and were allocated into 3 age- and sex-matched groups according to their body mass index. Group 1 included 23 morbidly obese, group 2 30 obese, and group 3 30 normal or overweight subjects.. In our study, we showed that miR-143 and miR-223 levels were significantly lower in groups 1 and 2 than the control group (normal BMI or overweight).. Obesity leads to alterations in miRNA expressions and miRNA-143 and -223s can be used as biomarkers for the metabolic changes in obesity.

Topics: Adult; Biomarkers; Body Mass Index; C-Reactive Protein; Case-Control Studies; Female; Hexosaminidases; Humans; Inflammation; Male; MicroRNAs; Middle Aged; Obesity; Peroxidase

Inflammation is a local tissue response to attacks characterized by vascular and cellular events, including intense oxidative stress. Riparin A, a compound obtained from Aniba riparia, has been shown to have antioxidant activity and cytotoxicity in vitro. This study was aimed at evaluating the anti-inflammatory effect of riparin A against acute inflammation. The results of our evaluations in various experimental models indicated that riparin A reduced paw edema induced by carrageenan, compound 48/80, histamine, and serotonin. Furthermore, it decreased leukocyte and neutrophil counts, myeloperoxidase activity, thiobarbituric acid reactive substance (TBARS) levels, and cytokine (tumor necrosis factor-α and interleukin-1β) levels increased by carrageenan-induced peritonitis, and reversed glutathione levels. Riparin A also reduced carrageenan-induced adhesion and rolling of leukocytes on epithelial cells and did not produce gastric-damage as compared with indomethacin. In conclusion, the data show that riparin A reduces inflammatory response by inhibiting vascular and cellular events, modulating neutrophil migration, inhibiting proinflammatory cytokine production, and reducing oxidative stress.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Benzamides; Carrageenan; Cell Adhesion; Cytokines; Edema; Extremities; Immune System Diseases; Inflammation; Lauraceae; Leukocyte Disorders; Leukocyte Rolling; Male; Mice; Neutrophils; Oxidative Stress; Peritonitis; Peroxidase; Phenethylamines

Isobrucein B (1) is a quassinoid isolated from the Amazonian medicinal plant Picrolemma sprucei. Herein we investigate the anti-inflammatory and antihyperalgesic effects of this quassinoid. Isobrucein B (1) (0.5-5 mg/kg) inhibited carrageenan-induced inflammatory hyperalgesia in mice in a dose-dependent manner. Reduced hyperalgesia was associated with reduction in both neutrophil migration and pronociceptive cytokine production. Pretreatment with 1 inhibited in vitro production/release of cytokines TNF, IL-1β, and KC/CXCL1 by lipopolysaccharide-stimulated macrophages. To investigate its molecular mechanism, RAW 264.7 macrophages with a luciferase reporter gene controlled by the NF-κB promoter were used (RAW 264.7-Luc). Quassinoid 1 reduced the luminescence emission by RAW 264.7-Luc stimulated by different compounds. Unexpectedly, NF-κB translocation to macrophage nuclei was not inhibited by 1 when evaluated by Western blotting and immunofluorescence. Furthermore, quassinoid 1 did not change the levels of TNF mRNA transcription in stimulated macrophages, suggesting post-transcriptional modulation. In addition, constitutive expression of luciferase in RAW 264.7 cells transiently transfected with a plasmid containing a universal promoter was inhibited by 1. Thus, isobrucein B (1) displays anti-inflammatory and antihyperalgesic activities by nonselective post-transcriptional modulation, resulting in decreased production/release of pro-inflammatory cytokines and neutrophil migration.

Topics: Animals; Anti-Inflammatory Agents; Brazil; Carrageenan; Cyclooxygenase 2; Cytokines; Dinoprostone; Hyperalgesia; I-kappa B Proteins; Inflammation; Interleukin-1beta; Lipopolysaccharides; Macrophages; Male; Mice; Mitogen-Activated Protein Kinases; Molecular Structure; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Peroxidase; Plants, Medicinal; Quassins; Simaroubaceae; Tumor Necrosis Factor-alpha

Here, we have evaluated the protective effect of the NO donor cis-[Ru(bpy)2(SO3)NO](PF6) (FOR0810) in experimental models of gastric damage induced by naproxen or ethanol in mice, and the involvement of soluble guanylate cyclase (sGC) and ATP-sensitive K(+) channels (KATP) in these events. Swiss mice were pre-treated with saline, ODQ (a soluble guanylate cyclase inhibitor; 10 mg kg(-1)) or glibenclamide (a KATP channels blocker; 10 mg kg(-1)). After either 30 min or 1 h, FOR0810 (3 mg kg(-1)) was administered. At the end of 30 min, the animals received naproxen (300 mg kg(-1)) by gavage. After 6 h, the animals were sacrificed and gastric damage, myeloperoxidase (MPO) activity, and TNF-α and IL-1β gastric concentrations were evaluated. In addition, the effects of FOR0810 on naproxen-induced mesenteric leukocyte adherence were determined by intravital microscopy. Other groups, were pre-treated with saline, ODQ or glibenclamide. After either 30 min or 1 h, FOR0810 was administered. At the end of 30 min, the animals received 50% ethanol by gavage. After 1 h, the animals were sacrificed, and gastric damage, gastric reduced glutathione (GSH) concentration and malondialdehyde (MDA) levels were determined. In naproxen-induced gastric damage, FOR0810 prevented gastric injury, decreased gastric MPO activity and leukocyte adherence, associated with a decrease in TNFα and IL-1β gastric concentrations. FOR0810 also prevented ethanol-induced gastric damage by increase in GSH levels and decrease in MDA levels. ODQ and glibenclamide completely reversed FOR0810's ability to prevent gastric damage by either naproxen or ethanol. We infer that FOR0810 prevented gastric damage through the activation of both sGC and KATP channels, which triggered a decrease in both free radical and cytokine production via the blocking of neutrophil adhesion and infiltration.

Topics: 2,2'-Dipyridyl; Animals; Cytokines; Ethanol; Gastric Mucosa; Guanylate Cyclase; Inflammation; KATP Channels; Mice; Naproxen; Nitrates; Nitric Oxide Donors; Nitrites; Organometallic Compounds; Peroxidase; Protective Agents; Receptors, Cytoplasmic and Nuclear; Soluble Guanylyl Cyclase

Inflammatory hyperalgesia is a complex process that depends on the sensitization of primary nociceptive neurons triggered by proinflammatory mediators, such as interleukin 1β (IL-1β). Recently, the peripheral activation of caspase-1 (previously known as IL-1β-converting enzyme) was implicated in the induction of acute inflammatory pain by promoting the processing of IL-1β from its precursor form, pro-IL-1β. Caspase-1 activation in several systems requires the assembly of an intracellular molecular platform called an inflammasome. Inflammasomes consist of 1 nucleotide-binding oligomerization domain-like receptor (NLR), the adapter molecule apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC), and caspase-1. NLRP3 and NLRC4 inflammasomes are well described. However, the identity of the inflammasome that is involved in the peripheral activation of caspase-1 that accounts for acute inflammatory hyperalgesia has not been described. The present findings demonstrated that mice deficient in NLRC4 or ASC, but not in NLRP3, present reduced mechanical and thermal acute inflammatory hyperalgesia induced by carrageenan. The reduced hyperalgesia was accompanied by significant impairments in the levels of mature forms of IL-1β (p17) and caspase-1 (p20) compared to wild-type mice at the inflammatory site. Therefore, these results identified the inflammasome components NLRC4 and ASC as the molecular platform involved in the peripheral activation of caspase-1 and IL-1β maturation, which are responsible for the induction of acute inflammatory pain. In conclusion, our study provides new therapeutic targets for the control of acute inflammatory pain.

Topics: Animals; Apoptosis Regulatory Proteins; Calcium-Binding Proteins; Caspase 1; Caspases; Caspases, Initiator; Cytokines; Dinoprostone; Disease Models, Animal; Gene Expression Regulation; Hyperalgesia; Inflammation; Interleukin-1beta; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Pain; Pain Measurement; Pain Threshold; Peroxidase; Receptors, Interleukin-1 Type I

Myeloperoxidase (MPO) is expressed by myeloid cells for the purpose of catalyzing the formation of hypochlorous acid, from chloride ions and reaction with a hydrogen peroxide-charged heme covalently bound to the enzyme. Most peroxidase enzymes both plant and mammalian are inhibited by benzoic acid hydrazide (BAH)-containing compounds, but the mechanism underlying MPO inhibition by BAH compounds is largely unknown. Recently, we reported MPO inhibition by BAH and 4-(trifluoromethyl)-BAH was due to hydrolysis of the ester bond between MPO heavy chain glutamate 242 ((HC)Glu(242)) residue and the heme pyrrole A ring, freeing the heme linked light chain MPO subunit from the larger remaining heavy chain portion. Here we probed the structure and function relationship behind this ester bond cleavage using a panel of BAH analogs to gain insight into the constraints imposed by the MPO active site and channel leading to the buried protoporphyrin IX ring. In addition, we show evidence that destruction of the heme ring does not occur by tracking the heme prosthetic group and provide evidence that the mechanism of hydrolysis follows a potential attack of the (HC)Glu(242) carbonyl leading to a rearrangement causing the release of the vinyl-sulfonium linkage between (HC)Met(243) and the pyrrole A ring.

Topics: Amino Acid Sequence; Aniline Compounds; Animals; Benzoic Acid; Carbocyanines; Catalytic Domain; Cattle; Electrons; Enzyme Inhibitors; Fluorescent Dyes; Free Radicals; Glutamic Acid; Heme; Humans; Hydrogen Peroxide; Inflammation; Lysine; Mass Spectrometry; Methionine; Molecular Conformation; Molecular Sequence Data; Neutrophils; Oxygen; Peroxidase; Spectrometry, Fluorescence

Mucopolysaccharidosis type IVA (MPS IVA) is an inborn error of glycosaminoglycan (GAG) catabolism due to the deficient activity of N-acetylgalactosamine-6-sulfate sulfatase that leads to accumulation of the keratan sulfate and chondroitin 6-sulfate in body fluids and in lysosomes. The pathophysiology of this lysosomal storage disorder is not completely understood. The aim of this study was to investigate oxidative stress parameters, pro-inflammatory cytokine and GAG levels in MPS IVA patients. We analyzed urine and blood samples from patients under ERT (n=17) and healthy age-matched controls (n=10-15). Patients presented a reduction of antioxidant defense levels, assessed by a decrease in glutathione content and by an increase in superoxide dismutase activity in erythrocytes. Concerning lipid and protein damage, it was verified increased urine isoprostanes and di-tyrosine levels and decreased plasma sulfhydryl groups in MPS IVA patients compared to controls. MPS IVA patients showed higher DNA damage than control group and this damage had an oxidative origin in both pyrimidine and purine bases. Interleukin 6 was increased in patients and presented an inverse correlation with GSH levels, showing a possible link between inflammation and oxidative stress in MPS IVA disease. The data presented suggest that pro-inflammatory and pro-oxidant states occur in MPS IVA patients even under ERT. Taking these results into account, supplementation of antioxidants in combination with ERT can be a tentative therapeutic approach with the purpose of improving the patient's quality of life. To the best of our knowledge, this is the first study relating MPS IVA patients with oxidative stress.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adolescent; Adult; Blood Proteins; Child; Chondroitinsulfatases; Creatinine; Cytokines; Deoxyguanosine; Enzyme Replacement Therapy; Erythrocytes; Female; Glutathione; Glycosaminoglycans; Humans; Inflammation; Isoprostanes; Male; Mucopolysaccharidosis IV; Oxidative Stress; Peroxidase; Superoxide Dismutase; Treatment Outcome; Tyrosine; Young Adult

It is currently accepted that superoxide anion (O2•-) is an important mediator in pain and inflammation. The role of superoxide anion in pain and inflammation has been mainly determined indirectly by modulating its production and inactivation. Direct evidence using potassium superoxide (KO2), a superoxide anion donor, demonstrated that it induced thermal hyperalgesia, as assessed by the Hargreaves method. However, it remains to be determined whether KO2 is capable of inducing other inflammatory and nociceptive responses attributed to superoxide anion. Therefore, in the present study, we investigated the nociceptive and inflammatory effects of KO2. The KO2-induced inflammatory responses evaluated in mice were: mechanical hyperalgesia (electronic version of von Frey filaments), thermal hyperalgesia (hot plate), edema (caliper rule), myeloperoxidase activity (colorimetric assay), overt pain-like behaviors (flinches, time spent licking and writhing score), leukocyte recruitment, oxidative stress, and cyclooxygenase-2 mRNA expression (quantitative PCR). Administration of KO2 induced mechanical hyperalgesia, thermal hyperalgesia, paw edema, leukocyte recruitment, the writhing response, paw flinching, and paw licking in a dose-dependent manner. KO2 also induced time-dependent cyclooxygenase-2 mRNA expression in the paw skin. The nociceptive, inflammatory, and oxidative stress components of KO2-induced responses were responsive to morphine (analgesic opioid), quercetin (antioxidant flavonoid), and/or celecoxib (anti-inflammatory cyclooxygenase-2 inhibitor) treatment. In conclusion, the well-established superoxide anion donor KO2 is a valuable tool for studying the mechanisms and pharmacological susceptibilities of superoxide anion-triggered nociceptive and inflammatory responses ranging from mechanical and thermal hyperalgesia to overt pain-like behaviors, edema, and leukocyte recruitment.

Topics: Analgesics, Opioid; Animals; Antioxidants; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Edema; Hindlimb; Hot Temperature; Hyperalgesia; Inflammation; Male; Mice; Nociceptive Pain; Pain Measurement; Peroxidase; Reactive Oxygen Species; Real-Time Polymerase Chain Reaction; Skin; Superoxides; Time Factors; Transcription, Genetic

Hypoxic-ischemic (HI) injury perinatal brain is a major contributor to morbidity and mortality to infants and children. Adenosine may play a role in the pathophysiology of HI, since it modulates the inflammatory process and the release of several neurotransmitters. Thus, the aim of this study was to identify the isoforms of adenosine deaminase (ADA) responsible for the enzymatic activity as well as the adenosine kinase (ADK) and A1 adenosine receptor (A1R) expression in the cerebral cortex eight days after HI. Myeloperoxidase (MPO) and N-acetyl-glucosaminidase (NAG) were assessed as inflammation markers. ADA activity was analyzed, in the presence or absence of a specific ADA1 inhibitor, erythro-9-(2-hydroxy-3-nonyl) adenine. The ADA1 activity (92.6%) was significantly higher than ADA2 (7.4%) activity in the cerebral cortex eight days after HI. A1Rs and ADK protein expression showed decreased 8 days after insult. Interestingly, the ADA1, MPO, and NAG activities were correlated positively. In view of this, we conclude that the inhibitor of ADA1, in in vitro conditions, was effective in decreasing the ADA activity, and that mainly ADA1 isoform is responsible for the increase in the ADA activity 8 days after HI insult. Therefore, HI neonatal was able to alter the ADK and A1R expression. Thus, due to the importance of adenosine signaling in the regulation of inflammatory and immune process and the crucial role of ADA in the postischemic homeostase of adenosine as well as during inflammatory process, we suggest that ADA1 inhibitors may play an important role in the regulation of events that follow the HI insult, favoring the increase in the adenosine in the sites of tissue injury. Together, these results highlight a role of the purinergic signaling cascade in the pathophysiology of HI neonatal.

Topics: Acetylglucosaminidase; Adenine; Adenosine Deaminase; Adenosine Kinase; Animals; Animals, Newborn; Blotting, Western; Brain; Cerebral Cortex; Hypoxia-Ischemia, Brain; Inflammation; Isoenzymes; Male; Peroxidase; Purines; Rats, Wistar; Receptor, Adenosine A1

Recent studies suggest that endothelial progenitor cells (EPCs) and platelets have an important role in repair following vascular injury. Although evidence suggest that platelets are essential in EPC attracting, homing and differentiation to the injury site; however, the platelet effects on EPC function in atherosclerosis have received less attention. In this context, we followed the consequences of circulating EPCs and platelet microparticles (PMPs) administration on platelet-EPC interaction in atherosclerosis and the involved mechanisms. The experiments were performed on Golden Syrian hamsters divided in five equal groups: control (C), hypertensive-hypercholesterolemic (HH), HH treated with EPCs (HH-EPCs) or PMPs (HH-PMPs) and HH treated with EPCs and PMPs (HH-EPCs-PMPs).. Compared with C group, EPCs isolated from HH and HH-PMPs groups presented a reduction of endothelial nitric oxide synthase and vascular endothelial growth factor expressions and an increase in thrombospondin-1 expression and inflammatory molecule secretion: interleukin 8 (IL)-8, myeloperoxidase (MPO) and plasminogen activator inhibitor-1 (PAI-1). EPC administration had beneficial effects, the obtained results being similar with those from the C group, while the combination with PMPs did not improve the EPC influences. Static coincubation of EPCs from HH and HH-PMPs with analogous platelets resulted in an increased EPC adhesion/migration, and IL-8, monocyte chemotactic protein-1, regulated on activation, normal T expressed and secreted, MPO and PAI-1 release, explained by the platelet hyperaggregability induced by pronounced distribution of vasodilator-stimulated phosphoprotein and filamentous actin, and the secretion of proinflammatory factors: IL-1β, -6, -8, CD40 ligand. EPC therapy alone revealed an impaired platelet-EPC interaction directly correlated with the reduction of inflammatory markers and platelet aggregability. Moreover, in a dynamic flow system, EPCs and platelets from HH and HH-PMPs exhibited weakened interplay abilities, while EPC transplantation reinforces them.. The present study demonstrates that HH animals revealed functional impairment of EPCs and platelets, which correlate with their reduced contribution to re-endothelialisation at the injury site, although in vitro exposure to immobilised platelets promotes their adhesion and migration. EPC administration alone recovers EPC/platelet functions and consolidates their interaction under dynamic flow conditions. These findings disclose new advances in understanding the platelet-EPC interaction and its role in the vascular repair.

Topics: Animals; Atherosclerosis; Blood Platelets; CD40 Ligand; Cell Adhesion; Cell Adhesion Molecules; Cell Movement; Chemokine CCL2; Cricetinae; Disease Models, Animal; Endothelial Progenitor Cells; Inflammation; Interleukin-8; Microfilament Proteins; Nitric Oxide Synthase Type III; Peroxidase; Phosphoproteins; Plasminogen Activator Inhibitor 1; Thrombospondin 1; Vascular Endothelial Growth Factor A

The aim of the study was to investigate the anti-inflammatory, antioxidant and antinociceptive actions of PFPe, a polysaccharide fraction isolated from the dried fruit of the Passiflora edulis.. Animals were pretreated with PFPe (0.3, 1 or 3 mg/kg, i.p.) 1 h before induction of paw oedema by carrageenan, histamine, serotonin, compound 48/80 or prostaglandin E2 (PGE2). Neutrophil migration and vascular permeability were measured after carrageenan injection into the peritoneum, and the action of the PFPe on the tumour necrosis factor-alpha, interleukin-1 beta (IL-1β), myeloperoxidase (MPO), glutathione (GSH) and malondialdehyde (MDA) levels was also evaluated. To assay nociception, we examined acetic acid-induced writhing, formalin-induced paw licking and response latency in the hot plate test.. Pretreatment with PFPe significantly inhibited carrageenan-induced paw oedema. PFPe also reduced paw oedema induced by compound 48/80, histamine, serotonin, and PGE2 and compound 48/80-induced vascular permeability. In addition, PFPe significantly reduced the MPO activity, MDA and GSH concentrations, and IL-1β level. In the nociception tests, PFPe reduced acetic acid-induced writhing and formalin-induced paw licking and did not increase the response latency time.. Our results suggest that PFPe administration reduces the inflammatory response by modulation of the liberation or synthesis of histamine and serotonin, by reduction of neutrophil migration, IL-1β levels, and oxidative stress and nociception.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Capillary Permeability; Carrageenan; Dinoprostone; Edema; Glutathione; Histamine; Inflammation; Interleukin-1beta; Male; Malondialdehyde; Mice; Neutrophils; Oxidative Stress; Pain Measurement; Passiflora; Peroxidase; Plant Extracts; Polysaccharides; Serotonin; Tumor Necrosis Factor-alpha

Thioredoxin (TRX) is a 12 kDa protein that is induced by oxidative stress, scavenges reactive oxygen species (ROS) and modulates chemotaxis. Furthermore it is thought to play a protective role in renal ischemia/reperfusion injury. Complement 5a (C5a) is a chemotactic factor of neutrophils and is produced after ischemia/reperfusion injury in the kidney. Both TRX and C5a increase after endurance exercise. Therefore, it may be possible that TRX has an association with C5a in renal disorders and/or renal protection caused by endurance exercise. Accordingly, the aim of this study was to investigate relationships among the changes of urine levels of TRX, C5a and acute kidney injury (AKI) caused by ischemia/reperfusion, inflammatory responses, and oxidative stress following intensive endurance exercise. Also, we applied a newly-developed measurement system of neutrophil migratory activity and ROS-production by use of ex vivo hydrogel methodology with an extracellular matrix to investigate the mechanisms of muscle damage. Fourteen male triathletes participated in a duathlon race consisting of 5 km of running, 40 km of cycling and 5 km of running were recruited to the study. Venous blood and urine samples were collected before, immediately following, 1.5 h and 3 h after the race. Plasma, serum and urine were analyzed using enzyme-linked immunosorbent assays, a free radical analytical system, and the ex vivo neutrophil functional measurement system. These data were analyzed by assigning participants to damaged and minor-damage groups by the presence and absence of renal tubular epithelial cells in the urinary sediments. We found strong associations among urinary TRX, C5a, interleukin (IL)-2, IL-4, IL-8, IL-10, interferon (IFN)-γ and monocyte chemotactic protein (MCP)-1. From the data it might be inferred that urinary TRX, MCP-1 and β-N-acetyl-D-glucosaminidase (NAG) were associated with renal tubular injury. Furthermore, TRX may be influenced by levels of IL-10, regulate chemotactic activity of C5a and IL-8, and control inflammatory progress by C5a and IL-8. In the longer duration group (minor-damage group), circulating neutrophil count, plasma concentration of myeloperoxidase (MPO) and serum concentration of myoglobin were markedly increased. In the higher intensity group (damaged group), neutrophil activation and degranulation of MPO might be inhibited, because not only was ROS production observed to be higher, but also antioxidant capacity and antiinflammatory c

Topics: Acute Kidney Injury; Adult; Athletes; Bicycling; Biomarkers; Cytokines; Exercise; Exercise Therapy; Humans; Inflammation; Kidney Failure, Chronic; Male; Muscle, Skeletal; Neutrophils; Oxidative Stress; Peroxidase; Physical Endurance; Reperfusion Injury; Running; Thioredoxins; Young Adult

Treatment of decompensated heart failure often includes administration of levosimendan. Myeloperoxidase (MPO) is released during polymorphonuclear neutrophil (PMN) degranulation, and mediates dysregulation of vascular tone in heart failure. We evaluated the effects of levosimendan-treatment on MPO in patients with acute decompensation of chronic heart failure over a one week course. Plasma MPO levels were significantly decreased after levosimendan treatment (from 252.1 ± 31.1 pmol/l at baseline to 215.02 ± 27.96 pmol/l at 6 h, p < 0.05). Ex vivo incubation of whole blood with levosimendan decreased MPO release after PMN-stimulation (8.2 ± 1.4-fold increase at baseline vs. 6.0 ± 1.1-fold increase with levosimendan). MPO levels also significantly correlated with diastolic blood pressure over the time course. In a multivariate linear model, the main contributor to systolic, diastolic and mean blood pressure was level of PMN elastase. MPO contributed only in heparin-treated patients, suggesting a more significant role for endothelial-bound MPO than for circulating MPO or elastase with respect to blood pressure regulation. We here provide the first evidence that levosimendan treatment inhibits MPO release by PMNs in decompensated heart failure patients. This mechanism may regulate endothelial function and vascular tone in heart failure patients.

Topics: Anti-Inflammatory Agents; Biomarkers; Blood Pressure; Cardiotonic Agents; Cell Degranulation; Female; Heart Failure; Humans; Hydrazones; Inflammation; Leukocytes; Male; Middle Aged; Neutrophils; Nitric Oxide; Peroxidase; Pyridazines; Severity of Illness Index; Simendan; Time Factors

Aminotriazole (ATZ) is commonly used as a catalase (CAT) inhibitor. We previously found ATZ attenuated oxidative liver injury, but the underlying mechanisms remain unknown. Acetaminophen (APAP) overdose frequently induces life-threatening oxidative hepatitis. In the present study, the potential hepatoprotective effects of ATZ on oxidative liver injury and the underlying mechanisms were further investigated in a mouse model with APAP poisoning. The experimental data indicated that pretreatment with ATZ dose- and time-dependently suppressed the elevation of plasma aminotransferases in APAP exposed mice, these effects were accompanied with alleviated histological abnormality and improved survival rate of APAP-challenged mice. In mice exposed to APAP, ATZ pretreatment decreased the CAT activities, hydrogen peroxide (H2O2) levels, malondialdehyde (MDA) contents, myeloperoxidase (MPO) levels in liver and reduced TNF-α levels in plasma. Pretreatment with ATZ also downregulated APAP-induced cytochrome P450 2E1 (CYP2E1) expression and JNK phosphorylation. In addition, posttreatment with ATZ after APAP challenge decreased the levels of plasma aminotransferases and increased the survival rate of experimental animals. Posttreatment with ATZ had no effects on CYP2E1 expression or JNK phosphorylation, but it significantly decreased the levels of plasma TNF-α. Our data indicated that the LD50 of ATZ in mice was 5367.4 mg/kg body weight, which is much higher than the therapeutic dose of ATZ in the present study. These data suggested that ATZ might be effective and safe in protect mice against APAP-induced hepatotoxicity, the beneficial effects might resulted from downregulation of CYP2E1 and inhibiton of inflammation.

Topics: Amitrole; Animals; Body Weight; Catalase; Chemical and Drug Induced Liver Injury; Cytochrome P-450 CYP2E1; Down-Regulation; Hydrogen Peroxide; Inflammation; Lethal Dose 50; Liver; Male; Malondialdehyde; Mice; Mice, Inbred C57BL; Peroxidase; Transaminases; Tumor Necrosis Factor-alpha

T helper (Th)1 and Th17 cells play a critical role in inflammatory bowel disease (IBD). 1,25-dihydroxyvitamin D3 (1,25(OH)2 D3 ) has emerged as a direct regulator of immune system function. Mice were grouped as follows: Control group (received PBS, n = 10), DSS group (received 2% DSS and PBS, n = 10), and DSS+VD group (received 2% DSS and 1,25(OH)2 D3 , n = 10). The disease activity index (DAI), colon length, and damage store of the mice were observed; the spleen length, weight, spleen index, and mononuclear cells of spleen were measured; mononuclear cells from mesenteric lymph nodes (MLN) were measured, and the levels of Th 1 and Th17 cytokines in the colon mucosa and spleen were measured. Mice in the DSS group developed severe diarrhea, rectal bleeding, and marked BW loss. Histological examination revealed extensive ulceration and inflammatory cell infiltration in the colon, and the structure of the spleen was disordered, infiltrated with inflammatory cytokines in red pulp. In the DSS group, mononuclear cell numbers from MLN and spleen were increased, and enhanced proteins and mRNA levels of Th 1 and Th17 cytokines were detected. In the DSS+VD group, 1,25(OH)2 D3 ameliorated the inflammation of the colon and spleen. In addition, 1,25(OH)2 D3 down-regulated the levels of Th 1 and Th17 cytokines. 1,25(OH)2 D3 represents a novel therapeutic drug for UC, which may correlate to inhibit the activation of Th1 and Th17 cells.

Topics: Animals; Calcitriol; Calcium; Chronic Disease; Colitis; Colon; Dextran Sulfate; Disease Models, Animal; Down-Regulation; Inflammation; Interferon-gamma; Interleukin-17; Interleukin-6; Intestinal Mucosa; Male; Mice; Mice, Inbred C57BL; Peroxidase; RNA, Messenger; Spleen; Th1 Cells; Th17 Cells; Tumor Necrosis Factor-alpha

We report the effect of gold nanoparticles (AuNP) in an acute inflammation model induced by carrageenan (CG) and compared this effect with those induced by the antioxidant N-acetylcysteine (NAC) alone and by the synergistic effect of NAC and AuNP together. Male Wistar rats received saline or saline containing CG administered into the pleural cavity, and some rats also received NAC (20 mg/kg) subcutaneously and/or AuNP administered into the pleural cavity immediately after surgery. Four hours later, the rats were sacrificed and pleural exudates obtained for evaluation of cytokine levels and myeloperoxidase activities. Oxidative stress parameters were also evaluated in the lungs. The results demonstrated that the inflammatory process caused by the administration of CG into the pleural cavity resulted in a substantial increase in the levels of tumor necrosis factor-α, interleukin-1β, and myeloperoxidase and a reduction in interleukin-10 levels. These levels seem to be reversed after different treatments in animals. Antioxidant enzymes exhibited positive responses after treatment of NAC + AuNP, and all treatments were effective at reducing lipid peroxidation and oxidation of thiol groups induced by CG. These findings suggest that small compounds, such as NAC plus AuNP, may be useful in the treatment of conditions associated with local inflammation.

Topics: Acetylcysteine; Animals; Carrageenan; Dose-Response Relationship, Drug; Gold; Inflammation; Interleukin-10; Interleukin-1beta; Male; Metal Nanoparticles; Oxidative Stress; Peroxidase; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

Although gut microbiota perturbation is recognized as a main contributing factor to the pathogenesis of inflammatory bowel disease, synbiotic therapies, as prevention or treatment, have remained overlooked.. To verify whether Lactobacillus paracasei B21060-based synbiotic therapy could prevent or repair colon damage in a mouse model of colitis, we performed treatments before and after colitis induction.. The experimental study lasted 19 d. Experimental colitis was induced in BALB/c mice by giving them dextran sodium sulfate (DSS, 2.5%) in drinking water (days 7-12) followed by DSS-free water (days 13-19) (DSS group). L. paracasei B21060 (2.5 × 10(7) bacteria/10 g body weight) was orally administered 7 d before DSS [synbiotic as preventive treatment (P-SYN) group] or 2 d after DSS [synbiotic as therapeutic treatment (T-SYN) group] until day 19. Another group was not treated with DSS or synbiotic and was given tap water (control group), for a total of 4 groups.. Compared with the DSS group, both synbiotic-treated groups had significantly less pronounced weight loss and colon damage. Consistently, mRNA levels of chemokine (C-C motif) ligand 5 in the colon were reduced in both P-SYN and T-SYN mice compared with the DSS group (51%, P < 0.05 and 72%, P < 0.001, respectively). In the P-SYN and T-SYN groups, neutrophil elastase transcription was also reduced (51%, P < 0.01 and 59%, P < 0.001, respectively). Accordingly, oxidative/nitrosative stress was lower in P-SYN and T-SYN mice than in the DSS group. In P-SYN and T-SYN mice, colonic gene expression of tumor necrosis factor (47%, P < 0.01 and 61%, P < 0.001, respectively) and prostaglandin-endoperoxide synthase 2 (45%, P < 0.01 and 35%, P < 0.05, respectively) was lower, whereas interleukin 10 mRNA was doubled compared with the DSS group (both P < 0.5). Remarkably, epithelial barrier integrity (zonulin and occludin) and gut protection (β-defensin and mucin expression) were completely restored in P-SYN and T-SYN mice.. Our data highlight the beneficial effects of this synbiotic formulation in acutely colitic mice, suggesting that it may have therapeutic and possibly preventive efficacy in human colitis.

Topics: Animals; beta-Defensins; Colitis; Cyclooxygenase 2; Dextran Sulfate; Disease Models, Animal; Gastrointestinal Tract; Inflammation; Interleukin-10; Lactobacillus; Male; Malondialdehyde; Mice; Mice, Inbred BALB C; Mucin-1; Oxidative Stress; Peroxidase; PPAR gamma; RNA, Messenger; Synbiotics; Up-Regulation

Recent researches suggest oxidative stress and generalized inflammatory state to be associated with bipolar I disorder (BID). Our aim is to evaluate Myeloperoxidase (MPO) and Catalase (CAT) activities in BID.. 73 BID patients and 73 healthy controls were enrolled. Patients were classified into manic, depressive and euthymic state. Serum MPO and CAT were measured in both patients and controls.. CAT activity was significantly lower in controls than manic, depressive and euthymics (p<0.001). MPO activity was significantly higher in controls compared to euthymics (p=0.007) and it was significantly higher in depressives compared to euthymics (p=0.023). CAT was negatively and MPO was positively correlated with disease duration in overall the patients. Positive Predictive Value was 94.5% and Negative Predictive Value was 100% above the cutoff point for CAT activity.. MPO and CAT activities are impaired in BID, which may be associated with oxidative stress and inflammation.

Topics: Adult; Biomarkers; Bipolar Disorder; Case-Control Studies; Catalase; Female; Humans; Inflammation; Male; Oxidative Stress; Peroxidase; Young Adult

To develop thalidomide-loaded poly-lactide-co-glycolide implants and evaluate its in vivo release and biological activity against inflammation and angiogenesis after subcutaneous administration.. Implants were prepared by the hot molding technique and characterized using stereomicroscopy, thermal analysis and X-ray diffraction. Swiss mice, divided in groups 1-3, received a subcutaneous implant containing 25% (w/w), 50% (w/w) or 75% (w/w) of thalidomide, respectively (n=6). The drug levels were determined during a 28-day study period. The toxicity associated with the implants was evaluated by light microscopy. The potential of the developed implant in the inhibition of inflammation and angiogenesis was evaluated in vivo using the sponge model.. Thalidomide implant was developed and its characterization proved the stability of the drug and the polymer during preparation. Release profiles in vivo demonstrated an extended release of thalidomide from the implants during the 28 days. Histological evaluation did not show any sign of intense local inflammatory response to the presence of the implants in the subcutaneous pouch. The thalidomide implant reduced the number of vessels and N-acetyl-b-glucosaminidase (NAG) in vivo.. The biodegradable implants delivered safe doses of thalidomide that were also effective to induce angiogenesis and inflammation regression.

Topics: Acetylglucosaminidase; Animals; Biocompatible Materials; Calorimetry, Differential Scanning; Disease Models, Animal; Female; Hemoglobins; Inflammation; Injections, Subcutaneous; Lactic Acid; Mice; Neovascularization, Pathologic; Peroxidase; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Skin; Thalidomide; X-Ray Diffraction

In this study we investigated the role of astragaloside IV (AS-IV), one of the major active constituents purified from the Chinese medicinal herb Astragalus membranaceus, in LPS-induced acute inflammatory responses in mice in vivo and examined possible underlying mechanisms. Mice were assigned to four groups: vehicle-treated control animals; AS-IV-treated animals (10 mg/kg b.w. AS-IV daily i.p. injection for 6 days); LPS-treated animals; and AS-IV plus LPS-treated animals. We found that AS-IV treatment significantly inhibited LPS-induced increases in serum levels of MCP-1 and TNF by 82% and 49%, respectively. AS-IV also inhibited LPS-induced upregulation of inflammatory gene expression in different organs. Lung mRNA levels of cellular adhesion molecules, MCP-1, TNFα, IL-6, and TLR4 were significantly attenuated, and lung neutrophil infiltration and activation were strongly inhibited, as reflected by decreased myeloperoxidase content, when the mice were pretreated with AS-IV. Similar results were observed in heart, aorta, kidney, and liver. Furthermore, AS-IV significantly suppressed LPS-induced NF-κB and AP-1 DNA-binding activities in lung and heart. In conclusion, our data provide new in vivo evidence that AS-IV effectively inhibits LPS-induced acute inflammatory responses by modulating NF-κB and AP-1 signaling pathways. Our results suggest that AS-IV may be useful for the prevention or treatment of inflammatory diseases.

Topics: Animals; Astragalus propinquus; Chemokine CCL2; Female; Inflammation; Interleukin-6; Lipopolysaccharides; Lung; Mice; Mice, Inbred C57BL; Myocardium; NF-kappa B; Peroxidase; Saponins; Signal Transduction; Tissue Distribution; Toll-Like Receptor 4; Transcription Factor AP-1; Triterpenes; Tumor Necrosis Factor-alpha

During an inflammatory response in the gut, some commensal bacteria such as E. coli can thrive and contribute to disease. Here we demonstrate that enterobactin (Ent), a catecholate siderophore released by E. coli, is a potent inhibitor of myeloperoxidase (MPO), a bactericidal enzyme of the host. Glycosylated Ent (salmochelin) and non-catecholate siderophores (yersiniabactin and ferrichrome) fail to inhibit MPO activity. An E. coli mutant (ΔfepA) that overproduces Ent, but not an Ent-deficient double mutant (ΔaroB/ΔfepA), inhibits MPO activity and exhibits enhanced survival in inflamed guts. This survival advantage is counter-regulated by lipocalin 2, a siderophore-binding host protein, which rescues MPO from Ent-mediated inhibition. Spectral analysis reveals that Ent interferes with compound I [oxoiron, Fe(IV)=O] and reverts the enzyme back to its native ferric [Fe(III)] state. These findings define a fundamental mechanism by which E. coli surpasses the host innate immune responses during inflammatory gut diseases and gains a distinct survival advantage.

Topics: Acute-Phase Proteins; Animals; Colitis; Dextran Sulfate; Enterobactin; Escherichia coli; Female; Gene Expression Regulation; Inflammation; Lipocalin-2; Lipocalins; Mice, Inbred BALB C; Oncogene Proteins; Peroxidase; Proto-Oncogene Proteins

Sepsis is characterized by systemic activation of coagulation and inflammation in response to microbial infection. Although cell-free DNA (cfDNA) released from activated neutrophils has antimicrobial properties, it may also exert harmful effects by activating coagulation and inflammation. The authors aimed to determine whether deoxyribonuclease (DNase) administration reduces cfDNA levels, attenuates coagulation and inflammation, suppresses organ damage, and improves outcome in a cecal ligation and puncture (CLP) model of polymicrobial sepsis. Healthy C57Bl/6 mice were subjected to CLP, a surgical procedure involving two punctures of the ligated cecum, or sham surgery (no ligation/puncture). Mice were given DNase or saline by intraperitoneal injection 2, 4, or 6 h after surgery. Two hours after treatment, organs were harvested and plasma levels of cfDNA, interleukin-6 (IL-6), IL-10, thrombin-antithrombin complexes, lung myeloperoxidase, creatinine, alanine transaminase, and bacterial load were quantified. Survival studies were also performed. The CLP-operated mice had rapid time-dependent elevations in cfDNA that correlated with elevations in IL-6, IL-10, and thrombin-antithrombin complexes and had organ damage in the lungs and kidneys. Administration of DNase at 2 h after CLP resulted in increased IL-6 and IL-10 levels and organ damage in the lungs and kidneys. In contrast, DNase administration at 4 or 6 h after CLP resulted in reduced cfDNA and IL-6 levels, increased IL-10, and suppressed organ damage and bacterial dissemination. Deoxyribonuclease administration every 6 h after CLP also rescued mice from death. Our studies are the first to demonstrate that delayed but not early administration of DNase may be protective in experimental sepsis.

Topics: Alanine Transaminase; Animals; Anti-Infective Agents; Antithrombins; Creatinine; Deoxyribonucleases; Disease Models, Animal; DNA; Drug Administration Schedule; Inflammation; Injections, Intraperitoneal; Interleukin-10; Interleukin-6; Lung; Male; Mice; Mice, Inbred C57BL; Multiple Organ Failure; Peroxidase; Sepsis; Thrombin; Time Factors

To investigate the effect of neurogenic neuroprotection conferred by cerebellar fastigial nucleus stimulation (FNS) and the role of PPARγ-mediated inflammation in a rat model of cerebral ischemia reperfusion.. After a continuous 1 hour fastigial nucleus electric stimulation, the male Sprague Dawley (SD) rats were given middle cerebral artery occlusion (MCAO) for 1, 3, 6, 9, 12 and 15 hours undergoing reperfusion with intravenous recombinant tissue plasminogen activator (rt-PA), while the control group received without FNS. After 72 h of reperfusion, the neurological deficits, infarct volume and brain edema were evaluated. The brain tissue in ischemic penumbra was determined the myeloperoxidase (MPO) activity by a spectrophotometer and expression of PPARγ was measured by Rt-PCR and Western blotting.. Our findings showed that FNS group had significantly reduced infarct volume and brain edema, and improved neurological deficits compared with the control group, especially in 6 h and 9 h reperfusion subgroups (p<0.05). The expression levels of PPARγ increased gradually and the peak may be before and after 9 h reperfusion, the 3 h, 6 h, 9 h, 12 h and 15 h reperfusion subgroups were higher than each control group (p<0.05). The MPO activity of 6 h, 12 h and 15 h reperfusion subgroups were higher than each control group (p<0.05).. The neuroprotective effects of FNS have been shown to prolong the therapeutic window in cerebral ischemia/reperfusion, which might be related to the PPARγ mediated-inflammation in penumbral region.

Topics: Animals; Brain; Brain Edema; Brain Ischemia; Cerebellar Nuclei; Electric Stimulation; Fibrinolysis; Fibrinolytic Agents; Infarction, Middle Cerebral Artery; Inflammation; Male; Neuroprotective Agents; Peroxidase; PPAR gamma; Rats; Rats, Sprague-Dawley; Reperfusion; Stroke; Tissue Plasminogen Activator

Ulcerative colitis (UC) is a chronic gastrointestinal disorder eliciting occurrence of colorectal cancer, the third most common human malignancy. The diagnosis of UC is based on clinical symptoms combined with typical findings on endoscopy, radiology, and ultimately pathology. We investigated the variation trend of CD4+CD29+T cells together with MPO, VCAM-1 in different periods of rat UC model and UC patients. We also evaluated the relationship between CD4+CD29+T cells and disease severity. UC model was induced by administering DNCB liquid and acetate solution. We found upregulated expression of CD4+CD29+T cells in both peripheral blood and colon from rats, and a similar trend for MPO and VCAM-1 in colon (P<0.05); the expression was especially enhanced in UC rats at two weeks after the model was established (P<0.01). Such upregulation was also indicated in active and remission UC patients as compared to the healthy and enteritis groups (P<0.05), with the highest expression level detected in the active UC patients (P<0.01). Pearson correlation analysis showed a positive correlation of CD4+CD29+T cells in rat and human peripheral blood with DAI score (rrat=0.712, rhuman=0.677, P<0.01), and MPO in colon (rrat=0.514, rhuman=0.682, P<0.05). These results suggest that CD4+CD29+T cells may act as major effector cell subsets in persistent inflammatory responses for UC and that infiltration into colon inflammation may be induced by the combination of VCAM-1 and CD29.

Topics: Animals; CD4-Positive T-Lymphocytes; Colitis, Ulcerative; Female; Flow Cytometry; Fluorescent Antibody Technique; Humans; Inflammation; Integrin beta1; Male; Peroxidase; Rats; Rats, Sprague-Dawley; T-Lymphocyte Subsets; Vascular Cell Adhesion Molecule-1

Early acute kidney injury (AKI) in severely burned patients predicts a high mortality that is multi-factorial. Hydrogen has been reported to alleviate organ injury via selective quenching of reactive oxygen species. This study investigated the potential protective effects of hydrogen against severe burn-induced early AKI in rats.. Severe burn were induced via immersing the shaved back of rats into a 100°C bath for 15 s. Fifty-six Sprague-Dawley rats were randomly divided into Sham, Burn + saline, and Burn + hydrogen-rich saline (HS) groups, and renal function and the apoptotic index were measured. Kidney histopathology and immunofluorescence staining, quantitative real-time PCR, ELISA and western blotting were performed on the sera or renal tissues of burned rats to explore the underlying effects and mechanisms at varying time points post burn.. Renal function and tubular apoptosis were improved by HS treatment. In addition, the oxidation-reduction potential and malondialdehyde levels were markedly reduced with HS treatment, whereas endogenous antioxidant enzyme activities were significantly increased. HS also decreased the myeloperoxidase levels and influenced the release of inflammatory mediators in the sera and renal tissues of the burned rats. The regulatory effects of HS included the inhibition of p38, JNK, ERK and NF-κB activation, and an increase in Akt phosphorylation.. Hydrogen can attenuate severe burn-induced early AKI; the mechanisms of protection include the inhibition of oxidative stress induced apoptosis and inflammation, which may be mediated by regulation of the MAPKs, Akt and NF-κB signalling pathways.

Topics: Acute Kidney Injury; Acute-Phase Proteins; Animals; Apoptosis; Blotting, Western; Burns; Creatinine; Hydrogen; Immunohistochemistry; Inflammation; Inflammation Mediators; Kidney Tubules; Lipocalin-2; Lipocalins; Male; Models, Biological; Oxidative Stress; Peroxidase; Proto-Oncogene Proteins; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Signal Transduction; Sodium Chloride

Chlorogenic acid (CGA) has been reported to prevent acetaminophen (AP)-induced hepatotoxicity when mice were pre-administered orally with CGA for consecutive 7days before AP intoxication in our previous study. This study investigated the therapeutic detoxification of CGA against AP-induced hepatotoxicity and the engaged mechanism. The mice were orally administered with CGA (10, 20, 40mg/kg) at 1h after given AP (400mg/kg), and another 3h later the mice were killed for the following experiments. Results of serum transaminases analysis and histological evaluation demonstrated the detoxification of CGA against AP-induced hepatotoxicity. CGA reduced AP-induced the increased myeloperoxidase (MPO) enzymatic activity and its expression. CGA reduced AP-induced the increased liver expression of toll-like receptor (TLR)-3/4 and MyD88, and the increased phosphorylation of inhibitor of kappa B (IκB) and p65 subunit of nuclear factor κB (NFκB). CGA reduced AP-induced the increased NFκBp65 expression in nucleus. In addition, CGA reduced AP-induced the increased serum levels and liver mRNA expression of tumor necrosis factor alpha (TNFα), interleukin (IL)-1β, IL-6, monocyte chemoattractant protein-1 (MCP-1), and keratinocyte chemoattractant (KC). Taken together, our results demonstrate the therapeutic detoxification of CGA against AP-induced liver injury, and TLR3/4 and NFκB signaling pathway are involved in such process.

Topics: Acetaminophen; Administration, Oral; Alanine Transaminase; Animals; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Chlorogenic Acid; Cytokines; I-kappa B Kinase; Inflammation; Liver; Male; Mice; Mice, Inbred ICR; Myeloid Differentiation Factor 88; Peroxidase; RNA, Messenger; Signal Transduction; Toll-Like Receptor 3; Toll-Like Receptor 4; Transcription Factor RelA

Based on the notion that inflammation favors tumorigenesis, our experiments comparatively assessed the influence of acute and chronic inflammation on the development of a murine mammary tumor (4T1). In addition, we characterized angiogenic and inflammatory markers in the tumor tissue and systemically. Subcutaneous implantation of polyether-polyurethane sponge discs in Balb/c mice was used to host 4T1 tumor cells (1x10(6)), which were inoculated intraimplant 24 h or 10 days post implantation. Flow cytometric analysis of enzyme-digested implants revealed that, after 24 hours, the population of leukocytes was primarily characterized by neutrophils (42.53% +/- 8.45) and monocytes (37.53% +/- 7.48), with some lymphocytes (16.27% +/- 4.0) and a few dendritic cells (1.82% +/- 0.36). At 10 days, macrophages were predominant (37.10% +/- 4.54), followed by lymphocytes (28.1% +/- 4.77), and monocytes (22.33% +/- 3.05), with some dendritic cells (13.60% +/- 0.55) and neutrophils (11.07% +/- 2.27). A mammary tumor grown in a chronic inflammatory environment was 2-fold when compared with one grown in acute inflammation and 5-fold when compared with tumor alone. The levels of pro-angiogenic cytokine (VEGF-Vascular Endothelial Growth Factor) were higher in implant-bearing tumor when 4T1 cells were grown in 10-day old implants as compared to the VEGF levels of the two other groups. Overall, the levels of the inflammatory markers evaluated (NAG -N-acetylglucosaminidase, TNF-α-Tumor Necrosis Factor-α) were higher in both groups of implant-bearing tumors and in serum from those animals when compared with the tumor alone levels. This inflammation-related difference in tumor growth may provide new insights into the contribution of different inflammatory cell populations to cancer progression.

Topics: Acetylglucosaminidase; Acute Disease; Animals; Biomarkers, Tumor; Chronic Disease; Disease Progression; Flow Cytometry; Inflammation; Lymphocytes; Macrophages; Male; Mammary Neoplasms, Experimental; Mice, Inbred BALB C; Monocytes; Neovascularization, Pathologic; Neutrophils; Peroxidase; Time Factors; Tumor Burden; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

Recent data has indicated that, besides its classical therapeutic indication in hyperurecemia and gout, xanthine oxidase inhibitors can be used to various forms of ischemia and other types of tissue and vascular injuries. We tested the hypothesis that allopurinol, an inhibitor of xanthine oxidase (XO), might modulate acute and/or chronic inflammatory angiogenesis induced by subcutaneous implantation of synthetic matrix in mice. C57/BL6 male mice (6-7 weeks) were implanted with polyether-polyurethane sponge discs. The animals received by oral gavage 1.0mg/kg of allopurinol for six consecutive days in two treatment regimen. In the first series of experiments, the treatment was initiated 24h post-implantation and the implants were removed at day 7 post-implantation. For the assessment of the effect of the compound on chronic inflammation, the treatment was initiated at day 8 post-implantation and the implants removed 14days post-implantation. Angiogenesis as determined by hemoglobin content, VEGF levels and number of vessels intraimplant, and inflammation (myeloperoxidase -MPO, n-acetyl-β-d-glucosaminidase -NAG, TNF-α and CCL2 levels) were reduced by allopurinol treatment in acute phase. Similarly, the treatment inhibited nitric oxide and H2O2 production. However, fibrogenesis determined by collagen deposition and levels of TGF-β1 increased in the implants after allopurinol treatment. In marked contrast with the effects when the treatment initiated 24h post-implantation, allopurinol increased angiogenesis and inflammation but reduced collagen and TGF-β1 levels intra-implant, when the treatment was started during the chronic inflammatory process. The dual effects of allopurinol described here, extend its range of actions as a potential agent able to modulate the components of the fibrovascular tissue present in both physiological (healing processes) as well as in chronic fibroproliferative diseases. These modulatory effects depended on the phase at which the treatment was initiated.

Topics: Acetylglucosaminidase; Allopurinol; Animals; Collagen; Ether; Hemoglobins; Hydrogen Peroxide; Inflammation; Male; Mice; Mice, Inbred C57BL; Models, Animal; Neovascularization, Pathologic; Nitric Oxide; Peroxidase; Polyurethanes; Time Factors; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A; Xanthine Oxidase

To characterize high-mobility group protein 1-toll-like receptor 4 (HMGB1-TLR4) and downstream signaling pathways in intestinal ischemia/reperfusion (I/R) injury.. Forty specific-pathogen-free male C57BL/6 mice were randomly divided into five groups (n = 8 per group): sham, control, anti-HMGB1, anti-myeloid differentiation gene 88 (MyD88), and anti-translocating-chain-associating membrane protein (TRIF) antibody groups. Vehicle with the control IgG antibody, anti-HMGB1, anti-MyD88, or anti-TRIF antibodies (all 1 mg/kg, 0.025%) were injected via the caudal vein 30 min prior to ischemia. After anesthetization, the abdominal wall was opened and the superior mesenteric artery was exposed, followed by 60 min mesenteric ischemia and then 60 min reperfusion. For the sham group, the abdominal wall was opened for 120 min without I/R. Levels of serum nuclear factor (NF)-κB p65, interleukin (IL)-6, and tumor necrosis factor (TNF)-α were measured, along with myeloperoxidase activity in the lung and liver. In addition,morphologic changes that occurred in the lung and intestinal tissues were evaluated. Levels of mRNA transcripts encoding HMGB1 and NF-κB were measured by real-time quantitative PCR, and levels of HMGB1 and NF-κB protein were measured by Western blot. Results were analyzed using one-way analysis of variance.. Blocking HMGB1, MyD88, and TRIF expression by injecting anti-HMGB1, anti-MyD88, or anti-TRIF antibodies prior to ischemia reduced the levels of inflammatory cytokines in serum; NF-κB p65: 104.64 ± 11.89, 228.53 ± 24.85, 145.00 ± 33.63, 191.12 ± 13.22, and 183.73 ± 10.81 (P < 0.05); IL-6: 50.02 ± 6.33, 104.91 ± 31.18, 62.28 ± 6.73, 85.90 ± 17.37, and 78.14 ± 7.38 (P < 0.05); TNF-α, 43.79 ± 4.18, 70.81 ± 6.97, 52.76 ± 5.71, 63.19 ± 5.47, and 59.70 ± 4.63 (P < 0.05) for the sham, control, anti-HMGB1, anti-MyD88, and anti-TRIF groups, respectively (all in pg/mL).Antibodies also alleviated tissue injury in the lung and small intestine compared with the control group in the mouse intestinal I/R model. The administration of anti-HMGB1, anti-MyD88, and anti-TRIF antibodies markedly reduced damage caused by I/R, for which anti-HMGB1 antibody had the most obvious effect.. HMGB1 and its downstream signaling pathway play important roles in the mouse intestinal I/R injury, and the effect of the TRIF-dependent pathway is slightly greater.

Topics: Adaptor Proteins, Vesicular Transport; Animals; Disease Models, Animal; Gene Expression Regulation; HMGB1 Protein; Inflammation; Inflammation Mediators; Interleukin-6; Intestine, Small; Liver; Lung; Male; Mesenteric Artery, Superior; Mesenteric Vascular Occlusion; Mice, Inbred C57BL; Myeloid Differentiation Factor 88; Peroxidase; Reperfusion Injury; RNA, Messenger; Signal Transduction; Toll-Like Receptor 4; Transcription Factor RelA; Tumor Necrosis Factor-alpha

The aim of this study was to investigate the effects of the administration of oral arachidonic acid (AA) in rats with or without dextran sulphate sodium (DSS)-induced inflammatory bowel disease. Male Wistar rats were administered AA at 0, 5, 35 or 240 mg/kg daily by gavage for 8 weeks. Inflammatory bowel disease was induced by replacing drinking water with 3 % DSS solution during the last 7 d of the AA dosing period. These animals passed loose stools, diarrhoea and red-stained faeces. Cyclo-oxygenase-2 concentration and myeloperoxidase activity in the colonic tissue were significantly increased in the animals given AA at 240 mg/kg compared with the animals given AA at 0 mg/kg. Thromboxane B2 concentration in the medium of cultured colonic mucosae isolated from these groups was found to be dose-dependently increased by AA, and the increase was significant at 35 and 240 mg/kg. Leukotriene B4 concentration was also significantly increased and saturated at 5 mg/kg. In addition, AA at 240 mg/kg promoted DSS-induced colonic mucosal oedema with macrophage infiltration. In contrast, administration of AA for 8 weeks, even at 240 mg/kg, showed no effects on the normal rats. These results suggest that in rats with bowel disease AA metabolism is affected by oral AA, even at 5 mg/kg per d, and that excessive AA may aggravate inflammation, whereas AA shows no effects in rats without inflammatory bowel disease.

Topics: Animals; Arachidonic Acid; Colitis; Colon; Cyclooxygenase 2; Dextran Sulfate; Diet; Inflammation; Inflammatory Bowel Diseases; Intestinal Mucosa; Leukotriene B4; Macrophages; Male; Peroxidase; Rats, Wistar; Thromboxane B2

During chronic inflammation, neutrophil-secreted hypochlorous acid can damage nearby cells inducing the genomic accumulation of 5-chlorocytosine (5ClC), a known inflammation biomarker. Although 5ClC has been shown to promote epigenetic changes, it has been unknown heretofore if 5ClC directly perpetrates a mutagenic outcome within the cell. The present work shows that 5ClC is intrinsically mutagenic, both in vitro and, at a level of a single molecule per cell, in vivo. Using biochemical and genetic approaches, we have quantified the mutagenic and toxic properties of 5ClC, showing that this lesion caused C→T transitions at frequencies ranging from 3-9% depending on the polymerase traversing the lesion. X-ray crystallographic studies provided a molecular basis for the mutagenicity of 5ClC; a snapshot of human polymerase β replicating across a primed 5ClC-containing template uncovered 5ClC engaged in a nascent base pair with an incoming dATP analog. Accommodation of the chlorine substituent in the template major groove enabled a unique interaction between 5ClC and the incoming dATP, which would facilitate mutagenic lesion bypass. The type of mutation induced by 5ClC, the C→T transition, has been previously shown to occur in substantial amounts both in tissues under inflammatory stress and in the genomes of many inflammation-associated cancers. In fact, many sequence-specific mutational signatures uncovered in sequenced cancer genomes feature C→T mutations. Therefore, the mutagenic ability of 5ClC documented in the present study may constitute a direct functional link between chronic inflammation and the genetic changes that enable and promote malignant transformation.

Topics: Biomarkers, Tumor; Carcinogenesis; Chromatography, High Pressure Liquid; Cytosine; DNA Mutational Analysis; Humans; Hypochlorous Acid; Inflammation; Inflammatory Bowel Diseases; Models, Molecular; Mutagenesis; Mutagens; Mutation; Neoplasms; Oligonucleotides; Peroxidase; Sequence Analysis, DNA

Cigarette smoke induces injury and neutrophilic inflammation in the airways of smokers. The stability and activity of inflammatory effectors, IL8 and neutrophil elastase (NE), can be prolonged by binding to airway heparan sulfate (HS)/syndecan-1, posing risk for developing chronic obstructive pulmonary disease(COPD). We hypothesize that antagonizing HS/syndecan-1 binding of the inflammatory effectors could reduce smoking-related neutrophil-mediated airway inflammation. Analysis of bronchoalveolar lavage fluid(BALF) of COPD patients found both total and unopposed NE levels to be significantly higher among smokers with COPD than non-COPD subjects. Similar NE burden was observed in smoke-exposed rats compared to sham air controls. We chose sulfated-maltoheptaose(SM), a heparin-mimetic, to antagonize HS/sydecan-1 binding of the inflammatory mediators in airway fluids and lung tissues of the smoke-exposed rat model. Airway treatment with SM resulted in displacement of CINC-1 and NE from complexation with bronchio-epithelial HS/syndecan-1, dissipating the chemokine gradient for neutrophil flux across to the bronchial lumen. Following SM displacement of NE from shed HS/syndecan-1 in bronchial fluids, NE became accessible to inhibition by α1-antitrypsin endogenous in test samples. The antagonistic actions of SM against syndecan-1 binding of NE and CINC-1 in smoke-exposed airways suggest new therapeutic opportunities for modulating airway inflammation in smokers with SM delivery.

Topics: Aged; alpha 1-Antitrypsin; Animals; Bronchi; Bronchoalveolar Lavage Fluid; Case-Control Studies; Chemokine CXCL1; Chitosan; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Glucans; Heparitin Sulfate; Humans; Inflammation; Inflammation Mediators; Leukocyte Elastase; Male; Middle Aged; Neutrophils; Peroxidase; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Sprague-Dawley; Smoking; Syndecan-1

Control of colorectal cancer needs to be tailored to its etiology. Tumor promotion mechanisms in colitis-associated colon cancer differ somewhat from the mechanisms involved in hereditary and sporadic colorectal cancer. Unlike sporadic or inherited tumors, some experimental models show that colitis-associated colon tumors do not require cyclooxygenase (COX) expression for progression, and non-steroidal anti-inflammatory drugs (NSAIDs) which prevent sporadic or inherited colon cancer do not prevent colitis-associated colon cancer. We report that myeloperoxidase (MPO), an ancestor of the COX isoenzymes, is a determinant of colitis-associated colon tumors in Apc(Min/+) mice. During experimentally induced colitis, inhibition of MPO by resorcinol dampened colon tumor development. Conversely, in the bowels of Apc(Min/+) mice without colitis, resorcinol administration or 'knockout' of MPO gene coincided with a slight, but discernible increase in colon tumor incidence. Acrolein, a by-product of MPO catalysis, formed a covalent adduct with the phosphatase tensin homolog (PTEN) tumor suppressor and enhanced the activity of the Akt kinase proto-oncogene in vitro and in vivo. Thus, MPO may be an important determinant of diet and inflammation on colon cancer risk via its effect on endogenous exposure to oxidants and acrolein. We propose a hypothetical model to explain an apparent dichotomy between colon tumor occurrence and MPO inhibition in inflamed versus non-inflamed colons.

Topics: Acrolein; Animals; Colitis; Colonic Neoplasms; Female; Gene Expression; Inflammation; Male; Mice; Mice, Transgenic; Oxidation-Reduction; Peroxidase; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Resorcinols; RNA, Small Interfering; Sodium Dodecyl Sulfate

This prospective experimental study aims to investigate whether matrilin-2 is released from burn injury and induces post-burn inflammatory responses as an endogenous danger signal.. Fifteen burn patients, 15 volunteers, 12 matrilin-2-deficient mice, 36 C57BL/6 mice and raw 264.7 cells.. Matrilin-2 levels were detected by enzyme-linked immunosorbent assay (ELISA) and real-time polymerase chain reaction. The inflammatory cytokines production in Matn2 deficient mice and wide type mice were detected by ELISA. Macrophages were activated by recombinant mouse MATN2 with or without adding anti-Toll-like receptor (TLR) 4 antibody. Student's t test and one-way analysis of variance were used for statistical analysis.. The matrilin-2 levels in serum of burned patients were drastically elevated as compared to those of healthy controls. The matrilin-2 levels in burned mice were significantly increased than those of non-burned controls, whereas the matrilin-2 mRNA expression was not significantly changed after burn. In addition, Matn2 deficient mice showed remarkably less inflammatory cytokines production and less neutrophil infiltration in lung. Exogenous MATN2 induced potent expression of proinflammatory cytokines production in macrophages, which was inhibited by anti-TLR4 antibody.. Matrilin-2 induces post-burn inflammatory responses as an endogenous danger signal, partly through a TLR4-mediated mechanism.

Topics: Adult; Animals; Burns; Cytokines; Female; Humans; Inflammation; Male; Matrilin Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Peroxidase; RAW 264.7 Cells; Toll-Like Receptor 4; Young Adult

δ-Amyrone (13(18)-Oleanen-3-one), which is an active constituent extracted and separated from Sedum lineare Thunb., has been found to possess a potent anti-inflammatory effect in different inflammation model animals. But its effects on lipopolysaccharide (LPS)-induced endotoxic shock have not been previous explored. The aim of this study is to evaluate the effect of δ-Amyrone on LPS-induced inflammatory cytokines and the protective effect on endotoxic shock mice. Experimental animals received δ-amyrone (4 and 8 mg/kg, i.p.) and dexamethasone (DEX) (5 mg/kg, i.p.) at 24 and 1 h before LPS injection. δ-Amyrone treatment significantly decreased mortality rate, tissues myeloperoxodase (MPO) activity, p65 NF-κB protein expression when compared with the LPS groups. The levels of tumor nectosis factor-alphagene (TNF-α) and interleukin-6 (IL-6) both in serum and lung, liver, kidney tissues, as well as the accumulation of nitric oxide (NO) in serum were decreased by δ-amyrone in response to p65 nuclear factors-kappa B (NF-κB). These results suggest that the protective activity of δ-amyrone on LPS-induced endotoxic shock is attributed to reducing NO production and mediating the pro-inflammatory cytokines, inhibited NF-κB expression.

Topics: Animals; Cytokines; Gene Expression Regulation, Enzymologic; Immunohistochemistry; Inflammation; Interleukin-6; Kidney; Lipopolysaccharides; Liver; Lung; Male; Mice; NF-kappa B; Peroxidase; Protective Agents; Shock, Septic; Triterpenes; Tumor Necrosis Factor-alpha

Inhibition of tumor necrosis factor-alpha (TNFα) and superoxide anion production reduces inflammation and pain. The present study investigated whether superoxide anion-induced pain depends on TNFα signaling and the role of superoxide anion in TNFα-induced hyperalgesia to clarify the interrelation between these two mediators in the context of pain. Intraplantar injection of a superoxide anion donor (potassium superoxide) induced mechanical hyperalgesia (0.5-5h after injection), neutrophil recruitment (myeloperoxidase activity), and overt pain-like behaviors (paw flinching, paw licking, and abdominal writhings) in wild-type mice. Tumor necrosis factor receptor 1 deficiency (TNFR1-/-) and treatment of wild-type mice with etanercept (a soluble TNFR2 receptor that inhibits TNFα actions) inhibited superoxide anion-induced pain-like behaviors. TNFR1(-/-) mice were also protected from superoxide anion donor-induced oxidative stress, suggesting the role of this pathway in the maintenance of oxidative stress. Finally, we demonstrated that Apocynin (an NADPH oxidase inhibitor) or Tempol (a superoxide dismutase mimetic) treatment inhibited TNFα-induced paw mechanical hyperalgesia and neutrophil recruitment (myeloperoxidase activity). These results demonstrate that TNFα/TNFR1 signaling is important in superoxide anion-triggered pain and that TNFα/TNFR1 signaling amplifies the oxidative stress triggered by superoxide anion, which contributes to sustaining pain and inflammation.

Topics: Animals; Anti-Inflammatory Agents; Etanercept; Hyperalgesia; Inflammation; Lipid Peroxidation; Mice; Mice, Inbred C57BL; Neutrophils; Oxidative Stress; Pain; Peroxidase; Physical Stimulation; Receptors, Tumor Necrosis Factor, Type I; Superoxides; Touch; Tumor Necrosis Factor-alpha

The relationship between dysthyroidism and antioxidant trace elements (ATE) status is very subtle during oxidative stress (OS). This relationship is mediated by thyroid hormone (TH) disorder, insulin resistance syndrome (IRS) and inflammation. The aim of this study was to investigate ATE such as selenium (Se), manganese (Mn), zinc (Zn) and copper (Cu) status on thyroid dysfunction, and their interaction with antioxidant enzyme activities, mainly, superoxide dismutase (SOD) and glutathione peroxidase (GPx), TH profile (TSH, T(3), T(4)) and IRS clusters. The study was undertaken on 220 Algerian adults (30-50 years), including 157 women and 63 men who were divided to 4 groups: subclinical hypothyroidism (n = 50), overt hypothyroidism (n = 60), Graves's disease hyperthyroidism (n = 60) and euthyroid controls (n = 50). The IRS was confirmed according to NCEP (National Cholesterol Education Program). Insulin resistance was evaluated by HOMA-IR model. Trace elements were determined by the Flame Atomic Absorption Spectrometry (Flame-AAS) technique. The antioxidant enzymes activity and metabolic parameters were determined by biochemical methods. The TH profile and anti-Thyroperoxidase Antibodies (anti-TPO-Ab) were evaluated by radioimmunoassay. Results showed that the plasma manganese levels were significantly increased in all dysthyroidism groups (p ≤ 0.01). However, the plasma copper and zinc concentrations were maintained normal or not very disturbed vs control group. In contrast, the plasma selenium levels were highly decreased (p ≤ 0.001) and positively correlated with depletion of glutathione peroxidase activity; and associated both with anti-TPO-Ab overexpression and fulminant HS-CRP levels. This study confirms the oxidative stress-inflammation relationship in the dysthyroidism. The thyroid follicles antioxidant protection appears preserved in the cytosol (Cu/Zn-SOD), while it is altered in the mitochondria (Mn-SOD), which gives this cell organelle, a status of real target therapy in thyroid dysfunction. The publisher would like to apologise for any inconvenience caused. [corrected].

Topics: Adult; Algeria; Antibodies; Antioxidants; Biomarkers; Cohort Studies; Erythrocytes; Female; Hemodynamics; Humans; Inflammation; Insulin Resistance; Lipids; Male; Manganese; Oxidative Stress; Peroxidase; Selenium; Thyroid Diseases; Trace Elements

The Eugenia jambolana is used in folklore medicine. Leaves of E. jambolana contain flavonoids as their active constituents which possess in vitro antiinflammatory, antioxidant and the antimicrobial activity. The aim of the present study was to investigate the antiinflammatory and antioxidant effects of a flavonoid glucoside, trimeric myricetin rhamnoside (TMR) isolated from leaves of E. jambolana. TMR was studied for antiinflammatory activity in carrageenan-induced hind paw oedema and antioxidant activity in lung by caecal ligation and puncture (CLP)-induced sepsis in mice. Results of the present study indicated that TMR significantly attenuated the oedema, myeloperoxidase (MPO), cytokines and prostaglandin levels in the paw after 5 h of carrageenan injection as compared to vehicle control. It also reduced the lung MPO, lipid peroxides, and serum nitrite plus nitrate levels and increased lung reduced glutathione levels 20 h of CLP as compared to vehicle control. Thus the results of this study concluded that the TMR appears to have potential benefits in diseases that are mediated by both inflammation and oxidative stress and support the pharmacological basis of use of E. jambolana plant as traditional herbal medicine for the treatment of inflammatory diseases.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Carrageenan; Cecum; Edema; Flavonoids; Glutathione; Inflammation; Ligation; Lung; Male; Mice; Oxidative Stress; Peroxidase; Phytotherapy; Plant Extracts; Plant Leaves; Punctures; Rats; Rats, Wistar; Sepsis; Syzygium

Among the most fascinating virulence attributes of Candida is the ability to transition to a biofilm lifestyle. As a biofilm, Candida cells adhere to a surface, such as a vascular catheter, and become encased in an extracellular matrix. During this mode of growth, Candida resists the normal immune response, often causing devastating disease. Based on scanning electron microscopy images, we hypothesized that host cells and proteins become incorporated into clinical biofilms. As a means to gain an understanding of these host-biofilm interactions, we explored biofilm-associated host components by using microscopy and liquid chromatography-mass spectrometry. Here we characterize the host proteins associated with several in vivo rat Candida albicans biofilms, including those from vascular catheter, denture, and urinary catheter models as well as uninfected devices. A conserved group of 14 host proteins were found to be more abundant during infection at each of the niches. The host proteins were leukocyte and erythrocyte associated and included proteins involved in inflammation, such as C-reactive protein, myeloperoxidase, and alarmin S100-A9. A group of 59 proteins were associated with both infected and uninfected devices, and these included matricellular and inflammatory proteins. In addition, site-specific proteins were identified, such as amylase in association with the denture device. Cellular analysis revealed neutrophils as the predominant leukocytes associating with biofilms. These experiments demonstrate that host cells and proteins are key components of in vivo Candida biofilms, likely with one subset associating with the device and another being recruited by the proliferating biofilm.

Topics: Amylases; Animals; Biofilms; Blood Proteins; C-Reactive Protein; Calgranulin B; Candida albicans; Candidiasis; Dentures; Gene Expression Regulation; Host-Pathogen Interactions; Inflammation; Microscopy, Electron, Scanning; Peroxidase; Rats; Rats, Sprague-Dawley; Urinary Catheters; Vascular Access Devices

Neurogenic pulmonary edema (NPE) is a serious non-neurological complication that can occur after a subarachnoid hemorrhage (SAH) and is associated with decreased survival and a poor neurological outcome. Melatonin is a strong antioxidant that has beneficial effects against SAH in rats, including reduced mortality and reduced neurological deficits. The molecular mechanisms underlying these clinical effects in the SAH model, however, have not been clearly identified. This study was undertaken to determine the influence of melatonin on SAH-induced NPE and the potential mechanism of these effects using the filament perforation model of SAH in male Sprague Dawley rats. Either melatonin (150 mg/kg) or a vehicle was given via an intraperitoneal injection 2 hr after an SAH induction. Lung samples were extracted 24 hr after SAH. The results show that the melatonin treatment attenuated SAH-induced NPE by preventing alveolar-capillary barrier dysfunctions via inhibiting the disruption of tight junction proteins (ZO-1 and occludin). Moreover, the treatment downregulated the levels of mature interleukin (IL) -1β, myeloperoxidase (MPO), and matrix metallopeptidase (MMP) 9 expression/activation, which were increased in the lung; also, melatonin treatment improved neurological deficits. Furthermore, the melatonin treatment markedly reduced caspase-3 activity and the number of TUNEL-positive cells in the lung. Taken together, these findings show that administration of melatonin attenuates NPE by preventing alveolar-capillary barrier dysfunctions via repressing the inflammatory response and by anti-apoptosis effects after SAH.

Topics: Animals; Antioxidants; Apoptosis; Inflammation; Interleukin-1beta; Matrix Metalloproteinase 9; Melatonin; Peroxidase; Pulmonary Edema; Rats; Rats, Sprague-Dawley; Subarachnoid Hemorrhage

Recent studies indicate that the abnormal microenvironment of tumors may play a critical role in carcinogenesis, including lung cancer. We comprehensively assessed the number of stromal cells, especially immune/inflammatory cells, in lung cancer and evaluated their infiltration in cancers of different stages, types and metastatic characteristics potential. Immunohistochemical analysis of lung cancer tissue arrays containing normal and lung cancer sections was performed. This analysis was combined with cyto-/histomorphological assessment and quantification of cells to classify/subclassify tumors accurately and to perform a high throughput analysis of stromal cell composition in different types of lung cancer. In human lung cancer sections we observed a significant elevation/infiltration of total-T lymphocytes (CD3+), cytotoxic-T cells (CD8+), T-helper cells (CD4+), B cells (CD20+), macrophages (CD68+), mast cells (CD117+), mononuclear cells (CD11c+), plasma cells, activated-T cells (MUM1+), B cells, myeloid cells (PD1+) and neutrophilic granulocytes (myeloperoxidase+) compared with healthy donor specimens. We observed all of these immune cell markers in different types of lung cancers including squamous cell carcinoma, adenocarcinoma, adenosquamous cell carcinoma, small cell carcinoma, papillary adenocarcinoma, metastatic adenocarcinoma, and bronchioloalveolar carcinoma. The numbers of all tumor-associated immune cells (except MUM1+ cells) in stage III cancer specimens was significantly greater than those in stage I samples. We observed substantial stage-dependent immune cell infiltration in human lung tumors suggesting that the tumor microenvironment plays a critical role during lung carcinogenesis. Strategies for therapeutic interference with lung cancer microenvironment should consider the complexity of its immune cell composition.

Topics: Antigens, CD; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Humans; Immunohistochemistry; Inflammation; Lung Neoplasms; Peroxidase; Stromal Cells; Tumor Microenvironment

The relationship between lower urinary tract symptoms (LUTS) and common mental health disorders such as depression and anxiety in men remains unclear. Inflammation has recently been identified as an independent risk factor for LUTS and depression. This study aimed to assess the association between depression, anxiety and LUTS, and the moderating influence of systemic inflammation, in the presence of other biopsychosocial confounders.. Participants were randomly-selected from urban, community-dwelling males aged 35-80 years at recruitment (n = 1195; sample response rate:67.8%). Of these, 730 men who attended baseline (2002-5) and follow-up clinic visits (2007-10), with complete outcome measures, and without prostate or bladder cancer and/or surgery, neurodegenerative conditions, or antipsychotic medications use, were selected for the present study. Unadjusted and multi-adjusted regression models of incident storage and voiding LUTS and incident depression and anxiety were combined with serum inflammatory markers (high-sensitive C-reactive protein (hsCRP), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), myeloperoxidase (MPO), soluble e-selectin (e-Sel)) and socio-demographic, lifestyle, and health-related factors. Hierarchical multiple regression was used to assessed the moderating effect of inflammatory markers.. The incidence of storage, voiding LUTS, depression and anxiety was 16.3% (n = 108), 12.1% (n = 88), 14.5% (n = 108), and 12.2% (n = 107). Regression models demonstrated that men with depression and anxiety at baseline were more likely to have incident storage, but not voiding LUTS (OR: 1.26, 99%CI: 1.01-4.02; and OR:1.74; 99%CI:1.05-2.21, respectively). Men with anxiety and storage LUTS at baseline were more likely to have incident depression (OR: 2.77, 99%CI: 1.65-7.89; and OR:1.45; 99%CI:1.05-2.36, respectively), while men with depression and voiding LUTS were more likely to have anxiety at follow-up (OR: 5.06, 99%CI: 2.81-9.11; and OR:2.40; 99%CI:1.16-4.98, respectively). CRP, TNF-α, and e-Sel were found to have significant moderating effects on the development of storage LUTS (1.06, 0.91-1.96, R2 change: 12.7%), depression (1.17, 1.01-1.54, R2 change: 9.8%), and anxiety (1.35, 1.03-1.76, R2 change: 10.6%), respectively.. There is a bidirectional relationship between storage, but not voiding, LUTS and both depression and anxiety. We observed variable moderation effects for selected inflammatory markers on the development of depression, anxiety and storage LUTS.

Topics: Adult; Aged; Aged, 80 and over; Anxiety; Anxiety Disorders; C-Reactive Protein; Depression; Depressive Disorder; E-Selectin; Humans; Inflammation; Interleukin-6; Life Style; Lower Urinary Tract Symptoms; Male; Middle Aged; Peroxidase; Surveys and Questionnaires; Tumor Necrosis Factor-alpha

Macrophage migration inhibitory factor (MIF) is an important player in the regulation of the inflammatory response. Elevated plasma MIF is found in sepsis, arthritis, cystic fibrosis and atherosclerosis. Immunomodulatory activities of MIF include the ability to promote survival and recruitment of inflammatory cells and to amplify pro-inflammatory cytokine production. MIF has an unusual nucleophilic N-terminal proline with catalytic tautomerase activity. It remains unclear whether tautomerase activity is required for MIF function, but small molecules that inhibit tautomerase activity also inhibit the pro-inflammatory activities of MIF. A prominent feature of the acute inflammatory response is neutrophil activation and production of reactive oxygen species, including myeloperoxidase (MPO)-derived hypochlorous acid and hypothiocyanous acid. We hypothesized that MPO-derived oxidants would oxidize the N-terminal proline of MIF and alter its biological activity. MIF was exposed to hypochlorous acid and hypothiocyanous acid and the oxidative modifications on MIF were examined by LC-MS/MS. Imine formation and carbamylation was observed on the N-terminal proline in response to MPO-dependent generation of hypochlorous and hypothiocyanous acid, respectively. These modifications led to a complete loss of tautomerase activity. However, modified MIF still increased CXCL-8/IL-8 production by peripheral blood mononuclear cells (PBMCs) and blocked neutrophil apoptosis, indicating that tautomerase activity is not essential for these biological functions. Pre-treatment of MIF with hypochlorous acid protected the protein from covalent modification by the MIF inhibitor 4-iodo-6-phenylpyrimidine (4-IPP). Therefore, oxidant generation at inflammatory sites may protect MIF from inactivation by more disruptive electrophiles, including drugs designed to target the tautomerase activity of MIF.

Topics: Apoptosis; Chromatography, Liquid; Humans; Inflammation; Interleukin-8; Intramolecular Oxidoreductases; Leukocytes, Mononuclear; Macrophage Migration-Inhibitory Factors; Neutrophils; Oxidants; Oxidation-Reduction; Peroxidase; Recombinant Proteins; Tandem Mass Spectrometry

At the sites of inflammation, hypohalous acids, such as hypochlorous acid and hypobromous acid (HOBr), are produced by myeloperoxidase. These hypohalous acids rapidly react with the primary amino groups to produce haloamines, which are relatively stable and can diffuse long distances and cross the plasma membrane. In this study, we examined the effects of taurine, the most abundant free amino acid in the leukocyte cytosol, on the hypohalous acid-dependent formation of 8-chloro-2'-deoxyguanosine (8-CldG) and 8-bromo-2'-deoxyguanosine (8-BrdG). The reaction of taurine with HOBr yielded taurine bromamine, which is the most stable among other bromamines of amino acids. Taurine also enhanced the bromination of only dG among the four 2'-deoxynucleosides, whereas it inhibited the 8-CldG formation. The specificity of taurine for the enhanced formation of halogenated dG is completely different from that of nicotine, an enhancer of chlorination. The amount of dibrominated taurine (taurine dibromamine) closely correlated with the formation of 8-BrdG, suggesting that taurine dibromamine might be a plausible mediator for the dG bromination in vivo.

Topics: Animals; Bromates; Chromatography, High Pressure Liquid; Deoxyguanosine; Halogenation; Humans; Hypochlorous Acid; In Vitro Techniques; Inflammation; Peroxidase; Tandem Mass Spectrometry; Taurine

To confirm whether class I histone deacetylase inhibitors (HDACIs) are effective in relief of peripheral inflammatory pain, the effects of two selective inhibitors, MS-275 and MGCD0103, were studied in rats inflamed by subcutaneous (s.c.) injection of bee venom (BV). The BV test is characterized by displaying both persistent spontaneous nociception (PSN) and primary hypersensitivity. Intrathecal (i.t.) pre-treatment of either MS-275 or MGCD0103 with a single dose of 60 nmol/20 μL resulted in profound suppression of both PSN and primary thermal hypersensitivity but without significant influence upon the primary mechanical hypersensitivity and mirror-image thermal hypersensitivity. Moreover, the up-regulation of both HDAC1 and HDAC2 induced by s.c. BV injection was completely suppressed by i.t. pre-treatment of MS-275. The present results provide with another new line of evidence showing involvement of epigenetic regulation of chromatin structure by HDAC1/2-mediated histone hypoacetylation in the BV-induced PSN and thermal hypersensitivity and demonstrate the beneficial effects of class I HDACIs in prevention of peripheral inflammatory pain from occurring.

Topics: Animals; Bee Venoms; Benzamides; Epigenesis, Genetic; Histone Deacetylase 1; Histone Deacetylase 2; Histone Deacetylase Inhibitors; Hot Temperature; Hyperalgesia; Inflammation; Injections, Subcutaneous; Nociception; Pain; Pain Measurement; Pyridines; Pyrimidines; Rats; Rats, Sprague-Dawley; Up-Regulation

Puerarin, the main isoflavone glycoside extracted from the root of Pueraria lobata, is widely prescribed for patients with cardiovascular disorders in China. This study investigates the effect of puerarin on severe burn-induced acute myocardial injury in rats and its underlying mechanisms.. Healthy adult Wistar rats were divided into three groups: (1) sham group, sham burn treatment; (2) burn group, third-degree burns over 30% of the total body surface area (TBSA) with lactated Ringer's solution for resuscitation; and (3) burn plus puerarin group, third-degree burns over 30% of TBSA with lactated Ringer's solution containing puerarin for resuscitation. The burned animals were sacrificed at 1, 3, 6, 12, and 24 h after burn injury. Myocardial injury was evaluated by analyzing serum creatine kinase MB fraction (CK-MB) activity and cardiac troponin T (cTNT) level. Changes in cardiomyocyte ultrastructure were also determined using a transmission electron microscope. Tumor necrosis factor (TNF)-α concentration in serum was measured by radioimmunoassay. Cardiac myeloperoxidase (MPO) activity and malondialdehyde (MDA) concentration were measured to determine neutrophil infiltration and oxidative stress in the heart, respectively. The expression of p38 mitogen-activated protein (MAP) kinase in the heart was determined by Western blot analysis.. After the 30% TBSA full-thickness burn injury, serum CK-MB activities and cTnT levels increased markedly, both of which were significantly decreased by the puerarin treatment. The level of serum TNF-α concentration in burn group at each time-point was obviously higher than those in sham group (1.09±0.09 ng/ml), and it reached the peak value at 12 h post burn. Burn trauma also resulted in worsen ultrastructural condition, elevated MPO activity and MDA content in heart tissue, and a significant activation of cardiac p38 MAP kinase. Administration of puerarin improved the ultrastructural changes in cardiomyocytes, decreased TNF-α concentration in serum as well as suppressed cardiac MPO activity and reduced MDA content, and abolished the activation of p38 MAP kinase in heart tissue after severe burn.. These results suggest that puerarin attenuates inflammatory responses, reduces neutrophil infiltration and oxidative stress in the heart, and protects against acute myocardial injury induced by severe burn.

Topics: Animals; Burns; Creatine Kinase, MB Form; Heart; Inflammation; Isoflavones; Malondialdehyde; Myocardial Ischemia; Myocardium; Neutrophil Infiltration; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Peroxidase; Rats; Rats, Wistar; Trauma Severity Indices; Troponin T; Vasodilator Agents

Heart failure (HF) is accompanied by the development of an imbalance between oxygen- and nitric oxide-derived free radical production leading to protein nitration. Both chlorinating and peroxidase cycle of Myeloperoxidase (MPO) contribute to oxidative and nitrosative stress and are involved in tyrosine nitration of protein. Ceruloplasmin (Cp) has antioxidant function through its ferroxidase I (FeOxI) activity and has recently been proposed as a physiological defense mechanism against MPO inappropriate actions.. We investigated the relationship between plasma MPO-related chlorinating activity, Cp and FeOxI, and nitrosative stress, inflammatory, neurohormonal, and nutritional biomarkers in HF patients.. In chronic HF patients (n = 81, 76 ± 9 years, NYHA Class II (26); Class III (29); Class IV (26)) and age-matched controls (n = 17, 75 ± 11 years, CTR), plasma MPO chlorinating activity, Cp, FeOxI, nitrated protein, free Malondialdehyde, BNP, norepinephrine, hsCRP, albumin, and prealbumin were measured. Plasma MPO chlorinating activity, Cp, BNP, norepinephrine, and hsCRP were increased in HF versus CTR. FeOxI, albumin, and prealbumin were decreased in HF. MPO-related chlorinating activity was positively related to Cp (r = 0.363, P < 0.001), nitrated protein, hsCRP, and BNP and inversely to albumin.. Plasma MPO chlorinated activity is increased in elderly chronic HF patients and positively associated with Cp, inflammatory, neurohormonal, and nitrosative parameters suggesting a role in HF progression.

Topics: Aged; Aged, 80 and over; Albumins; Biomarkers; C-Reactive Protein; Ceruloplasmin; Chronic Disease; Cross-Sectional Studies; Female; Halogenation; Heart Failure; Humans; Inflammation; Male; Natriuretic Peptide, Brain; Peroxidase

Diallyl trisulfide (DATS) is a garlic organosulfide that may have a therapeutic potential in the treatment of some diseases. We sought to determine whether DATS could inhibit naphthalene-induced oxidative injury and the production of inflammatory responses in vitro and in vivo. A549 cells were either pre-treated (PreTx, prevention) or concurrently treated (CoTx, treatment) with 20μM naphthalene and either 5 or 10μM DATS. PreTx and CoTx showed the prevention and the treatment potential of DATS to inhibit the generation of naphthalene-induced reactive oxygen species (ROS) in the A549 cells. DATS showed antioxidative activity by elevating the SOD activities in the low dose groups. The mechanistic study showed that the DATS-mediated inhibition of naphthalene-induced oxidative injury and the production of inflammatory responses (i.e., TNF-α, IL-6, and IL-8) were attributed to inhibiting the activity of nuclear factor-kappa B (NF-κB). In addition, DATS inhibited the production of serum nitric oxide NO and myeloperoxidase (MPO) in the lungs of Kunming mice. The histological analysis results indicate that DATS inhibited the naphthalene-induced lung damage, which is consistent with the in vitro study results. The in vivo and in vitro results suggest that DATS may be an effective attenuator of naphthalene-induced lung damage.

Topics: Allyl Compounds; Animals; Anti-Inflammatory Agents; Antioxidants; Cell Line, Tumor; Female; Inflammation; Inflammation Mediators; Male; Mice; Naphthalenes; NF-kappa B; Nitric Oxide; Oxidative Stress; Peroxidase; Reactive Oxygen Species; Sulfides; Superoxide Dismutase

Chagas disease, which is caused by the parasite Trypanosoma cruzi, is an important cause of cardiomyopathy in Latin America. It is estimated that 10%-30% of all infected individuals will acquire chronic chagasic cardiomyopathy (CCC). The etiology of CCC is multifactorial and involves parasite genotype, host genetic polymorphisms, immune response, signaling pathways and autoimmune progression. Herein we verified the impact of the recombinant form of P21 (rP21), a secreted T. cruzi protein involved in host cell invasion, on progression of inflammatory process in a polyester sponge-induced inflammation model. Results indicated that rP21 can recruit immune cells induce myeloperoxidase and IL-4 production and decrease blood vessels formation compared to controls in vitro and in vivo. In conclusion, T. cruzi P21 may be a potential target for the development of P21 antagonist compounds to treat chagasic cardiomyopathy.

Topics: Animals; Cardiomyopathies; Cell Adhesion; Cell Line; Cell Survival; Chagas Disease; Chemotaxis; Cytokines; Disease Models, Animal; Inflammation; Interleukin-4; Leukocytes; Male; Mice; Mice, Inbred C57BL; Neovascularization, Physiologic; Peroxidase; Protozoan Proteins; Recombinant Proteins; Trypanosoma cruzi

Hesperetin, a major bioflavonoid in sweet oranges and lemons, has been reported to have anti-inflammatory properties. However, the effect of hesperetin on ventilator-induced acute lung injury has not been studied. In present study, we investigated the protective effect of hesperetin on ventilator-induced acute lung injury in rats. Rats were orally administered hesperetin (10, 20, or 40mg/kg) two hour before acute lung injury was induced by mechanical ventilation. Rats were then randomly divided into six groups: the lung protective ventilation group (n=20, LV group), injurious ventilation group (n=20, HV group), vehicle-treated injurious ventilation group (n=20, LV+vehicle group), hesperetin (10mg/kg)-treated acute lung injury group (n=20, HV+Hsp (10mg)), hesperetin (20mg/kg)-treated acute lung injury group (n=20, HV+Hsp (20mg)), and hesperetin (40mg/kg)-treated acute lung injury group (n=20, HV+Hsp (40mg)). The lung tissues and bronchoalveolar lavage fluid were isolated for subsequent measurements. Treatment with hesperetin dramatically improved the histology of lung tissue, and reduced the wet/dry ratio, myeloperoxidase activity, protein concentration, and production of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, and MIP-2 in the bronchoalveolar lavage fluid of rats with ventilator-induced acute lung injury. Additionally, our study indicated that this protective effect of hesperetin results from its ability to increase the expression of peroxisome proliferator-activated receptor (PPAR)-γ and inhibit the activation of the nuclear factor (NF)-κB pathway. These results suggest that hesperetin may be a potential novel therapeutic candidate for protection against ventilator-induced acute lung injury.

Topics: Animals; Bronchoalveolar Lavage Fluid; Cell Survival; Cytokines; Gene Expression Regulation; Hesperidin; Inflammation; Lung; Macrophages; Male; Peroxidase; PPAR gamma; Rats; Rats, Sprague-Dawley; Signal Transduction; Transcription Factor RelA; Ventilator-Induced Lung Injury

Acute inflammation either resolves or proceeds to fibrotic repair that replaces functional tissue. Pro-fibrotic hedgehog signaling and induction of its Gli transcription factor in pericytes induces fibrosis in kidney, but molecular instructions connecting inflammation to fibrosis are opaque. We show acute kidney inflammation resulting from chronic ingestion of the common xenobiotic ethanol initiates Gli1 transcription and hedgehog synthesis in kidney pericytes, and promotes renal fibrosis. Ethanol ingestion stimulated transcription of TGF-ß, collagens I and IV, and alpha-smooth muscle actin with accumulation of these proteins. This was accompanied by deposition of extracellular fibrils. Ethanol catabolism by CYP2E1 in kidney generates local reactive oxygen species that oxidize cellular phospholipids to phospholipid products that activate the Platelet-activating Factor receptor (PTAFR) for inflammatory phospholipids. Genetically deleting this ptafr locus abolished accumulation of mRNA for TGF-ß, collagen IV, and α-smooth muscle actin. Loss of PTAFR also abolished ethanol-stimulated Sonic (Shh) and Indian hedgehog (Ihh) expression, and abolished transcription and accumulation of Gli1. Shh induced in pericytes and Ihh in tubules escaped to urine of ethanol-fed mice. Neutrophil myeloperoxidase (MPO) is required for ethanol-induced kidney inflammation, and Shh was not present in kidney or urine of mpo-/- mice. Shh also was present in urine of patients with acute kidney injury, but not in normal individuals or those with fibrotic liver cirrhosis We conclude neither endogenous PTAFR signaling nor CYP2E1-generated radicals alone are sufficient to initiate hedgehog signaling, but instead PTAFR-dependent neutrophil infiltration with myeloperoxidase activation is necessary to initiate ethanol-induced fibrosis in kidney. We also show fibrogenic mediators escape to urine, defining a new class of urinary mechanistic biomarkers of fibrogenesis for an organ not commonly biopsied.

Topics: Animals; Collagen Type IV; Cytochrome P-450 CYP2E1; Ethanol; Female; Fibroblasts; Fibrosis; Hedgehog Proteins; Inflammation; Kidney; Mice; Mice, Inbred C57BL; Pericytes; Peroxidase; Platelet Membrane Glycoproteins; Receptors, G-Protein-Coupled; Signal Transduction; Transcription Factors; Transforming Growth Factor beta

In this study, the methotrexate (MTX) was incorporated into the poly(e-caprolactone) (PCL) to design implants (MTX PCL implants) aiming the local treatment of inflammatory angiogenesis diseases without causing systemic side effects. Sponges were inserted into the subcutaneous tissue of mice as a framework for fibrovascular tissue growth. After 4days, MTX PCL implants were also introduced, and anti-inflammatory, antiangiogenic, and antifibrogenic activities of the MTX were determined. MTX reduced the vascularization (hemoglobin content), the neutrophil, and monocyte/macrophage infiltration (MPO and NAG activities, respectively), and the collagen deposition in sponges. MTX reduced tumor necrosis factor-a and IL-6 levels, demonstrating its local antiangiogenic and anti-inflammatory effects. Furthermore, hepatotoxicity, nephrotoxicity, and myelotoxicity, which could be induced by the drug, were evaluated. However, MTX did not promote toxicity to these organs, as the levels of AST and ALT (hepatic markers) and creatinine and urea (renal markers) were not increased, and the complete blood count was not decreased. In conclusion, MTX PCL implants demonstrated to be effective in regulating the components of the inflammatory angiogenesis locally established, and presented an acceptable safety profile. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:3731-3742, 2015.

Topics: Acetylglucosaminidase; Angiogenesis Inhibitors; Animals; Anti-Inflammatory Agents; Cell Proliferation; Collagen; Drug Delivery Systems; Drug Implants; Drug Liberation; Inflammation; Interleukin-6; Macrophages; Male; Methotrexate; Mice; Mice, Inbred BALB C; Neovascularization, Pathologic; Neutrophil Infiltration; Peroxidase; Polyesters; Tissue Distribution; Tumor Necrosis Factor-alpha

The pathophysiological features of chronic obstructive pulmonary disease (COPD)-asthma overlap are poorly understood and there has been no study of plasma or sputum biomarkers in overlap patients. In order to clarify the similarity and differences between overlap and COPD or asthma, we have investigated four potential biomarkers of COPD: surfactant protein A (SP-A), soluble receptor for advanced glycation end-products (sRAGE), myeloperoxidase (MPO) and neutrophil gelatinase-associated lipocalin (NGAL). SP-A and sRAGE are pneumocyte-derived markers. MPO and NGAL are neutrophil-derived molecules, but NGAL can also be expressed by respiratory epithelial cells. Plasma levels of SP-A and sRAGE and induced sputum levels of MPO and NGAL were measured by enzyme immunoassay/ELISA in 134 subjects: nonsmokers (n=26), smokers (n=23), asthma (n=32), COPD (n=39) and COPD-asthma overlap patients (n=14). In patients with COPD-asthma overlap, sputum MPO and plasma SP-A were significantly elevated whereas plasma sRAGE levels were reduced compared with asthma patients. Only sputum NGAL was significantly elevated in COPD-asthma overlap compared with COPD (p=0.00016) and could be used to differentiate patients with overlap from those with COPD. Increased induced sputum levels of NGAL might be a characteristic feature of overlap, suggesting enhanced neutrophilic airway inflammation and/or airway epithelial injury in COPD-asthma overlap.

Topics: Acute-Phase Proteins; Adult; Aged; Asthma; Biomarkers; Cell Differentiation; Comorbidity; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression Regulation; Humans; Inflammation; Lipocalin-2; Lipocalins; Male; Middle Aged; Neutrophils; Peroxidase; Proto-Oncogene Proteins; Pulmonary Disease, Chronic Obstructive; Pulmonary Surfactant-Associated Protein A; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Smoking; Sputum

The aim of this study was to investigate the anti-inflammatory effect of the crude hydroalcoholic extract (CHE) from the aerial parts of Croton antisyphiliticus, its fractions and isolated compounds derived from it on the mouse model of pleurisy induced by carrageenan. The aerial parts of C. antisyphiliticus were dried, macerated and extracted with ethanol to obtain the CHE, which was fractionated by liquid-liquid extraction using solvents with increasing polarity to obtain hexane (Hex), ethyl acetate (EA) and aqueous (Aq) fractions. Vitexin and quinic acid were isolated from Aq fraction. Capillary electrophoresis analysis, physical characteristics and spectral data produced by infrared (IR), nuclear magnetic resonance ((1)H and (13)C NMR) and mass spectrometry analyses were used to identify and elucidate the structure of the isolated compounds. The experimental model of pleurisy was induced in mice by a single intrapleural injection of carrageenan (1 %). Leukocytes, exudate concentrations, myeloperoxidase (MPO) and adenosine-deaminase (ADA) activities and nitrate/nitrite (NOx), tumor necrosis factor-α (TNF-α) and interleukin-17 (IL-17) levels were determined in the pleural fluid leakage at 4 h after pleurisy induction. Animals pre-treated with CHE, Hex, EA, Aq, vitexin and quinic acid exhibited decreases in leukocytes, exudate concentrations, MPO and ADA activities and NOx levels (p < 0.05). Also CHE, Hex, EA and vitexin but not quinic acid inhibited TNF-α and IL-17 levels (p < 0.05). C. antisyphiliticus caused anti-inflammatory effect by inhibiting the activated leukocytes, exudate concentrations, NOx, TNF-α, and IL-17 levels. The compounds vitexin and quinic acid may be responsible for this anti-inflammatory action.

Topics: Adenosine Deaminase; Animals; Anti-Inflammatory Agents; Carrageenan; Croton; Disease Models, Animal; Female; Inflammation; Interleukin-17; Leukocytes; Mice; Nitrates; Nitrites; Peroxidase; Plant Extracts; Pleurisy; Tumor Necrosis Factor-alpha

In patients with acute kidney injury (AKI) mortality remains high, despite the fact that the patients are treated with continuous renal replacement therapy. The interaction between the kidney and the immune system might explain the high mortality observed in AKI. In order to elucidate the interaction between the kidney and immune system we developed a two-hit model of AKI and endotoxemia. Our hypothesis was that ischemia/reperfusion (I/R) of the kidney simultaneously with endotoxemia would generate a more extensive inflammatory response compared to I/R of the hind legs. Our expectation was that elevated levels of cytokines would be found in both blood and in organs distant to the kidneys. Forty mice were divided into five groups. The mice were subjected to the following operations: A: Sham only, no lipopolysaccharide (LPS); B: I/R of both kidneys + LPS; C: LPS only; D: Nephrectomy + LPS; E: I/R of both hind legs + LPS. In groups B and E, I/R times were identical. All mice were kept alive for 24 h and then sacrificed. Levels of interleukin (IL)-1β, IL-6, IL-10, and tumor necrosis factor-α were measured in the blood. The activity of myeloperoxidase (MPO) in lungs, kidneys, and liver was evaluated as an indirect measurement of accumulation of granulocytes. In this study, significantly higher amount of IL-6 and IL-10 in the plasma was observed following renal I/R compared to hind leg I/R. The elevated levels of cytokine in plasma were observed following nephrectomy and endotoxemia. The neutrophil infiltration of distant organs measured by the levels of MPO in the lung and liver also showed a significantly higher level in renal I/R compared to hind leg I/R. Renal I/R is associated with a more pronounced inflammatory response in blood and distant organs. The high cytokine levels measured following nephrectomy might be explained by compromised elimination of cytokines by the kidney in AKI.

Topics: Acute Kidney Injury; Animals; Disease Models, Animal; Endotoxemia; Inflammation; Interleukin-10; Interleukin-1beta; Interleukin-6; Ischemia; Kidney; Lipopolysaccharides; Liver; Lung; Male; Mice; Mice, Inbred C57BL; Nephrectomy; Neutrophil Infiltration; Peroxidase; Reperfusion Injury; Tumor Necrosis Factor-alpha

Periodontitis is a common infectious disease associated with increased risk for ischemic stroke though presently unclear mechanisms. In a case-control study, we investigated salivary levels of four periodontal pathogens, as well as systemic and local inflammatory markers. The population comprised 98 patients with acute ischemic stroke (mean ± SD, 68.2 ± 9.7 yrs; 45.9% women) and 100 healthy controls (69.1 ± 5.2 yrs; 47.0% women). Patients were more often edentulous and had fewer teeth than controls (13.8 ± 10.8 versus 16.6 ± 10.1). After adjusting for stroke risk factors and number of teeth, controls had higher saliva matrix metalloproteinase-8 (MMP-8), myeloperoxidase (MPO), IL-1β, Aggregatibacter actinomycetemcomitans, and serum LPS activity levels. Patients had higher serum MMP-8 and MPO, and they were more often qPCR-positive for A. actinomycetemcomitans (37.9% versus 19.0%) and for ≥3 periodontopathic species combined (50.0% versus 33.0%). We conclude that controls more often had evidence of current periodontal infection with higher periodontal pathogen amount, endotoxemia, local inflammation and tissue destruction. Stroke patients more often had evidence of end-stage periodontitis with edentulism and missing teeth. They were more often carriers of several periodontopathic pathogens in saliva, especially A. actinomycetemcomitans. Additionally, inflammatory burden may contribute to high systemic inflammation associated with elevated stroke susceptibility.

Topics: Aged; Aggregatibacter actinomycetemcomitans; Biomarkers; Brain Ischemia; Case-Control Studies; Female; Humans; Inflammation; Interleukin-1beta; Male; Matrix Metalloproteinase 8; Mouth, Edentulous; Periodontitis; Peroxidase; Porphyromonas gingivalis; Risk Factors; Saliva; Stroke

Studies have shown that diterpenes have anti-inflammatory and redox-protective pharmacological activities. The present study aimed to investigate the anti-inflammatory properties of phytol, a diterpene alcohol, in a mouse model of acute inflammation, and phytol effect on leukocyte recruitment, cytokines levels, and oxidative stress. The anti-inflammatory activities of phytol were assessed by measuring paw edema induced by different inflammatory agents (e.g., λ-carrageenan, compound 48/80, histamine, serotonin, bradykinin, and prostaglandin E2 [PGE2 ]), myeloperoxidase (MPO) activity, peritonitis model and cytokine levels. Further, oxidative stress was evaluated by determining glutathione (GSH) levels and malondialdehyde (MDA) concentration. The results showed that phytol (7.5, 25, 50, and 75 mg/kg) significantly reduced carrageenan-induced paw edema, in a dose-dependent manner. In addition, phytol (75 mg/kg) inhibited compound 48/80-, histamine-, serotonin-, bradykinin- and PGE2 -induced paw edema. It also inhibited the recruitment of total leukocytes and neutrophils; decreased MPO activity, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) levels, and MDA concentration; and increased GSH levels during carrageenan-induced acute inflammation. These results suggest that phytol attenuates the inflammatory response by inhibiting neutrophil migration that is partly caused by reduction in IL-1β and TNF-α levels and oxidative stress.

Topics: Animals; Anti-Inflammatory Agents; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Glutathione; Inflammation; Interleukin-1beta; Leukocytes; Male; Malondialdehyde; Mice; Neutrophils; Oxidative Stress; Peroxidase; Phytol; Tumor Necrosis Factor-alpha

Cyclophosphamide induces urotoxicity characterized by the development of cystitis, which involves bladder overactivity and inflammation. Here, we investigated the roles of chemokine receptor 2 (CXCR2) and transient receptor potential vanilloid 1 (TRPV1) channels in a rat model of cyclophosphamide-induced cystitis.. Cystitis induced by cyclophosphamide in rats was assessed by gross morphology, histology and immunohistochemistry of bladder tissue. mRNA for CXCR2 and TRPV1 channels were measured by RT-PCR. Nociceptive responses in paw and abdomen, along with cystometric measures were recorded.. Cyclophosphamide, i.p., induced pain behaviour, bladder inflammation and voiding dysfunction. The CXCR2 antagonist, SB225002, the TRPV1 channel antagonist, SB366791 or their combination reduced the mechanical hypersensitivity of paw and abdominal area and nociceptive behaviour after cyclophosphamide. Cyclophosphamide-induced cystitis was characterized by haemorrhage, oedema, neutrophil infiltration and other inflammatory changes, which were markedly decreased by the antagonists. Up-regulation of CXCR2 and TRPV1 mRNA in the bladder after cyclophosphamide was inhibited by SB225002, SB366791 or their combination. Expression of CXCR2 and TRPV1 channels was increased in the urothelium after cyclophosphamide. Bladder dysfunction was shown by increased number of non-voiding contractions (NVCs) and bladder pressures and a reduction in bladder capacity (BC), voided volume (VV) and voiding efficiency (VE). SB225002 or its combination with SB366791 reduced bladder pressures, whereas SB225002, SB366791 or their combination increased BC, VV and VE, and also reduced the number of NVCs.. CXCR2 and TRPV1 channels play important roles in cyclophosphamide-induced cystitis in rats and could provide potential therapeutic targets for cystitis.

Topics: Animals; Antineoplastic Agents, Alkylating; Behavior, Animal; Cyclophosphamide; Cystitis; Cytokines; Female; Hemorrhagic Disorders; Hyperalgesia; Immunohistochemistry; Inflammation; Neutrophils; Organ Size; Pain Measurement; Peroxidase; Rats; Real-Time Polymerase Chain Reaction; Receptors, Interleukin-8B; TRPV Cation Channels; Urinary Bladder

Evidence is accumulating that chronic inflammation may have an important mechanism for the development and progression of lung cancer. Therefore, genetic polymorphisms in genes that involved in the inflammatory response may be associated with lung cancer risk. We evaluated the role of tumor necrosis factor α (TNFA) rs1799724, interleukin 1β (IL1B) rs16944, IL6 rs1800796, myeloperoxidase (MPO) rs2333227 and C-reactive protein (CRP) rs2794520 in a case-control study comprised of 462 lung cancer cases and 379 controls in a Japanese population. Unconditional logistic regression was used to assess the adjusted odds ratios (OR) and 95% confidence intervals (95% CI). CRP rs2794520 (OR=1.64, 95% CI=1.19-2.26) and IL6 rs1800796 (OR=1.41, 95% CI=1.02-1.96) were associated with lung cancer risk. In addition, we assessed interactions between the polymorphisms and smoking. The polymorphisms did not significantly modify the association between smoking and lung cancer. As TNFA triggers a cytokine cascade, the modifying effect of the TNFA rs1799724 genotypes on the association of any of the remaining polymorphisms with lung cancer risk was also examined. There was a significant interaction between TNFA rs1799724 and MPO rs2333227 (Pinteraction=0.058). Future studies involving larger control and case populations will undoubtedly lead to a more thorough understanding of the role of the polymorphisms involved in the inflammation pathway in lung cancer.

Topics: Aged; C-Reactive Protein; Case-Control Studies; Female; Genetic Predisposition to Disease; Humans; Inflammation; Interleukin-1beta; Interleukin-6; Japan; Lung Neoplasms; Male; Middle Aged; Peroxidase; Polymorphism, Single Nucleotide; Risk; Risk Factors; Smoking; Tumor Necrosis Factor-alpha

Recently, apprehension has been raised regarding "A1/A2 hypothesis" suggesting relationship between consumption of A1 "like" variants of cow β-casein and various physiological disorders. The information available is based on either the human epidemiological data of milk consumption or in vitro trials on cell lines with β-casomorphin peptides. The direct scientific evidence establishing the link between consumption of A1/A2 "like" milk and health is scanty. Thus, under present investigation, in vivo trials in mice were undertaken to study the effect of feeding three genetic variants (A1A1, A1A2 and A2A2) of cow β-casein milk on gastrointestinal immune system as it is the first and foremost site of immunological interactions.. Animals were divided into four groups for feeding with basal diet (control) and β-casein isolated from milk of genotyped (A1A1, A1A2 and A2A2) dairy animals, respectively. Gut immune response was analyzed by spectrophotometric assessment of MPO activity, quantitative sandwich ELISA of inflammatory cytokines (MCP-1 and IL-4), antibodies (total IgE, IgG, sIgA, IgG1 and IgG2a) and qRT-PCR of mRNA expression for toll-like receptors (TLR-2 and TLR-4). Histological enumeration of goblet cells, total leukocytes and IgA(+) cells was also carried out.. It was observed that consumption of A1 "like" variants (A1A1 and A1A2) significantly increased (p < 0.01) the levels of MPO, MCP-1, IL-4, total IgE, IgG, IgG1, IgG2a and leukocyte infiltration in intestine. TLR-2 and TLR-4 mRNA expression was also up-regulated (p < 0.01) on administration of A1 "like" variants. However, no changes in sIgA, IgA(+) and goblet cell numbers were recorded on consumption of any of the β-casein variants.. It is reasonable to conclude that consumption of A1 "like" variants of β-casein induced inflammatory response in gut by activating Th2 pathway as compared to A2A2 variants. The present study thus supports the purported deleterious impacts of consumption of A1 "like" variants of β-casein and suggests possible aggravation of inflammatory response for etiology of various health disorders.

Topics: Animals; Caseins; Cattle; Chemokine CCL2; Electrophoresis, Polyacrylamide Gel; Endorphins; Gastrointestinal Tract; Genetic Variation; Immunoglobulin A, Secretory; Immunoglobulin E; Immunoglobulin G; Inflammation; Interleukin-4; Male; Mice; Milk; Peroxidase; RNA, Messenger; Toll-Like Receptor 2; Toll-Like Receptor 4; Up-Regulation

Coumarins, also known as benzopyrones, are plant-derived products with several pharmacological properties, including antioxidant and anti-inflammatory activities. Based on the wide distribution of coumarin derivatives in plant-based foods and beverages in the human diet, our objective was to evaluate both the antioxidant and intestinal anti-inflammatory activities of six coumarin derivatives of plant origin (scopoletin, scoparone, fraxetin, 4-methyl-umbeliferone, esculin and daphnetin) to verify if potential intestinal anti-inflammatory activity was related to antioxidant properties.. Intestinal inflammation was induced by intracolonic instillation of TNBS in rats. The animals were treated with coumarins by oral route. The animals were killed 48 h after colitis induction. The colonic segments were obtained after laparotomy and macroscopic and biochemical parameters (determination of glutathione level and myeloperoxidase and alkaline phosphatase activities) were evaluated. The antioxidant properties of these coumarins were examined by lipid peroxidation and DPPH assays.. Treatment with esculin, scoparone and daphnetin produced the best protective effects. All coumarin derivatives showed antioxidant activity in the DPPH assay, while daphnetin and fraxetin also showed antioxidant activity by inhibiting lipid peroxidation. Coumarins, except 4-methyl-umbeliferone, also showed antioxidant activity through the counteraction of glutathione levels or through the inhibition of myeloperoxidase activity.. The intestinal anti-inflammatory activity of coumarin derivatives were related to their antioxidant properties, suggesting that consumption of coumarins and/or foods rich in coumarin derivatives, particularly daphnetin, esculin and scoparone, could prevent intestinal inflammatory disease.

Topics: Alkaline Phosphatase; Animals; Anti-Inflammatory Agents; Antioxidants; Biphenyl Compounds; Colitis; Colon; Coumarins; Esculin; Glutathione; Inflammation; Inflammatory Bowel Diseases; Lipid Peroxidation; Male; Oxidative Stress; Peroxidase; Phytotherapy; Picrates; Plant Extracts; Rats; Rats, Wistar; Umbelliferones

Paeonia lactiflora Pall is one of the most well-known herbs in China, Korea, and Japan for more than 1,200 years. Paeoniflorin, the major bioactive component of peony root, has recently been reported to have anticolitic activity. However, the underlying molecular mechanism is unclear. The present study was to explore the possible mechanism of paeoniflorin in attenuating dextran sulfate sodium (DSS)-induced colitis. Pre- and coadministration of paeoniflorin significantly reduced the severity of colitis and resulted in downregulation of several inflammatory parameters in the colon, including the activity of myeloperoxidase (MPO), the levels of TNF-α and IL-6, and the mRNA expression of proinflammatory mediators (MCP-1, Cox2, IFN-γ, TNF-α, IL-6, and IL-17). The decline in the activation of NF-κB p65, ERK, JNK, and p38 MAPK correlated with a decrease in mucosal Toll-like receptor 4 (TLR4) but not TLR2 or TLR5 expression. In accordance with the in vivo results, paeoniflorin downregulated TLR4 expression, blocked nuclear translocation of NF-κB p65, and reduced the production of IL-6 in LPS-stimulated mouse macrophage RAW264.7 cells. Transient transfection assay performed in LPS-stimulated human colon cancer HT-29 cells indicated that paeoniflorin inhibits NF-κB transcriptional activity in a dose-dependent manner. TLR4 knockdown and overexpression experiments demonstrated a requirement for TLR4 in paeoniflorin-mediated downregulation of inflammatory cytokines. Thus, for the first time, the present study indicates that paeoniflorin abrogates DSS-induced colitis via decreasing the expression of TLR4 and suppressing the activation of NF-κB and MAPK pathways.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzoates; Biological Availability; Bridged-Ring Compounds; Colitis; Dextran Sulfate; Drugs, Chinese Herbal; Gene Expression Profiling; Glucosides; HT29 Cells; Humans; Inflammation; Interleukin-6; MAP Kinase Signaling System; Mice; Mitogen-Activated Protein Kinases; Models, Animal; Monoterpenes; NF-kappa B; Paeonia; Peroxidase; Protein Biosynthesis; Toll-Like Receptor 4; Transcriptional Activation; Tumor Necrosis Factor-alpha

The present study aimed to investigate the potential anti-inflammatory and anti-nociceptive effects of carvacryl acetate, a derivative of carvacrol, in mice.. The anti-inflammatory activity was evaluated using various phlogistic agents that induce paw edema, peritonitis model, myeloperoxidase (MPO) activity, pro and anti-inflammatory cytokine levels. Evaluation of antinociceptive activity was conducted through acetic acid-induced writhing, hot plate test, formalin test, capsaicin and glutamate tests, as well as evaluation of motor performance on rotarod test.. Pretreatment of mice with carvacryl acetate (75 mg/kg) significantly reduced carrageenan-induced paw edema (P<0.05) when compared to vehicle-treated group. Likewise, carvacryl acetate (75 mg/kg) strongly inhibited edema induced by histamine, serotonin, prostaglandin E2 and compound 48/80. In the peritonitis model, carvacryl acetate significantly decreased total and differential leukocyte counts, and reduced levels of myeloperoxidase and interleukin-1 beta (IL-1β) in the peritoneal exudate. The levels of IL-10, an anti-inflammatory cytokine, were enhanced by carvacryl acetate. Pretreatment with carvacryl acetate also decreased the number of acetic acid-induced writhing, increased the latency time of the animals on the hot plate and decreased paw licking time in the formalin, capsaicin and glutamate tests. The pretreatment with naloxone did not reverse the carvacryl acetate-mediated nociceptive effect.. In conclusion, the current study demonstrated that carvacryl acetate exhibited anti-inflammatory activity in mice by reducing inflammatory mediators, neutrophil migration and cytokine concentration, and anti-nociceptive activity due to the involvement of capsaicin and glutamate pathways.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Cytokines; Disease Models, Animal; Edema; Immune System Diseases; Inflammation; Inflammation Mediators; Leukocyte Disorders; Male; Mice; Monoterpenes; Pain; Peritonitis; Peroxidase

The sulfated polysaccharide (PLS) fraction of Agardhiella ramosissima was characterized by microanalysis, infrared spectroscopy, NMR and gas-liquid-chromatography-mass-spectrometry. The main constituent of PLS was the ι carrageenan. The monosaccharide composition of the PLS showed galactose, 3,6-anhydrogalactose and 6-O-methylgalactose. The PLS (30 mg kg(-1)) significantly reduced the paw oedema induced by carrageenan, dextran, histamine and serotonin and also was able to significantly inhibit leucocyte migration into the peritoneal cavity and decrease the concentration of myeloperoxidase (MPO) in paw tissue. In the antinociceptive tests, the pre-treatment with PLS reduced the number of writhes, the licking time but did not increase the latency time of response. This study demonstrates for the first time the anti-inflammatory and anti-nociceptive effects of PLS from A. ramosissima. Thus, we concluded that PLS could be a new natural tool in pain and acute inflammatory conditions.

Topics: Animals; Anti-Inflammatory Agents; Carrageenan; Cell Movement; Dextrans; Edema; Galactose; Hindlimb; Histamine; Inflammation; Male; Methylgalactosides; Mice; Nociception; Pain; Peroxidase; Plant Extracts; Polysaccharides; Rhodophyta; Serotonin; Spectroscopy, Fourier Transform Infrared

Temporomandibular disorder (TMD) is prevalent in dental clinics and can involve problems with the masticatory muscles or the temporomandibular joints (TMJ). The pain of TMD is frequently associated with inflammation in the TMJs, but it's etiology is considered to be multifactorial and includes biologic, behavioral, environmental, social, emotional and cognitive factors. The purpose of this investigation was to evaluate the anxiety-like behavior in rats exposed to temporomandibular inflammation via injection of Freund's Adjuvant (CFA) with the elevated plus maze (EPM) and light/dark box (LDB) tests and to evaluate nociceptive behavior with the von Frey test at different periods. Moreover, this study measured TMJ inflammation using plasma extravasation (Evans blue test) and the intraarticular infiltration of polymorphonuclear neutrophils (myeloperoxidase quantification). The results showed that rats that were submitted to TMJ inflammation exhibited a decreased number of entries into the open arms of the EPM and a decrease in the time spent in the light compartment and in the number of transitions in the LDB. Additionally, the number of entries in closed arms in the EPM, used as indicator of locomotor activity, did not alter between treatments. Furthermore, increases in mechanical sensitivity and increases in plasma extravasation in the joint tissue occurred throughout the inflammation process, along with an increase in myeloperoxidase in the synovial fluid of TMJ. Our results suggest that the temporomandibular inflammation induced by CFA produced anxiety-like behaviors in rats and induced nociceptive behavior across different periods of inflammation.

Topics: Animals; Anxiety; Behavior, Animal; Extravasation of Diagnostic and Therapeutic Materials; Freund's Adjuvant; Inflammation; Male; Neutrophil Infiltration; Nociceptive Pain; Peroxidase; Rats; Synovial Fluid; Temporomandibular Joint Disorders; Time Factors

Inflammatory cells surround breast carcinomas and may act promoting tumor development or stimulating anti-tumor immunity. N-acetylglucosaminidase (NAG) has been employed to detect macrophage accumulation/activation. Myeloperoxidase (MPO) is considered a marker for neutrophils activity/accumulation. Vascular Endothelial Growth Factor (VEGF) is as strong pro-angiogenic cytokine. The aim of this study was to measure the systemic inflammatory response by measuring serum levels of NAG, MPO and VEGF in women diagnosed with breast cancer and associate this response to the peritumoral inflammatory infiltrate and to prognostic factors. Serum samples obtained from women with no evidence of disease (n=31) and with breast cancer (n=68) were analyzed for the activities of NAG, MPO and VEGF by enzymatic assay. Serum levels of NAG and VEGF were higher in healthy volunteers (P<0.0001) and serum levels of MPO were higher in patients with breast cancer (P=0.002). Serum levels of NAG were positively correlated to serum levels of MPO and VEGF (P<0.0001 and P=0.0012, respectively) and MPO and VEGF serum levels had also a positive correlation (P=0.0018). The inflammatory infiltrate was not associated to serum levels of the inflammatory markers, and higher levels of MPO were associated to lymphovascular invasion negativity (P=0.0175).

Topics: Acetylglucosaminidase; Adolescent; Adult; Aged; Breast Neoplasms; Case-Control Studies; Female; Humans; Inflammation; Middle Aged; Peroxidase; Prognosis; Prospective Studies; Surveys and Questionnaires; Vascular Endothelial Growth Factor A; Young Adult

The small G protein RhoA and its downstream effector Rho-kinase play an important role in various physiopathological processes including ischemia/reperfusion (I/R) injury. Reactive oxygen and nitrogen species produced by iNOS and NADPH oxidase are important mediators of inflammation and organ injury following an initial localized I/R event. The aim of this study was to determine whether RhoA/Rho-kinase signaling pathway increases the expression and activity of MEK1, ERK1/2, iNOS, gp91(phox), and p47(phox), and peroxynitrite formation which result in oxidative/nitrosative stress and inflammation leading to hindlimb I/R-induced injury in kidney as a distant organ and gastrocnemius muscle as a target organ. I/R-induced distant and target organ injury was performed by using the rat hindlimb tourniquet model. I/R caused an increase in the expression and/or activity of RhoA, MEK1, ERK1/2, iNOS, gp91(phox), p47(phox), and 3-nitrotyrosine and nitrotyrosine levels in the tissues. Although Rho-kinase activity was increased by I/R in the kidney, its activity was decreased in the muscle. Serum and tissue MDA levels and MPO activity were increased following I/R. I/R also caused an increase in SOD and catalase activities associated with decreased GSH levels in the tissues. Y-27632, a selective Rho-kinase inhibitor, (100µg/kg, i.p.; 1h before reperfusion) prevented the I/R-induced changes except Rho-kinase activity in the muscle. These results suggest that activation of RhoA/Rho-kinase/MEK1/ERK1/2/iNOS pathway associated with oxidative/nitrosative stress and inflammation contributes to hindlimb I/R-induced distant organ injury in rats. It also seems that hindlimb I/R induces target organ injury via upregulation of RhoA/MEK1/ERK1/2/iNOS pathway associated with decreased Rho-kinase activity.

Topics: Amides; Animals; Catalase; Glutathione; Inflammation; Kidney; Male; Malondialdehyde; MAP Kinase Kinase 1; MAP Kinase Signaling System; Muscle, Skeletal; NADPH Oxidases; Nitric Oxide Synthase Type II; Oxidative Stress; Peroxidase; Peroxynitrous Acid; Pyridines; Rats; Rats, Wistar; Reperfusion Injury; rho-Associated Kinases; rhoA GTP-Binding Protein; Superoxide Dismutase; Tyrosine

This study investigated the effect of dietary fish oil on systemic inflammation and hepatic injury in mice with polymicrobial sepsis. Male ICR mice were assigned to a control group (C, n=30) and a fish oil group (FO, n=30). Mice in the C group were fed a semi-purified diet with 10% soybean oil, and those in the FO group were fed a fish oil diet (2.5% fish oil+7.5% soybean oil; w/w). Three weeks later, sepsis was induced by cecal ligation and puncture (CLP), and mice were sacrificed at 0, 6 and 24 h after CLP, respectively. Results showed that compared with C group, the FO group had lower plasma levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10, and nitrite at 6 and 24 h after CLP. Also, peritoneal lavage fluid concentrations of TNF-α and prostaglandin (PG) E2 were significantly lower at 24 h in the FO than in the C group. The FO group had lower myeloperoxidase activities at 6 h after CLP in various organs. Plasma aminotransferase and alanine aminotransferase activities revealed significantly decreased in the FO group. The DNA-binding activity of peroxisome proliferators-activated receptor gamma (PPARγ) and mRNA expression of I kappaB alpha (IκBα) were up-regulated while nuclear factor (NF)-κB p65 DNA-binding activity, inducible nitric oxide synthase protein expression and the concentration of nitrotyrosine were significantly decreased in the FO group in liver after CLP. These results indicate that dietary fish oil administration may attenuate systemic inflammation and up-regulate hepatic PPARγ DNA-binding activity, which may consequently have ameliorated liver injury in these septic mice.

Topics: Animals; Biomarkers; Fatty Acids, Omega-3; Fish Oils; Inflammation; Interleukin-10; Interleukin-6; Liver; Liver Diseases; Male; Mice; Mice, Inbred ICR; NF-kappa B; Nitric Oxide Synthase Type II; Peroxidase; PPAR gamma; Sepsis; Tumor Necrosis Factor-alpha; Tyrosine; Up-Regulation

It is unclear whether changes in plasma levels of inflammatory markers could explain the link between ischemia and slow coronary flow (SCF). The aim of the study was to evaluate the plasma levels of high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, and myeloperoxidase (MPO) during myocardial perfusion imaging (MPI) in SCF patients.. The study population consisted of 53 SCF patients and 30 controls. Coronary flow rates were documented by TIMI frame count (TFC). Plasma levels of hsCRP, IL-6, MPO, and MPI were obtained in all participants.. hsCRP, IL-6 and MPO levels of SCF patients were higher than controls (hsCRP: 4.7 ± 2.5 vs. 1.7 ± 1.1 mg/L, p <0.001; IL-6: 8.2 ± 4.3 vs. 5.2 ± 2.1 pg/mL, p <0.001; and MPO: 75.9 ± 59.6 vs. 24.3 ± 16.7 ng/mL, p <0.001). Twenty-one SCF patients exhibited myocardial perfusion defect (MPD) on MPI. In SCF patients, the highest hsCRP, IL-6 and MPO levels were observed in patients with both MPD and three-vessel slow flow. Mean TFCs were positively correlated with plasma levels of hsCRP (r = 0.424, p = 0.002), IL-6 (r = 0.367, p = 0.007), MPO (r = 0.430, p = 0.001), and reversibility score (r = 0.671, p <0.001) in SCF patients. HsCRP and MPO were the independent variables, which predicted positive MPI results (hsCRP: OR, 2.176; 95% CI, 1.200-3.943; p = 0.010, MPO: OR, 1.026; 95% CI, 1.007-1.046; p = 0.008).. Inflammation may play a crucial role in both the pathogenesis and development of ischemia in SCF. Association of increased levels of inflammatory markers and ischemia suggests that endothelial inflammation may be largely responsible for clinical presentation. New combined treatment regimens should target endothelial activation and inflammation in SCF.

Topics: Adult; Biomarkers; C-Reactive Protein; Case-Control Studies; Coronary Angiography; Coronary Circulation; Female; Humans; Inflammation; Interleukin-6; Male; Middle Aged; Myocardial Ischemia; Myocardial Perfusion Imaging; Peroxidase

Camel milk has traditionally been used to treat cancer, but this practice awaits scientific scrutiny, in particular its role in tumor angiogenesis, the key step involved in tumor growth and metastasis. We aimed to investigate the effects of camel milk on key components of inflammatory angiogenesis in sponge implant angiogenesis model. Polyester-polyurethane sponges, used as a framework for fibrovascular tissue growth, were implanted in Swiss albino mice and camel milk (25, 50 and 100 mg/kg/day) was administered for 14 days through installed cannula. The implants collected at day 14 post-implantation were processed for the assessment of hemoglobin (Hb), myeloperoxidase (MPO), N-acetylglucosaminidase (NAG), and collagen, which were used as indices for angiogenesis, neutrophil, and macrophage accumulation and extracellular matrix deposition, respectively. Relevant inflammatory, angiogenic, and fibrogenic cytokines were also determined. Camel milk treatment attenuated the main components of the fibrovascular tissue, wet weight, vascularization (Hb content), macrophage recruitment (NAG activity), collagen deposition and the levels of vascular endothelial growth factor (VEGF), interleukin (IL)-1β, IL-6, IL-17, tumor necrosis factor-α, and transforming growth factor-β. A regulatory function of camel milk on multiple parameters of the main components of inflammatory angiogenesis has been revealed, giving insight into the potential therapeutic benefit underlying the anti-cancer actions of camel milk.

Topics: Acetylglucosaminidase; Angiogenesis Inhibitors; Animals; Camelus; Chemoprevention; Collagen; Cytokines; Disease Models, Animal; Hemoglobins; Inflammation; Interleukin-17; Interleukin-1beta; Interleukin-6; Lactation; Macrophages; Male; Mice; Milk; Neoplasms; Neovascularization, Pathologic; Neutrophils; Peroxidase; Polyesters; Polyurethanes; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

PGE2 has long been known as a potentiator of acute inflammation, but its mechanisms of action still remain to be defined. In this study, we employed inflammatory swelling induced in mice by arachidonate and PGE2 as models and dissected the role and mechanisms of action of each EP receptor at the molecular level. Arachidonate- or PGE2-induced vascular permeability was significantly reduced in EP3-deficient mice. Intriguingly, the PGE2-induced response was suppressed by histamine H1 antagonist treatment, histidine decarboxylase deficiency, and mast cell deficiency. The impaired PGE2-induced response in mast cell-deficient mice was rescued upon reconstitution with wild-type mast cells but not with EP3-deficient mast cells. Although the number of mast cells, protease activity, and histamine contents in ear tissues in EP3-deficient mice were comparable to those in wild-type mice, the histamine contents in ear tissues were attenuated upon PGE2 treatment in wild-type but not in EP3-deficient mice. Consistently, PGE2-EP3 signaling elicited histamine release in mouse peritoneal and bone marrow-derived mast cells, and it exerted degranulation and IL-6 production in a manner sensitive to pertussis toxin and a PI3K inhibitor and dependent on extracellular Ca(2+) ions. These results demonstrate that PGE2 triggers mast cell activation via an EP3-Gi/o-Ca(2+) influx/PI3K pathway, and this mechanism underlies PGE2-induced vascular permeability and consequent edema formation.

Topics: Animals; Arachidonic Acid; Calcium; Capillary Permeability; Cell Degranulation; Dinoprostone; Edema; Histamine Release; Inflammation; Interleukin-6; Mast Cells; Mice; Mice, Inbred C57BL; Neutrophil Activation; Peroxidase; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Receptors, Prostaglandin E, EP3 Subtype; Signal Transduction; Specific Pathogen-Free Organisms

Hemodialysis may acutely induce regional left ventricular (LV) systolic dysfunction, which is associated with increased mortality and progressive heart failure. We tested the hypothesis that hemodialysis-induced regional LV systolic dysfunction is associated with inflammation and endothelial injury. Additionally, we studied whether hemodialysis-induced LV systolic dysfunction is associated with an exaggerated bioincompatibility reaction to hemodialysis.. Cross-sectional study.. 105 hemodialysis patients on a thrice-weekly dialysis schedule were studied between March 2009 and March 2010.. Plasma indexes of inflammation (high-sensitivity C-reactive protein, pentraxin 3 [PTX3], interleukin 6 [IL-6], and IL-6:IL-10 ratio), bioincompatibility (leukocytes, neutrophils, complement C3, and myeloperoxidase), and endothelial function (soluble intercellular adhesion molecule 1 [ICAM-1], von Willebrand factor, proendothelin, and endothelin) were measured just before dialysis and at 60, 180, and 240 minutes intradialysis.. Hemodialysis-induced regional LV systolic function. Wall motion score was measured by echocardiography at 30 minutes predialysis, 60 and 180 minutes intradialysis, and 30 minutes postdialysis. We defined hemodialysis-induced regional LV systolic dysfunction as an increase in wall motion score in 2 or more segments.. Patients with hemodialysis-induced regional LV systolic dysfunction (n=29 [27%]) had significantly higher predialysis high-sensitivity C-reactive protein, PTX3, IL-6, and lL-6:IL-10 ratio values. Predialysis levels of bioincompatibility and endothelial markers did not differ between groups. Intradialysis courses of markers of inflammation, bioincompatibility, and endothelial function did not differ in patients with versus without hemodialysis-induced regional LV systolic dysfunction.. Coronary angiography or computed tomography for quantification of coronary calcifications in our patients was not performed; therefore, we could not relate markers of inflammation to the extent of atherosclerosis.. Patients with hemodialysis-induced regional LV systolic dysfunction have a proinflammatory cytokine profile. There was no indication of an association with an exaggerated bioincompatibility reaction to hemodialysis.

Topics: Aged; Biomarkers; C-Reactive Protein; Cross-Sectional Studies; Female; Humans; Inflammation; Inflammation Mediators; Intercellular Adhesion Molecule-1; Male; Middle Aged; Peroxidase; Renal Dialysis; Ventricular Dysfunction, Left

Non-invasive sampling of airway epithelial-lining-fluid by nasal lavage (NL) is an emerging method to monitor allergy, infection and inflammation in patients with respiratory diseases. However, the influences of collection-, processing- and storage-methods have not been sufficiently evaluated and standardized.. Influences of repeated NL, centrifugation setups, repeated freezing and thawing, and protease inhibitors on mediator concentration were evaluated in healthy controls and CF patients, which serve as a model for chronic bacterial infection and inflammation. Polymorphonuclear leukocyte elastase (NE)/myeloperoxidase (MPO)/interleukin (IL)-1/IL-6/IL-8 and tumour necrosis factor alpha (TNF) concentrations were measured using ELISA and Multiplex Bead-Arrays.. NL-repetition within 0.5-4h markedly decreased NE, IL-8 and MPO-concentrations for up to 70%. NL centrifugation up to 250×g for cellular differentiation did not significantly influence mediator concentration in native and processed NL fluid. NL freezing and thawing markedly decreased IL-8 and MPO concentrations by up to 50% while NE remained stable. In contrast to preceding reports, storing at -70°C for ≥5 years led to significantly reduced mediator concentrations in NL compared to contemporary analyses, being most pronounced for IL-1β, IL-6 and TNFa. Storing of samples in the presence of protease inhibitors led to an increase in marker concentration for IL-8 (+27%) and MPO (+15%) even after one year of storage.. NL is an easy and robust technique for inflammation monitoring of the upper airways. For the first time we have shown that diagnostic NL should be performed only once daily to get comparable results. Whereas NL-fluid can be stored unprocessed at -70°C for cytokine analysis over 1-2 years with protease inhibitors supporting stability, ≥5 years storage as well as repeated freezing and thawing should be avoided.

Topics: Adolescent; Adult; Aged; Biomarkers; Case-Control Studies; Centrifugation; Child; Child, Preschool; Cystic Fibrosis; Enzyme-Linked Immunosorbent Assay; Female; Freezing; Humans; Inflammation; Interleukin-1; Interleukin-6; Interleukin-8; Leukocyte Elastase; Male; Middle Aged; Nasal Lavage Fluid; Peroxidase; Protease Inhibitors; Specimen Handling; Tumor Necrosis Factor-alpha

Individual responses in creatine kinase (CK) release after eccentric exercise are divergent. This study aimed to identify whether this could be related to selected humoral or intramuscular inflammatory factors. Twenty-three subjects were divided into non-exercising (n = 5) and downhill run (DHR; n = 18) groups (12 × 5 min, 10% decline at 15 km/h). Blood samples were analyzed for white blood cell differential count, CK, myoglobin, tumor necrosis factor-α, granulocyte colony-stimulating factor, interleukin (IL)-1β, IL-6, and IL-10. Muscle biopsies were analyzed for signal transducer and activator of transcription-3 (STAT3), IκBα, and myeloperoxidase (MPO). DHR participants clustered as early (DHR1) recovery, biphasic response (DHR2), or classic delayed exaggerated CK response (DHR3), with a delayed CK peak (4784 ± 1496 U/L) on day 4. For DHR1 and DHR2, CK peaked on day 1 (DHR1: 1198 ± 837 U/L) or on day 1 and day 4 (DHR2: 1583 ± 448 U/L; 1878 ± 427 U/L), respectively. Immediately post-DHR, IL-6 increased in DHR2 and DHR3 whereas IL-10 increased in all DHR groups. STAT3 signaling increased for DHR1 and DHR2 at 4 h, but MPO at day 2 only in DHR2. Objective cluster analysis uncovered a group of subjects with a characteristic biphasic CK release after DHR. The second elevation was related to their early cytokine response. The results provide evidence that early responses following eccentric exercise are indicative of later variation.

Topics: Creatine Kinase; Granulocyte Colony-Stimulating Factor; Humans; Inflammation; Interleukin-10; Interleukin-1beta; Interleukin-6; Leukocyte Count; Male; Muscle Fatigue; Muscle, Skeletal; Myalgia; Myoglobin; Peroxidase; Phosphorylation; Running; Signal Transduction; STAT3 Transcription Factor; Time Factors; Tumor Necrosis Factor-alpha; Young Adult

Preclinical and clinical studies have shown beneficial effects of infusions of apolipoprotein A-I (ApoA-I) on atherosclerosis. ApoA-I is also a target for myeloperoxidase-mediated oxidation, leading in vitro to a loss of its ability to promote ATP-binding cassette transporter A1-dependent macrophage cholesterol efflux. Therefore, we hypothesized that myeloperoxidase-mediated ApoA-I oxidation would impair its promotion of reverse cholesterol transport in vivo and the beneficial effects on atherosclerotic plaques.. ApoA-I(-/-) or apolipoprotein E-deficient mice were subcutaneously injected with native human ApoA-I, oxidized human ApoA-I (myeloperoxidase/hydrogen peroxide/chloride treated), or carrier. Although early postinjection (8 hours) levels of total ApoA-I in plasma were similar for native versus oxidized human ApoA-I, native ApoA-I primarily resided within the high-density lipoprotein fraction, whereas the majority of oxidized human ApoA-I was highly cross-linked and not high-density lipoprotein particle associated, consistent with impaired ATP-binding cassette transporter A1 interaction. In ApoA-I(-/-) mice, ApoA-I oxidation significantly impaired reverse cholesterol transport in vivo. In advanced aortic root atherosclerotic plaques of apolipoprotein E-deficient mice, native ApoA-I injections led to significant decreases in lipid content, macrophage number, and an increase in collagen content; in contrast, oxidized human ApoA-I failed to mediate these changes. The decrease in plaque macrophages with native ApoA-I was accompanied by significant induction of their chemokine receptor CCR7. Furthermore, only native ApoA-I injections led to a significant reduction of inflammatory M1 and increase in anti-inflammatory M2 macrophage markers in the plaques.. Myeloperoxidase-mediated oxidation renders ApoA-I dysfunctional and unable to (1) promote reverse cholesterol transport, (2) mediate beneficial changes in the composition of atherosclerotic plaques, and (3) pacify the inflammatory status of plaque macrophages.

Topics: Animals; Aorta; Apolipoprotein A-I; Apolipoproteins E; Atherosclerosis; ATP Binding Cassette Transporter 1; Biological Transport; Cell Line; Cholesterol; Cholesterol, HDL; Collagen; Disease Models, Animal; Humans; Inflammation; Injections, Subcutaneous; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Oxidation-Reduction; Peroxidase; Plaque, Atherosclerotic; Receptors, CCR7

Data show that up to 38.2% of the European population have a mental disorder and that recurrent depressive disorder (rDD) is among the most commonly diagnosed disabling diseases. Over the last few years, neurocognitive impairments in rDD have become a new research front focusing on the role of cognitive decline during the course of rDD and in relation to its clinical presentation and prognosis. Both immune-inflammatory and oxidative and nitrosative stress (O&NS) processes potentially play a role in development of cognitive dysfunction in rDD. New evidence shows that chronic inflammatory and O&NS reactions occur in the brains of patients with neurodegenerative disorders and those with rDD. This narrative review presents the current state of knowledge on the possible impact of selected inflammatory and O&NS enzymes on cognitive functioning in patients with rDD. We focus on manganese superoxide dismutase (MnSOD), inducible nitric oxide synthase (iNOS), and myeloperoxidase (MPO).

Topics: Cognition; Depressive Disorder; Europe; Humans; Inflammation; Nitric Oxide Synthase Type II; Oxidative Stress; Peroxidase; Reactive Nitrogen Species; Recurrence; Superoxide Dismutase

While inflammation has been proposed to contribute to the adverse cardiovascular outcome in diabetic patients, the specific pathways involved have not been elucidated. The leukocyte derived product, myeloperoxidase (MPO), has been implicated in all stages of atherosclerosis. The relationship between MPO and accelerated disease progression observed in diabetic patients has not been studied.. We investigated the relationship between MPO and disease progression in diabetic patients. 881 patients with angiographic coronary artery disease underwent serial evaluation of atherosclerotic burden with intravascular ultrasound. Disease progression in diabetic (n = 199) and non-diabetic (n = 682) patients, stratified by baseline MPO levels was investigated.. MPO levels were similar in patients with and without diabetes (1362 vs. 1255 pmol/L, p = 0.43). No relationship was observed between increasing quartiles of MPO and either baseline (p = 0.81) or serial changes (p = 0.43) in levels of percent atheroma volume (PAV) in non-diabetic patients. In contrast, increasing MPO quartiles were associated with accelerated PAV progression in diabetic patients (p = 0.03). While optimal control of lipid and the use of high-dose statin were associated with less disease progression, a greater benefit was observed in diabetic patients with lower compared with higher MPO levels at baseline.. Increasing MPO levels are associated with greater progression of atherosclerosis in diabetic patients. This finding indicates the potential importance of MPO pathways in diabetic cardiovascular disease.

Topics: Aged; Cholesterol, LDL; Coronary Angiography; Coronary Artery Disease; Diabetes Complications; Diabetes Mellitus; Disease Progression; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Male; Middle Aged; Peroxidase; Plaque, Atherosclerotic; Ultrasonography, Interventional

As a water-soluble extracellular β-glucan produced by Agrobacterium sp. ZX09, Salecan has an excellent toxicological profile and exerts multiple physiological effects. The aims of the present study were to investigate the protective effects of a Salecan diet in the well-defined dextran sulphate sodium (DSS) model of experimental murine colitis and to elucidate the mechanism involved in its effects with special attention being paid to its effect on the production of TNF-α, a primary mediator involved in the inflammatory response. Male C57BL/6J mice were fed a diet supplemented with either 4 or 8 % Salecan for 26 d and DSS was administered to induce acute colitis during the last 5 d of the experimental period. Several clinical and inflammatory parameters as well as mRNA expression of TNF-α and Dectin-1 were evaluated. The results indicated that the dietary incorporation of Salecan attenuated the severity of DSS colitis as evidenced by the decreased disease activity index, reduced severity of anaemia, attenuated changes in colon architecture and reduced colonic myeloperoxidase activity. This protection was associated with the down-regulation of TNF-α mRNA levels, which might derive from its ability to increase Dectin-1 mRNA levels. In conclusion, the present study suggests that Salecan contributes to the reduction of colonic damage and inflammation in mice with DSS-induced colitis and holds promise as a new, effective nutritional supplement in the management of inflammatory bowel disease.

Topics: Analysis of Variance; Animals; beta-Glucans; Colitis; Colon; Dextran Sulfate; Dietary Supplements; Disease Models, Animal; Down-Regulation; Inflammation; Intestinal Mucosa; Lectins, C-Type; Male; Mice; Mice, Inbred C57BL; Peroxidase; Real-Time Polymerase Chain Reaction; RNA, Messenger; Tumor Necrosis Factor-alpha

Superoxide dismutase (SOD) can prevent and cure inflammatory bowel diseases by decreasing the amount of reactive oxygen species. Unfortunately, short half-life of SOD in the gastrointestinal tract limited its application in the intestinal tract. This study aimed to investigate the treatment effects of recombinant SOD Lactobacillus fermentum in a colitis mouse model.. In this study, we expressed the sodA gene in Lact. fermentum I5007 to obtain the SOD recombinant strain. Then, we determined the therapeutic effects of this SOD recombinant strain in a trinitrobenzene sulphonic acid (TNBS)-induced colitis mouse model. We found that SOD activity in the recombinant Lact. fermentum was increased by almost eightfold compared with that in the wild type. Additionally, both the wild type and the recombinant Lact. fermentum increased the numbers of lactobacilli in the colon of mice (P < 0·05). Colitis mice treated with recombinant Lact. fermentum showed a higher survival rate and lower disease activity index (P < 0·05). Recombinant Lact. fermentum significantly decreased colonic mucosa histological scoring for infiltration of inflammatory cells, lipid peroxidation, the expression of pro-inflammatory cytokines and myeloperoxidase (P < 0·05) and inhibited NF-κB activity in colitis mice (P < 0·05).. SOD recombinant Lact. fermentum significantly reduced oxidative stress and inflammation through inhibiting NF-κB activation in the TNBS-induced colitis model.. This study provides insights into the anti-inflammatory effects of SOD recombinant Lact. fermentum, indicating the potential therapeutic effects in preventing and curing intestinal bowel diseases.

Topics: Animals; Colitis; Cytokines; Disease Models, Animal; Female; Inflammation; Intestinal Mucosa; Limosilactobacillus fermentum; Lipid Peroxidation; Mice; Mice, Inbred BALB C; NF-kappa B; Organisms, Genetically Modified; Oxidative Stress; Peroxidase; Superoxide Dismutase

Cyane-carvone (CC) was studied to elucidate its anti-inflammatory, antinociceptive, and antioxidant effects in Mus musculus. Anti-inflammatory (bradykinin, histamine, prostaglandin E2, serotonin, and carrageenan) and antinociceptive (acetic acid and formalin) models were utilized. Myeloperoxidase activity, interleukin (IL)-1β, tumor necrosis factor alpha (TNF-α), and glutathione (GSH) levels were evaluated. Analysis of variance followed by Student-Newman-Keuls' test was done. Results were compared with control groups (significantly when p < 0.05). In bradykinin, histamine, prostaglandin E2, and serotonin tests, 75 mg/kg CC decreased significantly paw edema (t = 30, 60, 90, and/or 120 min). In carrageenan test, 50 and 75 mg/kg CC (t = 3 h and t = 4 h) and 25 mg/kg CC (t = 4 h) decreased significantly paw edema. CC (75 mg/kg) inhibited significantly mieloperoxidase activity and decreased IL-1β and TNF-α, and all doses increased GSH levels. CC (75 mg/kg) decreased significantly the number of contortions of animals and time of licking (phase 2). CC showed anti-inflammatory, antinociceptive, and antioxidant effects in mice.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Antioxidants; Bradykinin; Carrageenan; Cyclohexane Monoterpenes; Cytokines; Dinoprostone; Edema; Glutathione; Histamine Antagonists; Inflammation; Interleukin-1beta; Male; Mice; Monoterpenes; Oxidative Stress; Pain; Peroxidase; Serotonin Antagonists; Tumor Necrosis Factor-alpha

The hallmarks of acute lung injury (ALI) are the compromised alveolar-capillary barrier and the extravasation of leukocytes into the alveolar space. Given the fact that the peroxisome proliferator-activated receptor-γ agonist rosiglitazone holds significant anti-inflammatory properties, we aimed to evaluate whether rosiglitazone could dampen these hallmarks of local pulmonary inflammation in a porcine model of lung injury. For this purpose, we used a model of lipopolysaccharide (LPS, 50 μg/kg)-induced ALI. One hundred twenty minutes following the infusion of LPS, we started the exposure to rosiglitazone through inhalation or infusion. We found that intravenous rosiglitazone significantly controlled local pulmonary inflammation as determined through the expression of cytokines within the alveolar compartment. Furthermore, we found a significant reduction of the protein concentration and neutrophil activity within the alveolar space. In summary, we therefore conclude that the treatment with rosiglitazone might dampen local pulmonary inflammation during the initial stages of ALI.

Topics: Acute Lung Injury; Administration, Inhalation; Animals; Bronchoalveolar Lavage Fluid; Bronchoscopy; Catheterization; Disease Models, Animal; Endotoxins; Hemodynamics; Hypoglycemic Agents; Inflammation; Infusions, Intravenous; Lipopolysaccharides; Lung; Peroxidase; Pulmonary Alveoli; Rosiglitazone; Swine; Thiazolidinediones

A number of studies have shown that mental challenge under controlled experimental conditions is associated with elevations in inflammatory markers such as interleukin-6 (IL-6) and C-reactive protein (CRP). However, relatively little work has been done on the effects of 'naturalistic' stressors on acute changes in inflammatory markers. The present study examined whether perceived arousal, valence and dominance in musicians are associated with pro-inflammatory and oxidative responses to a concert situation. Blood and salivary samples obtained from 48 members of a symphony orchestra on the day of rehearsal (i.e., control situation) and on the following day of premiere concert (i.e., test situation) were used to determine changes in salivary cortisol, pro-inflammatory markers (plasma myeloperoxidase, serum CRP, plasma IL-6), oxidative stress markers (paraoxonase1 activity and malondialdehyde), and homocysteine, a risk factor for vascular disease. Results of regression analyses showed a significant trend to increased myeloperoxidase (MPO) response in individuals with low valence score. Both affective states, valence and arousal, were identified as significant predictors of cortisol response during concert. In addition, control levels of plasma malondialdehyde were positively correlated with differences in IL-6 levels between premiere and rehearsal (r=.38, p=.012), pointing to higher oxidative stress in individuals with pronounced IL-6 response. Our results indicate that stress of public performance leads to increased concentrations of plasma MPO (20%), IL-6 (27%) and salivary cortisol (44%) in musicians. The decreasing effect of pleasantness on the MPO response was highly pronounced in non-smokers (r=-.60, p<.001), suggesting a significant role of emotional valence in stress-induced secretion of MPO. Additional studies are needed to assess the generalizability of these findings to other 'naturalistic' stress situations.

Topics: Adult; Affect; C-Reactive Protein; Female; Humans; Hydrocortisone; Inflammation; Interleukin-6; Male; Middle Aged; Music; Oxidative Stress; Peroxidase; Stress, Psychological; Young Adult

We aimed to investigate the preventive and treatment effect of molsidomine (MOL) on bleomycin (BLC)-induced lung injury in rats. Rats were assigned into groups as follows: control group; MOL group, 10 mg/kg MOL was continued orally for 29 day; BLC group, a single intratracheal injection of BLC (2.5 mg/kg), MOL+BLC-preventive group, 10 mg/kg MOL was administered 1 day before the intratracheal BLC injection and continued for 14 days; BLC+MOL-treatment group 10 mg/kg MOL was given on 14th day after the intratracheal BLC injection and continued until sacrifice. All animals were sacrificed on 29th day after BLC administration. The semiquantitative histopathological assessment, tissue levels of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH), total antioxidant status (TAS), total oxidant status (TOS), myeloperoxidase (MPO), and oxidative stress index (OSI) were measured. BLC-provoked histological changes were significantly detected compared to the control group. MOL restored these histological damages in different quantity in the treatment and preventive groups. BLC administration significantly decreased levels of GSH and TAS when compared to controls and these reductions was significantly ameliorated by MOL given prophylactic setting. However, therapeutic MOL administration significantly increased the TAS level decreased by BLC. The levels of MDA, MPO, and TOS were significantly increased with BLM, and these augmentations of MDA and TOS were significantly reduced by MOL given prophylactic setting. Furthermore, the OSI was higher in the BLC group, and this increase was reversed by the MOL administration before and after BLC treatment. In this study, both protective and therapeutic effects of MOL against BLC-induced lung fibrosis were demonstrated for the first time.

Topics: Animals; Antibiotics, Antineoplastic; Antioxidants; Bleomycin; Bronchoalveolar Lavage; Catalase; Female; Glutathione; Glutathione Peroxidase; Inflammation; Malondialdehyde; Molsidomine; Nitric Oxide Donors; Oxidative Stress; Peroxidase; Pulmonary Fibrosis; Rats; Rats, Wistar; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances

The powerful oxidant HOCl (hypochlorous acid and its corresponding anion, (-)OCl) generated by the myeloperoxidase (MPO)-H2O2-Cl(-) system of activated leukocytes is strongly associated with multiple human inflammatory diseases; consequently there is considerable interest in inhibition of this enzyme. Nitroxides are established antioxidants of low toxicity that can attenuate oxidation in animal models, with this ascribed to superoxide dismutase or radical-scavenging activities. We have shown (M.D. Rees et al., Biochem. J. 421, 79-86, 2009) that nitroxides, including 4-amino-TEMPO (4-amino-2,2,6,6-tetramethylpiperidin-1-yloxyl radical), are potent inhibitors of HOCl formation by isolated MPO and activated neutrophils, with IC50 values of ~1 and ~6 µM respectively. The utility of tetramethyl-substituted nitroxides is, however, limited by their rapid reduction by biological reductants. The corresponding tetraethyl-substituted nitroxides have, however, been reported to be less susceptible to reduction. In this study we show that the tetraethyl species were reduced less rapidly than the tetramethyl species by both human plasma (89-99% decreased rate of reduction) and activated human neutrophils (62-75% decreased rate). The tetraethyl-substituted nitroxides retained their ability to inhibit HOCl production by MPO and activated neutrophils with IC50 values in the low-micromolar range; in some cases inhibition was enhanced compared to tetramethyl substitution. Nitroxides with rigid structures (fused oxaspiro rings) were, however, inactive. Overall, these data indicate that tetraethyl-substituted nitroxides are potent inhibitors of oxidant formation by MPO, with longer plasma and cellular half-lives compared to the tetramethyl species, potentially allowing lower doses to be employed.

Topics: Animals; Antioxidants; Cyclic N-Oxides; Humans; Hydrogen Peroxide; Hypochlorous Acid; Inflammation; Neutrophil Activation; Neutrophils; Peroxidase; Superoxide Dismutase; Superoxides

To investigate paraoxonase-1 (PON1) lactonase activity, myeloperoxidase (MPO) activity (as a marker of inflammation) and antioxidant status in plasma of patients with type 1 diabetes mellitus.. Whole blood and plasma samples were collected from patients with diabetes and healthy control subjects. PON1 lactonase and MPO activities and total antioxidant capacity (TEAC) were determined in plasma. Glycosylated haemoglobin (HbA1c) was quantified in whole blood.. Plasma PON1 lactonase and MPO activities were significantly higher and TEAC was significantly lower in patients with diabetes (n = 18) compared with healthy control subjects (n = 20). There were significant positive correlations between PON1 lactonase activity and MPO activity and HbA1c level, and plasma MPO and HbA1c. There were significant negative correlations between PON1 lactonase activity and TEAC, and MPO activity and TEAC.. Increased lactonase activity may inefficiently compensate for the high level of chronic inflammation and low antioxidant capacity in the plasma of patients with type 1 diabetes mellitus.

Topics: Adolescent; Adult; Antioxidants; Aryldialkylphosphatase; Biomarkers; Case-Control Studies; Diabetes Mellitus, Type 1; Female; Glycated Hemoglobin; Humans; Inflammation; Male; Middle Aged; Oxidation-Reduction; Peroxidase; Young Adult

When exacerbation of chronic obstructive pulmonary disease (AECOPD) occurs frequently, patients have high levels of airway and systemic inflammation and a poor quality of life. This study compared the nature and course of systemic and airway inflammation during AECOPD between patients who experienced frequent exacerbations and those with non-frequent exacerbations.. Consecutive hospitalized patients with AECOPD were recruited and divided into 2 groups according to the frequency of AECOPD they had experienced in the previous year. Frequent exacerbators (defined as 2 or more AECOPD in the previous year) and non-frequent exacerbators (defined as zero or 1 AECOPD in the previous year). Inflammatory (interleukin 6, interleukin 8, myeloperoxidase, and C-reactive protein) and clinical (dyspnea, COPD assessment test (CAT), and peak expiratory flow) indices were assessed on the day of admission before starting therapy, day 7 of treatment, the day of planned discharge (day 10-14), and 8 weeks after discharge.. We analyzed data from 135 patients; 78 (57.8%) were non-frequent exacerbators and 57 (42.2%) were frequent exacerbators. In both groups, the inflammatory and clinical indices at day 7, the day of planned discharge (day 10-14), and 8 weeks were significantly improved compared to those at admission. Frequent exacerbators had a smaller reduction in their inflammatory indices and CAT scores between exacerbation onset and all the other time points compared with infrequent exacerbators.. Frequent exacerbators have a reduced response to treatment of AECOPD in terms of inflammatory indices and quality of life.

Topics: Aged; Bronchitis; C-Reactive Protein; China; Dyspnea; Female; Humans; Inflammation; Interleukin-6; Interleukin-8; Lung Diseases, Obstructive; Male; Middle Aged; Peak Expiratory Flow Rate; Peroxidase; Prospective Studies; Quality of Life; Recurrence; Statistics, Nonparametric; Time Factors

Protectin D1 (PD1), derived from docosahexaenoic acid, has been shown to control and resolve inflammation in some experimental models of inflammatory disorders. We investigated the protective roles of protectin D1 in pulmonary inflammation and lung injury induced by lipopolysaccharide (LPS).. Mice were randomly assigned to six groups (n = 6 per group): sham-vehicle group, sham-PD1 group, sham-zVAD-fmk group, LPS-vehicle group, LPS-PD1 group, and LPS-PD1-zVAD-fmk group. Mice were injected intratracheally with 3 mg/kg LPS or saline, followed 24 hours later by intravenous injection of 200 µg/mouse PD1 or vehicle. At the same time, some mice were also injected intraperitoneally with the pan-caspase inhibitor zVAD-fmk. Seventy-two hours after LPS challenge, samples of pulmonary tissue and bronchoalveolar lavage fluid were collected. Optical microscopy was used to examine pathological changes in lungs. Cellularity and protein concentration in bronchoalveolar lavage fluid were analyzed. Lung wet/dry ratios and myeloperoxidase activity were measured. Apoptosis of neutrophils in bronchoalveolar lavage fluid (BALF) was also evaluated by flow cytometry.. Intratracheal instillation of LPS increased neutrophil counts, protein concentration in bronchoalveolar lavage fluid and myeloperoxidase activity, it induced lung histological injury and edema, and also suppressed apoptosis of neutrophils in BALF. Posttreatment with PD1 inhibited LPS-evoked changes in BALF neutrophil counts and protein concentration and lung myeloperoxidase activity, with the outcome of decreased pulmonary edema and histological injury. In addition, PD1 promoted apoptosis of neutrophils in BALF. The beneficial effects of PD1 were blocked by zVAD-fmk.. Posttreatment with PD1 enhances resolution of lung inflammation during LPS-induced acute lung injury by enhancing apoptosis in emigrated neutrophils, which is, at least in part, caspase-dependent.

Topics: Acute Lung Injury; Animals; Apoptosis; Docosahexaenoic Acids; Inflammation; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; Neutrophils; Peroxidase

The aim of this study was to evaluate the protective effect of the sulfated-polysaccharide (PLS) fraction extracted from the seaweed Gracilaria birdiae in rats with trinitrobenzenesulfonic acid (TNBS)-induced colitis.. In the experiments involving TNBS-induced colitis, rats were pretreated with polysaccharide extracted from G. birdiae (PLS: 30, 60 and 90 mg/kg, 500 μL p.o.) or dexamethasone (control group: 1 mg/kg) once daily for 3 days starting before TNBS instillation (day 1). The rats were killed on the third day, the portion of distal colon was excised and washed with 0.9% saline and pinned onto a wax block for the evaluation of macroscopic scores. Samples of the intestinal tissue were used for histological evaluation and assays for glutathione (GSH) levels, malonyldialdehyde (MDA) concentration, myeloperoxidase (MPO) activity, nitrate and nitrite (NO3 /NO2 ) concentration and cytokines levels.. PLS treatment reduced the macroscopic and microscopic TNBS-induced intestinal damage. Additionally, it avoided the consumption of GSH, decreased pro-inflammatory cytokine levels, MDA and NO3 /NO2 concentrations and diminished the MPO activity.. Our results suggest that the PLS fraction has a protective effect against intestinal damage through mechanisms that involve the inhibition of inflammatory cell infiltration, cytokine releasing and lipid peroxidation.

Topics: Animals; Colitis; Colon; Cytokines; Dexamethasone; Glutathione; Gracilaria; Inflammation; Lipid Peroxidation; Male; Malondialdehyde; Nitrates; Nitrites; Peroxidase; Polysaccharides; Rats; Rats, Wistar; Rhodophyta; Trinitrobenzenesulfonic Acid

Polymorphonuclear leukocyte (PMN)-derived myeloperoxidase (MPO) contributes to the pathophysiology of numerous systemic inflammatory disorders through: (1) direct peroxidation of targets and (2) production of strong oxidizing compounds, e.g., hypohalous acids, particularly hypochlorous acid, which furthers oxidant damage and contributes to the propagation of inflammation and tissue injury/dysfunction. Carbon monoxide-releasing molecules (CORMs) offer potent anti-inflammatory effects; however, the mechanism(s) of action is not fully understood. This study assessed the potential of MPO activity inhibition by a water-soluble CORM, CORM-3. To this end, we used in vitro assays to study CORM-3-dependent modulation of MPO activity with respect to: (1) the inhibition of MPO's catalytic activity generally and (2) the specific inhibition of MPO's peroxidation and halogenation (i.e., production of hypochlorous acid) reactions. Further, we employed primary human umbilical vein endothelial cells (HUVECs) to investigate MPO-dependent cellular activation and dysfunction by measuring intracellular oxidant stress (DHR-123 oxidation) and HUVEC permeability (flux of Texas red-dextran), respectively. The results indicate that CORM-3 significantly inhibits MPO activity as well as MPO's peroxidation and hypohalous acid cycles specifically (p<0.05 vs uninhibited MPO). In addition, CORM-3 significantly decreases PMN homogenate- or rhMPO-induced intracellular DHR-123 oxidation in HUVECs and rhMPO-induced HUVEC monolayer permeability (p<0.05 vs untreated). In all assays the inactivated CORM-3 was significantly less effective than CORM-3 (p<0.05). Taken together our findings indicate that CORM-3 is a novel MPO inhibitor and mitigates inflammatory damage at least in part through a mechanism involving the inhibition of neutrophilic MPO activity.

Topics: Carbon Monoxide; Cell Adhesion; Endothelial Cells; Endothelium, Vascular; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; NF-kappa B; Organometallic Compounds; Peroxidase

Caffeic acid (3,4-dihydroxycinnamic acid, CA) has been reported to have anti-inflammatory activity in animal models. However, the mechanisms underlying the anti-inflammatory effects of CA in skin inflammation are only partially understood. The present study was designed to investigate the effects and mechanisms of CA on acute and chronic skin inflammation in mice and the effect of CA in keratinocytes in vitro. The results showed that topical treatment with CA inhibited 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced skin edema in a dose-dependent manner, leading to substantial reductions in skin thickness and tissue weight, neutrophil-mediated myeloperoxidase activity, and various histopathological indicators. The CA treatment also significantly reduced the mRNA and protein levels of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and IL-1β at the application site, and the TNF-α production, the TNF-α-induced IL-6 and IL-1β production, and TNF-α-induced nuclear factor-kappa B (NF-κB) activation in human keratinocytes in vitro. Furthermore, CA was effective at reducing inflammatory damage induced by chronic TPA exposure. These results demonstrate that CA has anti-inflammatory activities in both acute and chronic contact dermatitis models via blockade of the mRNA and protein synthesis of these cytokines and neutrophil-mediated myeloperoxidase activity, and can target inflammatory mediators specifically in the keratinocytes. Taken together, the present results suggest that CA might be a therapeutic agent against inflammatory skin diseases.

Topics: Administration, Topical; Animals; Anti-Inflammatory Agents; Caffeic Acids; Dermatitis, Contact; Dose-Response Relationship, Drug; Edema; Humans; Inflammation; Inflammation Mediators; Interleukin-1beta; Interleukin-6; Keratinocytes; Mice; Mice, Inbred BALB C; Neutrophils; NF-kappa B; Peroxidase; Plant Extracts; RNA, Messenger; Skin; Tetradecanoylphorbol Acetate; Tumor Necrosis Factor-alpha

To investigate the role of the hydrogen-rich water (HRW) in the prevention of aspirin-induced gastric mucosal injury in rats.. Forty male rats were allocated into four groups: normal control group, HRW group, aspirin group, and HRW plus aspirin group. The protective efficacy was tested by determining the gastric mucosal damage score. Malondialdehyde (MDA), superoxide dismutase (SOD), myeloperoxidase (MPO), interleukin (IL)-06 and tumor necrosis factor (TNF)-α in gastric tissues were evaluated. The serum levels of IL-1β and TNF-α were also detected. Histopathology of gastric tissues and localization of Cyclooxygenase 2 (COX-2) were detected using hematoxylin and eosin staining and immunohistochemistry, respectively.. Pretreatment with HRW obviously reduced aspirin-induced gastric damage scores (4.04 ± 0.492 vs 2.10 ± 0.437, P < 0.05). The oxidative stress levels of MDA and MPO in the gastric tissues increased significantly in the aspirin-treated group compared with the HRW group (2.43 ± 0.145 vs 1.79 ± 0.116 nmol/mg prot, P < 0.05 and 2.53 ± 0.238 vs 1.40 ± 0.208 U/g tissue, P < 0.05, respectively). HRW could obviously elevated the SOD levels in the gastric tissues (37.94 ± 8.44 vs 59.55 ± 9.02 nmol/mg prot, P < 0.05). Pretreatment with HRW significantly reduced IL-06 and TNF-α in the gastric tissues (46.65 ± 5.50 vs 32.15 ± 4.83 pg/mg, P < 0.05 and 1305.08 ± 101.23 vs 855.96 ± 93.22 pg/mg, P < 0.05), and IL-1β and TNF-α in the serum (505.38 ± 32.97 vs 343.37 ± 25.09 pg/mL, P < 0.05 and 264.53 ± 28.63 vs 114.96 ± 21.79 pg/mL, P < 0.05) compared to treatment with aspirin alone. HRW could significantly decrease the COX-2 expression in the gastric tissues (staining score: 8.4 ± 2.1 vs 2.9 ± 1.5, P < 0.05).. HRW pretreatment alleviated the aspirin-induced gastric lesions by inhibiting the oxidative stress, inflammatory reaction and reducing the COX-2 in the gastric tissues.

Topics: Animals; Aspirin; Cyclooxygenase 2; Gastric Mucosa; Hydrogen; Inflammation; Interleukin-1beta; Interleukin-6; Male; Malondialdehyde; Oxidative Stress; Peroxidase; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Tumor Necrosis Factor-alpha; Water

The study was aimed to investigate the potential mechanism of inflammatory renal damage induced by shock wave. A total of 48 rats, with the right kidney cut, are randomly assigned into control group, ESWL group and ESWL + PDTC group. Rats were treated with shock wave at the left kidney. At post-shock wave 3 and 105 days, all the animals were sacrificed for detecting the expression of tumor necrosis factor (TNF)-α, intercellular adhesion molecule (ICAM)-1, and monocyte chemoattractant protein (MCP)-1. The inflammatory responses were evaluated by detecting the level of myeloperoxidase (MPO) and ED-1. The histological renal injury was also examined. Before the animals were sacrificed, the urine samples were collected for measuring the values of malondialdehyde (MDA), β2-microglobulin, interleukin (IL)-6, and IL-18. At post-shock wave 3 days, the higher expression of ICAM-1 and TNF-α were observed in shock wave-treated kidneys. The level of urine TNF-α, IL-6, and IL-18 were also increased significantly. Using PDTC obviously decreased the expression of ICAM-1 and TNF-α. It also effectively inhibited the degree of oxidative stress and neutrophil infiltration. At post-shock wave 105 days, the expression of MCP-1 and the level of urine β2-microglobulin and IL-18 were increased significantly. The histological analysis also indicated more ED-1-positive cells and serious fibrosis in shock wave-treated kidneys. PDTC significantly suppressed MCP-1 and IL-18 expression, decreased monocyte infiltration, and alleviate the degree of interstitium fibrosis. Shock wave triggered excessive inflammatory responses and aggravated renal biological damage. Several inflammatory factors including ICAM-1, MCP-1, and TNF-α were considered to play important role in this type of renal damage.

Topics: Animals; Chemokine CCL2; Fibrosis; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-18; Interleukin-6; Kidney; Leukocytes; Lithotripsy; Male; Malondialdehyde; Neutrophils; Peroxidase; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

Our previous studies demonstrated that inflammatory reaction and neuronal apoptosis are the most important pathological mechanisms in ischemia-induced brain damage. Propofol has been shown to attenuate ischemic brain damage via inhibiting neuronal apoptosis. The present study was performed to evaluate the effect of propofol on brain damage and inflammatory reaction in rats of focal cerebral ischemia. Sprague-Dawley rats underwent permanent middle cerebral artery occlusion, then received treatment with propofol (10 or 50 mg/kg) or vehicle after 2 h of ischemia. Neurological deficit scores, cerebral infarct size and morphological characteristic were measured 24 h after cerebral ischemia. The enzymatic activity of myeloperoxidase (MPO) was assessed 24 h after cerebral ischemia. Nuclear factor-kappa B (NF-κB) p65 expression in ischemic rat brain was detected by western blot. Cyclooxygenase-2 (COX-2) expression in ischemic rat brain was determined by immunohistochemistry. ELISA was performed to detect the serum concentration of tumor necrosis factor-α (TNF-α). Neurological deficit scores, cerebral infarct size and MPO activity were significantly reduced by propofol administration. Furthermore, expression of NF-κB, COX-2 and TNF-α were attenuated by propofol administration. Our results demonstrated that propofol (10 and 50 mg/kg) reduces inflammatory reaction and brain damage in focal cerebral ischemia in rats. Propofol exerts neuroprotection against ischemic brain damage, which might be associated with the attenuation of inflammatory reaction and the inhibition of inflammatory genes.

Topics: Animals; Brain Ischemia; Cerebral Infarction; Cyclooxygenase 2; Infarction, Middle Cerebral Artery; Inflammation; Male; Neuroprotective Agents; NF-kappa B; Peroxidase; Propofol; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

Extremely preterm birth is associated with subsequent behavioral problems. We hypothesized that perinatal systemic inflammation, a risk factor for cerebral white matter injury and cognitive impairment, is associated with behavior problems observed at 2 y.. In a cohort of 600 children born before 28 wk gestation, we measured 25 inflammation-related proteins in blood collected on postnatal days 1, 7, and 14, and identified behavior problems using parent responses to the Child Behavior Checklist for Ages 1.5-5 (CBCL/1.5-5) at 2 y of age. A persistent or recurrent protein elevation was defined as a concentration in the highest quartile (for gestational age and postnatal age) on at least 2 d ~1 wk apart. Behavior problems were defined by CBCL/1.5-5 subscale scores at or above the 93 rd percentile.. A single-day elevation of intercellular adhesion molecule-3 was associated with an increased risk of an attention problem, as were persistent or recurrent elevations of myeloperoxidase, interleukin-6, tumor necrosis factor-RI, interleukin-8, intercellular adhesion molecule-3, vascular endothelial growth factor-R1, and vascular endothelial growth factor-R2. These associations persisted among infants without white matter injury and cognitive impairment.. Among children born extremely prematurely, recurrent, or persistent elevations of inflammation-related proteins in blood during in the first two postnatal weeks are associated with an attention problem at age 2 y.

Topics: Antigens, CD; Attention Deficit Disorder with Hyperactivity; Birth Weight; Blood Proteins; Cell Adhesion Molecules; Child Behavior; Child, Preschool; Cohort Studies; Gestational Age; Humans; Infant, Extremely Premature; Infant, Newborn; Inflammation; Interleukin-6; Interleukin-8; Luminescent Measurements; Odds Ratio; Peroxidase; Tumor Necrosis Factors; United States; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2

We compared the gastrointestinal effects of milk-based diets in which the β-casein component was either the A1 or A2 type in male Wistar rats fed the experimental diets for 36 or 84 h. Gastrointestinal transit time was significantly greater in the A1 group, as measured by titanium dioxide recovery in the last 24 h of feeding. Co-administration of naloxone decreased gastrointestinal transit time in the A1 diet group but not in the A2 diet group. Colonic myeloperoxidase and jejunal dipeptidyl peptidase (DPP)-4 activities were greater in the A1 group than in the A2 group. Naloxone attenuated the increase in myeloperoxidase activity but not that in DPP-4 activity in the A1 group. Naloxone did not affect myeloperoxidase activity or DPP-4 activity in the A2 group. These results confirm that A1 β-casein consumption has direct effects on gastrointestinal function via opioid-dependent (gastrointestinal transit and myeloperoxidase activity) and opioid-independent (DPP-4 activity) pathways.

Topics: Animals; Caseins; Colon; Diet; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Gastrointestinal Transit; Inflammation; Jejunum; Male; Milk; Naloxone; Narcotic Antagonists; Peroxidase; Rats, Wistar

Glutathione is an important antioxidant in the lungs but its concentration is low in the airways of patients with cystic fibrosis. Whether this deficit occurs from an early age or how oxidative stress contributes to lowering glutathione is unknown. We measured glutathione, its oxidation products, myeloperoxidase, and biomarkers of hypochlorous acid in bronchoalveolar lavage from children with cystic fibrosis and disease controls using mass spectrometry and immunological techniques. The concentration of glutathione was lower in bronchoalveolar lavage from children with cystic fibrosis, whereas glutathione sulfonamide, a specific oxidation product of hypochlorous acid, was higher. Oxidised glutathione and glutathione sulfonamide correlated with myeloperoxidase and a biomarker of hypochlorous acid. The percentage of glutathione attached to proteins was higher in children with cystic fibrosis than controls. Pulmonary infections in cystic fibrosis resulted in lower levels of glutathione but higher levels of oxidised glutathione and glutathione sulfonamide in bronchoalveolar lavage. The concentration of glutathione is low in the airways of patients with cystic fibrosis from an early age. Increased oxidation of glutathione by hypochlorous acid and its attachment to proteins contribute to this deficiency. Therapies targeted against myeloperoxidase may boost antioxidant defence and slow the onset and progression of lung disease in cystic fibrosis.

Topics: Antioxidants; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Case-Control Studies; Child; Child, Preschool; Cystic Fibrosis; Glutathione; Humans; Hypochlorous Acid; Inflammation; Lung; Mass Spectrometry; Neutrophils; Oxidative Stress; Oxygen; Peroxidase; Radiography, Thoracic; Respiratory System; Retrospective Studies; Sulfones; Tomography, X-Ray Computed

Topics: Animals; Apolipoprotein A-I; Atherosclerosis; Cholesterol; Humans; Inflammation; Macrophages; Male; Peroxidase

Lipoxins (LXs) are proresolving and anti-inflammatory eicosanoids whose role in chronic heart failure (CHF) pathogenesis has never been investigated. This study evaluated levels of LXs in CHF patients, its relationship with disease severity and correlation with established CHF biomarkers. The effect of low-dose aspirin [acetylsalicylic acid (ASA)] on the levels of LXs was also studied.. Lipoxin A4 (LXA4 ), 15-epi-lipoxin A4 (15-epi-LXA4 ) and myeloperoxidase (MPO) concentration and activity were evaluated by immunoenzymatic and spectrophotometric assays in 34 CHF patients [New York Heart Association (NYHA) functional class I to IV]. B-type natriuretic peptide (BNP), troponin, myoglobin, C-reactive protein (CRP) and uric acid (UA) were also analyzed.. Patients were stratified into mild-to-moderate CHF (NYHA, classes I and II) and severe CHF (NYHA classes III and IV). Severe patients had lower plasma LXA4 (0·262 ± 0·034 vs. 0·362 ± 0·039 ng/mL, P < 0·05) and decreased urinary 15-epi-LXA4 levels (2·28 ± 0·44 vs. 4·88 ± 1·03 μg/day, P < 0·05) besides exhibiting increased plasma BNP (1464 ± 442 vs. 555 ± 162 pg/mL, P < 0·05) and MPO activity (45·15 ± 11·56 vs. 15·90 ± 2·80 μmol/min/mg protein, P < 0·05). Plasma LXA4 was inversely correlated with BNP, troponin, myoglobin, CRP, UA and MPO activity. ASA treatment was associated with higher urinary excretion of 15-epi-LXA4 (7·70 ± 1·48 vs. 2·06 ± 0·30 μg/day, P < 0·05) in mild-to-moderate CHF patients and lower BNP levels in both groups.. Higher severity of CHF is associated with reduced levels of LXs. Plasma LXA4 appears to be a valuable marker for risk stratification in CHF. Furthermore, the ASA-related increase in urinary 15-epi-LXA4 suggests enhanced renal synthesis of this eicosanoid and may represent a disregarded benefit of ASA.

Topics: Aged; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Biomarkers; Cardiovascular Diseases; Chronic Disease; Female; Glomerular Filtration Rate; Heart Failure; Humans; Inflammation; Leukocyte Count; Lipoxins; Male; Peroxidase; Risk Factors

Major depressive disorder (MDD) is accompanied with an imbalance in the immune system and cardiovascular impairments, such as atherosclerosis. Several mechanisms have been pointed out to underlie this rather unexpected association, and among them the activity of myeloperoxidase (MPO). The aim of our study was to find compounds that inhibit both MPO and serotonin transporter (SERT) for treating MDD associated with cardiovascular diseases.. SERT inhibition was assessed with measuring of [(3) H]-serotonin uptake using HEK-293 MSR cells. MPO inhibition was determined by taurine chloramine test on 3-(aminoalkyl)-5-fluoroindole derivatives and on clinically relevant antidepressants. All kinetic measurements were performed using a temperature-controlled stopped-flow apparatus (model SX-18 MV). Promising lead compounds were docked onto SERT 3D structure modelled using the LeuT structure complexed to tryptophan (PDB code 3F3A). Their toxicological profile was also assessed.. 3-(aminoalkyl)-5-fluoroindole derivative with 5 carbons on the side chain and paroxetine showed the best activity on both MPO and SERT at the nanomolar range. Paroxetine was found to be the first irreversible MPO inhibitor at nanomolar concentrations.. Our results put forward the first hybrid molecule (compound 25) and drug (paroxetine) that can be especially used in MDD associated with inflammatory syndrome.

Topics: Antidepressive Agents; Cardiovascular Diseases; Cell Line; Depressive Disorder, Major; HEK293 Cells; Humans; Indoles; Inflammation; Peroxidase; Selective Serotonin Reuptake Inhibitors; Serotonin; Serotonin Plasma Membrane Transport Proteins

Sulphated polysaccharides from marine algae are widely used in biotechnological and pharmaceutical areas. In this study, we evaluated the effects of sulphated polysaccharides from the green marine alga Caulerpa mexicana (Cm-SPs) in nociceptive and inflammatory models in rodents. Cm-SPs (10 or 20 mg/kg), administered i.v. in Swiss mice, significantly reduced nociceptive responses, as measured by the number of writhes in response to acetic acid. Cm-SPs (10 or 20 mg/kg) also reduced second-phase responses in the formalin test, but did not exhibit a significant antinociceptive effect in the hot plate test, suggesting that its antinociceptive action occurs through a peripheral mechanism. Cm-SPs (5, 10 or 20 mg/kg), administered s.c. in wistar rats 1 hr before carrageenan, dextran, histamine or serotonin, were tested in paw oedema models. Cm-SPs (10 or 20 mg/kg) reduced carrageenan-induced paw oedema and myeloperoxidase activity in the paw. In addition, Cm-SPs (20 mg/kg) inhibited dextran- or histamine-induced paw oedema, but not serotonin-induced oedema, suggesting that histamine is the major target of Cm-SPs anti-oedematogenic activity. Finally, Cm-SPs (20 mg/kg) administered in mice did not show significant signs of toxicity. In conclusion, Cm-SPs appear to be promising natural modulatory agents for pain and inflammatory conditions.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Carrageenan; Caulerpa; Dextrans; Disease Models, Animal; Edema; Female; Histamine; Inflammation; Male; Mice; Pain; Pain Measurement; Peroxidase; Polysaccharides; Rats; Rats, Wistar; Serotonin

Based on the fact that Synadenium grantii is used in folk medicine for the treatment of peptic ulcers and inflammatory diseases, this work describes its chemical and pharmacological properties. Pharmacological investigation of the crude bark extract showed a high antioxidant activity over several scavenger systems, such as 2,2'-azino-bis (3-ethylenebenzothiazoline-6-sulfonic acid)• +, 1-diphenyl-2-picrylhydrazyl•, O2 • - , and HOCl, as well as an enzymatic system with human myeloperoxidase and an ex vivo hemolysis system. Furthermore, the oral administration of the crude bark extract was able to reduce carrageenan-induced rat paw edema as effectively as ibuprofen. These biological activities may be associated with the presence of flavonoids and terpenes, as revealed by HPLC and NMR analyses of the crude stem bark extract. The phytochemical investigations in this study resulted in the isolation of friedelin and 3β-friedelinol for the first time, while euphol and lanosterol were also isolated.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Antioxidants; Benzothiazoles; Biphenyl Compounds; Carrageenan; Edema; Euphorbia; Female; Flavonoids; Humans; Inflammation; Lanosterol; Peroxidase; Phytotherapy; Picrates; Plant Bark; Plant Extracts; Plant Stems; Rats, Wistar; Sulfonic Acids; Triterpenes

Interleukin-17 (IL-17) is involved in a wide range of inflammatory disorders and in recruitment of inflammatory cells to injury sites. A recent study of IL-17 knock-out mice revealed that IL-17 contributes to neuroinflammation and neuropathic pain after peripheral nerve injury. Surprisingly, little is known of micro-environment modulation by IL-17 in injured sites and in pathologically related neuroinflammation and chronic neuropathic pain. Therefore, we investigated nociceptive sensitization, immune cell infiltration, myeloperoxidase (MPO) activity, and expression of multiple cytokines and opioid peptides in damaged nerves of wild-type (IL-17(+/+)) and IL-17 knock-out (IL-17(-/-)) mice after partial sciatic nerve ligation. Our results demonstrated that the IL-17(-/-) mice had less behavioral hypersensitivity after partial sciatic nerve ligation, and inflammatory cell infiltration and pro-inflammatory cytokine (tumor necrosis factor-α, IL-6, and interferon-γ) levels in damaged nerves were significantly decreased, with the levels of anti-inflammatory cytokines IL-10 and IL-13, and expressions of enkephalin, β-endorphin, and dynorphin were also decreased compared to those in wild-type control mice. In conclusion, we provided evidence that IL-17 modulates the micro-environment at the level of the peripheral injured nerve site and regulates progression of behavioral hypersensitivity in a murine chronic neuropathic pain model. The attenuated behavioral hypersensitivity in IL-17(-/-) mice could be a result of decreased inflammatory cell infiltration to the injured site, resulting in modulation of the pro- and anti-inflammatory cytokine milieu within the injured nerve. Therefore, IL-17 may be a critical component for neuropathic pain pathogenesis and a novel target for therapeutic intervention for this and other chronic pain states.

Topics: Animals; Behavior, Animal; beta-Endorphin; Central Nervous System Sensitization; Cytokines; Disease Models, Animal; Dynorphins; Enkephalins; Hyperalgesia; Inflammation; Interleukin-10; Interleukin-13; Interleukin-17; Interleukin-1beta; Interleukin-2; Interleukin-6; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuralgia; Neutrophils; Nociception; Peripheral Nerve Injuries; Peroxidase; Sciatic Nerve; T-Lymphocytes; Tumor Necrosis Factor-alpha

Bicuspid aortic valve (BAV) is associated with increased risk of valvular degeneration and ascending aortic aneurysm formation and rupture. We sought to evaluate the roles of endothelial dysfunction and inflammatory activation in modulating these processes.. We performed a case-control study of patients with BAV together with a multivariate analysis within the BAV group to identify factors associated with: development of significant valvular disease; dilatation of the ascending aorta; differential valve relative to aortic disease. Endothelial function of patients and controls was evaluated via flow-mediated dilatation (FMD) and plasma concentrations of asymmetric dimethylarginine (ADMA). Correlations with inflammatory markers and endothelial progenitor cell counts were also examined. Morphological and physiological assessment of the valve and ascending aorta was performed with transthoracic echocardiography and MRI.. Patients with BAV (n=43) and controls (n=25) were matched for age and gender. FMD was significantly lower in patients than controls (7.85±3.48% vs 11.58±3.98%, p=0.001), and these differences were age-independent. Within the BAV cohort, multivariate correlates of peak aortic valve velocity were plasma concentrations of ADMA and myeloperoxidase (MPO) (both p<0.01), while increasing age was an independent correlate of ascending aortic diameter (p<0.05). Furthermore, both low FMD and inflammatory activation were multivariate correlates of selectivity for valvular disease.. BAV is associated with endothelial dysfunction. The extent of inflammatory activation (specifically MPO release) and that of endothelial dysfunction impact primarily on integrity of the valve rather than aortic structure.

Topics: Aorta; Aortic Valve; Arginine; Bicuspid Aortic Valve Disease; Biomarkers; Disease Progression; Echocardiography; Endothelium, Vascular; Female; Follow-Up Studies; Heart Valve Diseases; Humans; Inflammation; Magnetic Resonance Imaging, Cine; Male; Middle Aged; Nitric Oxide Synthase; Peroxidase; Prognosis; Retrospective Studies; Severity of Illness Index; Vasodilation

Myeloperoxidase (MPO) is implicated as a local mediator of tissue damage when released extracellularly in many chronic inflammatory diseases. The purpose of this study was to explore the role of endogenous MPO in experimental rheumatoid arthritis (RA).. K/BxN serum-transfer arthritis was induced in C57BL/6 wild-type (WT) and MPO knockout (MPO(-/-) ) mice, and disease development was assessed. MPO activity was measured in joint tissues from mice with or without K/BxN arthritis. Collagen-induced arthritis (CIA) was induced in WT and MPO(-/-) mice, and disease development and immune responses were examined. MPO expression was assessed in synovial biopsy samples from patients with active RA, and the effect of MPO on synovial fibroblasts was tested in vitro.. MPO was up-regulated in the joints of mice with K/BxN arthritis, and MPO deficiency attenuated the severity of the disease without affecting circulating cytokine levels. In CIA, MPO(-/-) mice had enhanced CD4+ T cell responses and reduced frequency of regulatory T cells in the lymph nodes and spleen, as well as augmented interleukin-17A and diminished interferon-γ secretion by collagen-stimulated splenocytes, without an effect on circulating anticollagen antibody levels. Despite enhanced adaptive immunity in secondary lymphoid organs, CIA development was attenuated in MPO(-/-) mice. Intracellular and extracellular MPO was detected in the synovium of patients with active RA, and human MPO enhanced the proliferation and decreased the apoptosis of synovial fibroblasts in vitro.. MPO contributes to the development of arthritis despite suppressing adaptive immunity in secondary lymphoid organs. This suggests distinct effects of local MPO on arthritogenic effector responses.

Topics: Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Disease Progression; Inflammation; Joints; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Peroxidase; Synovial Membrane

Caffeine is presented in many commercial products and has been proven to induce ergogenic effects in exercise, mainly related to redox status homeostasis, inflammation and oxidative stress-related adaptation mechanisms. However, most studies have mainly focused on muscle adaptations, and the role of caffeine in different tissues during exercise training has not been fully described. The aim of this study was therefore, to analyze the effects of chronic caffeine intake and exercise training on liver mitochondria functioning and plasma inflammation markers. Rats were divided into control, control/caffeine, exercise, and exercise/caffeine groups. Exercise groups underwent four weeks of swimming training and caffeine groups were supplemented with 6 mg/kg/day. Liver mitochondrial swelling and complex I activity, and plasma myeloperoxidase (MPO) and acetylcholinesterase (AChE) activities were measured. An anti-inflammatory effect of exercise was evidenced by reduced plasma MPO activity. Additionally, caffeine intake alone and combined with exercise decreased the plasma AChE and MPO activities. The per se anti-inflammatory effect of caffeine intake should be highlighted considering its widespread use as an ergogenic aid. Therefore, caffeine seems to interfere on exercise-induced adaptations and could also be used in different exercise-related health treatments.

Topics: Acetylcholinesterase; Animals; Biomarkers; Caffeine; Inflammation; Male; Membrane Potentials; Mitochondria, Liver; Oxidative Stress; Peroxidase; Physical Conditioning, Animal; Rats; Rats, Wistar; Reactive Oxygen Species

Seaweed lectins have been widely investigated as anti-nociceptive and anti-inflammatory agents. This study analyzed the anti-nociceptive and anti-inflammatory responses of a lectin from the green seaweed Caulerpa cupressoides (CcL) on zymosan-induced arthritis of the rat temporomandibular joint (TMJ). Rats received i.v. CcL 30 min prior to injection of zymosan (2mg/art.) or 0.9% saline into the left TMJ. Mechanical hyper-nociception was measured by the electronic von Frey method at baseline and 4h after zymosan injection. Animals were euthanized 6h after zymosan injection and the synovial fluid was collected for leukocyte counting and myeloperoxidase activity assessment. Other animals were treated with ZnPP-IX (3mg/kg; s.c.), a specific heme oxygenase-1 pathway inhibitor, and naloxone (10 μg/art.), a nonselective opioid receptor antagonist. TMJ tissues were excised to perform histopathological and immunohistochemistry analyses. CcL (0.1, 1 or 10mg/kg) significantly reduced zymosan-induced hyper-nociception (81, 83 and 89.5%, respectively) and inhibited the leukocyte influx (77.3, 80.7 and 98.5%, respectively) compared with the zymosan-only group, as confirmed by myeloperoxidase activity; however, treatment with naloxone or ZnPP-IX did not revert the effects of CcL (10mg/kg), suggesting that the naloxone-sensitive opioid and heme oxygenase-1 pathways are not involved. CcL also reduced the leukocyte influx and the expression of IL-1β and TNF-α in the TMJ, based on histopathological and immunohistochemistry analyses, respectively. Therefore, CcL reduces TMJ hyper-nociception and inflammation with a mechanism that is partially dependent on TNF-α and IL-1β inhibition. CcL reveals a potentially valuable alternative tool for future studies of TMJ disorders.

Topics: Administration, Intravenous; Animals; Arthritis, Experimental; Caulerpa; Cell Movement; Inflammation; Interleukin-1beta; Leukocytes; Male; Nociception; Peroxidase; Plant Lectins; Rats; Rats, Wistar; Synovial Membrane; Temporomandibular Joint; Tumor Necrosis Factor-alpha; Zymosan

Occupational exposure to organophosphate pesticides is becoming a common and increasingly alarming world-wide phenomenon. The present study is designed to investigate the preventive effect of N-acetylcysteine on malathion-induced hepatic injury and inflammation in rats.. Adult male Wistar rats of body weight 200-230 g were used for the study. Malathion (200mg/kg b.w./day) was administered to rats by oral intubation and N-acetylcysteine (2g/l) in drinking water for 28 days. Rats were sacrificed on the 28th day, 2h after the last administration. Markers of liver injury (aspartate transaminase, alanine transaminase, alkaline phosphatase and lactate desyhdogenase), inflammation (leukocyte counts, myeloperoxidase, immunophenotyping of CD4(+) and CD8(+), interleukin-1β, interleukin-6 and interferon-γ expression) and oxidative stress (lipid peroxidation, reduced glutathione and antioxidant status) were assessed.. Malathion induced an increase in activities of hepatocellular enzymes in plasma, lipid peroxidation index, CD3(+)/CD4(+) and CD3(+)/CD4(+) percent and pro-inflammatory cytokines, when decreased antioxidant status in liver was noted. When malathion-treated rats were compared to NAC supplemented rats, leukocytosis, T cell count and IL-1β, IL-6, INF-γ expression were reduced. Furthermore, NAC restored liver enzyme activities and oxidative stress markers.. Malathion induces hepatotoxicity, oxidative stress and liver inflammation. N-acetylcysteine showed therapeutic effects against malathion toxicity.

Topics: Acetylcysteine; Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Biomarkers; Blotting, Western; Cell Proliferation; Chemical and Drug Induced Liver Injury; Cytokines; Flow Cytometry; Free Radical Scavengers; Inflammation; Insecticides; Leukocytes; Lipid Peroxidation; Liver; Lymphocytes; Malathion; Male; Oxidative Stress; Peroxidase; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Rutin has been shown to possess beneficial health effects, including hepatoprotection. However, to date, it has not been demonstrated to have a hepatoprotective effect against cholestatic liver injury. This is the first report to show a protective effect of rutin on cholestatic liver injury. Cholestasis was produced by bile duct ligation (BDL) in male Sprague-Dawley rats for 3 weeks. Daily oral administration of rutin was started 1 week before injury and was maintained for 4 weeks. In comparison with the control group, the BDL group showed liver injury as evidenced by histological changes and elevation in serum biochemicals, ductular reaction, fibrosis, inflammation, and oxidative stress. These pathophysiological changes were attenuated by rutin supplementation. Rutin alleviated BDL-induced transforming growth factor β1 (TGF-β1), interleukin-1β, connective tissue growth factor, and collagen expression. The antifibrotic effect of rutin was accompanied by reductions in α-smooth muscle actin-positive matrix-producing cells and Smad2/3 activity critical to the fibrogenic potential of TGF-β1. Rutin attenuated BDL-induced oxidative stress, leukocyte accumulation, NF-κB activation, and proinflammatory cytokine production. Further studies demonstrated an inhibitory effect of rutin on the redox-sensitive intracellular signaling molecule extracellular signal-regulated kinase (ERK). Rutin also attenuated BDL-induced reduction in NF-E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and AMP-activated protein kinase (AMPK). Taken together, the beneficial effects of rutin were shown to be associated with antioxidative and anti-inflammatory effects as well as the downregulation of NF-κB and TGF-β/Smad signaling, probably via interference of ERK activation and/or enhancement of Nrf2, HO-1, and AMPK activity.

Topics: Actins; AMP-Activated Protein Kinases; Animals; Anti-Inflammatory Agents; Antioxidants; Biliary Tract; Biliary Tract Surgical Procedures; Cholestasis; Collagen; Connective Tissue Growth Factor; Extracellular Signal-Regulated MAP Kinases; Glutathione; Heme Oxygenase-1; Inflammation; Interleukin-1beta; Liver; Liver Cirrhosis; Male; NF-E2-Related Factor 2; NF-kappa B; Oxidative Stress; Peroxidase; Random Allocation; Rats; Rats, Sprague-Dawley; Rutin; Smad2 Protein; Smad3 Protein; Transforming Growth Factor beta1

The present study was directed to investigate the possible modulatory effect of naringenin when co-administered with L-arginine in monocrotaline-induced pulmonary hypertension in rats. Pulmonary hypertension was induced by a single subcutaneous injection of monocrotaline (60 mg/kg). L-arginine (500 mg/kg) and naringenin (50 mg/kg) were orally administered daily, alone and in combination, for 3 weeks. Mean arterial blood pressure, electrocardiography and echocardiography were then recorded and rats were sacrificed and serum was separated for determination of total nitrate/nitrite level. Right ventricles and lungs were isolated for estimation of oxidative stress markers, tumor necrosis factor-alpha, total nitrate/nitrite and transforming growth factor-beta. Myeloperoxidase and caspase-3 activities in addition to endothelial and inducible nitric oxide synthase protein expression were also determined. Moreover, histological analysis of pulmonary arteries and cardiomyocyte cross-sectional area was performed. Combined therapy provided a significant improvement in L-arginine protective effect toward preserving hemodynamic changes and alleviating oxidative stress, inflammatory and apoptotic markers induced by monocrotaline treatment. Furthermore, combined therapy prevented monocrotaline-induced changes in endothelial and inducible nitric oxide synthase protein expression as well as histological analysis compared with either treatment alone. In conclusion, naringenin significantly adds to the protective effect of L-arginine in pulmonary hypertension induced by monocrotaline in rats.

Topics: Animals; Anti-Inflammatory Agents; Arginine; Caspase 3; Flavanones; Hypertension, Pulmonary; Inflammation; Male; Monocrotaline; Nitric Oxide; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Oxidative Stress; Peroxidase; Pulmonary Artery; Rats, Wistar; Tumor Necrosis Factor-alpha

Phosphatidylcholine with deoxycholic acid (PC/DA) is widely used to reduce localized fat deposits with mild adverse effects. We previously demonstrated that PC induces lipolysis with mild PMN infiltration, while DA induces adipose tissue damage. Therefore, the aim of this study was to extend our understanding of the pro-inflammatory responses of PC, DA, and PC/DA.. We evaluated the level of edema and polymononuclear (PMN) infiltration by histopathological examination. Myeloperoxidase (MPO) activity was analyzed using an MPO activity assay kit. Levels of inflammatory cytokines (IL-1β and IL-6) and PGE2 were measured by ELISA.. A low and high dose of PC failed to induce an inflammatory response, whereas DA led to an intense inflammatory response in a dose dependent manner. Combined PC/DA treatment resulted in a mild inflammatory response that was notably less severe than higher DA. Together, these results demonstrated that DA plays a role in inflammation caused by combined PC/DA. Histopathological examination and measurement of MPO activity indicated that DA was the primary cause of edema and PMN infiltration. Further, increased levels of cytokines (IL-1β and IL-6) and PGE2 demonstrated that DA might directly induce inflammation, whereas PC alone has no effect on inflammation.. These results indicate that DA rather than PC is responsible for inflammation, and that PC may not aggravate inflammatory responses induced by DA. Thus, the results of this study suggest that the adverse effects of PC/DA during localized fat treatment may be solely due to DA.

Topics: Animals; Deoxycholic Acid; Dinoprostone; Dose-Response Relationship, Drug; Edema; Enzyme-Linked Immunosorbent Assay; Inflammation; Interleukin-1beta; Interleukin-6; Male; Peroxidase; Phosphatidylcholines; Rats; Rats, Sprague-Dawley

Chronic inflammatory processes in the peritoneal cavity develop as a result of ischemia, foreign body reaction, and trauma. Brazilian green propolis, a beeswax product, has been shown to exhibit multiple actions on inflammation and tissue repair. Our aim was to investigate the effects of this natural product on the inflammatory, angiogenic, and fibrogenic components of the peritoneal fibroproliferative tissue induced by a synthetic matrix.. Chronic inflammation was induced by placing polyether-polyurethane sponge discs in the abdominal cavity of anesthetized Swiss mice. Oral administration of propolis (500/mg/kg/day) by gavage started 24 hours after injury for four days. The effect of propolis on peritoneal permeability was evaluated through fluorescein diffusion rate 4 days post implantation. The effects of propolis on the inflammatory (myeloperoxidase and n-acetyl-β-D-glucosaminidase activities and TNF-α levels), angiogenic (hemoglobin content-Hb), and fibrogenic (TGF-β1 and collagen deposition) components of the fibrovascular tissue in the implants were determined 5 days after the injury.. Propolis was able to decrease intraperitoneal permeability. The time taken for fluorescence to peak in the systemic circulation was 20±1 min in the treated group in contrast with 15±1 min in the control group. In addition, the treatment was shown to down-regulate angiogenesis (Hb content) and fibrosis by decreasing TGF-β1 levels and collagen deposition in fibroproliferative tissue induced by the synthetic implants. Conversely, the treatment up-regulated inflammatory enzyme activities, TNF-α levels and gene expression of NOS2 and IFN-γ (23 and 7 fold, respectively), and of FIZZ1 and YM1 (8 and 2 fold) when compared with the untreated group.. These observations show for the first time the effects of propolis modulating intraperitoneal inflammatory angiogenesis in mice and disclose important action mechanisms of the compound (downregulation of angiogenic components and activation of murine macrophage pathways).

Topics: Animals; Brazil; Collagen; Drug Evaluation, Preclinical; Fibrosis; Fluorescein; Foreign-Body Reaction; Hemoglobins; Inflammation; Male; Mice; Neovascularization, Pathologic; Peritonitis; Peroxidase; Propolis; Surgical Sponges; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha; Wound Healing

The nucleoside adenosine is a known regulator of immunity and inflammation that mediates, at least in part, the anti-inflammatory effect of methotrexate, an immunosuppressive agent widely used to treat autoimmune inflammatory diseases. Adenosine A2A receptors play a key role in the inhibition of the inflammatory process besides promoting wound healing. Therefore, we aimed to determine the topical effect of a selective agonist, CGS-21680, on a murine model of skin hyperplasia with a marked inflammatory component. Pretreatment with either CGS-21680 (5 μg per site) or the reference agent dexamethasone (200 μg/site) prevented the epidermal hyperplasia and inflammatory response induced by topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA, 2 nmol/site) for three consecutive days. The histological analysis showed that both CGS-21680 and dexamethasone produced a marked reduction of inflammatory cell infiltrate, which correlated with diminished myeloperoxidase (MPO) activity in skin homogenates. Both treatments reduced the levels of the chemotactic mediators LTB4 and CXCL-1, and the inflammatory cytokine TNF-α, through the suppression of NFκB phosphorylation. The immunohistochemical analysis of the hyperproliferative markers cytokeratin 6 (CK6) and Ki67 revealed that while both agents inhibit the number of proliferating cells in the epidermis, CGS-21680 treatment promoted dermal fibroblasts proliferation. Consistently, increased collagen deposition in dermis was observed in tissue sections from agonist-treated mice. Our results showed that CGS 21680 efficiently prevents phorbol-induced epidermal hyperplasia and inflammation in mice without the deleterious atrophic effect of topical corticosteroids.

Topics: Adenosine; Adenosine A2 Receptor Agonists; Administration, Topical; Animals; Anti-Inflammatory Agents; Cell Proliferation; Collagen; Cytokines; Dexamethasone; Disease Models, Animal; Epidermis; Female; Hyperplasia; Inflammation; Mice; Peroxidase; Phenethylamines; Skin Diseases; Tetradecanoylphorbol Acetate

The aim of this study was to investigate the alleviating effect of Lactobacillus paracasei subsp. paracasei LC-01 (LC-01) on the murine model of colitis induced by dextran sulphate sodium (DSS). 50 pathogen-free, 6-week-old male BALB/c mice were divided randomly into 5 groups, including a control group and four DSS-LC-01-treated groups (DSS, DSS-106, DSS-108, and DSS-1010 with 0, 1×106, 1×108 and 1×1010 cfu/ml LC-01, respectively). To test the effectiveness of LC-01 as a prophylactic it was administered for 7 days before the onset of the disease in DSS-LC-01-treated mice. After 7 days, colitis was induced by administration of 2.5% (w/v) DSS in drinking water for a further 7 days. The disease activity index (DAI), histological score, myeloperoxidase (MPO) activity and the level of the pro-inflammatory cytokines interleukin-1β (IL-1β) and tumour necrosis factor α (TNF-α) were measured. DAI, histological scores and MPO activity of mice treated with a medium or high dose of LC-01 were significantly lower compared to a low-dose of LC-01 and DSS treatment alone (P<0.05). Colon length shortening could be prevented with increasing dose of LC-01. In addition, the levels of IL-1β and TNF-α were suppressed significantly by treatment with a medium and high dose of LC-01. However, no significant difference in the indices mentioned above were observed between a low dose of LC-01 and treatment with DSS alone (P≯0.05). An appropriate dose of LC-01 can prevent intestinal damage in mice with DSS-induced colitis. The expression of inflammatory cytokines related to pathogenesis of DSS-induced colitis decreased following treatment with LC-01.

Topics: Administration, Oral; Animals; Colitis; Colon; Dextran Sulfate; Disease Models, Animal; Feces; Inflammation; Interleukin-1beta; Intestinal Mucosa; Lactobacillus; Male; Mice; Mice, Inbred BALB C; Peroxidase; Probiotics; Tumor Necrosis Factor-alpha

The pathophysiological pathways linking particulate air pollution to cardiovascular disease are still not fully understood. We examined the association between ambient air pollutants and blood markers of inflammation and coagulation/fibrinolysis in three potentially susceptible populations. Three panels of non-smoking individuals were examined between 3/2007 and 12/2008: 1) with type 2 diabetes mellitus (T2D, n=83), 2) with impaired glucose tolerance (IGT, n=104), and 3) with a potential genetic predisposition which could affect detoxifying and inflammatory pathways (n=87) defined by the null polymorphism for glutathione S-transferase M1 (GSTM1) in combination with a certain single nucleotide polymorphism on the C-reactive protein (CRP) or the fibrinogen gene. Study participants had blood drawn up to seven times every four to six weeks. In total, 1765 blood samples were analysed for CRP, interleukin (IL)-6, soluble CD40 ligand (sCD40L), fibrinogen, myeloperoxidase (MPO), and plasminogen activator inhibitor-1 (PAI-1). Hourly mean values of particulate air pollutants, particle number concentrations in different size ranges and gaseous pollutants were collected at fixed monitoring sites and individual 24hour averages calculated. Associations between air pollutants and blood markers were analysed for each panel separately and taking the T2D panel and the IGT panel together, using additive mixed models adjusted for long-term time trend and meteorology. For the panel with potential genetic susceptibility, CRP and MPO increased for most lags, especially with the 5-day average exposure (% change of geometric mean and 95% confidence interval: 22.9% [12.0;34.7] for CRP and 5.0% [0.3;9.9] for MPO per interquartile range of PM2.5). Small positive associations were seen for fibrinogen while sCD40L, PAI-1 and IL-6 mostly decreased in association with air pollution concentrations. Except for positive associations for fibrinogen we did not see significant results with the two other panels. Participants with potential genetic susceptibility showed a clear association between inflammatory blood biomarkers and ambient air pollutants. Our results support the hypothesis that air pollution increases systemic inflammation especially in susceptible populations which may aggravate atherosclerotic diseases and induce multi-organ damage.

Topics: Adult; Aged; Air Pollutants; Air Pollution; Biomarkers; Blood Coagulation; C-Reactive Protein; CD40 Antigens; Diabetes Mellitus, Type 2; Female; Fibrinogen; Fibrinolysis; Germany; Glutathione Transferase; Humans; Inflammation; Male; Middle Aged; Particulate Matter; Peroxidase; Polymorphism, Single Nucleotide

Long standing rheumatoid arthritis (RA) is associated with testicular dysfunction and subfertility. Few studies have addressed the pathogenesis of testicular injury in RA and its modulation by effective agents. Thus, the current study aimed at evaluating the effects of two testosterone boosting agents; chrysin, a natural flavone and celecoxib, a selective COX-2 inhibitor, in testicular impairment in rats with adjuvant arthritis, an experimental model of RA. Chrysin (25 and 50mg/kg) and celecoxib (5mg/kg) were orally administered to Wistar rats once daily for 21days starting 1h before arthritis induction. Chrysin suppressed paw edema with comparable efficacy to celecoxib. More important, chrysin, dose-dependently and celecoxib attenuated the testicular injury via reversing lowered gonadosomatic index and histopathologic alterations with preservation of spermatogenesis. Both agents upregulated steroidogenic acute regulatory (StAR) mRNA expression and serum testosterone with concomitant restoration of LH and FSH. Furthermore, they suppressed inflammation via abrogation of myeloperoxidase, TNF-α and protein expression of COX-2 and iNOS besides elevation of IL-10. Alleviation of the testicular impairment was accompanied with suppression of oxidative stress via lowering testicular lipid peroxides and nitric oxide. With respect to apoptosis, both agents downregulated FasL mRNA expression and caspase-3 activity in favor of cell survival. For the first time, these findings highlight the protective effects of chrysin and celecoxib against testicular dysfunction in experimental RA which were mediated via boosting testosterone in addition to attenuation of testicular inflammation, oxidative stress and apoptosis. Generally, the 50mg/kg dose of chrysin exerted comparable protective actions to celecoxib.

Topics: Administration, Oral; Animals; Apoptosis; Arthritis, Experimental; Caspase 3; Celecoxib; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dose-Response Relationship, Drug; Fas Ligand Protein; Flavonoids; Follicle Stimulating Hormone; Inflammation; Inflammation Mediators; Luteinizing Hormone; Male; Nitric Oxide Synthase Type II; Oxidative Stress; Peroxidase; Phosphoproteins; Pyrazoles; Rats; Rats, Wistar; RNA, Messenger; Spermatogenesis; Sulfonamides; Testis; Testosterone; Time Factors; Tumor Necrosis Factor-alpha

Idiopathic pulmonary fibrosis is a progressive fatal lung disease characterized by excessive collagen deposition, with no effective treatments. We investigated the efficacy of natural products with high anti-inflammatory activity, such as passion fruit peel extract (PFPE), in a mouse model of bleomycin-induced pulmonary fibrosis (PF). C57BL/6J mice were subjected to a single intratracheal instillation of bleomycin to induce PF. Daily PFPE treatment significantly reduced loss of body mass and mortality rate in mice compared with those treated with bleomycin. While bleomycin-induced PF resulted in elevated total numbers of inflammatory cells, macrophages, lymphocytes, and neutrophils in bronchoalveolar lavage fluid on both days 7 and 21, PFPE administration significantly attenuated these phenomena compared with bleomycin group. On day 7, the decreased superoxide dismutase and myeloperoxidase activities observed in the bleomycin group were significantly restored with PFPE treatment. On day 21, enhanced hydroxyproline deposition in the bleomycin group was also suppressed by PFPE administration. PFPE treatment significantly attenuated extensive inflammatory cell infiltration and accumulation of collagen in lung tissue sections of bleomycin-induced mice on days 7 and 21, respectively. Our results indicate that administration of PFPE decreased bleomycin-induced PF because of anti-inflammatory and antioxidant activities.

Topics: Animals; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antioxidants; Bleomycin; Body Weight; Bronchoalveolar Lavage Fluid; Female; Flavonoids; Hydroxyproline; Inflammation; Mice, Inbred C57BL; Oxidative Stress; Passiflora; Peroxidase; Phytotherapy; Plant Extracts; Pulmonary Fibrosis; Superoxide Dismutase

Cysteinyl leukotrienes (CysLTs) propagate inflammatory reactions that result from allergen exposure in asthma. Montelukast, a CysLT type-1 receptor antagonist, disrupts mediator-receptor interactions and minimizes inflammatory response. In this study, we have evaluated anti-asthmatic efficacy of inhalable montelukast-loaded large porous particulate formulations in ovalbumin-induced rat airway inflammation model that mimics asthma.. The anti-inflammatory effects of a montelukast-loaded formulation were investigated in rats by measuring the total protein content, levels of injury markers and number of inflammatory cells in the bronchoalveolar lavage fluid (BALF). The histopathological studies assessed the morphological and structural changes that occur in asthmatic lungs. Animals were also challenged with methacholine to examine the airway hyper-reactivity.. Compared with healthy animals, asthmatic animals showed a 3.8- and 4.77-fold increase in the protein content and number of inflammatory cells in BALF, respectively. Intratracheal montelukast particles reduced the protein content by 3.3-fold and the number of inflammatory cells by 2.62-fold. Also, montelukast particles reduced the lactate dehydrogenase (LDH) and myeloperoxidase (MPO) levels by a 4.87- and 6.8-fold in BALF, respectively. Montelukast particles reduced the airway wall thickness by 2.5-fold compared with untreated asthmatic lungs. Further, particulate formulation protected the lungs against methacholine-induced bronchial provocation (p < 0.05).. Respirable large porous particles containing montelukast alleviated allergen-induced inflammatory response in an animal model and prevented histological changes associated with asthma. Thus montelukast-loaded large porous polylactic acid (PLA) particles could be an aerosolized delivery approach for administration of currently available oral montelukast.

Topics: Acetates; Aerosols; Animals; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Bronchoalveolar Lavage Fluid; Cyclopropanes; Cysteine; Disease Models, Animal; Inflammation; L-Lactate Dehydrogenase; Lactic Acid; Leukotrienes; Lung; Ovalbumin; Peroxidase; Polyesters; Polymers; Quinolines; Rats; Rats, Sprague-Dawley; Sulfides

Lipids play a role in acute pancreatitis (AP) progression. We investigate the ability of pancreatic acinar cells to trigger inflammatory response in the presence of lipid compounds generated in necrotic areas of peripancreatic adipose tissue (AT) during AP induced in rats by 5% sodium taurocholate. Lipid composition of AT was analyzed by HPLC-mass spectrometry. Acinar inflammatory response to total lipids as well as to either the free fatty acid (FFA) fraction or their chlorinated products (Cl-FFAs) was evaluated. For this, mRNA expression of chemokine (C-C motif) ligand 2 (CCL2) and P-selectin as well as the activation of MAPKs, NF-κB and STAT-3 were analyzed in pancreatic acini. Myeloperoxidase (MPO) activity, as an inducer of Cl-FFA generation, was also analyzed in AT. MPO activity significantly increased in necrotic (AT-N) induced changes in lipid composition of necrotic fat, such as increase in FFA and phospholipid (PL) content, generation of Cl-FFAs and increases in saturated FFAs and in the poly-:mono-unsaturated FFA ratio. Total lipids from AT-N induced overexpression of CCL2 and P-selectin in pancreatic acini as well as MAPKs phosphorylation and activation of NF-κB and STAT3. FFAs, but not Cl-FFAs, up-regulated CCL2 and P-selectin in acinar cells. We conclude that FFAs are capable of up-regulating inflammatory mediators in pancreatic acini and given that they are highly produced during AP, mainly may contribute to the inflammatory response triggered in acinar cells by fat necrosis. No role is played by Cl-FFAs generated as a result of neutrophil infiltration.

Topics: Acinar Cells; Adipose Tissue; Animals; Biomarkers; Blotting, Western; Cell Proliferation; Chlorohydrins; Inflammation; Inflammation Mediators; Lipids; Male; Pancreas; Pancreatitis, Acute Necrotizing; Peroxidase; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

Ulcerative colitis is inflammatory conditions of the colon caused by interplay of genetic and environmental factors. Previous studies indicated that the gut microflora may be involved in the colonic inflammation. Bacteroides fragilis (BF) is a Gram-negative anaerobe belonging to the colonic symbiotic. We aimed to investigate the protective role of BF in a colitis model induced in germ-free (GF) mice by dextran sulfate sodium (DSS). GF C57BL/6JNarl mice were colonized with BF for 28 days before acute colitis was induced by DSS. BF colonization significantly increased animal survival by 40%, with less reduction in colon length, and decreased infiltration of inflammatory cells (macrophages and neutrophils) in colon mucosa following challenge with DSS. In addition, BF could enhance the mRNA expression of anti-inflammatory-related cytokine such as interleukin 10 (IL-10) with polymorphism cytokine IL-17 and diminish that of proinflammatory-related tumor necrosis factor α with inducible nitric oxide synthase in the ulcerated colon. Myeloperoxidase activity was also decreased in BF-DSS mice. Taking these together, the BF colonization significantly ameliorated DSS-induced colitis by suppressing the activity of inflammatory-related molecules and inducing the production of anti-inflammatory cytokines. BF may play an important role in maintaining intestinal immune system homeostasis and regulate inflammatory responses.

Topics: Acute Disease; Animals; Bacteroides fragilis; Blood Cell Count; Colitis; Colon; Colony Count, Microbial; Dextran Sulfate; Gene Expression Regulation; Germ-Free Life; Inflammation; Kaplan-Meier Estimate; Male; Mice, Inbred C57BL; Peroxidase; Real-Time Polymerase Chain Reaction

Noninvasive biomarkers of high- and low-grade intestinal inflammation and of mucosal healing (MH) in patients with inflammatory bowel disease are currently lacking. We have recently shown that fecal high mobility group box 1 (HMGB1) protein is a novel biomarker of gut inflammation. We aimed at investigating in a mouse model if HMGB1 was able to foresee both a clinically evident and a subclinical gut inflammation and if its normalization indicated MH. We also aimed at confirming the results in patients with Crohn's disease (CD) and ulcerative colitis.. C57BL6/J mice were treated with increasing doses of dextran sodium sulphate to induce colitis of different severity degrees; 28 with CD, 23 with ulcerative colitis, and 17 controls were also enrolled. Fecal HMGB1 was analyzed by enzyme-linked immunosorbent assay and immunoblotting.. Fecal HMGB1 increased by 5-, 11-, 18-, and 24-folds with dextran sodium sulphate doses of 0.25%, 0.50%, 1%, and 4%, respectively, showing that the protein detected a high-grade and a subclinical inflammation. After a recovery time of 4-week posttreatment, HMGB1 returned to control levels, paralleling MH. In patients, fecal HMGB1 significantly correlated with endoscopic indexes (Simple Endoscopic Score for Crohn's Disease [SES-CD], endoscopic Mayo subscore), but not with the disease activity indexes (Crohn's disease Activity Index, partial Mayo score).. Fecal HMGB1 is a robust noninvasive biomarker of clinically overt and subclinical gut inflammation; it can also be a surrogate marker of MH. We suggest the use of fecal HMGB1 to monitor the disease course and assess therapy outcomes in inflammatory bowel disease.

Topics: Adult; Aged; Animals; Biomarkers; Blotting, Western; Case-Control Studies; Cells, Cultured; Colitis; Colitis, Ulcerative; Crohn Disease; Dextran Sulfate; Disease Progression; Double-Blind Method; Enzyme-Linked Immunosorbent Assay; Feces; Female; Follow-Up Studies; HMGB1 Protein; Humans; Inflammation; Intestinal Mucosa; Male; Mice; Mice, Inbred C57BL; Middle Aged; Peroxidase; Prognosis; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Wound Healing; Young Adult

Activation of myeloperoxidase (MPO), a heme protein primarily expressed in granules of neutrophils, is associated with the development of obesity. However, whether MPO mediates high-fat diet (HFD)-induced obesity and obesity-associated insulin resistance remains to be determined. Here, we found that consumption of an HFD resulted in neutrophil infiltration and enhanced MPO expression and activity in epididymal white adipose tissue, with an increase in body weight gain and impaired insulin signaling. MPO knockout (MPO(-/-)) mice were protected from HFD-enhanced body weight gain and insulin resistance. The MPO inhibitor 4-aminobenzoic acid hydrazide reduced peroxidase activity of neutrophils and prevented HFD-enhanced insulin resistance. MPO deficiency caused high body temperature via upregulation of uncoupling protein-1 and mitochondrial oxygen consumption in brown adipose tissue. Lack of MPO also attenuated HFD-induced macrophage infiltration and expression of proinflammatory cytokines. We conclude that activation of MPO in adipose tissue contributes to the development of obesity and obesity-associated insulin resistance. Inhibition of MPO may be a potential strategy for prevention and treatment of obesity and insulin resistance.

Topics: Adipose Tissue; Adipose Tissue, Brown; Animals; Body Temperature Regulation; Cell Count; Diet, High-Fat; Glucose Tolerance Test; Inflammation; Insulin Resistance; Ion Channels; Macrophages; Mice; Mice, Knockout; Mitochondria; Mitochondrial Proteins; Neutrophils; Obesity; Oxygen Consumption; Peroxidase; Uncoupling Protein 1; Up-Regulation

Apolipoprotein A1 (ApoA1) and apolipoprotein E (ApoE) mimetic peptides have attracted attention due to their ability to reduce atherosclerosis and exhibit antioxidant, anti-inflammatory, and hypolipidemic properties. In this study, we tested whether three distinct and unrelated cationic peptides would inhibit the oxidation of lipoproteins and whether they would counteract and neutralize the negatively charged modified lipoproteins, inhibit their uptake and inflammation by macrophages.. 5F-mimetic peptide of ApoA1, LL27 derived from the anti-microbial peptide hCAP, and a human glycodelin derived peptide were commercially synthesized. We noted that these three distinct cationic lysine-rich peptides, two of which were unrelated to any known apolipoproteins, inhibited copper-mediated oxidation of lipoproteins and reduced lipid peroxides in a lysine dependent manner. The peptides also retarded the electrophoretic mobility of previously oxidized LDL and acetylated LDL by virtue of their net positive charge. Pre-incubation of peptides with modified lipoproteins reduced the uptake of the latter by macrophages, thus preventing the formation of foam cells. The cationic peptides inhibited oxidized LDL (Ox-LDL)-induced inflammatory response both in vitro and in vivo.. Based on these results, we suggest that in addition to the well known mimetic peptides, other suitable cationic peptides may be of use for controlling Ox-LDL mediated inflammation and atherosclerotic progression.

Topics: Amino Acid Sequence; Animals; Anti-Inflammatory Agents; Antimicrobial Cationic Peptides; Copper; Cytokines; Drug Evaluation, Preclinical; Gene Expression Regulation; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Intercellular Signaling Peptides and Proteins; Lipid Peroxidation; Lipoproteins, LDL; Macrophages; Macrophages, Peritoneal; Male; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Oxidation-Reduction; Peptide Fragments; Peptides; Peritonitis; Peroxidase

Growing evidence indicates that the presence of toll-like receptor 4 (TLR4) on platelets is a key regulator of platelet number and function. Platelets exposed to TLR4 agonists may serve to activate other cells such as neutrophils and endothelial cells in sepsis and other inflammatory conditions. The functional significance of platelet TLR4 in hemorrhagic shock (HS), however, remains unexplored.. Using thromboelastography and platelet aggregometry, we demonstrate that platelet function is impaired in a mouse model of HS with resuscitation. Further analysis using cellular-specific TLR4 deletion in mice revealed that platelet TLR4 is essential for platelet activation and function in HS with resuscitation and that platelet TLR4 regulates the development of coagulopathy after hemorrhage and resuscitation. Transfusion of TLR4-negative platelets into mice resulted in protection from coagulopathy and restored platelet function. Additionally, platelet-specific TLR4 knockout mice were protected from lung and liver injury and exhibited a marked reduction in systemic inflammation as measured by circulating interleukin-6 after HS with resuscitation.. We demonstrate for the first time that platelet TLR4 is an essential mediator of the inflammatory response as well as platelet activation and function in HS and resuscitation.

Topics: Animals; Blood Coagulation Disorders; Blood Platelets; Endotoxemia; Gene Deletion; Gene Expression Regulation; Hemostasis; Inflammation; Interleukin-6; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Peroxidase; Platelet Aggregation; Platelet Function Tests; Resuscitation; Shock, Hemorrhagic; Thrombelastography; Toll-Like Receptor 4

Pulmonary hypertension is a progressive disease of various origins that is associated with right ventricular dysfunction. In the present study, the protective effect of diosgenin was investigated in monocrotaline-induced pulmonary hypertension in rats. Pulmonary hypertension was induced by a single subcutaneous injection of monocrotaline (60 mg/kg). Diosgenin (100 mg/kg) was given by oral administration once daily for 3 weeks. At the end of the experiment, mean arterial blood pressure, electrocardiography and echocardiography were recorded. Rats were then sacrificed and serum was separated for determination of total nitrate/nitrite level. Right ventricles and lungs were isolated for estimation of oxidative stress markers, tumor necrosis factor-alpha, total nitrate/nitrite and transforming growth factor-beta contents. Myeloperoxidase and caspase-3 activities in addition to endothelial and inducible nitric oxide synthase protein expression were also determined. Moreover, histological analysis of pulmonary arteries and cardiomyocyte cross-sectional area was performed. Diosgenin treatment provided a significant improvement toward preserving hemodynamic changes and alleviating oxidative stress, inflammatory and apoptotic markers induced by monocrotaline in rats. Furthermore, diosgenin therapy prevented monocrotaline-induced changes in nitric oxide production, endothelial and inducible nitric oxide synthase protein expression as well as histological analysis. These findings support the beneficial effect of diosgenin in pulmonary hypertension induced by monocrotaline in rats.

Topics: Animals; Caspase 3; Diosgenin; Glutathione; Heart Ventricles; Hypertension, Pulmonary; Inflammation; Lung; Male; Monocrotaline; Nitric Oxide; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Oxidative Stress; Peroxidase; Protective Agents; Pulmonary Artery; Rats, Wistar; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

The pathophysiology of ventilator-induced lung injury (VILI) involves multiple mechanisms including inflammation and inflammatory cells infiltration. The anti-CD11c monoclonal antibody, Efalizumab has been demonstrated to inhibit the T cell activation, migration and adhesion to keratinocytes.. In this study, we induced lung injury with mechanical ventilation in male Sprague-Dawley rats, the rats were divided into four groups: lung-protective ventilation (LV), injurious ventilation (HV), HV+human IgG control and HV+ Efalizumab groups. Then we detected the lung tissue wet/dry ratio, and the activity of myeloperoxidase (MPO) was determined. The concentration of protein, TNF-a, IL-6, IL-1b and MIP-2 in the BALF were detected by ELISA. The expression ICAM-1 was measured by Realtime PCR.. Compared with the human IgG control treated group, the treatment of Efalizumab attenuate the ventilator-induced lung injury, including the wet/dry ratio and the activity of myeloperoxidase (MPO), meanwhile, the level of pro-inflammatory cytokines, such as TNF-a, IL-6, IL-1b and MIP-2 were decreased in the BALF of Efalizumab-treated group rats compared with the human IgG-treated control group. In addition, the histopathological index of ventilator-induced lung injury was improved after efalizumab treatment, that also reduced the recruitment of inflammatory cells into the lung, such as neutrophils.. Our data suggested that Efalizumab could protect rat from ventilator-induced lung injury and improve the survival time through the inhibition of intrapulmonary inflammatory response.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Bronchoalveolar Lavage Fluid; CD11c Antigen; Chemokine CXCL2; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-1beta; Interleukin-6; Male; Peroxidase; Pulmonary Edema; Rats; Rats, Sprague-Dawley; Respiration, Artificial; Tumor Necrosis Factor-alpha; Ventilator-Induced Lung Injury

Pro-inflammatory cytokines regulate the magnitude of allergic reactions during asthma. Tumor necrosis factor--alpha (TNF-α), interleukin-6 (IL-6) and interleukin-13 (IL-13) play a crucial role in aggravating the inflammatory conditions during allergic asthma. In addition, oxidative stress contributes to the pathogenesis of asthma by altering the physiological condition resulting in the development of status asthmaticus. Anti-inflammatory corticosteroids are being widely used for treating allergic asthma. In the present study 5-aminosalicylic acid (5-ASA), a salicylic acid derivative, was evaluated, in vivo for its potential to suppress TNF-α, IL-6 and IL-13 using ovalbumin (OVA) induced allergic asthma in Balb/C mice. Oral administration of 65, 130 and 195 mg/kg 5-ASA significantly reduced the OVA induced total and differential leucocyte count, TNF-α, IL-6, IL-13, nitrite, nitrate, MDA, MPO and TPL levels in the lung lavage samples. Collectively, these findings suggest that 5-ASA is a potent immunomodulator and suppresses key Th2 cytokines production and oxidative stress in OVA-induced asthma.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Asthma; Bronchoalveolar Lavage Fluid; Inflammation; Interleukin-13; Interleukin-6; Lung; Male; Malondialdehyde; Mesalamine; Mice, Inbred BALB C; Nitrates; Nitrites; Ovalbumin; Oxidative Stress; Peroxidase; Tumor Necrosis Factor-alpha

Myocardial infarction (MI) remains a major cause of death and disability worldwide, despite available reperfusion therapies. Inflammatory signaling is considered nodal in defining final infarct size. Activation of the innate immune receptor toll-like receptors (TLR) 9 prior to ischemia and reperfusion (I/R) reduces infarct size, but the consequence of TLR9 activation timed to the onset of ischemia is not known.. The TLR9-agonist; CpG B was injected i.p. in C57BL/6 mice immediately after induction of ischemia (30 minutes). Final infarct size, as well as area-at-risk, was measured after 24 hours of reperfusion. CpG B injection resulted in a significant increase in circulating granulocytes and monocytes both in sham and I/R mice. Paradoxically, clear evidence of reduced cardiac infiltration of both monocytes and granulocytes could be demonstrated in I/R mice treated with CpG B (immunocytochemistry, myeloperoxidase activity and mRNA expression patterns). In addition, systemic TLR9 activation elicited significant alterations of cardiac inflammatory genes. Despite these biochemical and cellular changes, there was no difference in infarct size between vehicle and CpG B treated I/R mice.. Systemic TLR9-stimulation upon onset of ischemia and subsequent reperfusion does not alter final infarct size despite causing clear alterations of both systemic and cardiac inflammatory parameters. Our results question the clinical usefulness of TLR9 activation during cardiac I/R.

Topics: Animals; Disease Models, Animal; Female; Inflammation; Male; Mice; Monocytes; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Oligonucleotides; Peroxidase; Toll-Like Receptor 9

A suitable small animal model may help in the screening and evaluation of new drugs, especially those from natural products, which can be administered at lower dosages, fulfilling an urgent worldwide need. In this study, we explore whether zebrafish could be a model organism for carrageenan-induced abdominal edema. The research results showed that intraperitoneal (i.p.) administration of 1.5% λ-carrageenan in a volume of 20 µL significantly increased abdominal edema in adult zebrafish. Levels of the proinflammatory proteins tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS) were increased in carrageenan-injected adult zebrafish during the development of abdominal edema. An associated enhancement was also observed in the leukocyte marker, myeloperoxidase (MPO). To support these results, we further observed that i.p. methylprednisolone (MP; 1 µg), a positive control, significantly inhibited carrageenan-induced inflammation 24 h after carrageenan administration. Furthermore, i.p. pretreatment with either an anti-TNF-α antibody (1∶5 dilution in a volume of 20 µL) or the iNOS-selective inhibitor aminoguanidine (AG; 1 µg) inhibited carrageenan-induced abdominal edema in adult zebrafish. This new animal model is uncomplicated, easy to develop, and involves a straightforward inducement of inflammatory edema for the evaluation of small volumes of drugs or test compounds.

Topics: Animals; Anti-Inflammatory Agents; Carrageenan; Disease Models, Animal; Edema; Inflammation; Male; Methylprednisolone; Nitric Oxide Synthase Type II; Peroxidase; Tumor Necrosis Factor-alpha; Zebrafish

The aim of our study was to determinate the impact of dipeptide (alanyl-glutamine) administration on inflammatory and proliferative changes in jejunal mucosa after acute mesenteric ischemia.. Male Wistar rats (n=30) were divided into three groups: ischemia/reperfusion (IR) group which undergoes 60min of mesenteric ischemia and 1 or 24h of reperfusion (IR1, IR24, n=12). Groups with dipeptide administration (D+IR1, D+IR24, Dipeptiven con inf., i.v., 0.75 g/kg) prior to IR injury were followed by 1 and 24h of reperfusion. At the end of reperfusion period jejunal bioptic samples were obtained for histological (H&E), histochemical (Alcian blue) and immunohistochemical (anti-PCNA, anti-MPO) evaluations.. Our results pointed out a significant (p<0.001) increase of histopathological injury score in IR1 group compared to D+IR1 group. Immunohistochemical evaluation showed that MPO-positivity was significantly increased in IR groups after 1 (p<0.001) as well as 24h of reperfusion (p<0.01) compared to dipeptide pretreated groups. Proliferative/reparatory rate was assessed using anti-PCNA antibody and showed a significant increase (p<0.01) in PCNA cell positivity in lamina propria in dipeptide treated group compared to IR group.. In conclusion we may suggest that administration of alanyl-glutamine dipeptide prior to IR injury may help to protect small intestine and its mucous membrane integrity against insult such as intestinal ischemic/reperfusion injury presents.

Topics: Animals; Apoptosis; Dipeptides; Immunohistochemistry; Inflammation; Intestinal Mucosa; Jejunum; Male; Mesenteric Ischemia; Peroxidase; Proliferating Cell Nuclear Antigen; Rats, Wistar; Reperfusion Injury

To investigate effects of endotoxin on leukocyte activation and infiltration of the laminar tissue in isolated perfused equine limbs.. 10 right forelimbs and 3 left forelimbs collected from 10 healthy adult horses after slaughter at a licensed abattoir. procedures: Isolated right forelimbs were randomly assigned to 2 groups (5 forelimbs/group): perfusion of the distal portion for 10 hours with 80 ng of endotoxin/L and perfusion under the same conditions without endotoxin. After perfusion, samples for immunohistochemical detection of leukocytes (by use of antibodies against calprotectin and myeloperoxidase) and transmission electron microscopy were collected from the laminar tissue of the dorsal aspect of the hooves. Additionally, control samples were collected from the 3 nonperfused left forelimbs.. Samples of laminar tissue from the endotoxin perfusion group had significantly higher scores for calprotectin and myeloperoxidase staining than did control samples and samples perfused without endotoxin. Ultrastructural examination revealed endotoxin-induced damage of the epidermal basal cells with loss of cell contacts including hemidesmosomes and anchoring filaments and a resulting separation of parts of the basement membrane. Additionally, local breakdown of the basement membrane was detected at the location of leukocyte adherence.. In isolated perfused equine limbs, endotoxin at a clinically relevant concentration induced a distinct inflammatory reaction with intravascular and extravascular accumulation of leukocytes in the laminar tissue, similar to that seen during the developmental phase of laminitis. Therefore, endotoxin should be considered as a causative factor for some types of laminitis.

Topics: Animals; Cadaver; Endotoxins; Forelimb; Hoof and Claw; Horses; Immunohistochemistry; Inflammation; Leukocyte L1 Antigen Complex; Leukocytes; Microscopy, Electron, Transmission; Perfusion; Peroxidase; Random Allocation

The fatty acid amide palmitoylethanolamide (PEA) has been studied extensively for its anti-inflammatory and neuroprotective actions. The lipidic nature and large particle size of PEA in the native state may limit its solubility and bioavailability when given orally, however. Micronized formulations of a drug enhance its rate of dissolution and reduce variability of absorption when orally administered. The present study was thus designed to evaluate the oral anti-inflammatory efficacy of micronized/ultramicronized versus nonmicronized PEA formulations.. Micronized/ultramicronized PEA was produced by the air-jet milling technique, and the various PEA preparations were subjected to physicochemical characterization to determine particle size distribution and purity. Each PEA formulation was then assessed for its anti-inflammatory effects when given orally in the carrageenan-induced rat paw model of inflammation, a well-established paradigm of edema formation and thermal hyperalgesia.. Intraplantar injection of carrageenan into the right hind paw led to a marked accumulation of infiltrating inflammatory cells and increased myeloperoxidase activity. Both parameters were significantly decreased by orally given micronized PEA (PEA-m; 10 mg/kg) or ultramicronized PEA (PEA-um; 10 mg/kg), but not nonmicronized PeaPure (10 mg/kg). Further, carrageenan-induced paw edema and thermal hyperalgesia were markedly and significantly reduced by oral treatment with micronized PEA-m and ultramicronized PEA-um at each time point compared to nonmicronized PeaPure. However, when given by the intraperitoneal route, all PEA formulations proved effective.. These findings illustrate the superior anti-inflammatory action exerted by orally administered, micronized PEA-m and ultramicronized PEA-um, versus that of nonmicronized PeaPure, in the rat paw carrageenan model of inflammatory pain.

Topics: Administration, Oral; Amides; Analgesics; Animals; Carrageenan; Chemistry, Pharmaceutical; Chromatography, High Pressure Liquid; Disease Models, Animal; Edema; Ethanolamines; Hyperalgesia; Inflammation; Male; Microscopy, Electron, Scanning; Pain; Palmitic Acids; Peroxidase; Rats; Rats, Sprague-Dawley

Activated platelets and neutrophils exacerbate atherosclerosis. Platelets release the chemokines CXCL4, CXCL4L1 and CCL5, whereas myeloperoxidase (MPO) and azurocidin are neutrophil-derived. We investigated whether plasma levels of these platelet and neutrophil mediators are affected by the acute coronary syndrome (ACS), its medical treatment, concomitant clinical or laboratory parameters, and predictive for the progression of coronary artery disease (CAD). In an observational study, the association of various factors with plasma concentrations of platelet chemokines and neutrophil mediators in 204 patients, either upon admission with ACS and 6 hours later or without ACS or CAD, was determined by multiple linear regression. Mediator release was further analysed after activation of blood with ACS-associated triggers such as plaque material. CXCL4, CXCL4L1, CCL5, MPO and azurocidin levels were elevated in ACS. CXCL4 and CCL5 but not CXCL4L1 or MPO were associated with platelet counts and CRP. CXCL4 (in association with heparin treatment) and MPO declined over 6 hours during ACS. Elevated CCL5 was associated with a progression of CAD. Incubating blood with plaque material, PAR1 and PAR4 activation induced a marked release of CXCL4 and CCL5, whereas CXCL4L1 and MPO were hardly or not altered. Platelet chemokines and neutrophil products are concomitantly elevated in ACS and differentially modulated by heparin treatment. CCL5 levels during ACS predict a progression of preexisting CAD. Platelet-derived products appear to dominate the inflammatory response during ACS, adding to the emerging evidence that ACS per se may promote vascular inflammation.

Topics: Acute Coronary Syndrome; Aged; Anticoagulants; Antimicrobial Cationic Peptides; Biomarkers; Blood Platelets; Blood Proteins; Carrier Proteins; Case-Control Studies; Chemokine CCL5; Chemokines; Disease Progression; Dose-Response Relationship, Drug; Female; Heparin; Humans; Inflammation; Inflammation Mediators; Linear Models; Male; Middle Aged; Neutrophils; Peroxidase; Platelet Count; Polymorphism, Single Nucleotide; Predictive Value of Tests; Prognosis; Prospective Studies; Time Factors

Despite Cryptostegia grandiflora Roxb. ex R. Br. (Apocynaceae) leaves are widely used in folk Caribbean Colombian medicine for their anti-inflammatory effects, there are no studies that support this traditional use. Therefore, this work aimed to evaluate the effect of the total extract and primary fractions obtained from Cryptostegia grandiflora leaves, using in vivo and in vitro models of inflammation, and further get new insights on the mechanisms involved in this activity.. Ethanolic extract of Cryptostegia grandiflora leaves, and its corresponding ether and dichloromethane fractions, significantly reduced inflammation and myeloperoxidase activity (MPO) in ear tissue of mice treated with 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Histological analysis revealed a reduction of edema and leukocyte infiltration. Complementarily, we demonstrated that extract and fractions reduced nitric oxide (NO•) and prostaglandin E2 (PGE2) production in LPS-stimulated RAW 264.7 macrophages, as well as scavenging activity on DPPH and ABTS radicals.. Our results demonstrated for the first time the anti-inflammatory activity of Cryptostegia grandiflora leaves, supporting its traditional use. This activity was related to inhibition of MPO activity, and PGE2 and NO• production. These mechanisms and its antioxidant activity could contribute, at least in part, to the anti-inflammatory effect showed by this plant.

Topics: Animals; Anti-Inflammatory Agents; Apocynaceae; Cell Line, Tumor; Cytotoxins; Dinoprostone; Edema; Female; Inflammation; Macrophages; Mice, Inbred ICR; Nitric Oxide; Oxytocics; Peroxidase; Plant Extracts; Plant Leaves

The aim of this study was to evaluate the presence of myeloperoxidase (MPO), N-acetyl-β-D-glucosaminidase (NAG), tumor necrosis factor alpha (TNF-α) and vascular endothelial growth factor (VEGF) in peripheral and menstrual blood in women with (n=10) and without (n=7) endometriosis. NAG and MPO activities were evaluated by enzymatic methods, whereas TNF-α and VEGF by immunoassay. No significant differences were found for these markers, neither in menstrual nor in peripheral blood between groups. Menstrual blood NAG (P=0.039) and MPO (P=0.0117) activities in the endometriosis group were significantly higher than in peripheral blood. NAG and MPO presented positive linear correlation in peripheral (P=0.07; r=0.641) and menstrual blood (P=0.01; r=0.603). These findings point to the existence of an increased local inflammatory activity in women with endometriosis.

Topics: Adult; Biomarkers; Endometriosis; Female; Humans; Inflammation; Menstrual Cycle; Middle Aged; Neoplasm Proteins; Neovascularization, Pathologic; Peroxidase; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

Besides the classical functions, neutrophils (PMNs) are able to release DNA in response to infectious stimuli, forming neutrophil extracellular traps (NETs) and killing pathogens. The pathogenesis of endometritis in the mare is not completely understood. The aim was to evaluate the in vitro capacity of equine PMNs to secrete NETs by chemical activation, or stimulated with Streptococcus equi subspecies zooepidemicus (Szoo), Escherichia coli (Ecoli) or Staphylococcus capitis (Scap) strains obtained from mares with endometritis. Ex vivo endometrial mucus from mares with bacterial endometritis were evaluated for the presence of NETs. Equine blood PMNs were used either without or with stimulation by phorbol-myristate-acetate (PMA), a strong inducer of NETs, for 1-3h. To evaluate PMN ability to produce NETs when phagocytosis was impaired, the phagocytosis inhibitor cytochalasin (Cyt) was added after PMA. After the addition of bacteria, a subsequent 1-h incubation was carried out in seven groups. NETs were visualized by 4',6-diamidino-2-phenylindole (DAPI) and anti-histone. Ex vivo samples were immunostained for myeloperoxidase and neutrophil elastase. A 3-h incubation period of PMN + PMA increased NETs (p < 0.05). Bacteria + 25 nM PMA and bacteria + PMA + Cyt increased NETs (p<0.05). Szoo induced fewer NETs than Ecoli or Scap (p < 0.05). Ex vivo NETs were present in mares with endometritis. Scanning electron microscopy showed the spread of NETs formed by smooth fibers and globules that can be aggregated in thick bundles. Formation of NETs and the subsequent entanglement of bacteria suggest that equine NETs might be a complementary mechanism in fighting some of the bacteria causing endometritis in the mare.

Topics: Animals; Cells, Cultured; Cytochalasins; Endometritis; Escherichia coli; Extracellular Traps; Female; Horses; Inflammation; Neutrophils; Peroxidase; Phagocytosis; Staphylococcus; Streptococcus equi; Tetradecanoylphorbol Acetate

The clinical significance of myeloperoxidase (MPO) has been the focus of investigation because it may contribute to the chronic, non-microbial inflammatory process in various diseases. Here, we determined serum MPO levels in rheumatoid arthritis (RA) and other autoimmune or inflammatory conditions, and investigated the associations between MPO levels and disease activity indicators in RA.. The distribution of MPO was determined in serum samples from patients with RA, systemic lupus erythematosus (SLE), primary Sjögren's syndrome (pSS), dermatomyositis (DM), or ankylosing spondylitis (AS) and from healthy controls using commercial ELISA kits. Associations of serum MPO levels with the disease variables of RA patients were evaluated.. All patient samples analyzed showed higher serum levels of MPO than healthy controls. Furthermore, MPO levels in RA were significantly higher than those in the other diseases with the exception of DM. Higher MPO levels were observed in RA patients with increased C-reactive protein (p=0.005) or neutrophil percentage (p<0.001), as well as in those with highly active disease (p<0.001). Moderate positive correlations between MPO levels and IgM (r=0.334, p=0.001), C-reactive protein (r=0.293, p=0.003), erythrocyte sedimentation rate (r=0.240, p=0.016), or DAS28 (r=0.350, p<0.001) were also demonstrated.. The MPO concentration is likely to increase in patients with chronic inflammation. The associations between MPO and the disease variables of RA patients support a role for MPO in the inflammatory process of the disease.

Topics: Adult; Aged; Arthritis, Rheumatoid; Biomarkers; Blood Sedimentation; C-Reactive Protein; Case-Control Studies; Dermatomyositis; Enzyme-Linked Immunosorbent Assay; Female; Humans; Inflammation; Lupus Erythematosus, Systemic; Male; Middle Aged; Peroxidase; Sjogren's Syndrome; Spondylitis, Ankylosing

Young stroke patients constitute 15%-30% of all stroke patients in India as against 3.0%-8.5% reported from the West. The mechanisms for stroke in the young may include unconventional risk factors such as infections. We aimed to investigate the role (if any) of Chlamydia pneumoniae antibodies in young patients with acute ischemic stroke (AIS). Several proinflammatory cytokines and biomarkers are released early after the onset of brain ischemia. We assessed the role of heat shock protein (hsp) 65, neopterin, and myeloperoxidase upregulation after AIS in predicting stroke severity. We also assessed relationship of upregulated inflammatory biomarkers with C pneumoniae antibody titres (IgG, IgA, and IgM).. Eighty acute stroke patients and healthy age- and sex-matched controls were recruited. Blood samples were drawn within 1 week from the onset of stroke. Detection of IgA, IgG, and IgM antibodies to C pneumoniae was done with a validated microimmunofluorescence technique from 5 mL of serum in all subjects. Inflammatory biomarkers such as neopterin, myeloperoxidase and hsp 65 were estimated with sandwich enzyme linked immunosorbent assay (ELISA) method.. hsp 65 and neopterin were significantly elevated in all stroke patients with respect to healthy controls (odds ratio [OR], 4.9; 95% confidence interval [CI], 23.5-67.8; P = .001 and OR, 4.4; 95% CI, 2.08-9.4; P = .04, respectively). Eighty-one percent of cases were seropositive for IgA versus 32% of controls (P = .003), and IgG was positive in 52.7% versus 17.3% of controls (P = .05). Myeloperoxidase levels were similar in patients and controls. Correlation and multiple regression indicated a high level of predictability and sensitivity of hsp 65 to IgA. C. pneumoniae antibody titres when all other variables were constant (F [4,90] = -6.8, P = .001). Patients with high NIHSS scores (>15) had elevated levels of hsp 65 (mean, 13.2 ng/mL) suggesting correlation with stroke severity.. The study demonstrated high levels of hsp 65 and neopterin levels in AIS correlated to significantly elevated IgA titres of C pneumoniae. Elevated levels of hsp 65 were associated with stroke severity.

Topics: Adolescent; Adult; Antibodies, Bacterial; Biomarkers; Brain Ischemia; Case-Control Studies; Chlamydia Infections; Chlamydophila pneumoniae; Female; Heat-Shock Proteins; Humans; Immunoglobulins; India; Inflammation; Male; Middle Aged; Neopterin; Peroxidase; Risk Factors; Stroke; Young Adult

Investigate the therapeutic effect of regional arterial infusion (RAI) with Aspirin-Triggered Lipoxin A4 (ATL) in experimental severe acute pancreatitis (SAP) in rats.. SAP was induced by injection of 5% sodium taurocholate into the pancreatic duct. Rats with SAP were treated with ATL (the ATL group) or physiological saline (the SAP group) infused via the left gastric artery 30 min after injection of sodium taurocholate. The sham group was subjected to the same surgical procedure, though without induction of SAP. Serum levels of amylase, phospholipase A2 (PLA2), interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α) were measured at 12 and 24 h after induction of SAP. Ascitic fluid, the pancreatic index (wet weight ratio) and myeloperoxidase (MPO) levels in the pancreas were determined and histopathological findings were evaluated. The expression of intercellular adhesion molecule-1 (ICAM-1), platelet endothelial cell adhesion molecule-1 (PECAM-1), NF-κB p65, and heme oxygenase-1 (HO-1) in the pancreas were estimated by immunofluorescence and western blot, respectively.. ATL rats had lower serum levels of TNF-α, IL-1β, and IL-6 (P<0.01), PLA2 (P<0.05), and amylase levels (P<0.05) studied as compared with the SAP group. The pancreatic index in the ATL group decreased only at 24 h as compared with the SAP group (P<0.05). The histopathological findings and MPO levels in the pancreas significantly decreased in the ATL group as compared to the SAP group (P<0.05 and P<0.01, respectively). Immunofluorescence and western blot showed that ATL attenuated the expression of NF-κB p65, ICAM-1 and PECAM-1 in the pancreas, and increased the expression of HO-1 in SAP animals.. We demonstrated that RAI with ATL attenuated the severity of experimental SAP, maybe achieved by improving the expression of HO-1, and down-regulating the NF-κB signaling pathway, with decreased expression of ICAM-1 and PECAM-1 and reduced generation of pro-inflammatory cytokines.

Topics: Amylases; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Cytokines; Heme Oxygenase-1; Inflammation; Infusions, Intra-Arterial; Intercellular Adhesion Molecule-1; Interleukin-1beta; Interleukin-6; Lipoxins; Male; Pancreas; Pancreatitis; Peroxidase; Phospholipases A2; Platelet Endothelial Cell Adhesion Molecule-1; Rats; Rats, Sprague-Dawley; Taurocholic Acid; Transcription Factor RelA; Tumor Necrosis Factor-alpha

Toll-like receptor 2 (TLR2) recognizes conserved molecular patterns associated with both gram-negative and gram-positive bacteria, and detects some endogenous ligands. Previous studies demonstrated that in ischemia-reperfusion (I/R) injury of the small intestine, the TLR2-dependent signaling exerted preventive effects on the damage in young mice, but did not have a significant effect in neonatal mice. We investigated the role of TLR2 in adult ischemia-reperfusion injury in the small intestine. Wild-type and TLR2 knockout mice at 16 weeks of age were subjected to intestinal I/R injury. Some wild-type mice received anti-Ly-6G antibodies to deplete circulating neutrophils. In wild-type mice, I/R induced severe small intestinal injury characterized by infiltration by inflammatory cells, disruption of the mucosal epithelium, and mucosal bleeding. Compared to wild-type mice, TLR2 knockout mice exhibited less severe mucosal injury induced by I/R, with a 35%, 33%, and 43% reduction in histological grading score and luminal concentration of hemoglobin, and the numbers of apoptotic epithelial cells, respectively. The I/R increased the activity of myeloperoxidase (MPO), a marker of neutrophil infiltration, and the levels of mRNA expression of tumor necrosis factor-α (TNF-α), intercellular adhesion molecule-1 (ICAM-1), and cyclooxygenase-2 (COX-2) in the small intestine of the wild-type mice by 3.3-, 3.2-, and 13.0-fold, respectively. TLR2 deficiency significantly inhibited the I/R-induced increase in MPO activity and the expression of mRNAs for TNF-α and ICAM-1, but did not affect the expression of COX-2 mRNA. I/R also enhanced TLR2 mRNA expression by 2.9-fold. TLR2 proteins were found to be expressed in the epithelial cells, inflammatory cells, and endothelial cells. Neutrophil depletion prevented intestinal I/R injury in wild-type mice. These findings suggest that TLR2 may mediate I/R injury of the small intestine in adult mice via induction of inflammatory mediators such as TNF-α and ICAM-1.

Topics: Animals; Apoptosis; Cyclooxygenase 2; Epithelial Cells; Gene Expression Regulation; Humans; Inflammation; Intercellular Adhesion Molecule-1; Intestine, Small; Mice; Mice, Knockout; Neutrophil Infiltration; Peroxidase; Reperfusion Injury; Signal Transduction; Toll-Like Receptor 2; Tumor Necrosis Factor-alpha

Abnormality in mitochondria has been suggested to be associated with development of allergic airway disorders. In this study, to evaluate the relationship between mitochondrial reactive oxygen species (ROS) and NLRP3 inflammasome activation in allergic asthma, we used a newly developed mitochondrial ROS inhibitor, NecroX-5. NecroX-5 reduced the increase of mitochondrial ROS generation in airway inflammatory cells, as well as bronchial epithelial cells, NLRP3 inflammasome activation, the nuclear translocation of nuclear factor-κB, increased expression of various inflammatory mediators and pathophysiological features of allergic asthma in mice. Finally, blockade of IL-1β substantially reduced airway inflammation and hyperresponsiveness in the asthmatic mice. These findings suggest that mitochondrial ROS have a critical role in the pathogenesis of allergic airway inflammation through the modulation of NLRP3 inflammasome activation, providing a novel role of airway epithelial cells expressing NLRP3 inflammasome as an immune responder.

Topics: Animals; Asthma; Bronchi; Bronchoalveolar Lavage Fluid; Carrier Proteins; Caspase 1; Cells, Cultured; DNA, Mitochondrial; Epithelial Cells; Heterocyclic Compounds, 4 or More Rings; Humans; Hypersensitivity; Inflammasomes; Inflammation; Interleukin-1beta; Intracellular Space; Lipopolysaccharides; Lung; Male; Mice; Middle Aged; Mitochondria; NLR Family, Pyrin Domain-Containing 3 Protein; Ovalbumin; Peroxidase; Reactive Oxygen Species; Sulfones; Trachea

Integrins are involved in a number of physio-pathological processes including wound healing, chronic inflammation and neoplasias. Blocking its activity is potentially of therapeutic value in these conditions. We investigated whether DisBa-01, a recombinant His-tag RGD-disintegrin from Bothrops alternatus snake venom, could modulate key events (inflammatory cell recruitment/activation, neovascularization and extracellular matrix deposition) of the proliferative fibrovascular tissue induced by polyether polyurethane sponge implants in mice. The hemoglobin content (μg/mg wet tissue), blood flow measurements (laser Doppler perfusion imaging) and number of vessels in the implants, used as indices of vascularization, showed that the disintegrin dose-dependently reduced angiogenesis in the implants relative to the Saline-treated group. DisBa-01 inhibited neutrophil and macrophage content as determined by the myeloperoxidase (MPO) and N-acetyl-β-D-glucosaminidase (NAG) activities, respectively. Similarly, down regulation of the fibrogenic component studied (collagen deposition) was observed in DisBa-01-treated implants. VEGF, bFGF, TNF-α, CXCL1 and CCL2 levels were also decreased by the disintegrin. The inhibitory effect of this αvβ3-blocking disintegrin on the angiogenic, inflammatory, and fibrogenic components of the fibrovascular tissue induced by the synthetic matrix extends the range of DisBa-01 actions and may indicate its therapeutic potential in controlling angiogenesis in fibroproliferative diseases.

Topics: Acetylglucosaminidase; Animals; Bothrops; Crotalid Venoms; Disintegrins; Drug Evaluation, Preclinical; Extracellular Matrix; Inflammation; Laser-Doppler Flowmetry; Macrophages; Mice; Neovascularization, Physiologic; Peroxidase; Polyurethanes; Recombinant Proteins; Regional Blood Flow

To explicit whether the functions of high density lipoprotein (HDL) are impaired in murine atherosclerosis by subcutaneous immunization with recombinant mycobacterial heat shock protein 65 (HSP65).. C57BL/6 mice were fed a normal chow-diet with non immunization as normal group. ApoE knockout (ApoE(-/-)) mice on high-fat diet were randomly divided into three groups (n = 8) and immunized subcutaneously with different concentrations of HSP65 or phosphate-buffered saline (PBS). All animals were treated for 16 weeks. Reverse cholesterol efflux, the anti-oxidant and anti-inflammatory functions of HDL were assayed. Hepatocytes and peritoneal macrophages were isolated to examine the expression of cholesterol transport regulating proteins, including SR-B1, ABCA1, ABCG1, PPAR-γ and LXR-α.. In HSP65-immunized mice, paraoxonase1 (PON1) activity and the expression of IL-10 were reduced, while High-density lipoprotein inflammatory index (HII), myeloperoxidase (MPO) activity, and the expression of IFN-γ were elevated gradually. The MPO/PON1 ratio amount was significantly higher in HSP65-immunized group than in normal or PBS-immunized group. In addition, compared with normal or PBS-immunized group, cholesterol efflux rate and the expression of regulating proteins were markedly decreased in HSP65-immunized group. The mice immunized with HSP65 developed significantly larger aorta atherosclerotic plaques when compared with PBS-treated littermates. The high MPO/PON1 ratio was correlated with HII, cholesterol efflux rate and atherosclerotic plaques.. This study demonstrates that subcutaneous immunization with HSP65 impairs the properties of HDL, which may contribute to its important pathogenic role of HSP65 in atherogenesis. Also, MPO/PON1 ratio may be a predictor of AS.

Topics: Animals; Antioxidants; Apolipoproteins E; Aryldialkylphosphatase; Atherosclerosis; Bacterial Proteins; Chaperonin 60; Cholesterol; Cytokines; Inflammation; Interferon-gamma; Lipoproteins, HDL; Macrophages; Male; Mice; Mice, Inbred C57BL; Peroxidase; Recombinant Proteins; RNA, Messenger; Scavenger Receptors, Class B

In a previous study, the anti-inflammatory effects of tectorigenin were disclosed. In this study, the anti-inflammatory effects of tectorigenin on acute lung injury using a lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model were investigated. The cell-count in the bronchoalveolar lavage fluid (BALF) was measured. The animal lung edema degree was evaluated by the wet/dry weight (W/D) ratio. The superoxidase dismutase (SOD) activity and myeloperoxidase (MPO) activity was assayed using SOD and MPO kits, respectively. The levels of inflammatory mediators, including tumor necrosis factor-α (TNF-α), IL-1β, and IL-6 were assayed using an enzyme-linked immunosorbent assay method. Pathological changes of lung tissues were observed through HE staining. The inflammatory signal pathway related protein nuclear factor NF-κB p65 mRNA expression was measured by real-time PCR, and the protein level of NF-κB p65 was measured using Western blotting analysis.. The data showed that treatment with the tectorigenin markedly attenuated the inflammatory cell numbers in the BALF, decreased nuclear factor NF-κB p65 mRNA level and protein level in the lungs, and improved SOD activity and inhibited MPO activity. Histological studies showed that tectorigenin substantially inhibited LPS-induced neutrophils in lung tissue compared with the model group.. The results indicated that tectorigenin had a protective effect on LPS-induced ALI in mice.

Topics: Acute Lung Injury; Animals; Bronchoalveolar Lavage Fluid; Cell Count; Female; Inflammation; Isoflavones; Lipopolysaccharides; Mice; Mice, Inbred BALB C; Peroxidase; Pulmonary Edema; Superoxide Dismutase

Liver dysfunction has been known to occur frequently in cases of sepsis. Excessive inflammation and apoptosis are pathological features of acute liver failure. Recent studies suggest that activation of glycogen synthase kinase- (GSK-) 3β is involved in inflammation and apoptosis. We aimed to investigate the protective effects of GSK-3β inhibition on polymicrobial sepsis-induced liver injury and to explore the possible mechanisms. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP), and SB216763 was used to inhibit GSK-3β in C57BL/6 mice. GSK-3β was activated following CLP. Administration of SB216763 decreased mortality, ameliorated liver injury, and reduced hepatic apoptosis. The inhibition of GSK-3β also reduced leukocyte infiltration and hepatic inflammatory cytokine expression and release. Moreover, GSK-3β inhibition suppressed the transcriptional activity of nuclear factor-kappa B (NF-κB) but enhanced the transcriptional activity of cAMP response element binding protein (CREB) in the liver. In in vitro studies, GSK-3β inhibition reduced inflammatory cytokine production via modulation of NF-κB and CREB signaling pathways in lipopolysaccharide-stimulated macrophages. In conclusion, these findings suggest that GSK-3β blockade protects against CLP-induced liver via inhibition of inflammation by modulating NF-κB and CREB activity and suppression of hepatic apoptosis.

Topics: Animals; Apoptosis; Cell Line; Cytokines; Enzyme-Linked Immunosorbent Assay; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Immunohistochemistry; Indoles; Inflammation; Interleukin-6; Leukocytes; Liver; Male; Maleimides; Mice; Mice, Inbred C57BL; NF-kappa B; Peroxidase; Signal Transduction

To investigate the effects of terminal ileostomy on bacterial translocation (BT) and systemic inflammation after intestinal ischemia/reperfusion (I/R) injury in rats.. Thirty-two rats were assigned to either the sham-operated group, I/R group, I/R + resection and anastomosis group, or the I/R + ileostomy group. The superior mesenteric artery was occluded for 60 min. After 4 h, tissue samples were collected for analysis. BT was assessed by bacteriologic cultures, intestinal permeability and serum levels of endotoxin; systemic inflammation was assessed by serum levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-10, as well as by the activity of myeloperoxidase (MPO) and by intestinal histopathology.. Intestinal I/R injury not only caused morphologic damage to ileal mucosa, but also induced BT, increased MPO activity and promoted the release of TNF-α, IL-6, and IL-10 in serum. BT and ileal mucosa injuries were significantly improved and levels of TNF-α and IL-6 in serum were decreased in the I/R + ileostomy group compared with the I/R + resection and anastomosis group.. Terminal ileostomy can prevent the detrimental effects of intestinal I/R injury on BT, intestinal tissue, and inflammation.

Topics: Animals; Bacterial Translocation; Biomarkers; Disease Models, Animal; Ileostomy; Ileum; Inflammation; Inflammation Mediators; Interleukin-10; Interleukin-6; Male; Permeability; Peroxidase; Rats, Sprague-Dawley; Reperfusion Injury; Time Factors; Tumor Necrosis Factor-alpha

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophic factor family. Outside the nervous system, BDNF has been shown to be expressed in various nonneural tissues, such as periodontal ligament, dental pulp, and odontoblasts. Although a role for BDNF in periodontal regeneration has been suggested, a function for BDNF in periodontal disease has not yet been studied. The aim of this study was to analyze the BDNF levels in periodontal tissues of patients with chronic periodontitis (CP) and periodontally healthy controls (HC). All subjects were genotyped for the rs4923463 and rs6265 BDNF polymorphisms. Periodontal tissues were collected for ELISA, myeloperoxidase (MPO), and microscopic analysis from 28 CP patients and 29 HC subjects. BDNF levels were increased in CP patients compared to HC subjects. A negative correlation was observed when analyzing concentration of BDNF and IL-10 in inflamed periodontium. No differences in frequencies of BDNF genotypes between CP and HC subjects were observed. However, BDNF genotype GG was associated with increased levels of BDNF, TNF-α, and CXCL10 in CP patients. In conclusion, BDNF seems to be associated with periodontal disease process, but the specific role of BDNF still needs to be clarified.

Topics: Adult; Alleles; Brain-Derived Neurotrophic Factor; Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression Regulation; Genotype; Humans; Inflammation; Interleukin-10; Male; Middle Aged; Periodontitis; Peroxidase; Polymorphism, Single Nucleotide; Sequence Analysis, DNA

Preclinical in vivo research on inflammatory bowel diseases requires proper animal models and techniques allowing longitudinal monitoring of colonic inflammation without the need to kill animals. We evaluated colonoscopy and μ-positron emission tomography/computed tomography (μPET/CT) as monitoring tools in a model for chronic colitis in mice.. Colitis was induced by adoptive transfer of CD4(+)CD25(-)CD62L(+) T cells in immunocompromised severe combined immunodeficient mice. Three study protocols were designed. In study 1, colonoscopy and µPET/CT were performed once, 4 weeks after transfer. In study 2 and study 3, colitis was sequentially followed up through colonoscopy (study 2) or colonoscopy plus µPET/CT (study 3). Each study included postmortem evaluation of colonic inflammation (macroscopy, microscopy, and myeloperoxidase activity).. In study 1, both colonoscopy and µPET/CT detected colitis 4 weeks after transfer. Study 2 showed a gradual increase in colonoscopic score from week 2 (1.4 ± 0.6) to week 8 (6.0 ± 1.1). In study 3, colitis was detected 2 weeks after transfer by µPET/CT (2.0 ± 0.4) but not by colonoscopy, whereas both techniques detected inflammation 4 and 6 weeks after transfer. Colonoscopy correlated with µPET/CT (r = 0.812, 0.884, and 0.781, respectively) and with postmortem analyses in all 3 studies.. Adoptive transfer of CD4(+)CD25(-)CD62L(+) T cells in severe combined immunodeficient mice results in a moderate chronic colitis. Evolution of colitis could be monitored over time by both colonoscopy and µPET/CT. µPET/CT seems to detect inflammation at an earlier time point than colonoscopy. Both techniques represent reliable and safe methods without the need to kill animals.

Topics: Adoptive Transfer; Animals; CD4-Positive T-Lymphocytes; Colitis; Colonoscopy; Disease Models, Animal; Female; Inflammation; Mice; Mice, Inbred BALB C; Mice, SCID; Peroxidase; Positron-Emission Tomography; Tomography, X-Ray Computed

Catechins, abundant in green tea, exhibit many biological actions for potential clinical applications. Our purpose was to explore the potential benefits of catechin ingestion on recovery of physical performance after downhill running.. Institute of Cancer Research mice were used to examine the effects of prior catechin ingestion (0.5% w/w in diet for 3 wk) on 1) wheel-running activity, 2) running endurance, 3) muscle force, and 4) muscle oxidative stress and inflammation after downhill running (16 m·min for 5 min, 18 m·min for 5 min, 20 m·min for 10 min, and 22 m·min for 130 min).. Voluntary wheel-running activity and the contractile force of the isolated soleus muscle decreased (P < 0.05) after downhill running. Notably, catechin ingestion significantly alleviated the running-induced decrease in voluntary wheel-running activity by 35%; the catechin-treated mice maintained endurance running capacity (214 ± 9 vs 189 ± 10 min, P < 0.05). Furthermore, catechins alleviated (P < 0.05) the decrease in tetanic force evident in the soleus muscle after downhill running. Catechins suppressed the running-induced increases in plasma creatine phosphokinase levels by 52%; this was also true of the carbonylated protein content of the soleus muscle by 17% (P < 0.05), malondialdehyde levels by 32% in the gastrocnemius muscle, and myeloperoxidase activity of the gastrocnemius by 22% (P < 0.05). The levels of tumor necrosis factor-α, interleukin-1β, and monocyte chemoattractant protein-1 in the gastrocnemius muscle were significantly lower (P < 0.05) by 33%, 29%, and 35%, respectively, in treated mice; the expression levels of mRNAs encoding these fell in parallel.. Our results suggest that long-term intake of catechins, perhaps through their antioxidant properties, attenuates downhill running-induced muscle damage by suppressing muscle oxidative stress and inflammation, hastening recovery of physical performance in mice.

Topics: Animals; Behavior, Animal; Catechin; Chemokine CCL2; Creatine Kinase; Inflammation; Interleukin-1beta; Male; Malondialdehyde; Mice; Mice, Inbred ICR; Muscle Contraction; Muscle Strength; Muscle, Skeletal; Peroxidase; Physical Endurance; Protein Carbonylation; RNA, Messenger; Running; Tumor Necrosis Factor-alpha

Chlorogenic acid (CA) exits widely in those Chinese herbal injections that have antibacterial and antiphlogistic effects and belongs to the ethnopharmacological family of medicines. Chinese herbal injections containing high levels of CA have been reported to increase the adverse drug reactions, but the mechanism for which is still unclear. In this study, we investigated the mechanism of the CA derived adverse drug reactions.. The present study was to explore the potential role of CA in initiating inflammatory reaction and the underlying mechanism.. Male Wistar rats were treated with different dosages of CA for different time period. The variables examined included microcirculation by intravital microscopy, histology of ileum tissue, expression of adhesion molecules CD11b and CD18 on leukocytes by flow cytometry, myeloperoxidase activity and maleic dialdehyde content in ileum tissue by spectrophotometry, activity of superoxide dismutase and catalase in serum by ELISA, and expression of NADPH oxidase subunits by PCR and Western blot.. High-dose CA increased the number of adherent leukocytes, generation of peroxides in the venular walls and induced albumin leakage from mesentery venules. High-dose CA induced changes also included an increase in maleic dialdehyde, myeloperoxidase, inflammatory cytokines and NADPH oxidase activities, and a decline in activity of superoxide dismutase and catalase.. High-dose, but not Low-dose CA induced inflammation reaction, and in this process an imbalance between oxidant and antioxidant mechanism may be involved, providing more information for better understanding the rationale behind the adverse effects of CA.

Topics: Animals; Blotting, Western; Capillary Permeability; Catalase; CD11b Antigen; CD18 Antigens; Cell Degranulation; Chlorogenic Acid; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Gene Expression Regulation, Enzymologic; Ileum; Inflammation; Inflammation Mediators; Interleukin-6; Leukocyte Rolling; Leukocytes; Male; Malondialdehyde; Mast Cells; Mesentery; Microcirculation; Microscopy, Video; NADPH Oxidase 4; NADPH Oxidases; Neutrophils; Oxidative Stress; Peroxidase; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; RNA, Messenger; Serum Albumin; Splanchnic Circulation; Superoxide Dismutase; Time Factors; Tumor Necrosis Factor-alpha; Venules

In multiply injured patients, bilateral femur fractures invoke a substantial systemic inflammatory impact and remote organ dysfunction. However, it is unclear whether isolated bone or soft tissue injury contributes to the systemic inflammatory response and organ injury after fracture.. We therefore asked whether the systemic inflammatory response and remote organ dysfunction are attributable to the bone fragment injection, adjacent soft tissue injury, or both.. Male C57/BL6 mice (8-10 weeks old, 20-30 g) were assigned to four groups: bone fragment injection (BF, n = 9) group; soft tissue injury (STI, n = 9) group; BF + STI (n = 9) group, in which both insults were applied; and control group, in which neither insult was applied. Animals were sacrificed at 6 hours. As surrogates for systemic inflammation, we measured serum IL-6, IL-10, osteopontin, and alanine aminotransferase (ALT) and nuclear factor (NF)-κB and myeloperoxidase (MPO) in the lung.. The systemic inflammatory response (mean IL-6 level) was similar in the BF (61.8 pg/mL) and STI (67.9 pg/mL) groups. The combination (BF + STI) of both traumatic insults induced an increase in mean levels of inflammatory parameters (IL-6: 189.1 pg/mL) but not in MPO levels (1.21 ng/mL) as compared with the BF (0.82 ng/mL) and STI (1.26 ng/mL) groups. The model produced little evidence of remote organ inflammation.. Our findings suggest both bone and soft tissue injury are required to induce systemic changes. The absence of remote organ inflammation suggests further fracture-associated factors, such as hemorrhage and fat liberation, may be more critical for induction of remote organ damage.. Both bone and soft tissue injuries contribute to the systemic inflammatory response.

Topics: Animals; Fractures, Bone; Inflammation; Interleukin-10; Interleukin-6; Lung; Male; Mice; NF-kappa B; Osteopontin; Peroxidase; Pilot Projects; Soft Tissue Injuries

The IKK/NF-κB signalling pathway plays a predominant role in the regulation of inflammation and apoptosis in spinal cord injury (SCI). We have previously demonstrated that targeting of the IKK/NF-κB pathway improved the recovery of locomotor function by reducing the infiltration of inflammatory cells and apoptosis after SCI in rats. Recently, the neuroprotective effects of butein have been shown via direct inhibition of the IKK/NF-κB pathway in vitro. In this study, we investigated the effects of butein on the IKK/NF-κB pathway in rats after SCI. Our results indicated that butein reduced the expression of NF-κB and activation of its inhibitor I-κBα at 24h after injury. Treatment with butein also resulted in significant inhibition of caspase-3 activation and neutrophil infiltration. Overall, our findings demonstrated the neuroprotective effects of butein in SCI in vivo and its potential mechanism. Our results further indicated that targeting of the IKK/NF-κB pathway may be useful in SCI therapy.

Topics: Animals; Apoptosis; Caspase 3; Chalcones; Enzyme Activation; Female; I-kappa B Proteins; Inflammation; Neuroprotective Agents; Neutrophil Infiltration; NF-kappa B; NF-KappaB Inhibitor alpha; Peroxidase; Phosphorylation; Rats; Rats, Sprague-Dawley; Spinal Cord; Spinal Cord Injuries; Transcription Factor RelA

Myeloperoxidase (MPO) is important in intracellular microbial killing by neutrophils but extracellularly causes tissue damage. Its role in adaptive immunity and T-cell-mediated diseases is poorly understood. Here, T-cell responses in lymph nodes (LNs) were enhanced by MPO deletion or in vivo inhibition, causing enhanced skin delayed-type hypersensitivity and antigen (Ag)-induced arthritis. Responses of adoptively transferred OT-II T cells were greater in MPO-deficient than wild-type (WT) recipients. MPO, deposited by neutrophils in LNs after Ag injection, interacted with dendritic cells (DCs) in vivo. Culture of murine or human DCs with purified MPO or neutrophil supernatant showed that enzymatically dependent MPO-mediated inhibition of DC activation occurs via MPO-generated reactive intermediates and involves DC Mac-1. Transfer of DCs cultured with WT, but not MPO-deficient, neutrophil supernatant attenuated Ag-specific immunity in vivo. MPO deficiency or in vivo inhibition increased DC activation in LNs after immunization. Studies with DQ-ovalbumin showed that MPO inhibits Ag uptake/processing by DCs. In vivo DC transfer and in vitro studies showed that MPO inhibits DC migration to LNs by reducing their expression of CCR7. Therefore, MPO, via its catalytic activity, inhibits the generation of adaptive immunity by suppressing DC activation, Ag uptake/processing, and migration to LNs to limit pathological tissue inflammation.

Topics: Adaptive Immunity; Animals; Antigen Presentation; Cells, Cultured; Dendritic Cells; Humans; Inflammation; Lymph Nodes; Lymphocyte Activation; Male; Metabolism, Inborn Errors; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophils; Peroxidase; T-Lymphocytes

In hemorrhagic shock with subsequent resuscitation (H/R), increased pro-inflammatory changes contribute to tissue injury and mortality in rodent models. Ethanol (EtOH) is assumed to modulate the inflammatory response and the subsequent organ injury after H/R. Therefore, we determined the contribution of acute ethanol gavage on intestinal inflammation and injury as well as survival after H/R in rats.. Fourteen hours before H/R, female LEWIS rats were gavaged with single dose of EtOH or saline (5 g/kg, 30% EtOH, H/R_EtOH group or H/R_ctrl group). Then, rats were hemorrhaged to a mean arterial blood pressure of 30 ± 2 mmHg for 60 min and resuscitated. Control groups underwent surgical procedures and gavage without H/R (sham_ctrl group and sham_EtOH group). Tissue was harvested 2 h after resuscitation. Mortality was assessed 72 h after H/R.. Ethanol gavage increased survival after H/R from 20% to 80%, but amplified plasma alanineaminotransferase (ALT) release compared to saline gavage (2847 ± 406 vs. 1159 ± 200 IU/L, p < 0.05). Intestinal mucosal damage index, intestinal permeability, ileal myeloperoxidase levels as indicators of polymorphonuclear leukocyte (PMNL) infiltration and systemic IL-6 levels as well as ileal IL-6 and TNF gene expressions after H/R were reduced and partly restored after ethanol gavage when compared to the saline gavaged group after H/R.. Taken together, we propose that acute ethanol gavage prior to H/R 1) did not enhance intestinal mucosa injury after H/R and 2) suppressed the H/R-induced inflammatory response. Both findings seem to contribute to the ethanol-induced survival benefit after H/R in our model.

Topics: Alanine Transaminase; Animals; Central Nervous System Depressants; Disease Models, Animal; Ethanol; Female; Inflammation; Interleukin-6; Intestinal Mucosa; Intestines; Neutrophils; Peroxidase; Rats; Rats, Inbred Lew; Resuscitation; Shock, Hemorrhagic; Sodium Chloride; Treatment Outcome; Tumor Necrosis Factor-alpha

Renal ischemia-reperfusion (I/R) injury is a primary cause of acute renal failure that results in high mortality. This study aimed to investigate the effect of osthole, a natural coumarin derivative, on renal I/R injury in a rat model.. Rats were randomly allocated to the sham operation + vehicle, I/R + vehicle, and I/R + osthole groups. Renal I/R injury was induced by clamping the left renal artery for 45 min followed by 12 h of reperfusion and a contralateral nephrectomy. Osthole (40 mg/kg) was intraperitoneally injected 30 min before inducing I/R. Renal function and histological damage were determined subsequently. Myeloperoxidase activity, monocyte/macrophage infiltration, as well as tumor necrosis factor-α, IL-1β, and activated p38 mitogen-activated protein kinase expression in kidneys were also assessed.. Osthole treatment significantly ameliorated I/R-induced renal functional and morphological injuries. Moreover, osthole treatment attenuated myeloperoxidase activity, monocyte/macrophage infiltration, and tumor necrosis factor-α, IL-1β, and activated p38 mitogen-activated protein kinase expression in kidneys.. Osthole treatment ameliorates renal I/R injury by inhibiting inflammatory responses in kidneys. Thus, osthole may represent a novel practical strategy to prevent renal I/R injury.

Topics: Acute Kidney Injury; Animals; Calcium Channel Blockers; Coumarins; Disease Models, Animal; Gene Expression Regulation, Enzymologic; Inflammation; Interleukin-1beta; Kidney; Male; Monocytes; p38 Mitogen-Activated Protein Kinases; Peroxidase; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Tumor Necrosis Factor-alpha

The pathogenesis of acute lung injury (ALI) involves bidirectional cooperation and close interaction between inflammatory and coagulation pathways. A key molecule linking coagulation and inflammation is the procoagulant thrombin, a serine protease whose concentration is elevated in plasma and lavage fluids of patients with ALI and acute respiratory distress syndrome (ARDS). However, little is known about the mechanism by which thrombin contributes to lung inflammatory response. In this study, we developed a new mouse model that permits investigation of lung inflammation associated with intravascular coagulation. Using this mouse model and in vitro approaches, we addressed the role of non-muscle myosin light chain kinase (nmMLCK) in thrombin-induced endothelial cell (EC) inflammation and lung neutrophil (PMN) infiltration. Our in vitro experiments revealed a key role of nmMLCK in ICAM-1 expression by its ability to control nuclear translocation and transcriptional capacity of RelA/p65 in EC. When subjected to intraperitoneal thrombin challenge, wild type mice showed a marked increase in lung PMN infiltration via expression of ICAM-1. However, these responses were markedly attenuated in mice deficient in nmMLCK. These results provide mechanistic insight into lung inflammatory response associated with intravascular coagulation and identify nmMLCK as a critical target for modulation of lung inflammation.

Topics: Animals; Blood Coagulation; Cell Nucleus; Endothelial Cells; Female; Gene Expression Regulation; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Intercellular Adhesion Molecule-1; Leukocytes, Mononuclear; Lung; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myosin-Light-Chain Kinase; Neutrophils; Peroxidase; Thrombin; Transcription Factor RelA

The present study evaluated the effects of curcumin on epithelial cell apoptosis, the immunoreactivity of the phospho-c-Jun N-terminal kinase (JNK) and phospho-p38 mitogen-activated protein kinases (MAPKs) in inflamed colon mucosa, and oxidative stress in a rat model of ulcerative colitis induced by acetic acid. Rats were randomly divided into three groups: control, acetic acid, and acetic acid+curcumin. Curcumin (100 mg/kg per day, intragastrically) was administered 10 days before the induction of colitis and was continued for two additional days. Acetic acid-induced colitis caused a significant increase in the macroscopic and microscopic tissue ranking scores as well as an elevation in colonic myeloperoxidase (MPO) activity, malondialdehyde (MDA) levels, and the number of apoptotic epithelial cells in colon tissue compared to controls. In the rat colon, immunoreactivity of phospho-p38 MAPK was increased, whereas the phospho-JNK activity was decreased following the induction of colitis. Curcumin treatment was associated with amelioration of macroscopic and microscopic colitis sores, decreased MPO activity, and decreased MDA levels in acetic acid-induced colitis. Furthermore, oral curcumin supplementation clearly prevented programmed cell death and restored immunreactivity of MAPKs in the colons of colitic rats. The results of this study suggest that oral curcumin treatment decreases colon injury and is associated with decreased inflammatory reactions, lipid peroxidation, apoptotic cell death, and modulating p38- and JNK-MAPK pathways.

Topics: Acetic Acid; Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Colitis, Ulcerative; Colon; Curcuma; Curcumin; Dietary Supplements; Disease Models, Animal; Inflammation; Intestinal Mucosa; JNK Mitogen-Activated Protein Kinases; Male; Malondialdehyde; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Peroxidase; Phytotherapy; Plant Extracts; Rats; Rats, Wistar; Signal Transduction

FasL was recently shown be required for bacterial clearance in C57BL/6 mice that express the FasL.1 allotype. The FasL.2 allotype is expressed in BALB/c mice and exhibits increased binding affinity to and increased cytotoxic activity against Fas(+) target cells. Therefore, we hypothesized that BALB/c mice would be more resistant to Staphylococcus aureus-induced endophthalmitis. To test this hypothesis, C57BL/6, BALB/c, and BALB(gld) mice received intravitreal injections of 2,500 CFU of S. aureus (RN6390). Clinical examinations, electroretinography (ERG), histology, and bacterial quantification were performed at 24, 48, 72, and 96 h postinjection. The myeloperoxidase (MPO) assay was used to quantitate neutrophil infiltration. At 96 h postinfection, 86% of C57BL/6 mice presented with complete destruction of the eye, compared to only 29% of BALB/c mice with complete destruction. To our surprise, in the absence of Fas ligand, BALB(gld) mice showed no difference in bacterial clearance compared to BALB/c mice. However, histology and ERG analysis revealed increased retinal damage and significant loss of retinal function. MPO analysis revealed equal numbers of neutrophils in BALB(gld) and BALB/c mice at 24 h postinfection. However, at 48 h, the neutrophil numbers remained significantly elevated in BALB(gld) mice, correlating with the increased retinal damage observed in BALB(gld) mice. We conclude that the increased resistance to S. aureus induced endophthalmitis in BALB/c mice is not dependent upon the FasL. However, in contrast to C57BL/6 mice, FasL is required for resolution of inflammation and protecting host tissue from nonspecific damage in BALB/c mice.

Topics: Animals; Endophthalmitis; Fas Ligand Protein; Female; Genetic Predisposition to Disease; Inflammation; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Peroxidase; Retina; Staphylococcal Infections; Staphylococcus aureus

The aim of this study was to evaluate the anti-inflammatory effect of a sulphated polysaccharide fraction (PLS) extracted from the alga Hypnea musciformis and investigate the possible involvement of the nitric oxide (NO) pathway in this effect.. The anti-inflammatory activity of PLS was evaluated using inflammatory agents (carrageenan and dextran) to induce paw oedema and peritonitis in Swiss mice. Samples of paw tissue and peritoneal fluid were removed to determine myeloperoxidase (MPO) activity, NO3 /NO2 levels, and interleukin-1β (IL-1β) level. The involvement of NO in the modulation of neutrophil migration in carrageenan-induced paw oedema or peritonitis was also investigated.. Compared with vehicle-treated mice, mice pretreated with PLS (10 mg/kg) inhibited carrageenan-induced and dextran-induced oedema; it also inhibited total and differential peritoneal leucocyte counts in a model of peritonitis. These PLS effects were reversed by l-arginine treatment and recovered with the administration of a NO synthase blocker (aminoguanidine). Furthermore, PLS reduced the MPO activity, decreased IL-1β levels, and increased NO3 /NO2 levels in the peritoneal cavity.. PLS reduced the inflammatory response by modulating neutrophil migration, which appeared to be dependent on the NO pathway.

Topics: Animals; Anti-Inflammatory Agents; Arginine; Carrageenan; Dextrans; Edema; Enzyme Inhibitors; Guanidines; Immune System Diseases; Inflammation; Interleukin-1beta; Leukocyte Count; Leukocyte Disorders; Male; Mice; Neutrophils; Nitric Oxide; Nitric Oxide Synthase; Nitrogen Oxides; Peritoneum; Peritonitis; Peroxidase; Phytotherapy; Plant Extracts; Polysaccharides; Rhodophyta; Signal Transduction; Sulfur Compounds

After spinal cord injury (SCI), a series of complex pathophysiological processes follows the initial injury. Because inflammation plays a key role in this secondary pathology damage, anti-inflammatory drug treatment may reduce secondary damage and protect neurons after SCI. Though nordihydroguaiaretic acid (NDGA) can inhibit inflammatory responses, its potential roles in neuroprotection and anti- inflammation in an SCI model have not been studied. In this study, we investigated the anti-inflammatory effects of NDGA in SCI. First, histopathological alterations were evaluated with hematoxylin/eosin (HE) and Nissl staining, showing an increased number of neurons after NDGA administration. Additionally, the extent of secondary damage was assessed by TUNEL assay and measurement of astrocyte proliferation. The data showed that the numbers of apoptotic cells and the proliferative extent of astrocytes were significantly decreased by the use of NDGA. The anti-inflammatory effect of NDGA was evaluated by measuring myeloperoxidase (MPO) levels as an indicator of neutrophil activity, macrophage/microglia numbers, and expression of inflammatory cytokines including IL-1β and TNF-α. NDGA treatment significantly decreased the MPO level and the number of macrophages/microglia. In addition, NDGA also suppressed the expression of IL-1β and TNF-α after SCI. These data suggest that anti-inflammatory action by NDGA can reduce secondary damage after SCI.

Topics: Animals; Anti-Inflammatory Agents; Astrocytes; Cell Death; Cell Proliferation; Disease Models, Animal; Gene Expression Regulation; Glial Fibrillary Acidic Protein; In Situ Nick-End Labeling; Inflammation; Interleukin-6; Male; Masoprocol; Peroxidase; Rats; Rats, Wistar; Spinal Cord Injuries; Tumor Necrosis Factor-alpha

Myeloperoxidase (MPO) is a heme-containing enzyme that generates hypochlorous acid (HOCl) from chloride (Cl(-)) and hydrogen peroxide (H₂O₂). It is implicated in the pathology of several chronic inflammatory conditions such as cardiovascular and pulmonary diseases and cancer. Recently we have shown that HOCl can destroy the heme prosthetic group of hemoproteins. Here, we investigated whether the HOCl formed during steady-state catalysis is able to destroy the MPO heme moiety and thereby function as a major source of free iron. UV-visible spectra and H₂O₂-specific electrode measurements recorded during steady-state HOCl synthesis by MPO showed that the degree of MPO heme destruction increased after multiple additions of H₂O₂ (10 µM), precluding the enzyme from functioning at maximum activity (80-90% inhibition). MPO heme destruction occurred only in the presence of Cl(-). Stopped-flow measurements revealed that the HOCl-mediated MPO heme destruction was complex and occurred through transient ferric species whose formation and decay kinetics indicated it participates in heme destruction along with subsequent free iron release. MPO heme depletion was confirmed by the buildup of free iron utilizing the ferrozine assay. Hypochlorous acid, once generated, first equilibrates in the solution as a whole before binding to the heme iron and initiating heme destruction. Eliminating HOCl from the MPO milieu by scavenging HOCl, destabilizing the MPO-Compound I-Cl complex that could be formed during catalysis, and/or inhibiting MPO catalytic activity partially or completely protects MPO from HOCl insults. Collectively, this study elucidates the bidirectional relationship between MPO and HOCl, which highlights the potential role of MPO as a source of free iron.

Topics: Catalysis; Chlorides; Feedback, Physiological; Ferrozine; Free Radicals; Heme; Humans; Hydrogen Peroxide; Hypochlorous Acid; Inflammation; Iron; Kinetics; Metabolic Networks and Pathways; Oxidation-Reduction; Peroxidase

During hematogenously disseminated infection, blood-borne Candida albicans invades the endothelial cell lining of the vasculature to invade the deep tissues. Although the C. albicans Als3 invasin is critical for invasion and damage of endothelial cells in vitro, a C. albicans als3Δ/Δ mutant has normal virulence in the mouse model of disseminated infection. We hypothesized that the contribution of Als3 to virulence is obscured by the presence of additional C. albicans invasins. To elucidate the in vivo function of Als3, we heterologously expressed C. albicans ALS3 in Candida glabrata, a yeast that lacks a close ALS3 ortholog and has low virulence in mice. We found that following intravenous inoculation into mice, the ALS3-expressing strain preferentially trafficked to the brain, where it induced significantly elevated levels of myeloperoxidase, tumor necrosis factor, monocyte chemoattractant protein 1, and gamma interferon. Also, the ALS3-expressing strain had enhanced adherence to and invasion of human brain microvascular endothelial cells in vitro, demonstrating a potential mechanism for ALS3-mediated neurotropism. In addition, upon initiation of infection, the ALS3-expressing strain had increased trafficking to the cortex of the kidneys. With prolonged infection, this strain persisted in the kidneys at significantly higher levels than the control strain but did not induce an elevated inflammatory response. Finally, the ALS3-expressing strain had increased resistance to neutrophil killing in vitro. These results indicate that during disseminated infection, Als3 mediates initial trafficking to the brain and renal cortex and contributes to fungal persistence in the kidneys.

Topics: Animals; Brain; Candida albicans; Candida glabrata; Candidiasis; Cell Adhesion; Cell Line; Colony Count, Microbial; Endocytosis; Fungal Proteins; Gene Expression Regulation, Fungal; Genes, Fungal; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Interleukin-8; Kidney Cortex; Male; Mice; Mice, Inbred BALB C; Neutrophils; Peroxidase; Protein Transport

Inflammatory bowel diseases are a critical public health issue, and as treatment options remain limited, there is a need to unravel the underlying pathomechanisms in order to identify new therapeutic targets. Complement activation was found in patients suffering from inflammatory bowel disease, and the complement anaphylatoxin C5a and its receptor C5aR have been implicated in disease pathogenesis in animal models of bowel inflammation. To further characterize complement-related pathomechanisms in inflammatory bowel disease, we have investigated the role of the anaphylatoxin C3a receptor in acute dextran sulfate sodium-induced colitis in mice. For this, colitis was induced in C3a receptor-deficient BALB/c and C57BL/6 mice, and disease severity was evaluated by clinical and histological examination, and by measuring the mRNA expression or protein levels of inflammatory mediators in the tissue. C3a receptor deficiency was partially protective in BALB/c mice, which had significantly reduced weight loss, clinical and histological scores, colon shortening, and CXCL-1/KC mRNA, myeloperoxidase and interleukin-6 tissue levels compared to the corresponding wild type mice. In C57BL/6 mice the differences between wild type and C3a receptor-deficient animals were much smaller and reached no significance. Our data demonstrate that the contribution of C3a receptor to disease pathogenesis and severity of dextran sulfate sodium-induced colitis in mice depends on the genetic background. Further studies will be required to clarify whether targeting of C3a receptor, possibly in combination with C5a receptor, might be considered as a therapeutic strategy for inflammatory bowel disease.

Topics: Acute Disease; Animals; Colitis; Colon; Complement Activation; Complement C3a; Cytokines; Dextran Sulfate; Gene Expression Regulation; Inflammation; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Peroxidase; Receptors, Complement; RNA, Messenger

To investigate the change of serum myeloperoxidase (MPO) and lipoxin A4 (LXA4) in coronary heart disease (CHD) patients with anxiety and depression and its clinical significance.. From December 2010 to February 2011, 143 CHD patients and 44 non-CHD patients (the control group) hospitalized in the Department of Cardiology at the Second Xiangya Hospital were enrolled. The hospital anxiety and depression scale (HADS) was used to evaluate the psychological state of all patients and the CHD patients were assigned to an anxiety and depression group (n=57) or a non-depression and anxiety group (n=86). The serum levels of high sensitive C-reactive protein (Hs-CRP), MPO, and LXA4 were examined, and the ratio of MPO and LXA4 (M/L) was calculated.. The levels of Hs-CRP, MPO, and LXA4 as well as M/L ratios in both CHD groups were significantly higher than those in the control group (all P<0.01). Compared with the non-anxiety and depression group, the levels of MPO and LXA4, and M/L ratios in the anxiety and depression group increased (all P<0.05). Correlation analysis showed that MPO was positively correlated with the score of HADS-total (HADS-t), HADS-anxiety (HADS-a), or HADS-depression (HADS-d), while LXA4 was negatively correlated with HADS-t or HADS-d. Multiple ordinal logistic regression analysis revealed that higher HADS-t score, stable angina, unstable angina, and acute myocardial infarction were the independent impact factors for the elevation of M/L ratio.. Anxiety and depression may aggravate the inflammatory response in CHD patients. The imbalance between inflammation and anti-inflammation may be part of the mechanism.

Topics: Aged; Anxiety; Case-Control Studies; Coronary Disease; Depression; Female; Humans; Inflammation; Lipoxins; Male; Middle Aged; Peroxidase

Alpinetin, a novel plant flavonoid derived from Alpinia katsumadai Hayata, has been reported to exhibit anti-inflammatory properties. However, the effect of alpinetin on mastitis has not been investigated. The aim of this study was to investigate the protective effect of alpinetin against lipopolysaccharide (LPS)-induced mastitis and to clarify the possible mechanism. In the present study, primary mouse mammary epithelial cells and an LPS-induced mouse mastitis model were used to investigate the effect of alpinetin on mastitis and the possible mechanism. In vivo, we observed that alpinetin significantly attenuated the infiltration of neutrophilic granulocytes, and the activation of myeloperoxidase; down-regulated the level of pro-inflammatory cytokines, including TNF-α, IL-1β and IL-6; inhibited the phosphorylation of IκB-α, NF-κB p65 and the expression of TLR4, caused by LPS. In vitro, we also observed that alpinetin inhibited the expression of TLR4 and the production of TNF-α, IL-1β and IL-6 in LPS-stimulated primary mouse mammary epithelial cells. However, alpinetin could not inhibit the production of IL-1β and IL-6 in TNF-α-stimulated primary mouse mammary epithelial cells. In conclusion, our results suggest that the anti-inflammatory effects of alpinetin against LPS-induced mastitis may be due to its ability to inhibit TLR4-mediated NF-κB signaling pathways. Alpinetin may be a promising potential therapeutic reagent for mastitis treatment.

Topics: Animals; Dose-Response Relationship, Drug; Epithelial Cells; Female; Flavanones; Gene Expression Regulation; Inflammation; Lipopolysaccharides; Male; Mammary Glands, Animal; Mastitis; Mice; Mice, Inbred BALB C; Molecular Structure; NF-kappa B; Peroxidase; Toll-Like Receptor 4

The mechanisms behind increased fecal calprotectin (FC) in healthy relatives of patients with inflammatory bowel disease (IBD) are unknown. Our aims were to explore if there is a subclinical inflammation with increased neutrophil activity in healthy twin siblings in discordant twin pairs with IBD and to assess the influence of genetics in this context.. Nuclear factor kappa B (NF-κB) and neutrophil activity, based on myeloperoxidase (MPO) and FC, were analyzed in healthy twin siblings in discordant twin pairs with IBD and compared with healthy controls. NF-κB and MPO were assessed by immunohistochemistry and FC by enzyme-linked immunosorbent assay.. In total, 33 of 34 healthy twin siblings were histologically normal. Increased NF-κB was more often observed in healthy twin siblings in discordant twin pairs with Crohn's disease (13/18 [73%]) and with ulcerative colitis (12/16 [75%]) than in healthy controls (8/45 [18%]). MPO was more often increased in healthy twin siblings in discordant pairs with Crohn's disease (12/18 [67%]) than in healthy controls (11/45 [24%]) and FC more often in healthy twin siblings in discordant pairs with ulcerative colitis (14/21 [67%]) than in healthy controls (6/31 [19%]). Interestingly, the observed differences remained when healthy monozygotic and dizygotic twin siblings were analyzed separately.. We observed increased NF-κB, MPO, and FC in healthy twins in both monozygotic and dizygotic discordant pairs with IBD. These novel findings speak for an ongoing subclinical inflammation with increased neutrophil activity in healthy first-degree relatives.

Topics: Adolescent; Adult; Biomarkers; Case-Control Studies; Child; Child, Preschool; Colitis, Ulcerative; Crohn Disease; Diseases in Twins; Environmental Exposure; Enzyme-Linked Immunosorbent Assay; Feces; Female; Follow-Up Studies; Humans; Immunoenzyme Techniques; Inflammation; Leukocyte L1 Antigen Complex; Male; Middle Aged; Neutrophils; NF-kappa B; Peroxidase; Prognosis; Siblings; Twins, Dizygotic; Twins, Monozygotic; Young Adult

In the present study, we evaluated omega-3 polyunsaturated fatty acid (PUFA) (consisting of 20:5n-3 and 22:6n-3) properties on inflammation and nociception. Among the in vivo tests, writhing, formalin, and hot plate tests were conducted in mice, and carrageenan-induced paw edema, peritonitis, and Hargreaves tests were performed in rats. Following the carrageenan-induced edema, immunohistochemistry for tumor necrosis factor-α (TNF-α) was also carried out. We found that omega-3 PUFA treatment significantly decreased acetic acid-induced abdominal contortions as well as the first and second phases of the formalin test, which were reversed by naloxone. The carrageenan-induced rat paw edema was significantly reduced, along with neutrophil migration to the peritoneal cavity in the omega-3 PUFA treatment. In addition, there was a decrease in TNF-α immunostained cells in the inflamed paw with the omega-3 treatment compared with no omega-3. Withdrawal threshold in response to the thermal stimulation was significantly increased by the omega-3 treatment in the Hargreaves and hot plate tests. The in vitro studies (myeloperoxidase, lactate dehydrogenase, MTT cell viability and lipid peroxidation assays) were performed in human neutrophils. These studies showed that omega-3 treatment significantly decreased myeloperoxidase release, presented no cytotoxicity, and did not alter lipid peroxidation. Our study suggests that omega-3 PUFA anti-inflammatory and antinociceptive actions may involve inhibition of cyclooxygenases and microglial activation, leading to a reduced release of proinflammatory cytokines such as TNF-α, among other factors. The omega-3 PUFAs are potential candidates used alone or in combination with conventional nonsteroidal anti-inflammatory drugs, for the treatment of diseases where inflammation plays an important role.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Carrageenan; Cell Survival; Docosahexaenoic Acids; Dose-Response Relationship, Drug; Edema; Eicosapentaenoic Acid; Formaldehyde; Humans; Immunohistochemistry; Inflammation; L-Lactate Dehydrogenase; Lipid Peroxidation; Male; Mice; Neutrophils; Nociception; Pain Measurement; Peritonitis; Peroxidase; Rats; Rats, Wistar; Thiobarbituric Acid Reactive Substances; Tumor Necrosis Factor-alpha

The challenge for the treatment of inflammatory bowel disease (IBD) is the delivery of the drug to the site of inflammation. Because nanoparticles have the ability to accumulate in inflamed regions, the aim of the present study was to evaluate nanostructured lipid carriers (NLCs) as nanoparticulate drug delivery systems for the treatment of IBD. Budesonide (BDS) was chosen as a candidate anti-inflammatory drug. BDS-loaded NLCs (BDS-NLC) produced by high-pressure homogenization had a size of 200 nm and a negative zeta potential. BDS-NLCs reduced the TNF-α secretion by activated macrophages (J774 cells). BDS-NLCs were more active in a murine model of dextran sulfate-induced colitis when compared with Blank-NLCs or a BDS suspension: BDS-NLCs decreased neutrophil infiltration, decreased the levels of the pro-inflammatory cytokines IL-1β and TNF-α in the colon and improved the histological scores of the colons. These data suggest that NLCs could be a promising alternative to polymeric nanoparticles as a targeted drug delivery system for IBD treatment.

Topics: Animals; Anti-Inflammatory Agents; Budesonide; Cell Line; Colitis; Colon; Dextran Sulfate; Drug Carriers; Female; Inflammation; Interleukin-1beta; Lipids; Mice; Mice, Inbred C57BL; Nanostructures; Peroxidase; Tumor Necrosis Factor-alpha

In this study, we investigated the myocardial inflammation and mitochondrial function during venovenous extracorporeal membrane oxygenation (VV ECMO) and further evaluated the effects of continuous renal replacement therapy (CRRT) on them. Eighteen piglets were assigned to the control group, ECMO group, and ECMO+CRRT group. Myocardial inflammation was assessed by the activity of myeloperoxidase (MPO), myocardial concentrations, and mRNA expression of TNF-α, IL-1β, and IL-6; mitochondrial function was assessed by activities of mitochondrial complexes I-V. VV ECMO elicited a general activation of serum and myocardial inflammation and significantly decreased the activities of mitochondrial complexes I and IV. After being combined with CRRT, serum and myocardial concentrations of IL-1β and IL-6, myocardial mRNA expression of IL-6, and the activity of MPO were decreased significantly; the activities of mitochondrial complexes were increased. We conclude that myocardial inflammation was activated during ECMO therapy, inducing mitochondrial injury; moreover, CRRT reduced myocardial inflammation and partially ameliorated mitochondrial function.

Topics: Animals; Cardiomyopathies; Electron Transport Complex I; Electron Transport Complex IV; Extracorporeal Membrane Oxygenation; Inflammation; Interleukin-1beta; Interleukin-6; Mitochondria; Myocardium; Peroxidase; Renal Replacement Therapy; RNA, Messenger; Swine; Tumor Necrosis Factor-alpha

Hepatic ischemia/reperfusion injury (IRI), an exogenous, antigen-independent, local inflammation response, occurs in multiple clinical settings, including liver transplantation, hepatic resection, trauma, and shock. The nervous system maintains extensive crosstalk with the immune system through neuropeptide and peptide hormone networks. This study examined the function and therapeutic potential of the vasoactive intestinal peptide (VIP) neuropeptide in a murine model of liver warm ischemia (90 minutes) followed by reperfusion. Liver ischemia/reperfusion (IR) triggered an induction of gene expression of intrinsic VIP; this peaked at 24 hours of reperfusion and coincided with a hepatic self-healing phase. Treatment with the VIP neuropeptide protected livers from IRI; this was evidenced by diminished serum alanine aminotransferase levels and well-preserved tissue architecture and was associated with elevated intracellular cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling. The hepatocellular protection rendered by VIP was accompanied by diminished neutrophil/macrophage infiltration and activation, reduced hepatocyte necrosis/apoptosis, and increased hepatic interleukin-10 (IL-10) expression. Strikingly, PKA inhibition restored liver damage in otherwise IR-resistant VIP-treated mice. In vitro, VIP not only diminished macrophage tumor necrosis factor α/IL-6/IL-12 expression in a PKA-dependent manner but also prevented necrosis/apoptosis in primary mouse hepatocyte cultures. In conclusion, our findings document the importance of VIP neuropeptide-mediated cAMP-PKA signaling in hepatic homeostasis and cytoprotection in vivo. Because the enhancement of neural modulation differentially regulates local inflammation and prevents hepatocyte death, these results provide the rationale for novel approaches to managing liver IRI in transplant patients.

Topics: Animals; Apoptosis; Caspase 3; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Flow Cytometry; Hepatocytes; Homeostasis; Immune System; Inflammation; Interleukin-10; L-Lactate Dehydrogenase; Liver; Macrophages; Male; Mice; Mice, Inbred C57BL; Necrosis; Neutrophils; Peroxidase; Reperfusion Injury; Time Factors; Vasoactive Intestinal Peptide

Sulfated polysaccharide ascophyllan was isolated from the brown algae Padina tetrastromatica and purified by ion-exchange chromatography. Anti-inflammatory effect of ascophyllan fraction against carrageenan-induced paw edema in rats was studied. Paw edema in rats was induced by injecting 0.1 ml, 1 % carrageenan suspension in 0.9 % NaCl solution into the sub-plantar tissue of the right hind paw. Carrageenan caused a significant increase in the activity of inflammatory marker enzymes like lipoxygenases and cyclooxygenase in peripheral blood mononuclear cells and paw tissue and also increased the concentration of prostaglandin E2 (PGE2) and myeloperoxidase (MPO) in paw tissue. When compared to the reference drug diclofenac, ascophyllan fraction-3 (AF3) treatment significantly reduced the activities of anti-inflammatory enzymes, concentration of PGE2 and MPO. AF3 treatment decreased the mRNA level expression of TNF-α and IL-6. Concentration of thiobarbituric acid reactive substances was decreased. Activities of antioxidant enzymes and reduced glutathione level were increased on treatment with AF3. Histopathology of paw tissue showed decreased edema formation and cellular infiltration on supplementation with AF3. Thus the results demonstrated the potential beneficiary effect of ascophyllan fraction on carrageenan-treated rats.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Carrageenan; Diclofenac; Dinoprostone; Edema; Inflammation; Interleukin-6; Male; Oxidative Stress; Peroxidase; Phaeophyceae; Plant Extracts; Polysaccharides; Rats; Rats, Sprague-Dawley; RNA, Messenger; Tumor Necrosis Factor-alpha

To evaluate the therapeutic utility of hyperbaric oxygen (HBO) therapy on testicular ischemia/reperfusion (I/R) injury and elucidate the underlying molecular mechanism, we tested whether HBO therapy provided rescue of the testes after torsion in rats.. Sprague-Dawley rats were randomly divided into 4 groups: control group, control plus HBO therapy, I/R group, and I/R plus HBO therapy. The I/R model was induced by torsion of the right testis.. I/R in the testis resulted in disrupted seminiferous tubules, germ cell-specific apoptosis, followed by a marked reduction in testis weight and daily sperm production. HBO therapy preserved seminiferous tubules, suppressed apoptosis, and prevented testicular atrophy in I/R testes. HBO therapy abated oxidative stress in I/R testes, marked by reduced malondialdehyde formation, enhanced activities of superoxide dismutase and heme oxygenase 1 (HO-1), and decreased activities of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and xanthine oxidase. HBO therapy resulted in a reduction of myeloperoxidase (MPO) activity in I/R testes, a marker of neutrophil recruitment. HBO therapy suppressed inflammation in I/R testes, marked by reduced messenger RNA (mRNA) levels of tumor necrosis factor-α (TNF-α), interleukin-1beta (IL-1β), and CD44. Furthermore, HBO therapy suppressed the activation of nuclear factor kappa B (NFκB), p38, and c-JUN-N-terminal kinase (JNK) signaling pathways in I/R testes. In addition, HBO therapy reduced nitric oxide formation in I/R testes through suppression of inducible nitric oxide synthase and dimethylarginine dimethylaminohydrolase.. HBO therapy in rats attenuated I/R-induced testicular injury, possibly through abating oxidative stress, suppressing inflammation, and reducing nitric oxide formation.

Topics: Animals; Apoptosis; Heme Oxygenase-1; Hyaluronan Receptors; Hyperbaric Oxygenation; Inflammation; Interleukin-1beta; Male; Malondialdehyde; MAP Kinase Signaling System; NADPH Oxidases; NF-kappa B; Nitric Oxide; Oxidative Stress; Peroxidase; Rats; Reperfusion Injury; RNA, Messenger; Seminiferous Tubules; Spermatozoa; Superoxide Dismutase; Testicular Diseases; Testis; Torsion Abnormality; Tumor Necrosis Factor-alpha; Xanthine Oxidase

Isoflavones are phytoestrogens known by their anti-inflammatory, antioxidant and immunomodulatory properties. Presently, there is no information on whether afrormosin, an isoflavone from Amburana cearensis A.C. Smith (Fabaceae), has some effect on the inflammatory response from stimulated human neutrophils. Thus, the aim of this study was to evaluate the anti-inflammatory and antioxidant potentials of afrormosin on human neutrophils. Neutrophils (2.5 × 10(6) cells/mL) were incubated with afrormosin (3.35-335.2 μM) prepared from a product isolated from Amburana cearensis A.C. Smith with a 78.5% degree of purity and stimulated by the addition of cytochalasin B and N-formyl-methionyl-leucyl-phenylalanine (fMLP) or phorbol 12-myristate-13-acetate (PMA). Afrormosin inhibited the neutrophil degranulation induced by fMLP (10.47-335.2 μM) or PMA (0.33-167.6 μM), myeloperoxidase activity (3.3-335.2 μM), TNF-α secretion (16.7-335.2 μM) and the reactive oxygen species (ROS) generation (16.7-335.2 μM). On the other hand, afrormosin did not show any effect either on elastase or as a free radical scavenger. These data suggest that afrormosin modulates intermediary steps of the neutrophil ROS generation process. In addition, the modulatory effect of afrormosin on human neutrophil degranulation seems to be directed towards PMA-induced activation, indicating a potent inhibition of the protein kinase C activity. This study provided evidence, for the first time, to support the anti-inflammatory and antioxidant activities of afrormosin, creating novel insights into the pharmacological actions of this natural isoflavone.

Topics: Adult; Antioxidants; Cell Degranulation; Fabaceae; Humans; Inflammation; Inflammation Mediators; Isoflavones; Neutrophils; Pancreatic Elastase; Peroxidase; Reactive Oxygen Species; Tumor Necrosis Factor-alpha

Valproic acid (VPA) has been shown to exert anti-inflammatory and antioxidant effects in a range of diseases including septic shock. However, the effects of VPA on lipopolysaccharide (LPS)-induced acute lung injury (ALI) remains not well understood. We found that VPA pretreatment attenuated the LPS-induced ALI, as evidenced by the reduced histological scores, myeloperoxidase activity, and wet-to-dry weight ratio in the lung tissues. This was accompanied by the downregulated nuclear factor kappa B (NF-κB) p65, nitric oxide, and inducible nitric oxide synthase in the lung tissues and the decreased levels of tumor necrosis factor alpha and interleukin-1β in the bronchoalveolar lavage fluid. Furthermore, VPA reduced the nuclear histone deacetylase (HDAC)3 expression whereas increased the cytoplasmic HDAC3 expression. Our results suggested that VPA attenuates the LPS-induced ALI via inhibiting the NF-κB activation probably through a mechanism depending on HDAC3 redistribution.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Antioxidants; Bronchoalveolar Lavage Fluid; Down-Regulation; Histone Deacetylases; Inflammation; Interleukin-1beta; Lipopolysaccharides; Lung; Male; Mice; Mice, Inbred C57BL; Neutrophil Infiltration; Nitric Oxide; Nitric Oxide Synthase Type II; Peroxidase; Sepsis; Transcription Factor RelA; Tumor Necrosis Factor-alpha; Valproic Acid

This study compared the effects of hydroxyethyl starch 130/0.4, hydroxyethyl starch 200/0.5, and succinylated gelatin on oxidative stress and the inflammatory response in a rodent hemorrhagic shock model.. Sodium pentobarbital-anesthetized adult male Wistar rats (200 g to 220 g) were subjected to a severe volume-controlled hemorrhage using arterial blood withdrawal (30 mL/kg to 33 mL/kg) and resuscitated with a colloid solution at the same volume as blood withdrawal (hydroxyethyl starch 130/0.4, hydroxyethyl starch 200/0.5, or succinylated gelatin). Arterial blood gas parameters were monitored. Malondialdehyde (MDA) content and myeloperoxidase (MPO) activity in the liver, lungs, intestine, and brain were measured two hours after resuscitation. The levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 in the intestine were also measured.. Infusions of hydroxyethyl starch 130/0.4, but not hydroxyethyl starch 200/0.5 or succinylated gelatin, significantly reduced MDA levels and MPO activity in the liver, intestine, lungs and brain, and it also inhibited the production of TNF-α in the intestine two hours after resuscitation. However, no significant difference between hydroxyethyl starch 200/0.5 and succinylated gelatin was observed.. Hydroxyethyl starch 130/0.4, but not hydroxyethyl starch 200/0.5 or succinylated gelatin, treatment after hemorrhagic shock ameliorated oxidative stress and the inflammatory response in this rat model. No significant differences were observed after hydroxyethyl starch 200/0.5 or succinylated gelatin administration at doses of approximately 33 mL/kg.

Topics: Animals; Blood Gas Analysis; Colloids; Disease Models, Animal; Gelatin; Hydroxyethyl Starch Derivatives; Inflammation; Interleukin-6; Intestinal Mucosa; Lipid Peroxidation; Male; Malondialdehyde; Neutrophils; Oxidative Stress; Peroxidase; Rats, Wistar; Shock, Hemorrhagic; Succinates; Tumor Necrosis Factor-alpha

Magnesium lithospermate B (MLB), an active polyphenol acid of Danshen [Radix Salviae miltiorrhizae (Labiatae)], showed renoprotective, neuroprotective and myocardial salvage effects. Previous studies demonstrated that MLB could effectively suppress the production of cytokines and their associated signaling pathways in activated human T cells.. The purpose of this study was to examine the beneficial effects of MLB on myocardial ischemia/reperfusion (MI/R) injury and to explore its potential mechanisms related to anti-inflammation.. Sprague-Dawley rats were grouped as sham group, model group and MLB-treated (15, 30 and 60 mg/kg) groups. Animals were subjected to MI/R injury by the occlusion of left anterior descending artery for 30 min followed by reperfusion for 3 h. At the end of reperfusion, blood samples were collected to determine the serum levels of cardiac troponin (cTnI), creatine kinase-MB (CK-MB), tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β) and interleukin 6 (IL-6). Hearts were harvested to assess infarct size, histopathological changes and the activity of myeloperoxidase (MPO). The expression of phosphor-IkB-α and phosphor-nuclear factor kappa B (NF-κB) were assayed by western blot.. MLB administration significantly (p < 0.05) reduced: (1) ST-segment elevation (0.23 mv), (2) the infarct size (22.5%), (3) histological scores of myocardial injury (1.67 score), (4) myocardial injury marker enzymes: cTnI (5.64 ng/ml) and CK-MB (49.57 ng/ml) levels, (5) pro-inflammatory cytokines: TNF-α (97.36 pg/ml), IL-1β (93.35 pg/ml) and IL-6 (96.84 pg/ml) levels, (6) MPO activity (1.82 U/mg), (7) phosphor-NF-κB (0.87) and phosphor-IkB-α (0.96) expression.. Our study provided evidence that MLB ameliorated the inflammatory process associated with MI/R injury via NF-κB inactivation.

Topics: Animals; Anti-Inflammatory Agents; Biomarkers; Creatine Kinase, MB Form; Cytokines; Disease Models, Animal; Drugs, Chinese Herbal; Electrocardiography; I-kappa B Proteins; Inflammation; Inflammation Mediators; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; NF-kappa B; NF-KappaB Inhibitor alpha; Peroxidase; Phosphorylation; Rats; Rats, Sprague-Dawley; Signal Transduction; Time Factors; Troponin I

High-mobility group box 1 protein (HMGB1), a ubiquitous nuclear protein, drives proinflammatory responses when released extracellularly. It plays a key role as a distal mediator in the development of acute lung injury (ALI). Sodium butyrate, an inhibitor of histone deacetylase, has been demonstrated to inhibit HMGB1 expression. This study investigates the effect of sodium butyrate on burn-induced lung injury. Sprague-Dawley rats were divided into three groups: 1) sham group, sham burn treatment; 2) burn group, third-degree burns over 30% total body surface area (TBSA) with lactated Ringer's solution for resuscitation; 3) burn plus sodium butyrate group, third-degree burns over 30% TBSA with lactated Ringer's solution containing sodium butyrate for resuscitation. The burned animals were sacrificed at 12, 24, and 48 h after burn injury. Lung injury was assessed in terms of histologic changes and wet weight to dry weight (W/D) ratio. Tumor necrosis factor (TNF)-α and interleukin (IL)-8 protein concentrations in bronchoalveolar lavage fluid (BALF) and serum were measured by enzyme-linked immunosorbent assay, and HMGB1 expression in the lung was determined by Western blot analysis. Pulmonary myeloperoxidase (MPO) activity and malondialdehyde (MDA) concentration were measured to reflect neutrophil infiltration and oxidative stress in the lung, respectively. As a result, sodium butyrate significantly inhibited the HMGB1 expressions in the lungs, reduced the lung W/D ratio, and improved the pulmonary histologic changes induced by burn trauma. Furthermore, sodium butyrate administration decreased the TNF-α and IL-8 concentrations in BALF and serum, suppressed MPO activity, and reduced the MDA content in the lungs after severe burn. These results suggest that sodium butyrate attenuates inflammatory responses, neutrophil infiltration, and oxidative stress in the lungs, and protects against remote ALI induced by severe burn, which is associated with inhibiting HMGB1 expression.

Topics: Acute Lung Injury; Animals; Bronchoalveolar Lavage Fluid; Burns; Butyric Acid; Female; Granulocyte Colony-Stimulating Factor; HMGB1 Protein; Inflammation; Interleukin-3; Interleukin-8; Lung; Malondialdehyde; Neutrophil Infiltration; Oxidative Stress; Peroxidase; Rats; Rats, Sprague-Dawley; Recombinant Fusion Proteins; Tumor Necrosis Factor-alpha

Intestinal ischemia/reperfusion (I/R) injury is a serious condition in intensive care patients, resulting in severe inflammation and remote organ damage. The activation of the mammalian target of rapamycin (mTOR)/p70 ribosomal S6 kinase (p70S6K) signaling pathway exerts protective effect against ischemia/reperfusion injury. Ghrelin, an orexigenic hormone, inhibits the release of pro-inflammatory cytokines, such as interleukin (IL)-1β, tumor necrosis factor-α and IL-6. In this study, we investigated the effects of ghrelin on gut I/R injury and the regulation of the mTOR/p70S6K signaling pathway following gut I/R injury in mice. C57BL/6 mice underwent superior mesenteric artery occlusion for 45 min, followed by reperfusion for 4 h. Ghrelin was administered at the onset of reperfusion. We assessed survival, organ injury variables, pro-inflammatory cytokine expression and observed the histological changes of the small intestine and lungs. Our results revealed that the administration of ghrelin inhibited the release of certain pro-inflammatory cytokines, reduced neutrophil infiltration, attenuated organ injury and improved survival following gut I/R injury. The administration of D-Lys-GHRP6, a specific ghrelin receptor antagonist, to a certain extent, counteracted the protective effects of ghrelin in gut I/R-induced organ injury and mortality. To determine whether the beneficial effects of ghrelin following gut I/R injury are associated with the mTOR/p70S6K signaling pathway, the phosphorylation levels of mTOR and p70S6K were detected by western blot analysis. Our results revealed that mTOR and p70S6K phosphorylation increased in the tissue from the small intestine and pulmonary tissue in the animals treated with ghrelin. These findings suggest that ghrelin attenuates organ injury following gut I/R by promoting the activation of the mTOR/p70S6K signaling pathway.

Topics: Animals; Ghrelin; Inflammation; Interleukin-1beta; Interleukin-6; Intestines; Lung; Male; Mice; Mice, Inbred C57BL; Neutrophil Infiltration; Peroxidase; Phosphorylation; Reperfusion Injury; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; TOR Serine-Threonine Kinases; Tumor Necrosis Factor-alpha

Formononetin has shown a variety of pharmacologic properties including anti-inflammatory effect. In the present study, we analyzed the role of formononetin in acute lung injury induced by lipopolysaccharide (LPS) in mice. The cell counting in the bronchoalveolar lavage fluid (BALF) was measured. The animal lung edema degree was evaluated by wet/dry weight ratio. The superoxidase dismutase (SOD) activity and myeloperoxidase (MPO) activity was assayed by SOD and MPO kits, respectively. The levels of inflammatory mediators, tumor necrosis factor-α (TNF-α) and IL-6,were assayed by enzyme-linked immunosorbent assay method. Pathological changes of hung tissues were observed by HE staining. Peroxisome proliferator-activated receptor (PPAR)-γ gene expression was measured by real-time PCR. The data showed that treatment with the formononetin group markedly attenuated inflammatory cell numbers in the BALF, increased PPAR-γ gene expression and improved SOD activity and inhibited MPO activity. The histological changes of the lungs were also significantly improved by formononetin compared to LPS group. The results indicated that formononetin has a protective effect on LPS-induced acute lung injury in mice.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Edema; Inflammation; Interleukin-6; Isoflavones; Lipopolysaccharides; Lung; Male; Mice; Mice, Inbred BALB C; Peroxidase; Phytoestrogens; PPAR gamma; Pulmonary Edema; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Recent investigations suggest that neutrophils play an important role in the immune response to lung cancer as well as chronic obstructive pulmonary disease (COPD). The aim of this study was to evaluate the amount of neutrophils and markers of their activity in lung cancer and COPD and in coexistence of these two diseases.. In total, 267 persons were included in the study: 139 patients with lung cancer, 55 patients with lung cancer and COPD, 40 patients with COPD, and 33 healthy subjects. Peripheral blood and BAL fluid samples were obtained for cell count analysis and determination of NE, MPO levels and ROS production. NE and MPO levels in the serum and BAL fluid were determined by ELISA. ROS production was analyzed by flow cytometer.. The percentage, cell count of neutrophils and neutrophil to lymphocyte ratio in the peripheral blood were significantly higher in lung cancer patients with or without COPD compared to COPD patients or healthy individuals (P < 0.05). The percentage and cell count of neutrophils in BAL fluid were significantly lower in patients with lung cancer with or without COPD than in patients with COPD (P < 0.05). However, BAL fluid and serum levels of both NE and MPO were significantly higher in patients with lung cancer than COPD patients or healthy individuals (P < 0.05). Neutrophils produced higher amounts of ROS in patients with lung cancer with or without COPD compared with COPD patients or healthy individuals (P < 0.05).. The results from this study demonstrate higher degree of local and systemic neutrophilic inflammation in patients with lung cancer (with or without COPD) than in patients with COPD.

Topics: Aged; Bronchoalveolar Lavage Fluid; Case-Control Studies; Cell Count; Female; Humans; Inflammation; Leukocyte Elastase; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Neutrophils; Peroxidase; Pulmonary Disease, Chronic Obstructive; Reactive Oxygen Species; Tetradecanoylphorbol Acetate

Airway inflammatory patterns in older asthmatics are poorly understood despite high asthma-related morbidity and mortality. In this study, we sought to define the relationship between exposure to traffic pollutants, biomarkers in induced sputum, and asthma control in older adults.. Induced sputum was collected from 35 non-smoking adults ≥65 years with a physician's diagnosis of asthma and reversibility with a bronchodilator or a positive methacholine challenge. Patients completed the Asthma Control Questionnaire (ACQ), and Elemental Carbon Attributable to Traffic (ECAT), a surrogate for chronic diesel particulate exposure, was determined. Equal numbers of subjects with high (≥0.39 µg/m(3)) versus low (<0.39 µg/m(3)) ECAT were included. Differential cell counts were performed on induced sputum, and myeloperoxidase (MPO) and eosinophil peroxidase (EPO) were measured in supernatants. Regression analyses were used to evaluate the relationship between sputum findings, ACQ scores, and ECAT.. After adjustment for potential confounders, subjects with poorly controlled asthma based on ACQ ≥ 1.5 (n = 7) had significantly higher sputum eosinophils (median = 4.4%) than those with ACQ < 1.5 (n = 28; eosinophils = 2.6%; β = 10.1 [95% CI = 0.1-21.0]; p = 0.05). Subjects with ACQ ≥ 1.5 also had significantly higher sputum neutrophils (84.2% versus 65.2%; β = 7.1 [0.2-14.6]; p = 0.05). Poorly controlled asthma was associated with higher sputum EPO (β = 2.4 [0.2-4.5], p = 0.04), but not MPO (p = 0.9). High ECAT was associated with higher eosinophils (β = 10.1 [1.8-18.4], p = 0.02) but not higher neutrophils (p = 0.6).. Poorly controlled asthma in older adults is associated with eosinophilic and neutrophilic inflammation. Chronic residential traffic pollution exposure may be associated with eosinophilic, but not neutrophilic inflammation in older asthmatics.

Topics: Adult; Aged; Air Pollution; Asthma; Cohort Studies; Eosinophils; Female; Humans; Inflammation; Inhalation Exposure; Male; Middle Aged; Neutrophils; Ohio; Peroxidase; Regression Analysis; Sputum; Surveys and Questionnaires; Vehicle Emissions

Autonomic nervous system dysfunction is implicated in the etiopathogenesis of inflammatory bowel diseases (IBD). Therapies that increase cardiovagal activity, such as Mind-Body interventions, are currently confirmed to be effective in clinical trials in IBD. However, a poor understanding of pathophysiological mechanisms limits the popularization of therapies in clinical practice. The aim of the present study was to explore the mechanisms of these therapies against 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats using a chronic vagus nerve stimulation model in vivo, as well as the lipopolysaccharide (LPS)-induced inflammatory response in human epithelial colorectal adenocarcinoma cells (Caco-2) by acetylcholine in vitro.. Colitis was induced in rats with rectal instillation of TNBS, and the effect of chronic VNS (0.25 mA, 20 Hz, 500 ms) on colonic inflammation was evaluated. Inflammatory responses were assessed by disease activity index (DAI), histological scores, myeloperoxidase (MPO) activity, inducible nitric oxide synthase (iNOS), TNF-α and IL-6 production. The expression of Mitogen-activated protein kinases (MAPK) family members, IκB-α, and nuclear NF-κB p65 were studied by immunoblotting. Heart rate variability (HRV) analysis was also applied to assess the sympathetic-vagal balance. DAI, histological scores, MPO activity, iNOS, TNF-α and IL-6 levels were significantly decreased by chronic VNS. Moreover, both VNS and acetylcholine reduced the phosphorylation of MAPKs and prevented the nuclear translocation of NF-κB p65. Methyllycaconitine (MLA) only reversed the inhibitory effect on p-ERK and intranuclear NF-κB p65 expression by ACh in vitro, no significant change was observed in the expression of p-p38 MAPK or p-JNK by MLA.. Vagal activity modification contributes to the beneficial effects of the cholinergic anti-inflammatory pathway in IBD-related inflamed colonic mucosa based on the activation of MAPKs and nuclear translocation of NF-κB. Our work may provide key pathophysiological mechanistic evidence for novel therapeutic strategies that increase the cardiovagal activity in IBD patients.

Topics: Acetylcholine; Animals; Anti-Inflammatory Agents; Caco-2 Cells; Colitis; Female; Humans; Immunoblotting; Immunoenzyme Techniques; Inflammation; Interleukin-6; Lipopolysaccharides; Male; Mitogen-Activated Protein Kinases; NF-kappa B; Nitric Oxide Synthase Type II; Peroxidase; Phosphorylation; Rats; Rats, Sprague-Dawley; Signal Transduction; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha; Vagus Nerve Stimulation

As adenosine monophosphate (AMP)-activated protein kinase both controls cytoskeleton organization in endothelial cells and exerts anti-inflammatory effects, we here postulated that it could influence vascular permeability and inflammation, thereby counteracting cardiac wall edema during sepsis.. Controlled animal study.. University research laboratory.. C57BL/6J, α1AMPK, and α1AMPK mice.. Sepsis was triggered in vivo using a sublethal injection of lipopolysaccharide (O55B5, 10 mg/kg), inducing systolic left ventricular dysfunction. Left ventricular function, edema, vascular permeability, and inflammation were assessed in vivo in both wild-type mice (α1AMPK) and α1AMP-activated protein kinase-deficient mice (α1AMPK). The 5-aminoimidazole-4-carboxamide riboside served to study the impact of AMP-activated protein kinase activation on vascular permeability in vivo. The integrity of endothelial cell monolayers was also examined in vitro after lipopolysaccharide challenge in the presence of aminoimidazole-4-carboxamide riboside and/or after α1AMP-activated protein kinase silencing.. α1AMP-activated protein kinase deficiency dramatically impaired tolerance to lipopolysaccharide challenge. Indeed, α1AMPK exhibited heightened cardiac vascular permeability after lipopolysaccharide challenge compared with α1AMPK. Consequently, an increase in left ventricular mass corresponding to exaggerated wall edema occurred in α1AMPK, without any further decrease in systolic function. Mechanistically, the lipopolysaccharide-induced α1AMPK cardiac phenotype could not be attributed to major changes in the systemic inflammatory response but was due to an increased disruption of interendothelial tight junctions. Accordingly, AMP-activated protein kinase activation by aminoimidazole-4-carboxamide riboside counteracted lipopolysaccharide-induced hyperpermeability in wild-type mice in vivo as well as in endothelial cells in vitro. This effect was associated with a potent protection of zonula occludens-1 linear border pattern in endothelial cells.. Our results demonstrate for the first time the involvement of a signaling pathway in the control of left ventricular wall edema during sepsis. AMP-activated protein kinase exerts a protective action through the preservation of interendothelial tight junctions. Interestingly, exaggerated left ventricular wall edema was not coupled with aggravated systolic dysfunction. However, it could contribute to diastolic dysfunction in patients with sepsis.

Topics: Aminoimidazole Carboxamide; AMP-Activated Protein Kinases; Animals; Capillary Permeability; Cells, Cultured; Coloring Agents; Cytokines; Echocardiography; Edema; Endothelial Cells; Endotoxemia; Evans Blue; Gene Silencing; Heart Diseases; Heart Ventricles; Humans; Inflammation; Lipopolysaccharides; Lung; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Peroxidase; Ribonucleosides; Tight Junctions

Inflammation is a fundamental aspect of many human diseases. In this video report, we demonstrate non-invasive bioluminescence imaging techniques that distinguish acute and chronic inflammation in mouse models. With tissue damage or pathogen invasion, neutrophils are the first line of defense, playing a major role in mediating the acute inflammatory response. As the inflammatory reaction progresses, circulating monocytes gradually migrate into the site of injury and differentiate into mature macrophages, which mediate chronic inflammation and promote tissue repair by removing tissue debris and producing anti-inflammatory cytokines. Intraperitoneal injection of luminol (5-amino-2,3-dihydro-1,4-phthalazinedione, sodium salt) enables detection of acute inflammation largely mediated by tissue-infiltrating neutrophils. Luminol specifically reacts with the superoxide generated within the phagosomes of neutrophils since bioluminescence results from a myeloperoxidase (MPO) mediated reaction. Lucigenin (bis-N-methylacridinium nitrate) also reacts with superoxide in order to generate bioluminescence. However, lucigenin bioluminescence is independent of MPO and it solely relies on phagocyte NADPH oxidase (Phox) in macrophages during chronic inflammation. Together, luminol and lucigenin allow non-invasive visualization and longitudinal assessment of different phagocyte populations across both acute and chronic inflammatory phases. Given the important role of inflammation in a variety of human diseases, we believe this non-invasive imaging method can help investigate the differential roles of neutrophils and macrophages in a variety of pathological conditions.

Topics: Acute Disease; Animals; Chronic Disease; Disease Models, Animal; Inflammation; Luminescent Measurements; Luminol; Mice; Mice, Inbred C57BL; Mice, Nude; Neutrophils; Peroxidase; Superoxides

Multiple sclerosis is considered to be initiated by a deregulated, myelin-specific T cell response. However, the formation of inflammatory CNS lesions and the contribution of different leukocyte subsets in setting up these lesions are still incompletely understood. In this study, we show that, in the mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis, neutrophil granulocytes are important contributors in preparing CNS inflammation. Preclinical single-dose Ab-mediated depletion of neutrophils delayed the onset and continuous depletion attenuated the development of experimental autoimmune encephalomyelitis, whereas the generation of a myelin-specific T cell response remained unaffected. Neutrophil-related enzymes such as myeloperoxidase and neutrophil elastase did not contribute in mounting CNS inflammation, as analyzed by using respective knockout mice and inhibitors. CNS-infiltrating neutrophils secreted proinflammatory molecules and matured bone marrow-derived dendritic cells in vitro, which in turn enhanced their ability to restimulate myelin-specific T cells. This was mirrored in vivo, in which depletion of neutrophils specifically impaired maturation of microglia and macrophages into professional APCs, resulting in a diminished amplification of early CNS inflammation. Therefore, inside the CNS neutrophils provide local cofactors that are required for the maturation of myeloid cells into professional APCs representing an essential step for the local restimulation of myelin-specific T cells and the development of autoimmune disease.

Topics: Animals; Antigen Presentation; Antigen-Presenting Cells; Autoimmunity; Cells, Cultured; Central Nervous System; Cytokines; Dendritic Cells; Encephalomyelitis, Autoimmune, Experimental; Inflammation; Leukocyte Elastase; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; Multiple Sclerosis; Neutrophils; Peroxidase; T-Lymphocytes

Polyunsaturated fatty acid (PUFA) metabolites are bioactive autoacoids that play an important role in the pathogenesis of a vast number of pathologies, including gut diseases. The induction and the resolution of inflammation depend on PUFA metabolic pathways that are favored. Therefore, understanding the profile of n-6 (eicosanoids)/n-3 (docosanoids) PUFA-derived metabolites appear to be as important as gene or protein array approaches, to uncover the molecules potentially implicated in inflammatory diseases. Using high sensitivity liquid chromatography tandem mass spectrometry, we characterized the tissue profile of PUFA metabolites in an experimental model of murine intestinal ischemia reperfusion. We identified temporal and quantitative differences in PUFA metabolite production, which correlated with inflammatory damage. Analysis revealed that early ischemia induces both pro-inflammatory and anti-inflammatory eicosanoid production. Primarily, LOX- (5/15/12/8-HETE, LTB4, LxA4) and CYP- (5, 6-EET) metabolites were produced upon ischemia, but also PGE3, and PDx. This suggests that different lipids simultaneously play a role in the induction and counterbalance of ischemic inflammatory response from its onset. COX-derived metabolites were more present from 2 to 5 hours after reperfusion, fitting with the concomitant inflammatory peaks. All metabolites were decreased 48 hours post-reperfusion except for to the pro-resolving RvE precursor 18-HEPE and the PPAR-γαμμα agonist, 15d-PGJ2. Data obtained through the pharmacological blockade of transient receptor potential vanilloid-4, which can be activated by 5, 6-EET, revealed that the endogenous activation of this receptor modulates post-ischemic intestinal inflammation. Altogether, these results demonstrate that different lipid pathways are involved in intestinal ischemia-reperfusion processes. Some metabolites, which expression is severely changed upon intestinal ischemia-reperfusion could provide novel targets and may facilitate the development of new pharmacological treatments.

Topics: Animals; Chromatography, Liquid; Cytokines; Fatty Acids, Unsaturated; Inflammation; Inflammation Mediators; Intestine, Small; Ischemia; Male; Mice; Mice, Inbred C57BL; Peroxidase; Reperfusion Injury; Survival Rate; Tandem Mass Spectrometry

Ischemia-reperfusion injury (IRI) remains a major problem in renal transplantation, and the inflammatory response to IRI exacerbates the resultant renal injury. We have investigated whether the systemic administration of cardiotrophin-1 (CT-1) is able to improve renal function and to decrease inflammatory responses in a rat model of renal IRI.. IRI was induced by renal pedicle clamping (60 min) followed by reperfusion and contralateral nephrectomy. CT-1 was injected through the penile vein 30 min before clamping release and its effects were compared with a saline-treated group at five different time points of reperfusion.. Survival in the CT-1-treated group was higher than in the untreated group and prevented IRI-induced reduction in the glomerular filtration rate, as shown by blunted increases in creatinine and urea plasma levels and less severe decrease in creatinine clearance. These effects of CT-1 seem to be mediated by reduction in oxygen-radical production, increased superoxide dismutase expression, attenuation of neutrophil and macrophage infiltration, lower adhesion molecule expression, lower inflammation demonstrated by a decrease of plasma levels of proinflammatory cytokine secretion such as tumor necrosis factor-α, interleukin-1β and interferon-γ, lower inducible nitric oxide synthase expression and lower nuclear factor-κB activation, and reduced apoptosis.. Therefore, these results suggest that CT-1 administration prevents IRI and it might be used as a therapeutic strategy to protect the kidney against IRI.

Topics: Animals; Apoptosis; Cytokines; Inflammation; Interferon-gamma; Interleukin-1beta; Kidney; Kidney Transplantation; Macrophages; Male; Neutrophils; NF-kappa B; Nitric Oxide Synthase Type II; Peroxidase; Rats; Rats, Wistar; Reactive Oxygen Species; Reperfusion Injury; Superoxide Dismutase; Superoxides; Time Factors; Tumor Necrosis Factor-alpha

This study aims to evaluate the effect of prostaglandins isolated from soft coral Plexaura homomalla, collected in Colombian Caribbean Sea, on in vivo and in vitro inflammation models.. Extracts from P. homomalla were fractionated and sequentially chromatographed to obtain the prostaglandins: (15R)-PGA2 (1), (15R)-PGA2 -Me (2), (15R)-O-Ac-PGA2 (3), (15R)-O-Ac-PGA2 -Me (4) and (15R)-PGE2 (5) in addition to three semi-synthetic prostaglandins obtained by transformations of the natural products. The anti-inflammatory properties of natural and semi-synthetic compounds were determined in vivo using 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse ear oedema model and in vitro leucocyte degranulation, myeloperoxidase (MPO) and elastase enzymatic activities from human polymorphonuclear cells (PMNs). The cell viability was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.. In the in vivo assay, (15R)-PGE2 (1) and (15R)-O-Ac-PGA2 (3) showed anti-inflammatory activity, as well as in vitro inhibition of elastase release from PMNs. In the PMNs degranulation assay, (15R)-PGE2 (5), was the most active compound in the inhibition of MPO release. Finally, all the tested prostaglandins showed moderate inhibition for elastase enzyme activity, whereas none of the prostaglandins exhibit significative inhibition on MPO activity.. (15R)-PGE2 (1) and (15R)-O-Ac-PGA2 (3) present significant inhibition on three important events related to the topical inflammatory response induced by TPA: the oedema formation, the PMNs degranulation, events that modulate MPO and elastase levels at inflammation site, and the inhibition of the enzyme activity.

Topics: Animals; Anthozoa; Anti-Inflammatory Agents; Biological Products; Caribbean Region; Cell Degranulation; Colombia; Edema; Enzyme Inhibitors; Humans; Inflammation; Mice; Mice, Inbred ICR; Neutrophil Infiltration; Neutrophils; Pancreatic Elastase; Peroxidase; Prostaglandins; Tetradecanoylphorbol Acetate

Brain-derived neurotrophic factor (BDNF) increases in failing hearts, but BDNF roles in cardiac remodeling following myocardial infarction (MI) are unclear. Male BDNF(+/+) [wild-type (WT)] and BDNF(+/-) heterozygous (HET) mice at 6-9 mo of age were subjected to MI and evaluated at days 1, 3, 5, 7, or 28 post-MI. At day 28 post-MI, 76% of HET versus 40% of WT survived, whereas fractional shortening improved and neovascularization levels were reduced in the HET (all, P < 0.05). At day 1, post-MI, matrix metalloproteinase-9, and myeloperoxidase (MPO) increased in WT, but not in HET. Concomitantly, monocyte chemotactic protein-1 and -5 levels increased and vascular endothelial growth factor (VEGF)-A decreased in HET. Neutrophil infiltration peaked at days 1-3 in WT mice, and this increase was blunted in HET. To determine if MPO administration could rescue the HET phenotype, MPO was injected at 3 h post-MI. MPO restored VEGF-A levels without altering matrix metalloproteinase-9 or neutrophil content. In conclusion, reduced BDNF levels modulated the early inflammatory and neovascularization responses, leading to improved survival and reduced cardiac remodeling at day 28 post-MI. Thus reduced BDNF attenuates early inflammation following MI by modulating MPO and angiogenic response through VEGF-A.

Topics: Animals; Brain-Derived Neurotrophic Factor; Heart; Heterozygote; Inflammation; Male; Matrix Metalloproteinase 9; Mice; Mice, Knockout; Myocardial Infarction; Myocardium; Neovascularization, Pathologic; Neutrophils; Peroxidase; Vascular Endothelial Growth Factor A

A significant increase in serum lipase, amylase, capase-1 and myeloperoxidase activities, oxidative stress index (OSI), IL-1beta and IL-18 was observed in rats receiving ethanol (EtOH) and high fat diet (HFD). Thymoquinone (TQ) supplementation along with EtOH and HFD significantly decreased the levels of serum lipase, amylase, capase-1, myeloperoxidase, OSI and maintained the antioxidant status when compared to untreated EtOH and HFD fed rats. Among the 4 doses, 100 mg of TQ/kg body weight was found to provide optimum protective effect on pancreas against EtOH and HFD induced abnormal changes. Histological observations added more evidence for the anti-inflammatory effect of TQ.

Topics: Animals; Antioxidants; Benzoquinones; Body Weight; Diet, High-Fat; Dose-Response Relationship, Drug; Ethanol; Glutathione; Inflammation; Interleukin-18; Interleukin-1beta; Lipase; Lipid Peroxides; Male; Oxidative Stress; Pancreatitis, Chronic; Peroxidase; Rats; Rats, Wistar

Myeloperoxidase (MPO) has emerged as an important pathophysiological determinant of inflammatory vascular artery disease. It is appreciated that vessel immobilized, rather than circulating, MPO is critical for the progression of atherosclerotic lesions. The objective of this study was to investigate whether vessel-immobilized MPO is associated with the extent of coronary plaque burden.. MPO plasma levels were determined by ELISA before and after heparin-release of vessel-bound MPO, to study the relation between vascular MPO deposition and densitometrically assessed coronary plaque burden in 77 patients with stable coronary artery disease.. Patients with a low increase in MPO plasma levels upon heparinization had a significantly smaller total plaque area and volume (12.1[IR:6.2-19.4]mm(2) vs. 19.8[IR:11.3-31.5]mm(2), p < 0.01; 27.8[IR:12.3-44.8]mm(3) vs. 55.2[IR:24.2-87.5]mm(3), p < 0.05). Multivariable linear regression revealed that ΔMPO was independently associated with plaque area, and that ΔMPO increased with the number of affected vessels. Selective sampling confirmed the predominant role of coronary MPO deposition.. Our data demonstrate that heparin-induced mobilization of vessel-bound MPO is closely linked to coronary plaque burden and thus further corroborate the evidence for the intimate involvement of this enzyme in vascular pathophysiology, as well as the importance of inflammation in atherosclerosis.

Topics: Aged; Atherosclerosis; Coronary Artery Disease; Coronary Vessels; Densitometry; Female; Heparin; Humans; Inflammation; Male; Middle Aged; Peroxidase; Plaque, Atherosclerotic; Regression Analysis

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

Rosmarinus officinalis, also named rosemary, is a native plant from the Mediterranean region that is useful for the treatment of inflammatory diseases. Studies using experimental models and/or in vitro tests have shown the important biological effects of rosemary. In this context, the mechanism of the anti-inflammatory activity of rosemary must be investigated to support the discovery of new substances with anti-inflammatory effects. The aim of the present study was to investigate the anti-inflammatory effects of crude extract oil free obtained from the leaves of rosemary in an animal model of inflammation, thus evaluating its medicinal use for the treatment of inflammatory conditions. Also its ethanol, hexane, and ethyl acetate fractions, as well as its isolated compounds carnosol and rosmarinic acid were analyzed. Swiss mice were used for the in vivo experiments. The effect of this herb on the inhibition of the leukocytes, exudation, myeloperoxidase, and adenosine-deaminase activities, nitrite/nitrate, interleukin 17A, and interleukin 10 levels and mRNA expression was determined. The crude extract and its derived fractions, in addition to its isolated compounds, inhibited leukocytes and decreased exudation and myeloperoxidase and adenosine-deaminase activities, as well as nitrite/nitrate and interleukin 17A levels and mRNA expression, besides increasing interleukin 10 levels and mRNA expression. Rosemary showed important anti-inflammatory activity by inhibiting leukocytes and decreasing exudation. These effects were associated with a decrease in the proinflammatory parameters (myeloperoxidase, adenosine-deaminase, nitrite/nitrate, and interleukin 17A) and an increase in the anti-inflammatory cytokine (interleukin 10). This study confirms the anti-inflammatory properties of rosemary and validates its use in folk medicine to treat inflammatory diseases such as rheumatism and asthma.

Topics: Abietanes; Adenosine Deaminase; Animals; Anti-Inflammatory Agents; Carrageenan; Cinnamates; Cytokines; Depsides; Disease Models, Animal; Inflammation; Inflammation Mediators; Leukocytes; Mice; Mice, Inbred Strains; Nitrates; Nitrites; Peroxidase; Phytotherapy; Plant Extracts; Plant Leaves; Pleurisy; RNA, Messenger; Rosmarinic Acid; Rosmarinus

Anesthetic isoflurane (ISO) has immunomodulatory effects. In the present study, we investigated whether a subanesthetic dose of ISO (0.7%) protected against zymosan (ZY) induced inflammatory responses in the murine lung and isolated neutrophils. At 1 and 6 hrs after ZY administration intraperitoneally, ISO was inhaled for 1 hr, and 24 hrs later, lung inflammation and injury were assessed. We found that ISO improved the survival rate of mice and mitigated lung injury as characterized by the histopathology, wet-to-dry weight ratio, protein leakage, and lung function index. ISO significantly attenuated ZY-induced lung neutrophil recruitment and inflammation. This was suggested by the downregulation of (a) endothelial adhesion molecule expression and myeloperoxidase (MPO) activity in lung tissue and polymorphonuclear neutrophils (b) chemokines, and (c) proinflammatory cytokines in BALF. Furthermore, ZY-induced nuclear translocation and DNA-binding activity of NF- κ B p65 were also reduced by ISO. ISO treatment inhibited iNOS expression and activity, as well as subsequent nitric oxide generation. Consistent with these in vivo observations, in vitro studies confirmed that ISO blocked NF- κ B and iNOS activation in primary mouse neutrophils challenged by ZY. These results provide evidence that 0.7% ISO ameliorates inflammatory responses in ZY-treated mouse lung and primary neutrophils.

Topics: Active Transport, Cell Nucleus; Animals; Blood Gas Analysis; Bronchoalveolar Lavage Fluid; Chemokines; Cytokines; Down-Regulation; Hydrogen-Ion Concentration; Inflammation; Isoflurane; Lung; Lung Injury; Male; Mice; Mice, Inbred BALB C; Neutrophils; NF-kappa B; Nitric Oxide Synthase Type II; Nitrites; Peroxidase; Pneumonia; Time Factors; Zymosan

Ischemic preconditioning (IPC) can reduce ischemia/reperfusion (I/R) injury in multiple organs and species. However, the effect of IPC on transplanted submandibular glands remains unknown. We explored the protection of IPC in transplanted submandibular glands in the rabbit and the underlying mechanism.. IPC was performed by clamping the lingual artery for 10 min, with 10 min of reperfusion before transplantation. Male rabbits were randomly divided into control, transplantation, and IPC groups (n = 6 each). Saliva secretion, oxidative stress, pro-inflammatory cytokine levels, and apoptosis-related protein levels were determined at 1, 12, and 24 h after reperfusion.. Salivary flow was significantly increased at 12 h and decreased at 24 h in the transplanted glands. IPC treatment prevented the reduced saliva secretion at 24 h after reperfusion (P < 0.01). The mRNA levels of tumor necrosis factor-α, interleukin-1β, and reactive oxygen species, as well as malondialodehyde (MDA) and myeloperoxidase activity, were significantly increased and superoxide dismutase activity was decreased in the transplanted glands. However, these changes were all attenuated with IPC treatment (all P < 0.05). Also, acinar cell apoptosis and Bax protein expression were decreased and Bcl-2 protein expression was increased in the IPC-treated glands at 1 and 12 h after reperfusion (all P < 0.05).. IPC protects the secretory function of transplanted submandibular gland in the rabbit by reducing the inflammatory response, attenuating oxidative stress, and an anti-apoptosis process.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Inflammation; Ischemic Preconditioning; Male; Models, Animal; Oxidative Stress; Peroxidase; Proto-Oncogene Proteins c-bcl-2; Rabbits; Reactive Oxygen Species; Saliva; Submandibular Gland; Superoxide Dismutase; Time Factors

Oxygen-induced lung injury is believed to lead to the development of bronchopulmonary dysplasia in premature infants. We have evaluated the beneficial effects of Nigella sativa oil (NSO) on rats with hyperoxia-induced lung injury.. Thirty newborn Sprague-Dawley rats were randomly divided into 3 groups as hyperoxia (95% O(2)), hyperoxia+NSO and control (21% O(2)). Pups in the hyperoxia+NSO group were administered intraperitoneal NSO at a dose of 4ml/kg daily during the study period. Histopathologic, immunochemical, and biochemical evaluations (superoxide dismutase [SOD], glutathione peroxidase [GSH-Px], malonaldehyde [MDA] and myeloperoxidase [MPO]) were performed.. In the histopathologic and immunochemical evaluation, severity of lung damage was significantly lower in the hyperoxia+NOS group (P<.05). Tissue GSH-Px and SOD levels were significantly preserved, and MDA, MPO levels were significantly lower in the hyperoxia+NSO group (P<.05).. NSO significantly reduced the severity of lung damage due to hyperoxia.

Topics: Acute Lung Injury; Animals; Animals, Newborn; Disease Models, Animal; Drug Evaluation, Preclinical; Glutathione Peroxidase; Hyperoxia; Inflammation; Injections, Intraperitoneal; Lung; Malondialdehyde; Nigella sativa; Oxygen Inhalation Therapy; Peroxidase; Phytotherapy; Plant Oils; Random Allocation; Rats; Rats, Sprague-Dawley; Severity of Illness Index; Single-Blind Method; Superoxide Dismutase

Recent advances have established a fundamental role for inflammation in mediating all stages of atherosclerosis, from initiation through progression. Quercetin may be a powerful bioactive constituent of the human diet, as a free radical scavenging agent and through interactions with various endogenous proteins. The present study focused on the effect of quercetin on inflammation induced by a hypercholesterolemic diet (HCD) in rabbits.. The animals were subjected to two different experiments, atherosclerotic progression and regression. In the atherosclerotic progression study, quercetin (25 mg/kg of body weight) was administered with the HCD for 90 d. In the atherosclerotic regression study, the animals were fed with the HCD for 90 d and then supplemented with quercetin (25 mg/kg of body weight) for another 90 d. The inflammatory enzyme activities were examined and a histopathologic examination of the aorta was performed.. In the atherosclerotic progression study, quercetin coadministered with the HCD significantly decreased the activities of inflammatory enzymes such as cyclooxygenase, lipoxygenases (LOX) such as 5-LOX and 12-LOX in monocytes, nitric oxide synthase activity in the plasma, myeloperoxidase activity in the aorta, and the level of C-reactive protein in serum. In the regression study, quercetin administration significantly decreased the increased activities of inflammatory mediators such as cyclooxygenase, 5-LOX, 12-LOX, myeloperoxidase, and nitric oxide synthase and the serum level of C-reactive protein in HCD-fed rabbits compared with regression control rabbits. This effect was confirmed by histopathologic examination of the aorta.. This study demonstrates that quercetin modulates the deleterious inflammatory effects induced by an HCD in vivo in rabbits, suggesting its beneficial effect in decreasing inflammation in atherosclerotic progression and regression.

Topics: Animals; Aorta; Atherosclerosis; C-Reactive Protein; Cells, Cultured; Cholesterol, Dietary; Dietary Supplements; Disease Models, Animal; Disease Progression; Female; Free Radical Scavengers; Humans; Inflammation; Inflammation Mediators; Lipids; Lipoproteins, LDL; Lipoxygenases; Nitric Oxide Synthase; Peroxidase; Prostaglandin-Endoperoxide Synthases; Quercetin; Rabbits

Many algal species contain relatively high concentrations of polysaccharide substances, a number of which have been shown to have anti-inflammatory and/or immunomodulatory activity. In this study, we evaluated the anti-inflammatory and antinociceptive effects in mice of a sulfated polysaccharide fraction (PLS) extracted from the algae Gracilaria caudata. The antiinflammatory activity of PLS was evaluated using several inflammatory agents (carrageenan, dextran, bradykinin, and histamine) to induce paw edema and peritonitis in Swiss mice. Samples of the paw tissue and peritoneal fluid were removed to determine myeloperoxidase (MPO) activity or TNF-α and IL-1β levels, respectively. Mechanical hypernociception was induced by subcutaneous injection of carrageenan into the plantar surface of the paw. Pretreatment of mice by intraperitoneal administration of PLS (2.5, 5, and 10 mg/kg) significantly and dose-dependently reduced carrageenan-induced paw edema (p < 0.05) compared to vehicle-treated mice. Similarly, PLS 10 mg/kg effectively inhibited edema induced by dextran and histamine; however, edema induced by bradykinin was unaffected by PLS. PLS 10 mg/kg inhibited total and differential peritoneal leukocyte counts following carrageenan-induced peritonitis. Furthermore, PLS reduced carrageenan-increased MPO activity in paws and reduced cytokine levels in the peritoneal cavity. Finally PLS pretreatment also reduced hypernociception 3-4 h after carrageenan. We conclude that PLS reduces the inflammatory response and hypernociception in mice by reducing neutrophil migration and cytokines concentration.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Carrageenan; Edema; Gracilaria; Inflammation; Interleukin-1beta; Leukocyte Count; Male; Mice; Peritonitis; Peroxidase; Plant Extracts; Polysaccharides; Rhodophyta; Sulfates; Tumor Necrosis Factor-alpha

Low-level laser therapy (LLLT) has been demonstrated to modulate inflammatory processes and immunological responses. The aim of this work was to investigate the hypothesis that near infrared LLLT (830 nm) over lymph nodes may reduce paw edema and contribute to the modulation of inflammation. The edema was induced by carrageenan inoculation (CGN) into the plantar surface of 100 male mice left hind paw. Animals were divided into five groups: CGN (control), no treatment; Diclo, sodium diclofenac; Paw, LLLT on the paw; Ly, LLLT on the inguinal lymph nodes; and Paw+Ly, LLLT in both paw and lymph nodes, and subdivided according to moment of irradiation: A-1 h and 2 h before CGN, B-1 h and immediately before CGN, C-1 and 2 h after CGN, and D-3.5 and 4.5 h after CGN. The parameters used were: energy=1 J, fluence=35 J/cm(2), power=100 mW during 10 s. Paw volume was measured before and 1 to 6 h after CGN, and myeloperoxidase (MPO) activity was analyzed. Edema prevention was obtained by the irradiation of Paw+Ly at moment A and at Ly at moment B, inhibition of edema formation was achieved by either Paw or Ly at moment C, and edema treatment was obtained by Paw or Ly at moment D (p<0.05). MPO activity was significantly reduced on Paw at moment A, Paw and Ly on C, and in all irradiated groups on B and D. Our results suggest that LLLT was able to produce both anti-inflammatory and pro-inflammatory effects depending on to the site and moment of irradiation.

Topics: Animals; Carrageenan; Edema; Inflammation; Infrared Rays; Low-Level Light Therapy; Lymph Nodes; Male; Mice; Peroxidase

To evaluate the generation of halogenated fatty acids in the areas of fat necrosis during acute pancreatitis and to evaluate the effects of these molecules on the ensuing inflammatory process.. Lipid mediators derived from adipose tissue have been implicated in the progression of acute pancreatitis, although their precise role remains unknown.. Acute pancreatitis was induced in rats by intraductal infusion of 3.5% sodium taurocholate. Fatty acid chlorohydrins (FA-Cl) were measured in adipose tissue, ascitic fluid, and plasma by mass spectrometry. Chlorohydrins were also instilled in the rats' peritoneal cavity, and their effects on peritoneal macrophages activation and in systemic inflammation were evaluated. Finally, they have also been measured in plasma from human patients with acute pancreatitis.. Induced acute pancreatitis results in a substantial release not only of free fatty acids but also of the chlorohydrins of both oleic and linoleic acids from adipose tissue. In plasma, only the chlorohydrin of oleic acid was detected. Administration of 250-μM lipid chlorohydrins, which is the concentration found in ascitic fluid, induces the expression of TNFα and interleukin-1β in peritoneal macrophages and increases the systemic inflammatory response in pancreatitis. Finally, increased concentrations of oleic acid chlorohydrin have been found in plasma of human patients with pancreatitis.. During acute pancreatitis, adipose tissue release FA-Cl, which exacerbate the systemic inflammatory response.

Topics: Acute Disease; Animals; Biomarkers; Case-Control Studies; Chlorohydrins; Cholagogues and Choleretics; Chromatography, Liquid; Fat Necrosis; Gas Chromatography-Mass Spectrometry; Humans; Inflammation; Linoleic Acid; Macrophage Activation; Male; Mass Spectrometry; Oleic Acid; Pancreatitis; Peroxidase; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Taurocholic Acid

Stevioside, a diterpene glycoside component of Stevia rebaudiana, has been known to exhibit anti-inflammatory properties. To evaluate the effect and the possible mechanism of stevioside in lipopolysaccharide (LPS)-induced acute lung injury, male BALB/c mice were pretreated with stevioside or dexamethasone 1 h before intranasal instillation of LPS. Seven hours later, tumor necrosis factor-α, interleukin-1β, and interleukin-6 in bronchoalveolar lavage fluid (BALF) were measured by using enzyme-linked immunosorbent assay. The number of total cells, neutrophils, and macrophages in the BALF were also determined. The right lung was excised for histological examination and analysis of myeloperoxidase activity and nitrate/nitrite content. Cyclooxygenase 2 (COX-2), inducible NO synthase (iNOS), nuclear factor-kappa B (NF-κB), inhibitory kappa B protein were detected by western blot. The results showed that stevioside markedly attenuated the LPS-induced histological alterations in the lung. Stevioside inhibited the production of pro-inflammatory cytokines and the expression of COX-2 and iNOS induced by LPS. In addition, not only was the wet-to-dry weight ratio of lung tissue significantly decreased, the number of total cells, neutrophils, and macrophages in the BALF were also significantly reduced after treatment with stevioside. Moreover, western blotting showed that stevioside inhibited the phosphorylation of IκB-α and NF-κB caused by LPS. Taken together, our results suggest that anti-inflammatory effect of stevioside against the LPS-induced acute lung injury may be due to its ability of inhibition of the NF-κB signaling pathway. Stevioside may be a promising potential therapeutic reagent for acute lung injury treatment.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; Cell Count; Cyclooxygenase 2; Dexamethasone; Diterpenes, Kaurane; Glucosides; I-kappa B Kinase; Inflammation; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; Lung; Macrophages; Male; Mice; Mice, Inbred BALB C; Neutrophils; NF-kappa B; Nitrates; Nitric Oxide Synthase Type II; Nitrites; Peroxidase; Phosphorylation; Random Allocation; Signal Transduction; Tumor Necrosis Factor-alpha

Asiaticoside (AS), a triterpenoid isolated from Centella asiatica, has been found to exhibit antioxidant and anti-inflammatory activities in several experimental animal models. However, the underlying mechanisms remain elusive. In this study, we provide experimental evidences that AS dose-dependently inhibited lipopolysaccharide (LPS)-induced fever and inflammatory response, including serum tumor necrosis factor (TNF)-α and interleukin (IL)-6 production, liver myeloperoxidase (MPO) activity, brain cyclooxygenase-2 (COX-2) protein expression and prostaglandin E2 (PGE2 ) production. Interestingly, AS increased serum IL-10 level, liver heme oxygenase-1 (HO-1) protein expression and activity. Furthermore, we found that the suppressive effects of AS on LPS-induced fever and inflammation were reversed by pretreatment with ZnPPIX, a HO-1 activity inhibitor. In summary, our results suggest that AS has the antipyretic and anti-inflammatory effects in LPS-treated rat. These effects could be associated with the inhibition of pro-inflammatory mediators, including TNF-α and IL-6 levels, COX-2 expression and PGE2 production, as well as MPO activity, which might be mediated by the up-regulation of HO-1.

Topics: Animals; Anti-Inflammatory Agents; Antipyretics; Centella; Cyclooxygenase 2; Dinoprostone; Heme Oxygenase (Decyclizing); Inflammation; Interleukin-10; Interleukin-6; Lipopolysaccharides; Liver; Male; Peroxidase; Rats; Rats, Sprague-Dawley; Triterpenes; Tumor Necrosis Factor-alpha; Up-Regulation

Anethole has been reported to have antioxidant, antibacterial, antifungal, antiinflammatory, and anesthetic properties. In the present study, we evaluated the effects of anethole in two pain models of inflammatory origin: acute inflammation induced by carrageenan and persistent inflammation induced by Complete Freund's adjuvant. We evaluated the effects of anethole (125, 250, and 500 mg/kg) on the development of paw oedema and mechanical hypernociception. The liver was collected for histological analysis. Paw skin was collected to determine the levels of the cytokines tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-17 (IL-17), and myeloperoxidase activity. Blood was collected to assess alanine transaminase (ALT) and aspartate transaminase (AST). The chemical composition of star anise oil was determined by gas chromatography/mass spectrometry (GC/MS), showing a presence of anethole of 98.1%. Oral pretreatment with anethole in mice inhibited paw oedema, mechanical pernociception, myelopewroxidase activity, TNF-α, IL-1β and IL-17 levels in acute and persistent inflammation models. Additionally, anethole treatment did not alter prostaglandin E2-induced mechanical hypernociception. Possible side effects were also examined. Seven-day anethole treatment did not alter plasma AST and ALT levels, and the histological profile of liver tissue was normal. The present study provides evidence of the antiinflammatory and analgesic activities of anethole in acute and persistent inflammation models.

Topics: Alanine Transaminase; Allylbenzene Derivatives; Analgesics; Animals; Anisoles; Anti-Inflammatory Agents; Aspartate Aminotransferases; Edema; Illicium; Inflammation; Interleukin-17; Interleukin-1beta; Liver; Male; Mice; Neutrophils; Nociception; Oils, Volatile; Pain; Peroxidase; Tumor Necrosis Factor-alpha

Clopidogrel and prasugrel belong to a thienopyridine class of oral antiplatelet drugs that, after having been metabolized in the liver, can inhibit platelet function by irreversibly antagonizing the P2Y(12) receptor. Furthermore, thienopyridines influence numerous inflammatory conditions, but their effects on neutrophils have not been evaluated, despite the important role of these cells in inflammation. Therefore, we investigated the effect of prasugrel metabolites on neutrophils to further clarify the role of thienopyridines in inflammation. Interestingly, a prasugrel metabolite mixture, produced in vitro using rat liver microsomes, significantly inhibited N-formyl-methionyl-leucyl-phenylalanine (fMLP)- and platelet-activating factor (PAF)-induced neutrophil activation. More specifically, prasugrel metabolites inhibited neutrophil transmigration, CD16 surface expression, and neutrophil-platelet aggregation. Moreover, prasugrel metabolite pretreatment also significantly decreased fMLP- or PAF-induced extracellular-signal-regulated kinase phosphorylation as well as calcium mobilization. To determine the target of prasugrel in neutrophils, the role of both P2Y(12) and P2Y(13) receptors was studied using specific reversible antagonists, AR-C69931MX and MRS2211, respectively. Neither antagonist had any direct effect on the agonist-induced neutrophil functional responses. Our findings indicate that prasugrel metabolites may directly target neutrophils and inhibit their activation, suggesting a possible explanation for their anti-inflammatory effects previously observed. However, these metabolites do not act through either the P2Y(12) or P2Y(13) receptor in neutrophils.

Topics: Animals; Blotting, Western; Calcium; CD11b Antigen; Cell Separation; Cell Survival; Chemotaxis, Leukocyte; Humans; Inflammation; Lipopolysaccharides; Lung; Male; Mice; Mice, Inbred C57BL; Microsomes, Liver; Neutrophils; Peroxidase; Piperazines; Platelet Aggregation; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Thiophenes

Studies showed that nicotine has a positive influence on symptoms of ulcerative colitis. In the present study, we explored the effect of nicotine treatment using different routes of administration in the dextran sodium sulfate (DSS) colitis mouse model. We also investigated the effects of cotinine, a major metabolite of nicotine, in the model. C57BL6 adult male mice were given DSS solution freely in the drinking water for seven consecutive days, and tap water was given thereafter. Disease severity, length of the colon, colon tissue histology, and inflammatory markers, including colonic myeloperoxidase activity and colonic tumor necrosis factor-α levels, were evaluated. The effect of nicotine and cotinine treatments via various different routes of administration were examined the DSS model. In addition, we measured the plasma levels of nicotine and cotinine in our treatment protocols. Administration of low, but not high, doses of oral nicotine in DSS-treated mice resulted in a significant decrease in disease severity, histologic damage scores, as well as colonic level of tumor necrosis factor-α. However, the anti-inflammatory effect of nicotine was not seen after chronic s.c. or minipump infusion of the drug. Differences in plasma levels of nicotine and cotinine do not seem to account for this lack of effect. Finally, oral cotinine alone failed to show a significant effect in the DSS model of colitis. These results highlight that dose and route of administration play a critical role in the protective effect of nicotine in the DSS mouse colitis model.

Topics: Animals; Chromatography, High Pressure Liquid; Colitis, Ulcerative; Colon; Cotinine; Dextran Sulfate; Dose-Response Relationship, Drug; Inflammation; Infusions, Intravenous; Injections, Subcutaneous; Male; Mass Spectrometry; Mice; Mice, Inbred C57BL; Nicotine; Nicotinic Agonists; Peroxidase; Smoking; Tumor Necrosis Factor-alpha

An association of intraluminal thrombus (ILT) with abdominal aortic aneurysm (AAA) growth has been suggested. Previous in vitro experiments have demonstrated that aneurysm-associated thrombus may secrete proteolytic enzymes and may develop local hypoxia that might lead to the formation of tissue-damaging reactive oxygen species. In this study, we assessed the hypothesis that ventral ILT thickness is associated with markers of proteolysis and with lipid oxidation in the underlying AAA vessel wall.. Ventral AAA tissue was collected from asymptomatic patients at the site of maximal diameter during open aneurysm repair. Segments were divided, one part for biochemical measurements and one for histologic analyses. We measured total cathepsin B, cathepsin S levels, and matrix metalloproteinase (MMP)-2 and MMP-9 activity. Myeloperoxidase and thiobarbituric acid reactive substances were determined as measures of lipid oxidation. Histologic segments were analyzed semiquantitatively for the presence of collagen, elastin, vascular smooth muscle cells (VSMCs), and inflammatory cells. Preoperative computed tomography angiography scans of 83 consecutive patients were analyzed. A three-dimensional reconstruction was obtained, and a center lumen line of the aorta was constructed. Ventral ILT thickness was measured in the anteroposterior direction at the level of maximal aneurysm diameter on the orthogonal slices.. Ventral ILT thickness was positively correlated with aortic diameter (r=0.25; P=.02) and with MMP-2 levels (r=0.27; P=.02). No biochemical correlations were observed with MMP-9 activity or cathepsin B and S expression. No correlation between ventral ILT thickness and myeloperoxidase or thiobarbituric acid reactive substances was observed. Ventral ILT thickness was negatively correlated with VSMCs (no staining, 18.5 [interquartile range, 12.0-25.5] mm; minor, 17.6 [10.7-22.1] mm; moderate, 14.5 [4.6-21.7] mm; and heavy, 8.0 [0.0-12.3] mm, respectively; P=.01) and the amount of elastin (no staining, 18.6 [12.2-30.0] mm; minor, 16.5 [9.0-22.1] mm; moderate, 11.7 [2.5-15.3] mm; and heavy 7.7 [0.0-7.7] mm, respectively; P=.01) in the medial aortic layer.. ILT thickness appeared to be associated with VSMCs apoptosis and elastin degradation and was positively associated with MMP-2 concentrations in the underlying wall. This suggests that ILT thickness affects AAA wall stability and might contribute to AAA growth and rupture. ILT thickness was not correlated with markers of lipid oxidation.

Topics: Aged; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Aortic Rupture; Aortography; Apoptosis; Biopsy; Cathepsin B; Cathepsins; Collagen; Elastin; Female; Humans; Inflammation; Linear Models; Lipid Peroxidation; Logistic Models; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Multivariate Analysis; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Observer Variation; Peroxidase; Predictive Value of Tests; Reproducibility of Results; Thiobarbituric Acid Reactive Substances; Thrombosis; Tomography, X-Ray Computed

6b,11b-Dihydroxy-6b,11b-dihydro-7H-indeno[1,2-b]naphtho[2,1-d]furan-7-one (DHFO), an easily synthesisable, orally bioavailable and relatively non-toxic small molecule synthesised in our lab, was previously reported to possess anti-oxidant, 5-lipoxygenase inhibitory, anti-inflammatory and peripheral analgesic activities. The present work deals with exploration of DHFO's efficacy in immunopathogenic chronic inflammatory conditions - arthritis and allergy. In carrageenan-induced inflammatory air pouch, which resembles the arthritic synovium, DHFO effectively reduced inflammatory redness and swelling and neutrophil infiltration. In complete Freund's adjuvant-induced arthritis, DHFO significantly decreased paw oedema and nitrite levels with efficacy comparable to diclofenac. DHFO inhibited neutrophil activation (observed as decreased myeloperoxidase levels), in both the in vivo models of inflammation. Interestingly, DHFO did not ulcerate the gastrointestinal tract, while diclofenac was observed to be extremely ulcerogenic. In antigen-induced active and passive anaphylaxis (allergy) models, DHFO dose-dependently prevented mesenteric mast cell (MC) degranulation with efficacy comparable to ketotifen. DHFO also inhibited compound 48/80 (C48/80)-induced paw oedema and peritoneal MC degranulation. DHFO stabilised p815 murine MCs stimulated by C48/80 and calcium ionophore-A23187, indicating an action downstream of calcium mobilisation. DHFO's anti-allergic mechanism could be two-pronged involving (1) inhibition of IgE production and/or (2) MC stabilisation. DHFO inhibited lipopolysaccharide (LPS)-induced pro-inflammatory mediator release (ROS, NO, IL-6 levels) and COX2 expression in RAW264.7 murine macrophages. Protein expression studies confirmed DHFO's ability to reduce nuclear levels of NF-κB in LPS-stimulated macrophages. Thus, DHFO is a promising non-ulcerogenic synthetic small molecule lead for immunopathogenic chronic inflammatory conditions.

Topics: Animals; Anti-Inflammatory Agents; Antigens; Arthritis; Carrageenan; Cell Line; Cyclooxygenase 2; Edema; Freund's Adjuvant; Furans; Histamine Release; Hypersensitivity; Indenes; Inflammation; Interleukin-6; Mice; Naphthalenes; NF-kappa B; Nitric Oxide; p-Methoxy-N-methylphenethylamine; Peroxidase; Rats; Rats, Wistar; Reactive Oxygen Species; Serum; Sheep

Previous studies demonstrated methane generation in aerobic cells. Our aims were to investigate the methanogenic features of sodium azide (NaN(3))-induced chemical hypoxia in the whole animal and to study the effects of l-α-glycerylphosphorylcholine (GPC) on endogenous methane production and inflammatory events as indicators of a NaN(3)-elicited mitochondrial dysfunction. Group 1 of Sprague-Dawley rats served as the sham-operated control; in group 2, the animals were treated with NaN(3) (14 mg·kg(-1)·day(-1) sc) for 8 days. In group 3, the chronic NaN(3) administration was supplemented with daily oral GPC treatment. Group 4 served as an oral antibiotic-treated control (rifaximin, 10 mg·kg(-1)·day(-1)) targeting the intestinal bacterial flora, while group 5 received this antibiotic in parallel with NaN(3) treatment. The whole body methane production of the rats was measured by means of a newly developed method based on photoacoustic spectroscopy, the microcirculation of the liver was observed by intravital videomicroscopy, and structural changes were assessed via in vivo fluorescent confocal laser-scanning microscopy. NaN(3) administration induced a significant inflammatory reaction and methane generation independently of the methanogenic flora. After 8 days, the hepatic microcirculation was disturbed and the ATP content was decreased, without major structural damage. Methane generation, the hepatic microcirculatory changes, and the increased tissue myeloperoxidase and xanthine oxidoreductase activities were reduced by GPC treatment. In conclusion, the results suggest that methane production in mammals is connected with hypoxic events associated with a mitochondrial dysfunction. GPC is protective against the inflammatory consequences of a hypoxic reaction that might involve cellular or mitochondrial methane generation.

Topics: Adenosine Triphosphate; Animals; Cell Hypoxia; Enzyme Inhibitors; Gastrointestinal Agents; Gastrointestinal Tract; Glycerylphosphorylcholine; Inflammation; Liver Circulation; Male; Methane; Microcirculation; Microscopy, Confocal; Microscopy, Video; Peroxidase; Photoacoustic Techniques; Rats; Rats, Sprague-Dawley; Rifamycins; Rifaximin; Sodium Azide; Xanthine Dehydrogenase

The hemorrhagic shock (HS) model is commonly used to initiate a systemic post-traumatic inflammatory response. Numerous experimental protocols exist and it is unclear how differences in these models affect the immune response making it difficult to compare results between studies. The aim of this study was to compare the inflammatory response of different established protocols for volume-controlled shock in a murine model.. Male C57/BL6 mice 6-10 weeks and weighing 20-25 g were subjected to volume-controlled or pressure-controlled hemorrhagic shock. In the volume-controlled group 300 μl, 500 μl, or 700 μl blood was collected over 15 min and mean arterial pressure was continuously monitored during the period of shock. In the pressure-controlled hemorrhagic shock group, blood volume was depleted with a goal mean arterial pressure of 35 mmHg for 90 min. Following hemorrhage, mice from all groups were resuscitated with the extracted blood and an equal volume of lactated ringer solution. Six hours from the initiation of hemorrhagic shock, serum IL-6, KC, MCP-1 and MPO activity within the lung and liver tissue were assessed.. In the volume-controlled group, the mice were able to compensate the initial blood loss within 30 min. Approximately 800 μl of blood volume was removed to achieve a MAP of 35 mmHg (p<0.001). No difference in the pro-inflammatory cytokine (IL-6 and KC) profile was measured between the volume-controlled groups (300 μl, 500 μl, or 700 μl). The pressure-controlled group demonstrated significantly higher cytokine levels (IL-6 and KC) than all volume-controlled groups. Pulmonary MPO activity increased with the severity of the HS (p<0.05). This relationship could not be observed in the liver.. Volume-controlled hemorrhagic shock performed following current literature recommendations may be insufficient to produce a profound post-traumatic inflammatory response. A decrease in the MAP following blood withdrawal (300 μl, 500 μl or 700 μl) was usually compensated within 30 min. Pressure-controlled hemorrhagic shock is a more reliable for induction of a systemic inflammatory response.

Topics: Animals; Blood Pressure; Cytokines; Inflammation; Liver; Lung; Male; Mice; Mice, Inbred C57BL; Models, Biological; Organ Specificity; Peroxidase; Shock, Hemorrhagic

The present study aimed to investigate the protective role of limonene in lipopolysaccharide (LPS)-induced acute lung injury (ALI). ALI was induced in mice by intratracheal instillation of LPS (0.5 mg/kg), and limonene (25, 50, and 75 mg/kg) was injected intraperitoneally 1 h prior to LPS administration. After 12 h, bronchoalveolar lavage fluid (BALF) and lung tissue were collected. Limonene pretreatment at doses of 25, 50, and 75 mg/kg decreased LPS-induced evident lung histopathological changes, lung wet-to-dry weight ratio, and lung myeloperoxidase activity. In addition, pretreatment with limonene inhibited inflammatory cells and proinflammatory cytokines including tumor necrosis factor-α, interleukin-1β, and interleukin-6 in BALF. Furthermore, we demonstrated that limonene blocked the phosphorylation of IκBα, nuclear factor-κB (NF-κB) p65, p38 mitogen-activated protein kinase (MAPK), c-Jun NH2-terminal kinase, and extracellular signal-regulated kinase in LPS-induced ALI. The results presented here suggest that the protective mechanism of limonene may be attributed partly to decreased production of proinflammatory cytokines through the inhibition of NF-κB and MAPK activation.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; Cyclohexenes; Dexamethasone; Inflammation; Interleukins; Limonene; Lipopolysaccharides; Lung; Male; MAP Kinase Signaling System; Mice; Mice, Inbred BALB C; Mitogen-Activated Protein Kinases; NF-kappa B; NF-kappa B p50 Subunit; Peroxidase; Phosphorylation; Terpenes; Transcription Factor RelA; Tumor Necrosis Factor-alpha

Enteric infections are associated with linear growth failure in children. To quantify the association between intestinal inflammation and linear growth failure three commercially available enzyme-linked immunosorbent assays (neopterin [NEO], alpha-anti-trypsin [AAT], and myeloperoxidase [MPO]) were performed in a structured sampling of asymptomatic stool from children under longitudinal surveillance for diarrheal illness in eight countries. Samples from 537 children contributed 1,169 AAT, 916 MPO, and 954 NEO test results that were significantly associated with linear growth. When combined to form a disease activity score, children with the highest score grew 1.08 cm less than children with the lowest score over the 6-month period following the tests after controlling for the incidence of diarrheal disease. This set of affordable non-invasive tests delineates those at risk of linear growth failure and may be used for the improved assessments of interventions to optimize growth during a critical period of early childhood.

Topics: alpha 1-Antitrypsin; Biomarkers; Child, Preschool; Cohort Studies; Developing Countries; Diarrhea; Enzyme-Linked Immunosorbent Assay; Feces; Growth Disorders; Humans; Infant; Inflammation; Intestinal Mucosa; Intestines; Linear Models; Longitudinal Studies; Malnutrition; Neopterin; Permeability; Peroxidase; Poverty

Transient episodes of ischemia in a remote organ (remote ischemic preconditioning, RIPC) bears the potential to attenuate myocardial injury, but the underlying mechanisms are only poorly understood. In the pilot experimental study presented we investigated cellular and molecular effects of RIPC in heart tissue of cardiosurgical patients with cardiopulmonary bypass (CPB) and focussed on apoptotic events, local and systemic inflammation as well as the regulation of the hypoxia induced factor-1α (HIF-1α). RIPC was induced by four 5-min cycles of transient upper limb ischemia/reperfusion using a blood-pressure cuff. Right atrial tissue and serum were obtained from patients receiving RIPC (N = 32) and control patients (N = 29) before and after CPB. RIPC patients showed reduced troponin T serum concentrations in the first 48 h after surgery (P < 0.05 vs. control) indicating cardioprotective effects of RIPC. Samples from RIPC patients that were collected before CPB contained significantly increased amounts of HIF-1α and procaspase-3 (HIF-1α: P < 0.05 vs. control, procaspase-3: P < 0.05 vs. control), whereas activities of caspases 3 and 7 were by trend reduced. Samples from RIPC patients that were taken after CPB showed an increased activity of myeloperoxidase (P < 0.05 vs. control; P < 0.05 vs. RIPC before CPB) as well as elevated tissue concentrations of the interleukin (IL)-1β (P < 0.05 vs. RIPC before CPB). Serum levels of IL-8, IL-1β and TNFα were significantly increased in RIPC patients before CPB (P < 0.05 vs. control before CPB). In summary, RIPC regulates HIF-1α levels, apoptosis and inflammation in the myocardium of cardiosurgical patients and leads to increased concentrations of circulating cytokines.

Topics: Aged; Apoptosis; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Caspases; Cytokines; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Ischemic Preconditioning; Male; Middle Aged; Myocardium; Peroxidase; Pilot Projects; Troponin T

Alginates are unbranched polymers of polysaccharide presented as the structural components of marine brown algae. The proinflammatory activity of SVHV, an alginate isolated from Sargassum vulgare, was investigated using models of paw edema, mast cells degranulation and neutrophil migration in vivo. SVHV induced a dose dependent paw edema, with a peak at 2 h, associated with an increased myeloperoxidase activity and production of TNF-α and IL-1β. Pharmacological modulators, remarkably dexamethasone and indomethacin, inhibited the edema. SVHV (1.0 mg) also led to a significant induction of neutrophil migration in the peritoneal cavity of rats. This neutrophil migration was significantly reduced by peritoneal resident macrophages depletion, but was not affected by the depletion of mast cells. Our data suggest that SVHV has proinflammatory activity dependent of the activation of resident cells, being the macrophages the main cells involved.

Topics: Alginates; Animals; Cell Proliferation; Edema; Glucuronic Acid; Hexuronic Acids; Immune System Diseases; Inflammation; Interleukin-1beta; Leukocyte Disorders; Male; Mast Cells; Peritoneal Cavity; Peroxidase; Rats; Sargassum; Tumor Necrosis Factor-alpha

The aim of this study was to examine whether administration of ulinastatin inhibits pro-inflammatory mediators and ameliorate visceral vasopermeability both in a rat model of major burn, and also in rat cultured endothelial cells stimulated with permeability-evoking mediators.. Plasma levels of tumor necrosis factor-alpha (TNF-α), C-reactive protein (CRP), myeloperoxidase (MPO), microvascular permeability, and water content of organ tissues were evaluated in a rodent model of a 55% TBSA full-thickness scald injury. Microvascular permeability was also evaluated with a cultured pulmonary microvascular endothelial cells (PMECs) monolayer after stimulation with trypsin, bradykinin, histamine, prostaglandin E2 and burn serum.. We found that the plasma levels of TNF-α, CRP, MPO, vascular permeability and water content of heart, lung, kidney, and small intestine tissues were significantly increased in animals after scald injury, and administration of ulinastatin lowered the levels TNF-α, CRP, MPO, vascular permeability and water content of those organ tissues. In vitro, ulinastatin lowered the levels of TNF-α, interleukin-6 (IL-6) and attenuated permeability in PMEC monolayers after being stimulated with burn serum or trypsin, but not by bradykinin, histamine or prostaglandin E2.. These results indicate that ulinastatin attenuates the systemic inflammatory response and visceral vasopermeability both in vivo and vitro, and may serve as a therapeutic agent for prevention of systemic inflammatory response and leakage of fluid into tissue after major burn.

Topics: Animals; Biomarkers; Burns; C-Reactive Protein; Capillary Permeability; Disease Models, Animal; Glycoproteins; Inflammation; Inflammation Mediators; Interleukin-6; Intestine, Small; Kidney; Lung; Male; Peroxidase; Rats; Trypsin Inhibitors; Tumor Necrosis Factor-alpha; Water

A previous study indicated that intrathecal administration of morphine reduces experimental inflammatory edema in rats by activating the nitric oxide/cyclic guanosine monophosphate pathway. This evidence supports the hypothesis that potassium channel opening may play an important role in mediating morphine's effect under such conditions.. Male Wistar rats received intrathecal injections of drugs (20 μL) 30 minutes before paw stimulation with carrageenan (150 µg). Edema was measured as paw volume increase (in milliliters), and plasma leakage was measured by Evans blue dye leakage. Neutrophil migration was evaluated indirectly by myeloperoxidase assay. The inflammatory infiltration and vascular congestion were observed by histologic examination.. Morphine (37 nmol) inhibited inflammatory edema, plasma leakage, and vascular congestion but had no effect on myeloperoxidase activity or neutrophil content compared with phosphate-buffered saline. Coinjection with 4-aminopyridine (10 nmol), glibenclamide (5 nmol), and dequalinium (10 pmol) reversed, but nicorandil (0.03 nmol) enhanced the effect of morphine.. These results support the hypothesis that the peripheral antiedematogenic effect produced by intrathecal morphine is mediated by potassium channel activation. Furthermore, this opioid effect does not involve the inhibition of acute neutrophil migration but does involve a reduction in capillary recruitment.

Topics: Analgesics, Opioid; Animals; Blood Vessels; Carrageenan; Cell Migration Assays, Macrophage; Coloring Agents; Edema; Evans Blue; Foot; Inflammation; Injections, Spinal; Male; Morphine; Nicorandil; Peroxidase; Potassium Channel Blockers; Potassium Channels; Rats; Rats, Wistar

Peri-operative atrial fibrillation (peri-op AF) is a common complication following thoracic surgery. This arrhythmia is thought to be triggered by an inflammatory response and can be reproduced in various animal models. Previous work has shown that the lipid inflammatory mediator, platelet-activating factor (PAF), synthesized by activated neutrophils, can induce atrial and ventricular arrhythmias as well as repolarization abnormalities in isolated ventricular myocytes. We have previously shown that carbamylated PAF-induced repolarization abnormalities result from the protein kinase C (PKC) ε-dependent phosphorylation of the two-pore domain potassium channel TASK-1. We now demonstrate that canine peri-op AF is associated with the phosphorylation-dependent loss of TASK-1 current. Further studies identified threonine 383 in the C terminus of human and canine TASK-1 as the phosphorylation site required for PAF-dependent inhibition of the channel. Using a novel phosphorylation site-specific antibody targeting the phosphorylated channel, we have determined that peri-op AF is associated with the loss of TASK-1 current and increased phosphorylation of TASK-1 at this site.

Topics: Animals; Atrial Fibrillation; CHO Cells; Cricetinae; Cricetulus; Dogs; Electrophysiology; Humans; Inflammation; Male; Muscle Cells; Nerve Tissue Proteins; Perioperative Period; Peroxidase; Phosphorylation; Platelet Activating Factor; Potassium Channels, Tandem Pore Domain; Protein Kinase C; Threonine

Anethole [1-methoxy-4-(1-propenyl)benzene] occurs naturally as a major component of the essential oil of star anise (Illicium verum Hook.f., family Illiciaceae), comprising more than 90 % of its volatile components. Studies showed that this substance has antioxidant, antibacterial, antifungal, and anesthetic properties. In this study, the anti-inflammatory properties of anethole in animal models of nonimmune acute inflammation such as croton oil-induced ear edema and carrageenan-induced pleurisy were investigated. The investigated parameters were edema formation, leukocyte migration, and inflammatory mediators involved. Oral administration of anethole at a dose of 250 and 500 mg/kg reduced both the volume of pleural exudates and the number of migrated leukocytes. Levels of nitric oxide (NO) and prostaglandins (PGE2) in the inflammatory exudate were reduced by treatment with anethole, but levels of tumor necrosis factor-α and interleukin-1β were not significantly altered. In ear edema, the oral treatment with anethole inhibited the formation of exudate and the activity of myeloperoxidase, but not after topical administration. These results suggest that the anethole may be effective in controlling some nonimmune acute inflammation-related disease, probably by an inhibitory action on production and/or release of PGE2 and NO.

Topics: Allylbenzene Derivatives; Animals; Anisoles; Anti-Inflammatory Agents; Carrageenan; Croton Oil; Dinoprostone; Edema; Illicium; Inflammation; Interleukin-1beta; Male; Nitrates; Nitric Oxide; Oils, Volatile; Peroxidase; Pleurisy; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

Curcumin is a widely used spice with anti-inflammatory and anticancer properties. It has been reported to have beneficial effects in experimental colitis. This study explored whether curcumin improves colonic inflammation in a rat colitis model through inhibition of the TLR4/NF-κB signaling pathway and IL-27 expression. After induction of colitis with 2,4,6-trinitrobenzene sulfonic acid, rats were intragastrically administered with curcumin or sulfasalazine daily for one week. Rat intestinal mucosa was collected for evaluation of the disease activity index, colonic mucosa damage index, and histological score. Myeloperoxidase activity was detected by immunohistochemistry, and mRNA and protein expression levels of TLR4, NF-κB, and IL-27 in colonic mucosa were detected by RT-PCR and Western blot. Compared with the untreated colitis group, the curcumin-treated group showed significant decreases in the disease activity index, colonic mucosa damage index, histological score, myeloperoxidase activity, and expressions of NF-κB mRNA, IL-27 mRNA, TLR4 protein, NF-κB p65 protein, and IL-27 p28 protein (p < 0.05). TLR4 mRNA expression did not differ between groups. Disease activity index decreased more rapidly in the curcumin-treated group than in the sulfasalazine-treated group (p < 0.05). There was no significant difference in TLR4, NF-κB, and IL-27 mRNA and proteins between curcumin-treated and sulfasalazine-treated groups. Curcumin shows significant therapeutic effects on 2,4,6-trinitrobenzene sulfonic acid-induced colitis that are comparable to sulfasalazine. The anti-inflammatory actions of curcumin on colitis may involve inhibition of the TLR4/NF-κB signaling pathway and of IL-27 expression.

Topics: Animals; Anti-Inflammatory Agents; Colitis; Colon; Curcumin; Disease Models, Animal; Gastrointestinal Agents; Inflammation; Interleukins; Intestinal Mucosa; Male; NF-kappa B; Peroxidase; Random Allocation; Rats; Signal Transduction; Sulfasalazine; Toll-Like Receptor 4; Transcription Factor RelA; Trinitrobenzenesulfonic Acid

To date, no sufficiently sensitive and specific single marker has been found to predict the clinical course of sarcoidosis. We designed a cohort study to investigate whether a panel of biomarkers measured in bronchoalveolar lavage (BAL) and peripheral blood could help predict pulmonary function worsening during the clinical course of sarcoidosis.. We analyzed 30 individuals with histologically proven sarcoidosis. At baseline, participants underwent pulmonary function tests (PFTs), fiberoptic bronchoscopy and radiological investigations. BAL and blood cellular profiles were obtained from all individuals and six pro-inflammatory molecules were quantified in BAL and serum. PFTs were performed at follow-up visits over a 2-year period. Using discriminant function analysis, a canonical variable was generated to optimize the accuracy of selected variables in predicting pulmonary function worsening and was validated on a subset of nine consecutive individuals with sarcoidosis.. A combination of 6 markers from BAL was able to predict pulmonary function worsening in 96 % of patients [95 % confidence interval (CI) 84.4-99.81]. We validated the generated formula on a group of nine patients with sarcoidosis, obtaining 77.8 % correct classification (95 % CI 45.3-93.7).. Our results show that a combinational approach could contribute to identifying individuals likely to experience pulmonary function worsening, thus helping to decide the correct therapeutic strategies.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Bronchoalveolar Lavage; Bronchoscopy; Cohort Studies; Disease Progression; Eosinophil Cationic Protein; Female; Follow-Up Studies; Humans; Inflammation; Longitudinal Studies; Lung; Male; Middle Aged; Peptide Fragments; Peroxidase; Procollagen; Receptors, Interleukin-2; Respiratory Function Tests; Sarcoidosis, Pulmonary; Sensitivity and Specificity; Tryptases; Tumor Necrosis Factor-alpha

Saccharomyces boulardii is a probiotic used for the prevention of antibiotic-associated diarrhoea. We aimed to investigate whether S. boulardii could alter the effects of clarithromycin (CLA) and methotrexate (MTX) on oro-caecal intestinal transit and oxidative damage in rats. Rats were divided into two groups receiving a single dose of MTX (20 mg/kg) or CLA (20 mg/kg per d) for 1 week. Groups were treated with either saline or S. boulardii (500 mg/kg) twice per d throughout the experiment. The control group was administered only saline. Following decapitation, intestinal transit and inflammation markers of glutathione (GSH), malondialdehyde and myeloperoxidase were measured in intestinal and hepatic tissues. CLA and MTX increased intestinal transit, while S. boulardii treatment slowed down CLA-facilitated transit back to control level. Both MTX and CLA increased lipid peroxidation while depleting the antioxidant GSH content in the hepatic and ileal tissues. Conversely, lipid peroxidation was depressed and GSH levels were increased in the ileal and hepatic tissues of S. boulardii-treated rats. Increased ileal neutrophil infiltration due to MTX and CLA treatments was also reduced by S. boulardii treatment. Histological analysis supported that S. boulardii protected intestinal tissues against the inflammatory effects of both agents. These findings suggest that S. boulardii ameliorates intestinal injury and the accompanying hepatic inflammation by supporting the antioxidant state of the tissues and by inhibiting the recruitment of neutrophils. Moreover, a preventive effect on MTXinduced toxicity is a novel finding of S. boulardii, proposing it as an adjunct to chemotherapy regimens.

Topics: Animals; Anti-Bacterial Agents; Antimetabolites, Antineoplastic; Antioxidants; Chemical and Drug Induced Liver Injury; Clarithromycin; Diarrhea; Gastrointestinal Transit; Glutathione; Ileum; Inflammation; Intestinal Diseases; Lipid Peroxidation; Liver; Male; Malondialdehyde; Methotrexate; Neutrophil Infiltration; Oxidative Stress; Peroxidase; Probiotics; Rats; Rats, Sprague-Dawley; Saccharomyces

Systemic administration of endotoxin, which closely mimics the bacteria-induced systemic inflammatory response syndrome (SIRS) can ultimately lead to organ failure. Adrenal gland insufficiency is frequently diagnosed in critically ill patients; however, the underlying mechanisms are still unclear. In the present study, we studied comprehensively the characteristics of adrenal gland dysregulation, including inflammation, leukocyte infiltration and cell death in the adrenal glands in the course of LPS-induced systemic inflammation in mice. LPS enhanced expression of many proinflammatory cytokines, chemokines and adhesion molecules, which resulted in rapid recruitment of leukocytes into the adrenal gland. Furthermore, LPS-mediated inflammation was associated with increased apoptosis of adrenocortical and chromaffin cells. Our results performed in mice, suggest that LPS-induced adrenal gland inflammation and cell death might be mechanisms potentially involved in the adrenal gland dysfunction in patients with sepsis.

Topics: Adrenal Glands; Adrenal Insufficiency; Animals; Apoptosis; Cell Adhesion Molecules; Chemokines; Chromaffin Cells; Cytokines; Inflammation; Leukocytes; Lipopolysaccharides; Mice; Peroxidase; Sepsis; Systemic Inflammatory Response Syndrome

Myeloperoxidase is a neutrophil enzyme that promotes oxidative stress in numerous inflammatory pathologies. It uses hydrogen peroxide to catalyze the production of strong oxidants including chlorine bleach and free radicals. A physiological defense against the inappropriate action of this enzyme has yet to be identified. We found that myeloperoxidase oxidized 75% of the ascorbate in plasma from ceruloplasmin knock-out mice, but there was no significant loss in plasma from wild type animals. When myeloperoxidase was added to human plasma it became bound to other proteins and was reversibly inhibited. Ceruloplasmin was the predominant protein associated with myeloperoxidase. When the purified proteins were mixed, they became strongly but reversibly associated. Ceruloplasmin was a potent inhibitor of purified myeloperoxidase, inhibiting production of hypochlorous acid by 50% at 25 nm. Ceruloplasmin rapidly reduced Compound I, the Fe(V) redox intermediate of myeloperoxidase, to Compound II, which has Fe(IV) in its heme prosthetic groups. It also prevented the fast reduction of Compound II by tyrosine. In the presence of chloride and hydrogen peroxide, ceruloplasmin converted myeloperoxidase to Compound II and slowed its conversion back to the ferric enzyme. Collectively, our results indicate that ceruloplasmin inhibits myeloperoxidase by reducing Compound I and then trapping the enzyme as inactive Compound II. We propose that ceruloplasmin should provide a protective shield against inadvertent oxidant production by myeloperoxidase during inflammation.

Topics: Animals; Ascorbic Acid; Ceruloplasmin; Enzyme Inhibitors; Humans; Hypochlorous Acid; Inflammation; Mice; Mice, Knockout; Oxidation-Reduction; Peroxidase; Protein Binding

Haemorrhage-induced immunosuppression has been linked to nosocomial infections. We assessed the impact of monophosphoryl lipid A, a Toll/interleukin-1 receptor-domain-containing adaptor protein inducing interferon-biased Toll-like receptor-4 agonist currently used as a vaccine adjuvant in humans, on post-haemorrhage susceptibility to infection. We used a mouse model of post-haemorrhage pneumonia induced by methicillin-susceptible Staphylococcus aureus. Monophosphoryl lipid A was administered intravenously after haemorrhage and before pneumonia onset. Haemorrhage altered survival rate, increased lung damage (neutrophil accumulation, oedema and cytokine release) and altered the functions of dendritic and natural killer cells. Here, we show that monophosphoryl lipid A decreased systemic dissemination of S. aureus and dampened inflammatory lung lesions. Monophosphoryl lipid A partially restored the capacity for antigen presentation and the transcriptional activity in dendritic cells. Monophosphoryl lipid A did not restore the interferon-γ mRNA but prevented interleukin-10 mRNA overexpression in natural killer cells compared with untreated mice. Ex vivo monophosphoryl lipid A-stimulated dendritic cells or natural killer cells harvested from haemorrhaged animals were adoptively transferred into mice undergoing post-haemorrhage pneumonia. Stimulated dendritic cells (but not stimulated natural killer cells) improved the survival rate compared with mice left untreated. In vivo depletion of natural killer cells decreased survival rate of monophosphoryl lipid A-treated mice. Dendritic and natural killer cells are critically involved in the beneficial effects of monophosphoryl lipid A within post-haemorrhage pneumonia.

Topics: Animals; Bronchoalveolar Lavage; Dendritic Cells; Endothelial Cells; Hemorrhage; Immunocompromised Host; Immunosuppression Therapy; Inflammation; Interferon-gamma; Interleukin-10; Killer Cells, Natural; Lipid A; Lung; Male; Mice; Mice, Inbred BALB C; Peroxidase; Phenotype; Pneumonia; Spleen; Staphylococcus aureus; Toll-Like Receptor 4

The present study evaluates the anti-inflammatory effect of the quinoline alkaloid skimmianine (SKM), isolated from Ruta graveolens L., against carrageenan-induced acute inflammation.. SKM at a dose of 5.0 mg/kg body weight was found to be the minimal concentration for maximal edema inhibition. Carrageenan suspension was administered into the sub-plantar tissue of the right hind paw 1 h after SKM and diclofenac (20 mg/kg) administration (i.p.). Paw edema was determined 3 h after carrageenan administration. The rats were then killed and mRNA expressions of TNF-α and IL-6, levels of PGE2 and TBARS, activities of COX-2, 5-LOX, SOD, catalase, glutathione peroxidase (GPx) and myeloperoxidase (MPO) and the level of nitrite were measured.. SKM treatment resulted in a decrease in the mRNA levels of TNF-α and IL-6, which are upstream events of the inflammatory cascade. The levels of PGE2 and NO and the activities of COX-2 and 5-LOX were also significantly reduced after SKM treatment. Neutrophil infiltration, lipid peroxidation and associated oxidative stress in the paw tissue were reduced following SKM treatment.. These results support the anti-inflammatory properties of skimmianine and its multi-targeted mechanism of action, suggesting its potential therapeutic efficacy in various inflammatory diseases.

Topics: Animals; Anti-Inflammatory Agents; Carrageenan; Catalase; Cyclooxygenase 2; Dinoprostone; Glutathione Peroxidase; Inflammation; Male; Nitric Oxide; Peroxidase; Phytotherapy; Plant Components, Aerial; Plant Extracts; Quinolines; Rats; Rats, Wistar; Ruta; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances

Nephrotoxicity is an important complication in cancer patients undergoing cisplatin therapy. Oxidative stress, inflammation and apoptosis/necrosis are the major patho-mechanisms of cisplatin induced nephrotoxicity. In the present study, hesperidin, a naturally-occurring bioflavonoid has been demonstrated to have protective effect on cisplatin-induced renal injury in rats. Cisplatin intoxication resulted in structural and functional renal impairment which was revealed by massive histopathological changes and elevated blood urea nitrogen and serum creatinine levels, respectively. Renal injury was associated with oxidative stress/lipid peroxidation as evident by increased reactive oxygen species (ROS) and malondialdehyde (MDA) formation with decreased levels of antioxidants such as reduced glutathione, vitamin C, catalase, superoxide dismutase, glutathione reductase, glutathione peroxidase and glutathione-S-transferase. Cisplatin administration also triggered inflammatory response in rat kidneys by inducing pro-inflammatory cytokine, TNF-α, with the increased expression of myeloperoxidase (MPO). Furthermore, cisplatin increased the activity of caspase-3 and DNA damage with decreased tissue nitric oxide levels. Hesperidin treatment significantly attenuated the cisplatin-induced oxidative stress/lipid peroxidation, inflammation (infiltration of leukocytes and pro-inflammatory cytokine), apoptosis/necrosis (caspase-3 activity with DNA damage) as well as increased expression of nitric oxide in the kidney and improved renal function. Thus, our results suggest that hesperidin co-administration may serve as a novel and promising preventive strategy against cisplatin-induced nephrotoxicity.

Topics: Acute Kidney Injury; Animals; Apoptosis; Blood Urea Nitrogen; Caspase 3; Cisplatin; Creatinine; Cytoprotection; DNA Damage; Glutathione; Glutathione Peroxidase; Glutathione Reductase; Hesperidin; Inflammation; Kidney; Lipid Peroxidation; Male; Malondialdehyde; Nitric Oxide; Oxidative Stress; Peroxidase; Rats; Rats, Wistar; Reactive Oxygen Species; Superoxide Dismutase; Tumor Necrosis Factor-alpha

The exact alterations of the immune system after polytrauma leading to sepsis and multiple-organ failure are poorly understood. Thus, the early local and systemic inflammatory and apoptotic response was characterized in a new polytrauma model and compared with the alterations seen after single or combined injuries.. Anesthetized C57BL/6 mice were subjected to either blunt bilateral chest trauma (Tx), closed head injury, right femur fracture including contralateral soft tissue injury, or a combination of injuries (PTx). After 2 hours or 6 hours, animals were sacrificed, and the systemic as well as the local pulmonary immune response (bronchoalveolar lavage [BAL]/plasma cytokines, lung myeloperoxidase [MPO] activity, and alveolocapillary barrier dysfunction) were evaluated along with lung/brain apoptosis (lung caspase 3 Western blotting, immunohistochemistry, and polymorphonuclear leukocytes [PMN] Annexin V).. Hemoglobin, PO2 saturation, and pH did not differ between the experimental groups. Local BAL cytokines/chemokines were significantly increased in almost all groups, which included Tx. There was no further enhancement of this local inflammatory response in the lungs in case of PTx. At 2 hours, all groups except sham and closed head injury alone revealed an increased activity of lung MPO. However, 6 hours after injury, lung MPO remained increased only in the PTx group. Increased BAL protein levels were found, reflecting enhanced lung leakage in all groups with Tx 6 hours after trauma. Only after PTx was neutrophil apoptosis significantly decreased, whereas lung caspase 3 and plasma interleukin 6/keratinocyte chemoattractant (KC) were substantially increased.. The combination of different injuries leads to an earlier systemic inflammatory response when compared with the single insults. Interestingly, only after PTx but not after single or double hits was lung apoptosis increased, and PMN apoptosis was decreased along with a prolonged presence of neutrophils in the lungs, which may therefore represent a possible pathomechanism for lung injury after polytrauma.

Topics: Animals; Apoptosis; Blotting, Western; Brain; Bronchoalveolar Lavage Fluid; Caspase 3; Chemokines; Cytokines; Flow Cytometry; Hemoglobins; Inflammation; Lung; Male; Mice; Mice, Inbred C57BL; Multiple Trauma; Peroxidase; Wounds and Injuries

Septic shock is a systemic inflammatory response syndrome, and it is the leading cause of death in intensive care units. Mycophenolate mofetil (MMF) is an immunosuppressant that has been shown to be effective in the treatment of various inflammatory diseases. In this study, the anti-inflammatory effect of MMF in a mouse model of acute lung injury (ALI) induced by lipopolysaccharide (LPS) was evaluated. ALI was induced by intrapleural injection of LPS (250 ng/cavity). The leukocyte migration, exudation, myeloperoxidase and adenosine deaminase activities, nitric oxide products, tumor necrosis factor alpha (TNF-α), and interleukin 1 beta (IL-1β) levels, as well as mRNA expression of TNF-α and IL-1β, were evaluated. This study showed that MMF significantly decreased all parameters studied in a manner comparable to treatment with dexamethasone. In conclusion, MMF has important anti-inflammatory effects that may be useful as an auxiliary treatment for septic shock.

Topics: Acute Lung Injury; Adenosine Deaminase; Animals; Anti-Inflammatory Agents; Cell Movement; Dexamethasone; Disease Models, Animal; Immunosuppressive Agents; Inflammation; Interleukin-1beta; Leukocytes; Lipopolysaccharides; Lung; Mice; Mycophenolic Acid; Nitric Oxide; Peroxidase; RNA, Messenger; Shock, Septic; Tumor Necrosis Factor-alpha

Strychnine is known to possess anti-inflammatory and antitumour activity, but its roles in tumour angiogenesis, the key step involved in tumour growth and metastasis, and the involved molecular mechanism are still unknown. We aimed to investigate the effects of strychnine on key components of inflammatory angiogenesis in the murine cannulated sponge implant angiogenesis model. Polyester-polyurethane sponges, used as a framework for fibrovascular tissue growth, were implanted in Swiss albino mice and strychnine (0.25, and 0.5 mg/kg/day) was given through installed cannulas for 9 days. The implants collected at day 9 postimplantation were processed for the assessment of haemoglobin (Hb), myeloperoxidase (MPO), N-acetylglucosaminidase (NAG) and collagen used as indexes for angiogenesis, neutrophil and macrophage accumulation and extracellular matrix deposition, respectively. Relevant inflammatory, angiogenic and fibrogenic cytokines were also determined. Strychnine treatment attenuated the main components of the fibrovascular tissue, wet weight, vascularization (Hb content), macrophage recruitment (NAG activity), collagen deposition and the levels of vascular endothelial growth factor (VEGF), tumour necrosis factor (TNF)-α and transforming growth factor (TGF-β). A regulatory function of strychnine on multiple parameters of main components of inflammatory angiogenesis has been revealed giving insight into the potential therapeutic underlying the actions of strychnine.

Topics: Acetylglucosaminidase; Angiogenesis Inhibitors; Animals; Anti-Inflammatory Agents; Biomarkers; Collagen; Dose-Response Relationship, Drug; Down-Regulation; Extracellular Matrix; Hemoglobins; Inflammation; Inflammation Mediators; Macrophages; Male; Mice; Neovascularization, Pathologic; Neutrophils; Peroxidase; Polyesters; Polyurethanes; Strychnine; Surgical Sponges; Time Factors; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

The aim of this study was to investigate the anti-inflammatory efficacy of rosiglitazone (ROSI) in a pleurisy model of carrageenan-induced inflammation. Efficacy was monitored in the mouse pleural cavity by evaluating leukocyte migration, exudate concentration, and myeloperoxidase (MPO) and adenosine deaminase (ADA) activities concomitantly with nitrate/nitrite (NOx), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-17A (IL-17A), and vascular endothelial growth factor-alpha (VEGF-α) levels 4 and 48 h after pleurisy induction. In both phases (4 and 48 h) of pleurisy, ROSI inhibited all the inflammation parameters that were tested (p<0.05). These results provide evidence that ROSI was efficacious in inhibiting pro-inflammatory mediators. These anti-inflammatory effects are assumed to mainly result from the inhibition of products released from activated leukocytes, such as MPO, ADA, NOx, TNF-α, IL-1β, IL-17A, and VEGF-α.

Topics: Adenosine Deaminase; Animals; Carrageenan; Cell Movement; Disease Models, Animal; Inflammation; Inflammation Mediators; Interleukin-17; Interleukin-1beta; Leukocytes, Mononuclear; Mice; Peroxidase; Pleurisy; PPAR gamma; Rosiglitazone; Thiazolidinediones; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

Oxidative and nitrative stress responses resulting from inflammation exacerbate liver injury associated with nonalcoholic steatohepatitis (NASH) by inducing lipid peroxidation and protein nitration. The objective of this study was to investigate whether the anti-inflammatory properties of green tea extract (GTE) would protect against NASH by suppressing oxidative and nitrative damage mediated by proinflammatory enzymes. Obese mice (ob/ob) and their 5-week-old C57BL6 lean littermates were fed 0%, 0.5% or 1% GTE for 6 weeks (n=12-13 mice/group). In obese mice, hepatic lipid accumulation, inflammatory infiltrates and serum alanine aminotransferase activity were markedly increased, whereas these markers of hepatic steatosis, inflammation and injury were significantly reduced among obese mice fed GTE. GTE also normalized hepatic 4-hydroxynonenal and 3-nitro-tyrosine (N-Tyr) concentrations to those observed in lean controls. These oxidative and nitrative damage markers were correlated with alanine aminotransferase (P<.05; r=0.410-0.471). Improvements in oxidative and nitrative damage by GTE were also associated with lower hepatic nicotinamide adenine dinucleotide phosphate oxidase activity. Likewise, GTE reduced protein expression levels of hepatic myeloperoxidase and inducible nitric oxide synthase and decreased the concentrations of nitric oxide metabolites. Correlative relationships between nicotinamide adenine dinucleotide phosphate oxidase and hepatic 4-hydroxynonenal (r=0.364) as well as nitric oxide metabolites and N-Tyr (r=0.598) suggest that GTE mitigates lipid peroxidation and protein nitration by suppressing the generation of reactive oxygen and nitrogen species. Further study is warranted to determine whether GTE can be recommended as an effective dietary strategy to reduce the risk of obesity-triggered NASH.

Topics: Alanine Transaminase; Aldehydes; Animals; Anti-Inflammatory Agents; Fatty Liver; Inflammation; Lipid Peroxidation; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; NADPH Oxidases; Nitric Oxide Synthase Type II; Non-alcoholic Fatty Liver Disease; Obesity; Oxidative Stress; Peroxidase; Plant Extracts; Reactive Oxygen Species; Stress, Physiological; Tea; Tyrosine

Release and activation of pro-inflammatory mediators are among the most important induced factors that are involved in the scorpion envenomation pathogenesis. Inflammatory response and lung reactivity were studied in mice following subcutaneous injection with Androctonus australis hector (Aah) venom. Venom immunodetection in lungs and sequestered cell population in the airways were determined. Cytokines, cellular peroxidase activities (eosinophil peroxidase, myeloperoxydase), and IgE antibodies were also assessed. Immunohistochemical study revealed a positive detection of the Aah venom in the alveolar wall, venule lumens, and inside inflammatory cells. Severe lung edema associated with rapid inflammatory response was observed after animal envenomation. Lung neutrophilia and eosinophilia were accompanied with IL-4, IL-5 release, and IgE synthesis. In conclusion, high cytokine levels, recruitment of inflammatory cells (eosinophils and neutrophils), and increased IgE concentration may contribute to the exacerbation and maintenance of the induced inflammatory response in lungs by scorpion venom. These results lead to the better understanding of this induced pathogenesis and could help the physicians to take care of envenomed patients.

Topics: Animals; Eosinophil Peroxidase; Eosinophilia; Immunoglobulin E; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-4; Interleukin-5; Lung; Mice; Peroxidase; Pulmonary Edema; Scorpion Stings; Scorpion Venoms; Scorpions

The possibility of inflammation and neutrophil activation in response to indoor air pollution (IAP) from biomass fuel use has been investigated. For this, 142 premenopausal, never-smoking women (median age, 34 years) who cook exclusively with biomass (wood, dung, crop wastes) and 126 age-matched control women who cook with cleaner fuel liquefied petroleum gas (LPG) were enrolled. The neutrophil count in blood and sputum was significantly higher (p < 0.05) in biomass users than the control group. Flow cytometric analysis revealed marked increase in the surface expression of CD35 (complement receptor-1), CD16 (F(C)γ receptor III), and β(2) Mac-1 integrin (CD11b/CD18) on circulating neutrophils of biomass users. Besides, enzyme-linked immunosorbent assay showed that they had 72%, 67%, and 54% higher plasma levels of the proinflammatory cytokines tumor necrosis factor-alpha, interleukin-6, and interleukin-12, respectively, and doubled neutrophil chemoattractant interleukin-8. Immunocytochemical study revealed significantly higher percentage of airway neutrophils expressing inducible nitric oxide synthase, while the serum level of nitric oxide was doubled in women who cooked with biomass. Spectrophotometric analysis documented higher myeloperoxidase activity in circulating neutrophils of biomass users, suggesting neutrophil activation. Flow cytometry showed excess generation of reactive oxygen species (ROS) by leukocytes of biomass-using women, whereas their erythrocytes contained a depleted level of antioxidant enzyme superoxide dismutase (SOD). Indoor air of biomass-using households had two to four times more particulate matter with diameters of <10 μm (PM(10)) and <2.5 μm (PM(2.5)) as measured by real-time laser photometer. After controlling potential confounders, rise in proinflammatory mediators among biomass users were positively associated with PM(10) and PM(2.5) in indoor air, suggesting a close relationship between IAP and neutrophil activation. Besides, the levels of neutrophil activation and inflammation markers were positively associated with generation of ROS and negatively with SOD, indicating a role of oxidative stress in mediating neutrophilic inflammatory response following chronic inhalation of biomass smoke.

Topics: Adult; Air Pollution, Indoor; Biofuels; CD11b Antigen; CD18 Antigens; Female; Humans; Inflammation; Interleukins; Leukocyte Count; Neutrophil Activation; Neutrophils; Nitric Oxide; Nitric Oxide Synthase Type II; Oxidative Stress; Particulate Matter; Peroxidase; Premenopause; Reactive Oxygen Species; Receptors, Complement 3b; Receptors, IgG; Smoke; Superoxide Dismutase; Tumor Necrosis Factor-alpha; Young Adult

Olive leaf extract (OLE) has antioxidant and antiinflammatory actions. However, the role of OLE in mechanical inflammatory arthritis (osteoarthritis, OA) is unclear. This study investigated the effect of OLE on the development of kaolin and carrageenan-induced arthritis, a murine model of OA. Administration of OLE significantly ameliorated paw swelling, the paw Evans blue content and the histopathological scores. In the human monocyte cell line, THP-1, the OLE reduced the LPS-induced TNF-α production and was dose dependent. Croton oil-induced ear edema in mice also revealed that treatment with OLE suppressed ear edema, myeloperoxidase (MPO) production and was dose dependent. These results indicated that OLE is an effective antiarthritis agent through an antiinflammation mechanism. Also OLE may be beneficial for the treatment of OA in humans.

Topics: Animals; Anti-Inflammatory Agents; Arthritis, Experimental; Carrageenan; Cell Line, Tumor; Croton Oil; Dose-Response Relationship, Drug; Edema; Evans Blue; Humans; Inflammation; Kaolin; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; Olea; Peroxidase; Phytotherapy; Plant Extracts; Plant Leaves; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

Taurine (Tau) is reported to have a key role in the regulation of the innate immune response and thus reduce tissue damage induced by bacterial infection. In this study, the effects of Tau on a rat model of mastitis induced by Streptococcus uberis (S. uberis) and the changes of T regulatory cells (Tregs) were assessed. Starting on gestation day 14 and continuing until parturition, 100 mg/kg of taurine (group TS) or an equal volume of physiological saline (group CS) was administered daily, per os. Seventy-two hours after parturition, rats were infused with approximately 100 cfu of S. uberis into each of two mammary glands. The results showed that the resultant inflammation, evidenced by swelling, secretory epithelial cell degeneration, increased adipose tissue and neutrophil (PMN) infiltration were evident in mammary tissue following injection with S. uberis. Pre-treatment with Tau attenuated these morphologic changes, the expression of interleukin (IL)-2, interferon (INF)-γ mRNA, myeloperoxidase (MPO) activity and N-acetyl-β-D-glucosaminidase (NAGase) in mammary tissue. The percentages of Foxp3+CD25+CD4+/lymphocytes (Tregs) were dramatically increased after the S. uberis challenge. Significant differences (P<0.05) were observed at 24, and 72 h post S. uberis-injection (PI) in CS. Pre-treatment further increased the percentage of Tregs and a significant difference between CS and TS (P<0.05) was apparent at 24 h PI. Our data indicate that in rats, Tau can be used to regulate the immune response following infection by S. uberis and consequently prevent mammary tissue damage by increasing Tregs.

Topics: Acetylglucosaminidase; Animals; Anti-Inflammatory Agents, Non-Steroidal; CD4 Lymphocyte Count; Disease Models, Animal; Female; Inflammation; Interferon-gamma; Interleukin-2; Mammary Glands, Animal; Mastitis; Parturition; Peroxidase; Pregnancy; Rats; Streptococcus; T-Lymphocytes, Regulatory; Taurine

Sleep-disordered breathing (SDB) is a risk factor for cardiovascular disease (CVD). The underlying pathogenesis is not clear. In patients with obstructive sleep apnoea syndrome (OSAS) elevated levels of inflammatory markers, such as C-reactive protein (CRP), interleukin-6 (IL-6) and tumour necrosis factor α (TNFα) have been found. These markers have also been shown as independent markers of CVD in other populations. The aim of the study was to investigate the association between SDB and systemic inflammation in a population-based cohort of women. From 6817 women who previously answered a questionnaire concerning snoring habits, 230 habitually snoring women and 170 women regardless of snoring status went through polysomnography, anthropometric measurements and blood sampling. Analyses were made for CRP, TNFα, IL-6, myeloperoxidase (MPO) and lysozyme. The levels of CRP, IL-6 and lysozyme were significantly higher in subjects with apnoea-hypopnoea index (AHI) ≥15 compared with women with lower AHI. All inflammatory markers except MPO correlated to AHI and oxygen desaturation measures, and to waist circumference. In multiple linear regressions adjusting for age, waist circumference and smoking, independent correlations between oxygen desaturation indices (ODI) and inflammation were found for IL-6 (P = 0.03 for % sleep time with saturation <90%) and TNFα (P = 0.03 for ODI 3%). No significant correlations were found between AHI and inflammation. Also, for women from the general population there is an independent correlation between SDB and inflammation, even after adjusting for obesity. The results indicate that intermittent hypoxia, and not the AHI, is related to systemic inflammation seen in OSAS.

Topics: Adult; Aged; Biomarkers; C-Reactive Protein; Female; Humans; Inflammation; Interleukin-6; Middle Aged; Muramidase; Peroxidase; Polysomnography; Sleep Apnea Syndromes; Snoring; Surveys and Questionnaires; Tumor Necrosis Factor-alpha; Young Adult

We previously reported that 3-(benzo[d]-1,3-dioxol-5-yl)-4-phenylfuran-2,5-dione (BPD) showed strong inhibitory effects on PGE(2) production. However, the exact mechanism for the anti-inflammatory effect of BPD is not completely understood. In this study, we investigated the molecular mechanism involved in the effects of BPD on inflammatory mediators in LPS-stimulated macrophages and animal models of inflammation.. The expressions of COX-2, inducible NOS (iNOS), TNF-α, IL-6 and IL-1β, in LPS-stimulated RAW 264.7 cells and murine peritoneal macrophages, were determined by Western blot and/or qRT-PCR, respectively. NF-κB activation was investigated by EMSA, reporter gene assay and Western blotting. Anti-inflammatory effects of BPD were evaluated in vivo in carrageenan-induced paw oedema in rats and LPS-induced septic shock in mice.. BPD not only inhibited COX-2 activity but also reduced the expression of COX-2. In addition, BPD inhibited the expression of iNOS, TNF-α, IL-6 and IL-1β at the transcriptional level. BPD attenuated LPS-induced DNA-binding activity and the transcription activity of NF-κB; this was associated with a decrease in the phosphorylation level of inhibitory κB-α (IκB-α) and reduced nuclear translocation of NF-κB. Furthermore, BPD suppressed the formation of TGF-β-activated kinase-1 (TAK1)/TAK-binding protein1 (TAB1), which was accompanied by a parallel reduction of phosphorylation of TAK1 and IκB kinase (IKK). Pretreatment with BPD inhibited carrageenan-induced paw oedema and LPS-induced septic death.. Taken together, our data indicate that BPD is involved in the dual inhibition of COX-2 activity and TAK1-NF-κB pathway, providing a molecular basis for the anti-inflammatory properties of BPD.

Topics: Animals; Benzodioxoles; Carrageenan; Cell Line; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cytokines; Dinoprostone; Edema; Gene Expression; I-kappa B Proteins; Inflammation; Lipopolysaccharides; Macrophages, Peritoneal; Male; Maleic Anhydrides; MAP Kinase Kinase Kinases; Mice; Mice, Inbred C57BL; NF-kappa B; NF-KappaB Inhibitor alpha; Peroxidase; Rats; Rats, Sprague-Dawley; Sepsis; Transcription Factor AP-1

Restraint stress is known to catalyse the pathogenesis of the variety of chronic inflammatory disorders. The present study was designed to evaluate the effect of repeated short-term stress (RRS) on cellular transduction apart from oxidative burden and early tumour promotional biomarkers induced due to combined exposure of trichloroethylene (TCE) and Ultra-violet radiation (UVB). RRS leads to the increase in the expression of the stress responsive cellular transduction elements NFkB-p65 and activity of iNOS in the epidermal tissues of mice after toxicant exposure. RRS augments the steep depletion of the cellular antioxidant machinery which was evidenced by the marked depletion in GSH (Glutathione and GSH dependant enzymes), superoxide dismutase and catalase activity that were observed at significance level of P < 0.001 with increase in lipid peroxidation, H(2)O(2) and xanthine oxidase activity (P < 0.001) in the stressed animals and down regulation of DT-diaphorase activity (P < 0.001). Since, the induction of NFkB-p65 and inducible nitric oxide synthase expression mediated can lead to the hyperproliferation, we estimated a significant increment (P < 0.001) in the synthesis of polyamines in mice skin evidenced here by the ornithine decarboxylase which is the early marker of tumour promotion and further evaluated PCNA expression. All these findings cues towards the synergising ability of repeated short-term stress in the toxic response of TCE and UVB radiation.

Topics: Animals; Antioxidants; Biogenic Polyamines; Cell Proliferation; Hazardous Substances; Inflammation; Keratinocytes; Lipid Peroxidation; Male; Mice; NF-kappa B; Nitric Oxide Synthase Type II; Ornithine Decarboxylase; Oxidative Stress; Peroxidase; Proliferating Cell Nuclear Antigen; Reactive Oxygen Species; Skin; Stress, Psychological; Trichloroethylene; Ultraviolet Rays; Up-Regulation; Xanthine Oxidase

Heart rate (HR) and rhythm disturbances are common after cardiac surgery. This study tests the hypothesis that the inflammation caused by cardiac surgery is an underlying mechanism for postoperative changes in HR, rhythm, and HR variability (HRV).. Normal canines (n = 6 per group) were divided into 4 groups: (1) anesthesia, (2) sternotomy and pericardiotomy, (3) atriotomy, and (4) corticosteroids combined with an atriotomy. Continuous electrocardiographic recordings were done preoperatively and for 3 postoperative days. Electrophysiologic testing was done at the initial and terminal surgeries. C-reactive protein level was assessed at each study day, and tissue myeloperoxidase activity was assessed at the terminal study. Measurements of HRV were determined daily to detect changes in autonomic tone. Postoperatively, the HR increased in the pericardiotomy (P = .0005) and atriotomy (P = .001) groups and HRV decreased in both the groups. No significant change occurred in either the HR or HRV in the anesthesia (P = .52) and steroid (P = .16) groups. HRV (triangular index) on postoperative day 3 was correlated with the tissue myeloperoxidase levels (r = -.83; P = .0004). Autonomic blockade with atropine and esmolol resulted in an HR and HRV that were not significantly different between groups. Atrial premature beats occurred postoperatively in the all the groups except the anesthesia group and were independent of the degree of inflammation.. Cardiac surgery increases the postoperative HR by reducing HRV, mostly because of a reduction in vagal tone. Furthermore, the magnitude of these changes is dependent on the degree of inflammation and is normalized by corticosteroids.

Topics: Adrenal Cortex Hormones; Anesthesia; Animals; Atrial Fibrillation; Atropine; Autonomic Nervous System; C-Reactive Protein; Cardiac Surgical Procedures; Dogs; Electrophysiologic Techniques, Cardiac; Heart Rate; Inflammation; Monitoring, Physiologic; Perioperative Period; Peroxidase; Postoperative Complications

Inflammation and oxidative stress are linked to the deleterious effects of cigarette smoke in producing chronic obstructive pulmonary disease (COPD). Myeloperoxidase (MPO), a neutrophil and macrophage product, is important in bacterial killing, but also drives inflammatory reactions and tissue oxidation.. To determine the role of MPO in COPD.. We treated guinea pigs with a 2-thioxanthine MPO inhibitor, AZ1, in a 6-month cigarette smoke exposure model, with one group receiving compound from Smoking Day 1 and another group treated after 3 months of smoke exposure.. At 6 months both treatments abolished smoke-induced increases in lavage inflammatory cells, largely ameliorated physiological changes, and prevented or stopped progression of morphologic emphysema and small airway remodeling. Cigarette smoke caused a marked increase in immunohistochemical staining for the myeloperoxidase-generated protein oxidation marker dityrosine, and this effect was considerably decreased with both treatment arms. Serum 8-isoprostane, another marker of oxidative stress, showed similar trends. Both treatments also prevented muscularization of the small intrapulmonary arteries, but only partially ameliorated smoke-induced pulmonary hypertension. Acutely, AZ1 prevented smoke-induced increases in expression of cytokine mediators and nuclear factor-κB binding.. We conclude that an MPO inhibitor is able to stop progression of emphysema and small airway remodeling and to partially protect against pulmonary hypertension, even when treatment starts relatively late in the course of long-term smoke exposure, suggesting that inhibition of MPO may be a novel and useful therapeutic treatment for COPD. Protection appears to relate to inhibition of oxidative damage and down-regulation of the smoke-induced inflammatory response.

Topics: Airway Remodeling; Animals; Dinoprost; Disease Models, Animal; Disease Progression; Enzyme Inhibitors; Female; Guinea Pigs; Hypertension, Pulmonary; Inflammation; Lung; Oxidative Stress; Peroxidase; Pulmonary Disease, Chronic Obstructive; Purines; Smoking; Thiones; Thioxanthenes; Tyrosine

Extracts of the mushroom Agaricus blazei (A. blazei) have been described as possessing immunomodulatory and potentially cancer-protective activities. However, these effects of A. blazei as a functional food have not been fully investigated in vivo.. Using apolipoprotein E-deficient (ApoE(-/-)) mice, an experimental model of atherosclerosis, we evaluated the effects of 6 or 12 weeks of A. blazei supplementation on the activation of immune cells in the spleen and blood and on the development of atherosclerosis.. Food intake, weight gain, blood lipid profile, and glycemia were similar between the groups. To evaluate leukocyte homing and activation, mice were injected with (99m)Tc-radiolabeled leukocytes, which showed enhanced leukocyte migration to the spleen and heart of A. blazei-supplemented animals. Analysis of the spleen showed higher levels of activation of neutrophils, NKT cells, and monocytes as well as increased production of TNF-α and IFN-γ. Circulating NKT cells and monocytes were also more activated in the supplemented group. Atherosclerotic lesion areas were larger in the aorta of supplemented mice and exhibited increased numbers of macrophages and neutrophils and a thinner fibrous cap. A. blazei-induced transcriptional upregulation of molecules linked to macrophage activation (CD36, TLR4), neutrophil chemotaxy (CXCL1), leukocyte adhesion (VCAM-1), and plaque vulnerability (MMP9) were seen after 12 weeks of supplementation.. This is the first in vivo study showing that the immunostimulatory effect of A. blazei has proatherogenic repercussions. A. blazei enhances local and systemic inflammation, upregulating pro-inflammatory molecules, and enhancing leukocyte homing to atherosclerosis sites without affecting the lipoprotein profile.

Topics: Agaricus; Animals; Aorta; Apolipoproteins E; Atherosclerosis; CD36 Antigens; Cell Adhesion; Chemokine CXCL1; Dietary Supplements; Disease Models, Animal; Fruiting Bodies, Fungal; Immunologic Factors; Inflammation; Interferon-gamma; Leukocytes; Liver; Macrophage Activation; Matrix Metalloproteinase 9; Mice; Mice, Knockout; Monocytes; Natural Killer T-Cells; Neutrophils; Peroxidase; RNA, Messenger; Spleen; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha; Up-Regulation; Vascular Cell Adhesion Molecule-1

Chronic inflammation is characterized by the influx of neutrophils and is associated with an increased production of reactive oxygen species that can damage DNA. Oxidative DNA damage is generally thought to be involved in the increased risk of cancer in inflamed tissues. We previously demonstrated that activated neutrophil mediated oxidative stress results in a reduction in nucleotide excision repair (NER) capacity, which could further enhance mutagenesis. Inflammation and oxidative stress are critical factors in the progression of nonalcoholic fatty liver disease that is linked with enhanced liver cancer risk. In this report, we therefore evaluated the role of neutrophils and the associated oxidative stress in damage recognition and DNA repair in steatotic livers of 35 severely obese subjects with either nonalcoholic steatohepatitis (NASH) (n=17) or steatosis alone (n=18). The neutrophilic influx in liver was assessed by myeloperoxidase (MPO) staining and the amount of oxidative DNA damage by measuring M(1)dG adducts. No differences in M(1)dG adduct levels were observed between patients with or without NASH and also not between individuals with high or low MPO immunoreactivity. However, we found that high expression of MPO in the liver, irrespective of disease status, reduced the damage recognition capacity as determined by staining for histone 2AX phosphorylation (γH2AX). This reduction in γH2AX formation in individuals with high MPO immunoreactivity was paralleled by a significant decrease in NER capacity as assessed by a functional repair assay, and was not related to cell proliferation. Thus, the observed reduction in NER capacity upon hepatic inflammation is associated with and may be a consequence of reduced damage recognition. These findings suggest a novel mechanism of liver cancer development in patients with nonalcoholic fatty liver disease.

Topics: Adult; DNA Damage; DNA Repair; Fatty Liver; Female; Histones; Humans; Inflammation; Male; Middle Aged; Neutrophils; Obesity; Oxidative Stress; Peroxidase; Reactive Oxygen Species

Spinal cord injury (SCI) is a traumatic event that causes a secondary and extended inflammation characterized by infiltration of immune cells, including T lymphocytes, release of pro-inflammatory mediators in the lesion site, and tissue degeneration. Current therapeutic approaches for SCI are limited to glucocorticoids (GC) due to their potent anti-inflammatory activity. GC efficacy resides, in part, in the capability to inhibit NF-κB, T lymphocyte activation, and the consequent cytokine production. In this study, we performed experiments aimed to test the susceptibility of glucocorticoid-induced leucine zipper (GILZ) transgenic (GILZ(TG)) mice, in which GILZ is selectively over-expressed in T lymphocytes, to SCI induction. Consistent with a decreased inflammatory response, GILZ(TG) were less susceptible to SCI as compared to wild-type littermates. Notably, inhibition of NF-κB activation and nuclear translocation, diminished T lymphocytes activation and tissue infiltration, as well as decreased release of cytokines were evident in GILZ(TG) as compared to wild-type mice. Moreover, GILZ(TG) showed a reduced tumor necrosis factor-α, IL-1β, Inductible nitric oxide synthase (iNOS) and nytrotyrosine production, apoptosis, and neuronal tissue damage. Together these results indicate that GILZ mimics the anti-inflammatory effect of GC and represents a potential pharmacological target for modulation of T lymphocyte-mediated immune response in inflammatory disorders, such as SCI.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Cyclin D1; Cytokines; Dinoprostone; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Glial Fibrillary Acidic Protein; In Situ Nick-End Labeling; Inflammation; Mice; Mice, Transgenic; Nitric Oxide Synthase Type II; Peroxidase; Signal Transduction; Spinal Cord Injuries; T-Lymphocytes; Transcription Factors

The proinflammatory stimulus of chorioamnionitis is commonly associated with preterm delivery. Women at risk of preterm delivery receive antenatal glucocorticoids to functionally mature the fetal lung. However, the effects of the combined exposures of chorioamnionitis and antenatal glucocorticoids on the fetus are poorly understood. Time-mated ewes with singleton fetuses received an intra-amniotic injection of lipopolysaccharide (LPS) either preceding or following maternal intramuscular betamethasone 7 or 14 days before delivery, and the fetuses were delivered at 120 days gestational age (GA) (term = 150 days GA). Gestation matched controls received intra-amniotic and maternal intramuscular saline. Compared with saline controls, intra-amniotic LPS increased inflammatory cells in the bronchoalveolar lavage and myeloperoxidase, Toll-like receptor 2 and 4 mRNA, PU.1, CD3, and Foxp3-positive cells in the fetal lung. LPS-induced lung maturation measured as increased airway surfactant and improved lung gas volumes. Intra-amniotic LPS-induced inflammation persisted until 14 days after exposure. Betamethasone treatment alone induced modest lung maturation but, when administered before intra-amniotic LPS, suppressed lung inflammation. Interestingly, betamethasone treatment after LPS did not counteract inflammation but enhanced lung maturation. We conclude that the order of exposures of intra-amniotic LPS or maternal betamethasone had large effects on fetal lung inflammation and maturation.

Topics: Amnion; Animals; Betamethasone; Bronchoalveolar Lavage Fluid; Chorioamnionitis; Cytokines; Female; Fetal Development; Fetal Organ Maturity; Gene Expression; Glucocorticoids; Inflammation; Lipopolysaccharides; Lung; Male; Medroxyprogesterone Acetate; Peroxidase; Phosphatidylcholines; Pregnancy; Premature Birth; Pulmonary Surfactant-Associated Protein C; Pulmonary Surfactant-Associated Protein D; Random Allocation; Sheep; Toll-Like Receptors

Neutrophils expel extracellular traps (NETs) to entrap and exterminate the invaded micro-organisms. Acute/chronic inflammatory disorders are often observed with aberrantly enhanced NETs formation and high nitric oxide (NO) availability. Recent study from this laboratory demonstrated release of NETs from human neutrophils following treatment with SNP or SNAP. This study is an extension of our previous finding to explore the extracellular bacterial killing, source of DNA in the expelled NETs, their ability to induce proinflammatory cytokines release from platelets/THP-1 cells, and assessment of NO-mediated free radical formation by using a consistent NO donor, DETA-NONOate. NO-mediated NETs exhibited extracellular bacterial killing as determined by colony forming units. NO-mediated NETs formation was due to the activation of NADPH oxidase and myeloperoxidase. NO- or PMA-mediated NETs were positive for both nuclear and mitochondrial DNA as well as proteolytic enzymes. Incubation of NETs with human platelets enhanced the release of IL-1β and IL-8, while with THP-1 cells, release of IL-1β, IL-8, and TNFα was observed. This study demonstrates that NO by augmenting enzymatic free radical generation release NETs to promote extracellular bacterial killing. These NETs were made up of mitochondrial and nuclear DNA and potentiated release of proinflammatory cytokines.

Topics: Adult; Blood Platelets; DNA; DNA, Mitochondrial; Free Radicals; Humans; Inflammation; Interleukin-1beta; Interleukin-8; Mitochondria; NADPH Oxidases; Neutrophil Activation; Neutrophils; Nitric Oxide; Peroxidase; Tumor Necrosis Factor-alpha

Nitric oxide (NO) generated by vascular NO synthases can exert anti-inflammatory effects, partly through its ability to decrease leukocyte recruitment. Inorganic nitrate and nitrite, from endogenous or dietary sources, have emerged as alternative substrates for NO formation in mammals. Bioactivation of nitrate is believed to require initial reduction to nitrite by oral commensal bacteria. Here we investigated the effects of inorganic nitrate and nitrite on leukocyte recruitment in microvascular inflammation and in NSAID-induced small-intestinal injury. We show that leukocyte emigration in response to the proinflammatory chemokine MIP-2 is reduced by 70% after 7 days of dietary nitrate supplementation as well as by acute intravenous nitrite administration. Nitrite also reduced leukocyte adhesion to a similar extent and this effect was inhibited by the soluble guanylyl cyclase inhibitor ODQ, whereas the effect on emigrated leukocytes was not altered by this treatment. Further studies in TNF-α-stimulated endothelial cells revealed that nitrite dose-dependently reduced the expression of ICAM-1. In rats and mice subjected to a challenge with diclofenac, dietary nitrate prevented the increase in myeloperoxidase and P-selectin levels in small-intestinal tissue. Antiseptic mouthwash, which eliminates oral nitrate reduction, markedly blunted the protective effect of dietary nitrate on P-selectin levels. Despite attenuation of the acute immune response, the overall ability to clear an infection with Staphylococcus aureus was not suppressed by dietary nitrate as revealed by noninvasive IVIS imaging. We conclude that dietary nitrate markedly reduces leukocyte recruitment to inflammation in a process involving attenuation of P-selectin and ICAM-1 upregulation. Bioactivation of dietary nitrate requires intermediate formation of nitrite by oral nitrate-reducing bacteria and then probably further reduction to NO and other bioactive nitrogen oxides in the tissues.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Adhesion; Cell Movement; Cells, Cultured; Chemokine CXCL2; Cyclic GMP; Diclofenac; Dietary Supplements; Endothelial Cells; Gene Expression; Humans; Inflammation; Intercellular Adhesion Molecule-1; Intestine, Small; Leukocyte Count; Male; Mice; Mice, Inbred C57BL; Microvessels; Mouthwashes; Neutrophil Infiltration; Nitrates; Nitrites; P-Selectin; Peroxidase; Rats; Rats, Sprague-Dawley; Staphylococcal Infections; Staphylococcus aureus

In our previous study, the remarkable analgesic and anti-inflammatory effects of the combination of sodium ferulate (SF) and oxymatrine (OMT) had been found. In this study, we investigated the effect of the combination of SF and OMT on acute lung injury using lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model. The cell counting and the protein concentration in the bronchoalveolar lavage fluid (BALF) were measured. The animal lung edema degree was evaluated by wet/dry weight (W/D) ratio. The superoxidase dismutase (SOD) activity and myeloperoxidase (MPO) activity was assayed by SOD and MPO kits, respectively. The levels of inflammatory mediators including C-reactive protein (CRP) and tumor necrosis factor-α (TNF-α) were assayed by enzyme-linked immunosorbent assay method. The data showed that treatment with the combination of SF and OMT markedly attenuated inflammatory cell numbers and protein concentration in the BALF and improved SOD activity and inhibited MPO activity compared to LPS group. Moreover, the combination significantly inhibited the production of CRP and TNF-α in lung homogenate. The histological changes of the lungs were also more significantly improved by the combination. At the same dose, the obvious protective effect was not found in SF or OMT-treated alone group except that the protein concentration slightly decreased in SF group. The results indicated that the combination SF and OMT had a protective effect on LPS-induced ALI in mice, and the effect was much better than that of SF or OMT used alone.

Topics: Acute Lung Injury; Alkaloids; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bronchoalveolar Lavage Fluid; C-Reactive Protein; Coumaric Acids; Disease Models, Animal; Drug Combinations; Edema; Inflammation; Lipopolysaccharides; Lung; Mice; Peroxidase; Quinolizines; Random Allocation; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Gastric ulcer is a multifaceted process that involves reactive oxygen species (ROS) generation, extracellular matrix degradation and mitochondrial damage. Mitochondria play a crucial role for homeostasis of ROS and cell survival. In our study, we investigated the efficacy and mechanism of polymeric nanocapsuled quercetin (NQC) over the free quercetin (QC) molecule in prevention of ethanol-induced gastric ulcer in rat. NQC possessed significantly higher efficacy (~20 fold) than free QC while preventing gastric ulcers. Our data show that prior administration of NQC and/or QC significantly blocked synthesis and secretion of matrix metalloproteinase (MMP)-9 as well as infiltration of inflammatory cells and oxidative damage in rat gastric tissues. As compared to free QC, NQC protected much better the mitochondrial integrity and size along with mitochondrial functions by controlling succinate dehydrogenase and NADH oxidase in rat gastric tissues. In addition, both free QC and NQC down regulated PARP-1 as well as apoptosis during protection against ethanol-induced gastric ulcer. Herein, the effect of NQC was greater than QC on expression of enzymes like cyclooxygenase and nitric oxidase synthase (NOS)-2. We conclude that NQC with greater bioavailability offers significantly higher potency in downregulating MMP-9 and NOS-2 as well as oxidative stress in blocking ethanol-induced gastric ulcer.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Cytochromes c; Cytokines; Ethanol; Gastric Mucosa; Glutathione; Inflammation; Lactic Acid; Male; Matrix Metalloproteinase 9; Membrane Potential, Mitochondrial; Mitochondria; Nanoparticles; Nitric Oxide Synthase Type II; Particle Size; Peroxidase; Poly(ADP-ribose) Polymerases; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Quercetin; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Stomach; Stomach Ulcer; Up-Regulation

A series of 5-aryl-1,4-benzodiazepines with chloro- or fluoro-substituents in the second ring have been synthesized and their anti-inflammatory, myeloperoxidase and anticancer properties studied. The synthesized compounds showed potential anti-inflammatory and anticancer activities, which were enhanced in the presence of a chloro-substituent in the second ring of the 5-aryl-1,4- benzodiazepine.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Benzodiazepines; Cell Line, Tumor; Crystallography, X-Ray; Dose-Response Relationship, Drug; Edema; Female; Halogenation; Humans; Inflammation; Inhibitory Concentration 50; Male; Mice; Neoplasms; Peroxidase; Structure-Activity Relationship

Although the systemic inflammatory condition can be confirmed in cancer patients, the pathophysiological importance of reactive oxygen species (ROS) produced by neutrophils has not yet been defined.. Twenty-one patients with inoperable, chemoresistant and radioresistant cancer were enrolled in this study. At least 4 weeks prior to sampling, the patients were free from antitumor treatments. Control samples were also obtained from a healthy donor (39-year-old male). Peripheral blood samples were set 150 μl each on the 2 ml tube with 50 μl Mebiol Gel, and the production of ROS from neutrophils was detected by luminol-dependent chemiluminescence (LmCL) in a kinetic mode at 30-minute intervals for 2.5 hours with a luminometer at 37°C.. Each point, peak value and sum of values of LmCL in the patient group was statistically higher than those in the healthy donor. There were no differences in LmCL according to performance status (PS), type of cancer, age, or gender in cancer patients.. Our findings suggested that ROS produced by neutrophils universally reflects the systemic inflammatory condition in cancer patients.

Topics: Adult; Aged; Female; Humans; Inflammation; Luminescent Measurements; Luminol; Male; Middle Aged; Neoplasms; Neutrophils; Peroxidase; Reactive Oxygen Species

Cyclooxygenase (COX)-inhibiting nitric oxide (NO) donors (CINODs) are designed to inhibit COX-1 and COX-2 while releasing NO. COX inhibition is responsible for anti-inflammatory and pain-relieving effects, whereas NO donation can improve microcirculation and exert anti-inflammatory and antioxidant actions. In an in vivo mouse model of bleomycin-induced lung fibrosis, we evaluated whether a prototype CINOD compound, (S)-(5S)-5,6-bis(nitrooxy)hexyl)2-(6-methoxynaphthalen-2-yl)propanoate (NCX 466), may show an advantage over naproxen, its congener drug not releasing NO. Bleomycin (0.05 IU) was instilled intratracheally to C57BL/6 mice, which were then treated orally with vehicle, NCX 466 (1.9 or 19 mg/kg), or an equimolar dose of naproxen (1 or 10 mg/kg) once daily for 14 days. Afterward, airway resistance, assumed as lung stiffness index, was assayed, and lung specimens were collected for analysis of lung inflammation and fibrosis. NCX 466 and naproxen dose-dependently prevented bleomycin-induced airway stiffness and collagen accumulation. NCX 466, at the highest dose, was significantly more effective than naproxen in reducing the levels of the profibrotic cytokine transforming growth factor-β and the oxidative stress markers thiobarbituric acid reactive substance and 8-hydroxy-2'-deoxyguanosine. NCX 466 also decreased myeloperoxidase activity, a leukocyte recruitment index, to a greater extent than naproxen. A similar inhibition of prostaglandin E₂ was achieved by both compounds. In conclusion, NCX 466 has shown a significantly higher efficacy than naproxen in reducing lung inflammation and preventing collagen accumulation. These findings suggest that COX inhibition along with NO donation may possess a therapeutic potential in lung inflammatory diseases with fibrotic outcome.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Bleomycin; Collagen; Cyclooxygenase Inhibitors; Deoxyguanosine; Dinoprostone; Inflammation; Lung; Male; Mice; Mice, Inbred C57BL; Naproxen; Nitrates; Nitric Oxide; Nitric Oxide Donors; Oxidative Stress; Peroxidase; Propionates; Prostaglandin-Endoperoxide Synthases; Pulmonary Fibrosis; Thiobarbiturates; Transforming Growth Factor beta

Subclinical inflammation in ulcerative colitis (UC) can predispose to relapses and biomarkers can detect mucosal inflammation.. To study the role of fecal myeloperoxidase (FMPO) in assessing disease activity and response to therapy in UC.. Patients with UC attending our hospital from July 2005 to September 2006 were studied. All patients underwent clinical, endoscopic, and histological assessment for disease extent and severity. Estimation of FMPO levels at baseline and on follow-up was carried out. Age-matched healthy controls were studied for FMPO levels.. A total of 55 patients of UC (30 males, 25 females, mean age 38.6 ± 12 years) and 54 age-matched controls (mean age 37.6 ± 13.6 years) were studied. Cases had higher median MPO levels than controls (0.42 [IQR 0.84] vs. 0.06 [IQR 0.12]); (p < 0.001). Cases with endoscopically more severe disease (Gr III & IV; n = 18) had higher median FMPO levels compared to those with milder disease (Gr II, n = 37), [0.075 (IQR 1.315) vs. 0.315 (IQR 0.813); p = 0.02]. The median MPO level in 27 patients was 0.58 [IQR 0.89] units/ml at presentation which on follow-up decreased significantly to 0.18 [IQR 0.42] units/ml (p value 0.002). However, there was no significant association between FMPO and endoscopic extent and histological scores of activity and chronicity.. Fecal MPO is an effective biomarker for assessing disease activity and response to therapy in patients with ulcerative colitis.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Biomarkers; Biopsy; Colitis, Ulcerative; Colonoscopy; Drug Monitoring; Feces; Female; Gastrointestinal Contents; Humans; Inflammation; Intestinal Mucosa; Male; Mesalamine; Middle Aged; Peroxidase; Predictive Value of Tests; Severity of Illness Index; Treatment Outcome

This study examined the effect of weight loss after 3, 6 and 12 months of Roux-en-Y Gastric Bypass (RYGB) on energy intake and on several biomarkers of oxidative stress such as levels of vitamin C, beta-carotene, vitamin E (diet/blood), nitric oxide metabolites (NOx), myeloperoxidase (MPO), thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and activity of catalase (CAT).. Study with a control group (CG), assessed once, and a bariatric group (BG) assessed at the basal period as well as at 3, 6 and 12 months post-surgery; both groups were composed of 5 men and 31 women (n=36). Age was 38.7 ± 9.4 and 39.6 ± 9.2 years old and body mass index (BMI) was 22.2 0 ± 2.1 and 47.6 ± 9.1 kg/m(2), respectively. The variance measure quoted was SEM.. The body weight at 12 months was 35.8 ± 1.0% (P<0.001) lower than that of the basal period. At the basal period BG showed higher levels of NOx (P=0.007) and TBARS (P<0.001) and lower levels of vitamins C and E (P<0.001) compared with CG. After 3 months the activity of MPO was decreased (P<0.001). Six months after surgery GSH levels were decreased (P=0.037), whereas CAT activity was increased (P=0.029). After 12 months levels of NOx (P=0.004), TBARS (P<0.001), beta-carotene (P<0.001) and vitamin E (P<0.001) were decreased, whereas those of vitamin C (P<0.001) were increased compared with controls.. RYGB followed by a daily vitamin supplement apparently attenuated pro-inflammatory and oxidative stress markers 1 year after surgery, but additional antioxidant supplementation appears necessary.

Topics: Adult; Antioxidants; Ascorbic Acid; beta Carotene; Biomarkers; Body Mass Index; Case-Control Studies; Catalase; Diet; Dietary Supplements; Energy Intake; Female; Follow-Up Studies; Gastric Bypass; Glutathione; Humans; Inflammation; Male; Middle Aged; Oxidative Stress; Peroxidase; Prospective Studies; Thiobarbituric Acid Reactive Substances; Vitamin E; Weight Loss

Topical delivery of 5-aminosalicylic acid (5-ASA) to the colonic mucosa is important in order to achieve effective drug concentration in the site of inflammation and to minimize its systemic availability. 5-ASA loaded pellets were prepared by an extrusion/spheronization method. Mucoadhesive biopolymer chitosan was incorporated into the pellets, and drug delivery to the colon was controlled by the pH-sensitive polymer Eudragit® FS. Dissolution profiles of coated pellets revealed no drug release at pH 1.2 within 2h and release as intended in the simulated distal ileum and colon. In vivo, chitosan-core drug loaded pellets (AMCh) showed 2.5-fold higher drug metabolite concentration than after chitosan free pellets (AM) administration in the inflamed colonic tissue. Additionally, AMCh demonstrated decreased in AUC in colitis group (1507 ± 400 ng h/ml) compared with AM (1907 ± 122 ng h/ml). In terms of therapeutic efficiency, administration of pellets markedly decreased the colon/body weight ratio (colitis: 0.0355 ± 0.0028; AM 0.0092 ± 0.0033; AMCh 0.0086 ± 0.0022) and myeloperoxidase activity (colitis: 3212 ± 294 U/g tissue; AM 796 ± 211 U/g; AMCh 552 ± 319 U/g). Bioadhesive chitosan pellets showed additional beneficial properties for colonic 5-ASA delivery in the treatment of inflammatory bowel disease by increasing the drug concentration locally.

Topics: Animals; Anti-Inflammatory Agents; Biopolymers; Chitosan; Colitis; Colon; Drug Delivery Systems; Drug Implants; Hydrogen-Ion Concentration; Inflammation; Male; Mesalamine; Particle Size; Peroxidase; Rats; Rats, Wistar; Solubility

Hydrogen sulfide (H(2)S), a novel gaseous messenger, is synthesized endogenously from L-cysteine by two pyridoxal-5'-phosphate-dependent enzymes, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE). S-propargyl-cysteine (SPRC) is a slow H(2)S releasing drug that provides cysteine, a substrate of CSE. The present study was aimed to investigate the effects of SPRC in an in vivo model of acute pancreatitis (AP) in mice. AP was induced in mice by hourly caerulein injections (50 µg/kg) for 10 hours. Mice were treated with SPRC (10 mg/kg) or vehicle (distilled water). SPRC was administered either 12 h before or 3 h before the induction of pancreatitis. Mice were sacrificed 1 h after the last caerulein injection. Blood, pancreas and lung tissues were collected and processed to measure the plasma amylase, plasma H(2)S, myeloperoxidase (MPO) activities and cytokine levels in pancreas and lung. The results revealed that significant reduction of inflammation, both in pancreas and lung was associated with SPRC given 3 h prior to the induction of AP. Furthermore, the beneficial effects of SPRC were associated with reduction of pancreatic and pulmonary pro-inflammatory cytokines and increase of anti-inflammatory cytokine. SPRC administered 12 h before AP induction did not cause significant improvement in pancreatic and lung inflammation. Plasma H(2)S concentration showed significant difference in H(2)S levels between control, vehicle and SPRC (administered 3 h before AP) treatment groups. In conclusion, these data provide evidence for protective effects of SPRC in AP possibly by virtue of its slow release of endogenous H(2)S.

Topics: Acute Disease; Amylases; Animals; Anti-Inflammatory Agents, Non-Steroidal; Ceruletide; Cysteine; Cytokines; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Gases; Hydrogen Sulfide; Inflammation; Lung; Male; Mice; Pancreas; Pancreatitis; Peroxidase; Time Factors

Envenomation by Loxosceles spider bite leads to a set of signs and symptoms, called loxoscelism, which in most cases manifests through the dermonecrotic frame. The development of a smaller size animal model, of easy handling and maintenance, and lower cost is needed to study the loxoscelism pathogenesis. The inflammatory effects of the Loxosceles similis crude venom was evaluated considering neutrophil and macrophage activation, vasodilatation, hyperhaemia, edema and hemorrhage and TNF-α and VEGF production using the murine sponge implant model. Thirty two male Swiss mice (6-8 weeks old) were implanted subcutaneously with polyether-polyurethane sponge discs. Fourteen days post implantation, animals were separated into two groups: (1) control group--16 mice received 30 μL of saline intra-implant; (2) treated group-sixteen mice injected with 0.5 μg/30 μL of L. similis crude venom intra-implant. The animals were euthanized with xylazine/ketamine after 1 and 4 h post- injection. Microscopically, implants of the treated groups presented an acute inflammation characterized by: neutrophilic infiltrate, edema, vasodilatation hyperhaemia, and severe hemorrhage. Some vessels presented ruptured walls. Under morphometric analysis, vessel area was bigger in the treated groups compared with the control ones. The biochemical parameters, hemoglobin content, inflammatory enzyme activities (myeloperoxidase and n-acethyl-β-D glucosaminidase) and levels of the cytokines, TNF-α and VEGF, were also significantly higher in the venom-treated groups. The effects of Loxosceles venom in the granulation tissue of the implant in mice were similar to those observed in cutaneous loxoscelism in other species (human and rabbits). Consequently, the murine sponge implant model provides a new method to investigate cellular/molecular mechanisms associated with cutaneous loxoscelism.

Topics: Animals; Edema; Granulation Tissue; Hemoglobins; Hemorrhage; Hexosaminidases; Inflammation; Male; Mice; Models, Animal; Neutrophils; Peroxidase; Phosphoric Diester Hydrolases; Spider Bites; Spider Venoms; Spiders; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A; Vasodilation

Although increased expression of hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein (HIP/PAP) has been reported in ulcerative colitis (UC), its role in UC remains unclear. This study was designed to assess the function of HIP/PAP in experimental UC and further to explore its underlying mechanisms.. Recombinant adenovirus was prepared to mediate ectopic expression of HIP/PAP in the colon of rats. The effect of HIP/PAP on dextran sodium sulfate (DSS)-induced colitis was assessed by disease activity index (DAI), macroscopic, and histological evaluations. Superoxide dismutase (SOD) and myeloperoxidase (MPO) activities, malondialdehyde (MDA) content, and tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) production were determined in colonic mucosa. Proliferation cell nuclear antigen (PCNA) was immunostained to reflect the proliferation of colonic epithelia. The effects of HIP/PAP on proliferation and H(2)O(2) -induced apoptosis of SW480 and LoVo colonic adenocarcinoma cells were also determined. Gene expression profiles in SW480 after HIP/PAP overexpression were analyzed by microarray analysis.. The protective effect of HIP/PAP against DSS-induced colitis in rats was confirmed. Ectopic expression of HIP/PAP resulted in attenuation of oxidative damage, reduction of TNF-α and IL-6 expression, and elevation of epithelial proliferation in colonic mucosa and led to decreased apoptosis and increased proliferation in colonic adenocarcinoma cells. Microarray analysis revealed altered expression of inflammation-related molecules, growth factors, proliferation-related molecules, and antioxidant enzymes under overexpression of HIP/PAP.. HIP/PAP has a protective effect against DSS-induced colitis in rats via inhibiting inflammation, alleviating oxidative damage, and promoting colonic epithelium regeneration. HIP/PAP might represent a new promising therapeutic strategy in UC.

Topics: Acute Disease; Adenocarcinoma; Adenoviridae; Animals; Antigens, Neoplasm; Apoptosis; Biomarkers, Tumor; Blotting, Western; Cell Proliferation; Colitis, Ulcerative; Colon; Colonic Neoplasms; Disease Models, Animal; Gene Expression Profiling; Hydrogen Peroxide; Immunoenzyme Techniques; Inflammation; Interleukin-6; Intestinal Mucosa; Lectins, C-Type; Malondialdehyde; Oligonucleotide Array Sequence Analysis; Oxidants; Oxidative Stress; Pancreatitis-Associated Proteins; Peroxidase; Rats; Superoxide Dismutase; Trinitrobenzenesulfonic Acid; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

It is common practice during one lung ventilation (OLV) to use 100% oxygen, although this may cause hyperoxia- and oxidative stress-related lung injury. We hypothesized that lower oxygen (FiO(2) ) during OLV will result in less inflammatory and oxidative lung injury and improved lung function.. Twenty pigs (8.88 ± 0.84 kg; 38 ± 4.6 days) were assigned to either the hyperoxia group (n = 10; FiO(2)  = 100%) or the normoxia group (n = 10; FiO(2)  < 50%). Both groups were subjected to 3 hr of OLV. Blood samples were tested for pro-inflammatory cytokines and lung tissue was tested for these cytokines and oxidative biomarkers.. There were no differences between groups for partial pressure of CO(2) , tidal volume, end-tidal CO(2) , plasma cytokines, or respiratory compliance. Total respiratory resistance was greater in the hyperoxia group (P = 0.02). There were higher levels of TNF-α, IL-1β, and IL-6 in the lung homogenates of the hyperoxia group than in the normoxia group (P ≤ 0.01, 0.001, and 0.001, respectively). Myeloperoxidase and protein carbonyls (PC) were higher (P = 0.03 and P = 0.01, respectively) and superoxide dismutase (SOD) was lower in the lung homogenates of the hyperoxia group (P ≤ 0.001).. Higher myeloperoxidase, PC, and cytokine levels, and lower SOD availability indicate a greater degree of injury in the lungs of the hyperoxia animals, possibly from using 100% oxygen. In this translational study using a pig model, FiO(2)  ≤ 50% during OLV reduced hyperoxic injury and improved function in the lungs.

Topics: Acute Lung Injury; Animals; Carbon Dioxide; Cytokines; Hyperoxia; Inflammation; Lung; One-Lung Ventilation; Oxidative Stress; Oxygen; Peroxidase; Protein Carbonylation; Superoxide Dismutase; Swine

Inflammation is as an important factor in ovulation with the active participation of leucocytes and their inflammatory mediators. The present study was performed to compare the activity of the inflammatory enzymes myeloperoxidase (MPO) and N-acetylglucosaminidase (NAG) in patients with endometriosis-related infertility and in normally ovulating women undergoing intracytoplasmic sperm injection (ICSI).. This prospective study included infertile women undergoing ICSI treatment. These women were divided into two groups: endometriosis anovulation (n = 18) and normally ovulating (n = 20). NAG and MPO activity was evaluated colorimetrically in serum and in follicular fluids obtained at the time of oocyte retrieval.. There was a significant correlation between the serum and follicular fluid activities of NAG and MPO (τ = 0.256, P = 0.025; and τ = -0.234, P = 0.041; respectively). Both serum and follicular fluid NAG activities were higher in patients with endometriosis compared to the control group (P < 0.001). MPO follicular fluid activity was lower in patients with endometriosis compared to normally ovulating women (P = 0.016).. Infertile patients with endometriosis show a distinct pattern of serum and follicular fluid macrophage/neutrophil activation compared to normally ovulating women undergoing ICSI, which may reflect the role of immune and inflammatory alterations in endometriosis-related infertility.

Topics: Acetylglucosaminidase; Adult; Endometriosis; Female; Follicular Fluid; Humans; Infertility, Female; Inflammation; Peroxidase; Prospective Studies; Sperm Injections, Intracytoplasmic

This study investigated the antinociceptive and anti-inflammatory effects of electroacupuncture (EA) on zymosan-induced acute arthritis of the rat temporomandibular joint (TMJ). Male Wistar rats were injected with saline or zymosan (control group; 2 mg) into the left TMJ. Low frequency EA (10 Hz, 30 min) was performed at acupoints (LI4, LI11, ST36, ST44) or sham points 2 h after or 1 h before zymosan administration. Mechanical hypernociception was accessed by the electronic Von Frey method after zymosan administration. Rats were sacrificed 6 h after zymosan administration and the joint was removed for histopathological analysis, myeloperoxidase activity assessment, vascular permeability observations, and immunohistochemical verification of inflammatory mediators. The results showed that EA inhibited zymosan-induced hypernociception, compared with the control group and with the sham group (p < 0.05). The results showed that EA inhibited inflammatory parameters such as neutrophil migration, vascular permeability, and tumour necrosis factor α (TNF-α), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) expression in the TMJ compared with the sham group (p < 0.05). Histopathological analysis showed that EA significantly inhibited edema and periarticular infiltration (p < 0.05) compared with the control and sham groups. EA at acupoints produced antinociceptive and anti-inflammatory effects on zymosan-induced arthritis in the rat TMJ.

Topics: Acupuncture Points; Animals; Arthritis, Experimental; Capillary Permeability; Edema; Electroacupuncture; Inflammation; Inflammation Mediators; Male; Nociceptive Pain; Peroxidase; Rats; Temporomandibular Joint; Zymosan

Dietary products are among the therapeutic approaches used to modify intestinal microflora and to promote protective effects during the intestinal inflammatory process. Because the banana plant is rich in resistant starch, which is used by colonic microbiota for the anaerobic production of the short-chain fatty acids that serve as a major fuel source for colonocytes: first, green dwarf banana flour produces protective effects on the intestinal inflammation acting as a prebiotic and, second, combination of this dietary supplementation with prednisolone presents synergistic effects. For this, we used the trinitrobenzenesulphonic acid (TNBS) model of rat colitis. Our results revealed that the protective effect produced by a combination of 10% green dwarf banana flour with prednisolone was more pronounced than those promoted by a single administration of prednisolone or a diet containing 10% or 20% banana flour. This beneficial effect was associated with an improvement in the colonic oxidative status because the banana flour diet prevented the glutathione depletion and inhibited myeloperoxidase activity and lipid peroxidation. In addition, the intestinal anti-inflammatory activity was associated with an inhibition of alkaline phosphatase activity, a reduction in macroscopic and microscopic scores, and an extension of the lesions. In conclusion, the dietary use of the green dwarf banana flour constitutes an important dietary supplement and complementary medicine product to prevention and treatment of human inflammatory bowel disease.

Topics: Alkaline Phosphatase; Animals; Anti-Inflammatory Agents; Colitis; Colon; Dietary Supplements; Disease Models, Animal; Drug Synergism; Flour; Fruit; Glutathione; Inflammation; Lipid Peroxidation; Male; Musa; Oxidation-Reduction; Peroxidase; Phytotherapy; Plant Preparations; Prebiotics; Prednisolone; Rats, Wistar; Starch; Trinitrobenzenesulfonic Acid

Protocatechuic acid (PCA) is a major metabolite of anthocyanins. It has numerous pharmacological effects, including anti-inflammatory, antioxidant, and antitumoral activities. In the present study, we investigated the in vivo protective effect of PCA on acute lung injury (ALI) induced by lipolysaccharide (LPS) in mice. We treated mice with PCA 1 h before the intratracheal (i.n.) administration of LPS. The pulmonary injury severity was evaluated 6 h after LPS administration. We found that pretreatment with a 30 mg/kg of PCA markedly attenuated the LPS-induced histological alterations in the lung. In addition, PCA inhibited the production of several inflammatory cytokines, including tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and IL-6, at 6 h in the bronchoalveolar lavage fluid (BALF) after LPS challenge. Furthermore, PCA significantly reduced the number of total cells, neutrophils, and macrophages in the BALF, and it significantly decreased the wet/dry weight (W/D) ratio of lungs and the protein concentration in the BALF. Additionally, Western blotting showed that PCA efficiently blunted nuclear factor-kappa B (NF-κB) activation by inhibiting the degradation and phosphorylation of IκBα, as well as the translocation of p65 from cytoplasm to the nucleus. In conclusion, these results indicate that PCA was highly effective in inhibiting acute lung injury (ALI) and may be a promising potential therapeutic reagent for ALI treatment. PCA may utilize the NF-κB pathway to attenuate the nonspecific pulmonary inflammation induced by LPS administration.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bronchoalveolar Lavage Fluid; Drugs, Chinese Herbal; Hydroxybenzoates; I-kappa B Proteins; Inflammation; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; Lung; Macrophages; Male; Mice; Mice, Inbred BALB C; Neutrophils; NF-kappa B; Peroxidase; Phosphorylation; Transcription Factor RelA; Tumor Necrosis Factor-alpha

The main hypothesis of the study was that as serum myeloperoxidase (MPO) concentration is known to indicate the progression of the atherosclerotic process, MPO may be associated with common risk factors of atherosclerosis. Therefore, the presence of these risk factors (especially elevated glucose and lipid concentrations) should predict an increased MPO level during the subsequent months. We also hypothesized an association of MPO with markers of other chronic diseases involving inflammation.. Fifty-three patients with ischemic heart disease were followed for 24 weeks by biweekly visits, during which the basic MPO level was measured (500 measurements in total, 2-12 per patient). The association of the patients' typical MPO with the risk factors of atherosclerosis and other personal determinants was examined by trend analysis and analysis of variance.. MPO was statistically significantly associated with blood leukocyte, neutrophil, and lymphocyte concentrations of the patients (P=0.001-0.003). MPO was also associated with high-sensitivity C-reactive protein (P=0.02). MPO was not associated with markers of lipid and glucose metabolism, of atherosclerosis, or of other chronic diseases.. Contradictory to our hypotheses, the results indicate that the serum MPO level is independent of the commonly measured risk factors of atherosclerosis and markers of other chronic diseases. Consequently, the findings suggest that MPO-related acute pathologic events (such as plaque destabilization) are not associated with the preceding glucose or lipid values. However, the results support the third hypothesis and previously reported view that MPO is a marker of inflammation in patients of ischemic heart disease.

Topics: Aged; Aged, 80 and over; Atherosclerosis; Biomarkers; Blood Glucose; C-Reactive Protein; Cohort Studies; Disease Progression; Female; Humans; Inflammation; Leukocyte Count; Lipids; Male; Middle Aged; Myocardial Ischemia; Peroxidase; Risk Factors

Myrsinoic acid B (MAB) is a diprenylated benzoic acid widely found in the vegetal kingdom. Recent studies demonstrate that MAB has important antinociceptive effects in models of chemically or thermally induced nociception in mice.. In the present study we evaluated the effect of MAB in different models of inflammatory and neuropathic hypersensitivity in mice.. This study demonstrates that the pretreatment with MAB, given orally (8.4 to 83.8 μmol/kg), inhibited carrageenan- and complete Freund adjuvant-induced mechanical hypersensitivity. When administered after the induction of hypersensitivity, MAB also reduced the mechanical hypersensitivity in the ipsilateral and in the contralateral hindpaws of mice injected with complete Freund adjuvant, interfering with a signaling cascade already established. MAB reversed the hypersensitivity (mechanical and thermal) of operated animals, with similar results to those observed with gabapentin. MAB activity was evident when administered either systemically (PO or IV) or intrathecally, suggesting interference in the central pathways of pain control. Furthermore, MAB seems to present an antiinflammatory effect evidenced by the interference in both the neutrophil migration and in the increase of interleukin-1β levels after carrageenan injection. Of note, MAB treatment did not interfere with mechanical or thermal sensitivity in healthy mice, a frequent characteristic of commonly used analgesics, such as morphine or gabapentin. Side effects including interference in locomotor activity, motor performance, and body temperature in animals treated with MAB were absent.. MAB reduced mechanical and thermal hypersensitivity in mice submitted to models of inflammatory and neuropathic pain, showing excellent potential for treating persistent pain in humans.

Topics: Administration, Oral; Alkenes; Analgesics; Animals; Behavior, Animal; Benzofurans; Carrageenan; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Freund's Adjuvant; Hyperalgesia; Inflammation; Injections, Intravenous; Interleukin-1beta; Mice; Motor Activity; Neuralgia; Neutrophil Infiltration; Pain; Pain Measurement; Pain Threshold; Peroxidase; Time Factors

The authors conducted a cross-sectional study to assess the relation between arsenic exposure from drinking water and plasma levels of markers of systemic inflammation and endothelial dysfunction (matrix metalloproteinase-9, myeloperoxidase, plasminogen activator inhibitor-1, soluble E-selectin, soluble intercellular adhesion molecule-1 (ICAM-1), and soluble vascular adhesion molecule-1 (VCAM-1)) using baseline data from 668 participants (age, >30 years) in the Health Effects of Arsenic Longitudinal Study in Bangladesh (2007-2008). Both well water arsenic and urinary arsenic were positively associated with plasma levels of soluble VCAM-1. For every 1-unit increase in log-transformed well water arsenic (ln μg/L) and urinary arsenic (ln μg/g creatinine), plasma soluble VCAM-1 was 1.02 (95% confidence interval: 1.01, 1.03) and 1.04 (95% confidence interval: 1.01, 1.07) times greater, respectively. There was a significant interaction between arsenic exposure and higher body mass index, such that the increased levels of plasminogen activator inhibitor-1 and soluble VCAM-1 associated with arsenic exposure were stronger among people with higher body mass index. The findings indicate an effect of chronic arsenic exposure from drinking water on vascular inflammation and endothelial dysfunction that could be modified by body mass index and also suggest a potential mechanism underlying the association between arsenic exposure and cardiovascular disease.

Topics: Adult; Arsenic; Bangladesh; Biomarkers; Body Mass Index; Cardiovascular Diseases; Cross-Sectional Studies; Drinking Water; E-Selectin; Endothelium, Vascular; Environmental Exposure; Female; Humans; Inflammation; Intercellular Adhesion Molecule-1; Linear Models; Longitudinal Studies; Male; Matrix Metalloproteinase 9; Middle Aged; Peroxidase; Plasminogen Activator Inhibitor 1; Prospective Studies; Vascular Cell Adhesion Molecule-1; Water Pollutants, Chemical; Water Pollution, Chemical

Methylthioadenosine (MTA) is a precursor of the methionine salvage pathway and has been shown to have anti-inflammatory properties in various models of acute and chronic inflammation. However, the anti-inflammatory properties of MTA in models of intestinal inflammation are not defined. We hypothesized that orally administered MTA would be bioavailable and reduce morbidity associated with experimental colitis. We examined clinical, histological, and molecular markers of disease in mice provided oral MTA before (preventative) or after (therapy) the induction of colitis with 3% dextran sulfate sodium (DSS). We found a reduction in disease activity, weight loss, myeloperoxidase activity, and histological damage in mice given preventative MTA compared with DSS alone. We also found that equivalent supplementation with methionine could not reproduce the anti-inflammatory effects of MTA, and that MTA had no detectable adverse effects in control or DSS mice. Expression microarray analysis of colonic tissue showed several dominant pathways related to inflammatory cytokines/chemokines and extracellular matrix remodeling were upregulation by DSS and suppressed in MTA-supplemented mice. MTA is rapidly absorbed in the gastrointestinal tract and disseminated throughout the body, based on a time course analysis of an oral bolus of MTA. This effect is transient, with MTA levels falling to near baseline within 90 min in most organs. Moreover, MTA did not lead to increased blood or tissue methionine levels, suggesting that its effects are specific. However, MTA provided limited therapeutic benefit when administered after the onset of colitis. Our results show that oral MTA supplementation is a safe and effective strategy to prevent inflammation and tissue injury associated with DSS colitis in mice. Additional studies in chronic inflammatory models are necessary to determine if MTA is a safe and beneficial option for the maintenance of remission in human inflammatory bowel disease.

Topics: Adenosine; Animals; Anti-Inflammatory Agents, Non-Steroidal; Biological Availability; Colitis; Dextran Sulfate; Diet; Gene Expression; Inflammation; Inflammatory Bowel Diseases; Male; Mice; Mice, Inbred C57BL; Microarray Analysis; Peroxidase; RNA, Messenger; Thionucleosides

Inflammatory bowel disease (IBD) is a chronic inflammation of the intestinal epithelium that is driven by the intestinal immune system, oxidative stress and the loss of tolerance to the luminal microbiota. The use of dietary products containing ingredients such as fibres and carbohydrates and/or antioxidant compounds have been used as a therapeutic strategy for intestinal diseases because these products are considered effective in the modulation of the immune system and colonic microbiota. We investigated the beneficial effects of cattail rhizome flour (Typha angustifolia L.) in the trinitrobenzenesulphonic acid (TNBS) model of rat colitis. In addition, we investigated the effects of cattail rhizome flour on the intestinal anti-inflammatory activity of prednisolone, which is a reference drug that is used for treatment of human IBD.. The present study included the preparation of flour from rhizomes of cattail (Typha angustifolia L.); an evaluation of the qualitative phytochemical profile of cattail rhizomes; an evaluation of the efficacy of cattail rhizome flour in TNBS-induced rat colitis; an evaluation of the synergistic effects of cattail rhizome flour on the intestinal anti-inflammatory activity of prednisolone; and macroscopic, clinical, biochemical, histopathological and microbiological studies to assess the healing effects of cattail rhizome flour and its synergistic effects in TNBS-induced rat colitis. The data were analysed by ANOVA, Kruskal-Wallis and χ(2) tests.. We tested several concentrations of cattail rhizome flour and found that dietary supplementation with 10% cattail rhizome flour showed the best effects at reducing the extension of the lesion, the colon weight ratio, adherences to adjacent organs and diarrhoea. These effects were related to inhibition of myeloperoxidase (MPO) and alkaline phosphatase (AP) activities and an attenuation of glutathione (GSH) depletion. The 10% cattail rhizome flour was as effective as prednisolone, and no synergistic effects were observed. Saponins, flavonoids and coumarins were detected in the rhizome flour. No changes were observed in the total number of lactic bacteria after dietary supplementation with cattail rhizome flour.. Dietary supplementation with 10% cattail rhizome flour and its combination with prednisolone prevent TNBS-induced colonic damage in rats, but no synergistic effects were observed. The prevention of TNBS-induced colon damage was associated with an improvement in intestinal oxidative stress, which likely resulted from the antioxidant properties of the active compounds detected in the cattail rhizome. This protective effect was not related to an improvement in lactic bacteria counts.

Topics: Alkaline Phosphatase; Animals; Anti-Inflammatory Agents; Antioxidants; Colitis; Colon; Diarrhea; Dietary Fiber; Dietary Supplements; Disease Models, Animal; Flour; Glutathione; Inflammation; Intestinal Mucosa; Male; Organ Size; Peroxidase; Phytotherapy; Plant Preparations; Prednisolone; Rats; Rats, Wistar; Rhizome; Trinitrobenzenesulfonic Acid; Typhaceae

Although the mechanisms for sustained chemokine gradients and recurring cell infiltration in sterile peritonitis have not been elucidated, toll-like receptors (TLRs) have been implicated. To abate the deleterious recruitment of neutrophils in sterile inflammation, we repeatedly administered a TLR7 ligand that hyposensitized to TLR7 and receptors that converged on the MyD88-signaling intermediary and reduced cellular infiltration in murine autoimmune models of multiple sclerosis and arthritis. To reduce potential adverse effects, a polyethylene glycol polymer was covalently attached to the parent compound (Tolerimod1). The proinflammatory potency of Tolerimod1 was 10-fold less than the unconjugated TLR7 ligand, and Tolerimod1 reduced neutrophil recruitment in chemically induced peritonitis and colitis. The effects of Tolerimod1 were mediated by the radioresistant cells in radiation chimeric mice and by mast cells in reconstituted mast cell-deficient mice (Kit(W-sh)). Although the Tolerimod1 had weak proinflammatory agonist activity, it effectively reduced neutrophil recruitment in sterile peritoneal inflammation.

Topics: Animals; Autoimmunity; Cell Line; Inflammation; Ligands; Mast Cells; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myeloid Differentiation Factor 88; Neutrophils; Peritonitis; Permeability; Peroxidase; Polyethylene Glycols; Polymers; Purines; Stem Cell Factor; Toll-Like Receptor 7

Caesalpinia pyramidalis Tul. (Fabaceae) is a plant found in the Northeast of Brazil that is popularly used to treat inflammation. Acute pancreatitis (AP) is an inflammatory disease for which abdominal pain is a relevant symptom. As there is no specific therapy for AP, we investigated the effect of the ethanol extract from the inner bark of C. pyramidalis (EECp) on the AP induced by common bile duct obstruction (CBDO) in rats.. AP was induced in male Wistar rats (200-250 g, n=6-8) through laparotomy and subsequent CBDO. Animals were euthanized after 6 (G6h) or 24 h (G24h) of induction. In the G6h protocol, animals were pretreated with EECp (100-400 mg/kg, p.o.) or vehicle (Tween 80; 0.2%) 1h before CBDO or sham surgery. For the G24h protocol, rats were pretreated with EECp (400mg/kg, 1h before CBDO or 1 h before and 12 h after CBDO) or vehicle. The following parameters were measured: inflammatory/oxidative (myeloperoxidase activity and malondialdehyde formation in the pancreas and lung, leukocyte counts in the blood and serum nitrate/nitrite), enzymatic (serum amylase and lipase levels) and nociceptive (abdominal hyperalgesia).. Induction of AP by CBDO significantly increased all the parameters evaluated in both G6h and G24h protocols when compared with the respective sham group. In the G6h protocol, the EECp pretreatment (400 mg/kg) significantly reduced all these parameters, besides completely inhibiting abdominal hyperalgesia. The same profile of reduction was observed from two administrations of EECp in the G24h protocol, while one single dose of EECp was able to significantly reduce pancreatic MDA, serum lipase levels, leukocyte counts in the blood and abdominal hyperalgesia without affecting the other parameters in the G24h protocol. Furthermore, rutin was found in the EECp.. Our results demonstrated that EECp decreases inflammation, lipoperoxidation and hyperalgesia in CBDO-induced AP, making it of interest in future approaches to treat this condition.

Topics: Abdominal Pain; Acute Disease; Amylases; Analgesics; Animals; Anti-Inflammatory Agents; Brazil; Caesalpinia; Cholestasis; Common Bile Duct; Hyperalgesia; Inflammation; Leukocyte Count; Leukocytes; Lipase; Lung; Male; Malondialdehyde; Nitrates; Nitrites; Pancreas; Pancreatitis; Peroxidase; Phytotherapy; Plant Bark; Plant Extracts; Rats; Rats, Wistar; Rutin

The possible role of β-2 adrenergic receptors in modulation of inflammatory and nociceptive conditions suggests that the β-2 adrenergic receptor agonist, salbutamol, may have beneficial anti-inflammatory and analgesic effects. Therefore, in this study, we induced inflammatory and nociceptive responses with carrageenan-induced paw edema or cotton-pellet-induced granuloma models, both of which result in oxidative stress. We hypothesized that salbutamol would prevent inflammatory and nociceptive responses by stimulating β-2 adrenergic receptors and the prevention of generation of ROS during the acute inflammation process in rats. Both doses of salbutamol used in the study (1 and 2 mg/kg) effectively blocked the acute inflammation and inflammatory nociception induced by carrageenan. In the cotton-pellet-induced granuloma test, both doses of salbutamol also significantly decreased the weight of granuloma tissue on the cotton pellets when compared to the control. Anti-inflammatory and analgesic effects of salbutamol were found to be comparable with those of indomethacin. Salbutamol decreased myeloperoxidase (MPO) activity and lipid peroxidation (LPO) level and increased the activity of superoxide dismutase (SOD) and level of glutathione (GSH) during the acute phase of inflammation. In conclusion, salbutamol can decrease acute and chronic inflammation, possibly through the stimulation of β-2 adrenergic receptors. This anti-inflammatory effect may be of significance in asthma treatment, where inflammation also takes part in the etiopathology. This study reveals that salbutamol has significant antioxidative effects, which at least partially explain its anti-inflammatory capabilities. These findings presented here may also shed light on the roles of β-2 adrenergic receptors in inflammatory and hyperalgesic conditions.

Topics: Albuterol; Animals; Anti-Inflammatory Agents; Carrageenan; Edema; Glutathione; Hyperalgesia; Inflammation; Lipid Peroxidation; Male; Peroxidase; Rats; Rats, Wistar; Superoxide Dismutase

Maillard reaction products (MRPs) are a mixture of compounds generated after the heat treatment of food. High circulating levels of MRPs have been associated with degenerative pathologies such as diabetes, but little is known about their effect on the gut, the main organ in contact with food-derived MRPs. This study was aimed at determining whether repeated low-level exposure to MRPs, generated via two different heat treatments, can contribute to the modulation of experimental colitis in mice. In the first series of experiments, we tested whether pellets rich in MRPs would increase plasmatic and faecal concentration of MRPs. In the second series, we assessed whether two levels of pellet-derived MRPs would be able to modulate chemically-induced inflammation and affect tissue healing. The ingestion of MRPs correlates with the increase of its plasmatic and faecal concentration. Highly treated pellets were proved to significantly protect against inflammation whereas standard or moderately heated pellets had no effect on the inflammatory course. The chemical analysis of the different pellets indicated that high heating generates more melanoidins. There is a correlation between the exposure to highly heated foods and the reduction of murine inflammation, of which the mechanisms remain to be elucidated.

Topics: Animals; Blood; Blood Chemical Analysis; Colitis; Colon; Disease Models, Animal; Feces; Food Handling; Hot Temperature; Inflammation; Maillard Reaction; Male; Mice; Peroxidase; Polymers

The aim of the present study was to investigate the effects of sodium butyrate (SB) on systemic inflammation, lung injury and survival rate of mice with endotoxemia. Balb/c mice were pre-treated with SB or vehicle, and then endotoxemia was induced by lethal dose of lipopolysaccharide (LPS, 20 mg/kg, i.p.) and the survival rate of mice was monitored. A separated set of animals were sacrificed at 18 h after LPS challenge, and blood samples were harvested for measuring TNF-α and IL-6 levels. Lung tissues were also harvested to determine the ratio of wet weight to dry weight of lung tissue and myeloperoxidase (MPO) activity in lung tissue. In addition, the formalin-fixed lung specimens were stained with HE routinely for morphologic evaluation. The results showed that pre-treatment with SB alleviated LPS-induced morphological damage in lung tissue. This was accompanied by reduced ratio of wet weight to dry weight of lung tissue and MPO activity in lung homogenates. Additionally, the up-regulation of pro-inflammatory cytokines TNF-α and IL-6 was also suppressed by SB, while the survival rate of mice with lethal endotoxemia was significantly increased by SB pre-treatment. The results suggest that SB effectively attenuates intrapulmonary inflammatory response and improves the survival of endotoxemic mice.

Topics: Animals; Butyric Acid; Endotoxemia; Inflammation; Interleukin-6; Lipopolysaccharides; Lung; Lung Injury; Male; Mice; Mice, Inbred BALB C; Peroxidase; Tumor Necrosis Factor-alpha

Interleukin-10 is known to modulate the systemic inflammatory response after trauma. This study investigates differences in the systemic and end-organ inflammation in animals treated with either inhalative or systemic IL-10 after experimental hemorrhagic shock (HS). Pressure controlled HS was performed in C57/BL6 mice for 1.5h (6 animals per group). Inhalative or systemic recombinant mouse IL-10 (50 μg/kg dissolved in 50 μl PBS) was administered after resuscitation. Animals were sacrificed after 4.5 or 22.5h of recovery. Serum levels of IL-6, IL-10, KC, MCP-1, and LBP were determined by ELISA. Pulmonary and liver inflammation was analyzed by standardized Myeloperoxidase (MPO) kits. Systemic and inhalative IL-10 administration affected the systemic inflammatory response as well as end-organ inflammation differently. Differences were obvious in the early (6h) but not later (24h) inflammatory phase. Systemic IL-10 application was associated with a decreased systemic inflammatory response as well as hepatic inflammation, whereas nebulized IL-10 solely reduced the pulmonary inflammation. Our study demonstrates that systemic and nebulized IL-10 administration differentially influenced the systemic cytokine response and end-organ inflammation. Early pulmonary but not hepatic protection appears to be possible by inhalative IL-10 application. Further studies are necessary to assess exact pathways.

Topics: Acute-Phase Proteins; Administration, Inhalation; Animals; Carrier Proteins; Chemokine CCL2; Enzyme-Linked Immunosorbent Assay; Hepatitis; Inflammation; Injections, Intra-Arterial; Interleukin-10; Interleukin-6; Liver; Lung; Male; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Peroxidase; Pneumonia; Shock, Hemorrhagic; Time Factors

The objective of this study was to test the hypothesis that p-cymene can attenuate acute lung injury induced by lipopolysaccharide (LPS) in vivo. In the mouse model of LPS-induced acute lung injury, intraperitoneal preconditioning with p-cymene resulted in a significant reduction of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6), lung water gain, inflammatory cell infiltration, lung tissue myeloperoxidase activity. In addition, p-cymene blocked the phosphorylation of IκBα protein and mitogen-activated protein kinases (MAPK) signaling pathway activation. Histopathologic examination of lung tissue indicated that p-cymene treatment markedly decreased focal thickening, congestion, pulmonary edema, and inflammatory cells infiltration. The results showed that p-cymene had a protective effect on LPS-induced ALI in mice.

Topics: Acute Lung Injury; Animals; Bronchoalveolar Lavage Fluid; Cell Count; Cymenes; Cytokines; Inflammation; Inflammation Mediators; Lipopolysaccharides; Lung; MAP Kinase Signaling System; Mice; Mitogen-Activated Protein Kinases; Monoterpenes; NF-kappa B; Peroxidase; Protective Agents; Water

Heparin, a potent blood anticoagulant, is known to possess anti-inflammatory activity. In this work, we investigated whether heparin can ameliorate acute lung injury and lethal response in lipopolysaccharide (LPS)-induced mouse model of sepsis. We found that heparin effectively rescued lethality, improved lung pathological changes, inhibited myeloperoxidase (MPO) activity, and reduced malondialdehyde (MDA) level, lung wet/dry weight ratio and Evans blue values in LPS-induced septic mice. In addition, heparin also inhibited the release of tumor necrosis factor (TNF)-α, interleukin-6 (IL-6) and IL-1β in serum and decreased the expression of p-p38, nuclear factor κB (NF-κB) and p-c-SRC kinase in lungs of septic mice. Our findings suggest that heparin is capable of suppressing the lethal response and acute lung injury associated with sepsis, and support the notion that heparin may be a potential therapeutic agent for the conditions associated with septic shock.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Disease Models, Animal; Heparin; Inflammation; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; Lung; Male; Malondialdehyde; Mice; Mice, Inbred C57BL; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Peroxidase; Sepsis; Shock, Septic; src-Family Kinases; Tumor Necrosis Factor-alpha

There was no direct correlation between plasma and placental oxidative damage parameters and inflammation and evidence of TLR4 pathway activation in the placenta in preeclamptic (PE) patients.. 33 PE patients and 33 normotensive pregnant women were included. The maternal section of the placenta and blood were collected to the determination of oxidative damage markers (thiobarbituric acid reactive species and protein carbonyls), inflammatory response (interleukin-6 and myeloperoxidase activity), and activation of the TLR-4-NF-kB pathway.. An increase of IL-6 levels in both plasma and placenta was observed, but myeloperoxidase activity was not significantly different comparing the groups. Oxidative damage parameters were increased in plasma and placenta in PE patients. A significant increase of the protein levels of TLR-4 and NF-kB was observed in the placenta.. The TLR4-NF-kB pathway is upregulated in PE, probably generating local and systemic inflammatory response that is followed by local and systemic oxidative damage.

Topics: Adult; Biomarkers; Case-Control Studies; Female; Humans; Inflammation; Interleukin-6; Myeloid Differentiation Factor 88; NF-kappa B; Oxidative Stress; Peroxidase; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Proteins; Protein Carbonylation; Signal Transduction; Thiobarbituric Acid Reactive Substances; Toll-Like Receptor 4

Methyl palmitate (MP) and ethyl palmitate (EP) are naturally occurring fatty acid esters reported as inflammatory cell inhibitors. In the current study, the potential anti-inflammatory activity of MP and EP was evaluated in different experimental rat models. Results showed that MP and EP caused reduction of carrageenan-induced rat paw edema in addition to diminishing prostaglandin E2 (PGE2) level in the inflammatory exudates. In lipopolysaccharide (LPS)-induced endotoxemia in rats, MP and EP reduced plasma levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). MP and EP decreased NF-κB expression in liver and lung tissues and ameliorated histopathological changes caused by LPS. Topical application of MP and EP reduced ear edema induced by croton oil in rats. In the same animal model, MP and EP reduced neutrophil infiltration, as indicated by decreased myeloperoxidase (MPO) activity. In conclusion, this study demonstrates the effectiveness of MP and EP in combating inflammation in several experimental models.

Topics: Animals; Anti-Inflammatory Agents; Dinoprostone; Disease Models, Animal; Edema; Endotoxemia; Inflammation; Lipopolysaccharides; Liver; Lung; Male; Neutrophil Infiltration; NF-kappa B; Palmitates; Palmitic Acids; Peroxidase; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

The problems associated with small-for-size liver grafts (ie, high mortality rates, postoperative complications, and acute rejection) remain critical issues in partial orthotopic liver transplantation (OLT). In association with partial OLT, splenectomy (SP) is a procedure used to reduce the portal pressure. However, the precise effects of SP on partial OLT have been unclear. In this study, using small-for-size liver grafts in rats, we examined the cytoprotective effects of SP on OLT. Liver grafts were assigned to 2 groups: a control group (OLT alone) and an SP group (OLT after SP). SP significantly increased animal survival and decreased liver damage. SP exerted the following cytoprotective effects: (1) it improved hepatic microcirculation and prevented increases in the portal pressure after OLT, (2) it suppressed the hepatic infiltration of neutrophils and macrophages through the direct elimination of splenic inflammatory cells before OLT, (3) it decreased the hepatic expression of tumor necrosis factor α and interleukin-6, (4) it attenuated sinusoidal endothelial injury, (5) it decreased plasma endothelin 1 levels and increased hepatic heme oxygenase 1 expression, (6) it suppressed hepatocellular apoptosis through the down-regulation of hepatic caspase-3 and caspase-8 activity, and (7) it increased hepatic regeneration. In conclusion, SP for small-for-size grafts exerts dual cytoprotective effects by preventing excessive portal vein hepatic inflow and eliminating splenic inflammatory cell recruitment into the liver; this in turn inhibits hepatocellular apoptosis and improves liver regeneration.

Topics: Animals; Caspase 3; Caspase 8; Cytoprotection; Endothelin-1; Gene Expression Regulation; Inflammation; Interleukin-6; Liver; Liver Transplantation; Macrophages; Male; Neutrophils; Peroxidase; Portal Vein; Rats; Rats, Wistar; Splenectomy

Perspectives for the use of carbon nanotubes in biomedical applications depend largely on their ability to degrade in the body into products that can be easily cleared out. Carboxylated single-walled carbon nanotubes (c-SWCNTs) were shown to be degraded by oxidants generated by peroxidases in the presence of hydrogen peroxide. In the present study we demonstrated that conjugation of poly(ethylene glycol) (PEG) to c-SWCNTs does not interfere with their degradation by peroxidase/H(2)O(2) system or by hypochlorite. Comparison of different heme-containing proteins for their ability to degrade PEG-SWCNTs has led us to conclude that the myeloperoxidase (MPO) product hypochlorous acid (HOCl) is the major oxidant that may be responsible for biodegradation of PEG-SWCNTs in vivo. MPO is secreted mainly by neutrophils upon activation. We hypothesize that SWCNTs may enhance neutrophil activation and therefore stimulate their own biodegradation due to MPO-generated HOCl. PEG-SWCNTs at concentrations similar to those commonly used in in vivo studies were found to activate isolated human neutrophils to produce HOCl. Both PEG-SWCNTs and c-SWCNTs enhanced HOCl generation from isolated neutrophils upon serum-opsonized zymosan stimulation. Both types of nanotubes were also found to activate neutrophils in whole blood samples. Intraperitoneal injection of a low dose of PEG-SWCNTs into mice induced an increase in percentage of circulating neutrophils and activation of neutrophils and macrophages in the peritoneal cavity, suggesting the evolution of an inflammatory response. Activated neutrophils can produce high local concentrations of HOCl, thereby creating the conditions favorable for degradation of the nanotubes.

Topics: Animals; Humans; Hydrogen Peroxide; Hypochlorous Acid; Inflammation; Injections, Intraperitoneal; Macrophages; Male; Mice; Mice, Inbred CBA; Nanotubes, Carbon; Neutrophil Activation; Neutrophils; Oxidants; Peritoneal Cavity; Peroxidase; Polyethylene Glycols; Sodium Hypochlorite

Lippia gracilis Schauer (Verbenaceae) has long been recognized in folk medicine as a medicinal plant. The essential oil of Lippia gracilis has antimicrobial activity and is used externally to treat cutaneous diseases, burns, wounds, and ulcers. Recently, our research group demonstrated that the essential oil of Lippia gracilis leaves possesses antinociceptive and anti-inflammatory actions and its major component identified was thymol. The objective of this study was to assess the anti-inflammatory and wound healing activities of thymol in rodents.. For the anti-inflammatory analysis the paw oedema and peritonitis models were used, followed by the assessment of the mieloperoxidase (MPO) activity, total cell counting, and histological analysis. The animals were treated (i.p., n=6/group) with thymol (10, 30, and 100 mg/kg), dexamethasone (2 mg/kg), or vehicle (1% Tween 80). In order to assess the wound healing potential, thymol was vehiculated into collagen-based dressing films and a biological wound healing test was conducted. The retraction index of the wounds and histological analysis were performed on the 3rd, 7th, 14th, and 21th days, split into three groups: undressed wounds (CTR), dressed with collagen-based films (COL), and dressed with collagen-based containing thymol (COLTHY) films.. Thymol reduced significantly the oedema (100 mg/kg, P<0.001) and, besides, diminished the influx of leukocytes to the injured area (10, 30, and 100 mg/kg), according to the assessment of MPO activity (P<0.001), total cell count (P<0.05), and histological analysis. Wounds dressed with COLTHY films showed significantly bigger wound retraction rates (7 and 14 day, P<0.05) and improved the granulation reaction, as well provided better collagenization density and arrangement during wound healing.. This study suggests that thymol is a promising compound to be used in treatment of inflammatory processes as well as wound healing. The pharmacological actions of Lippia gracilis in popular medicine practices may be related, at least in part, to the presence of thymol in the essential oil.

Topics: Animals; Anti-Inflammatory Agents; Carrageenan; Cell Migration Assays, Leukocyte; Cicatrix; Collagen; Drug Delivery Systems; Edema; Female; Inflammation; Lippia; Male; Mice; Oils, Volatile; Peritonitis; Peroxidase; Rats; Rats, Wistar; Thymol; Wound Healing

Recent evidence suggests that molecular hydrogen has therapeutic value for disease states that involve inflammation. We hypothesized that drinking hydrogen-rich water (HW) daily would protect cardiac and aortic allograft recipients from inflammation-associated deterioration. Heterotopic heart transplantation with short-course tacrolimus immunosuppression and orthotopic aortic transplantation were performed in allogeneic rat strains. HW was generated either by bubbling hydrogen gas through tap water (Bu-HW) or via chemical reaction using a magnesium stick [Mg + 2H(2) O → Mg (OH)(2)  + H(2) ] immersed in tap water (Mg-HW). Recipients were given either regular water (RW), Mg-HW, Bu-HW, or Mg-HW that had been subsequently degassed (DW). Graft survival was assessed by daily palpation for a heartbeat. Drinking Mg-HW or Bu-HW was remarkably effective in prolonging heart graft survival and reducing intimal hyperplasia in transplanted aortas as compared with grafts treated with RW or DW. Furthermore, T cell proliferation was significantly inhibited in the presence of hydrogen in vitro, accompanied by less production of interleukin-2 and interferon-γ. Hydrogen treatment was also associated with increased graft ATP levels and increased activity of the enzymes in mitochondrial respiratory chain. Drinking HW prolongs survival of cardiac allografts and reduces intimal hyperplasia of aortic allografts.

Topics: Adenosine Triphosphate; Animals; Drinking; Graft Rejection; Heart Transplantation; Hydrogen; Inflammation; Interferon-gamma; Interleukin-2; Male; Mitochondria, Heart; Myocardium; Peroxidase; Rats; Rats, Inbred Lew; Transplantation, Heterotopic; Transplantation, Homologous; Water

Obesity is associated with a state of chronic low-grade inflammation. Myeloperoxidase (MPO) plays an important role in the initiation and progression of acute and chronic inflammatory diseases, such as cardiovascular disease (CVD). The objectives of the current study were to evaluate plasma MPO levels in prepubertal obese children and to determine whether MPO could be an early biomarker of inflammation and CVD risk.. In a prospective multicenter case-control study paired by age and sex of 446 Caucasian prepubertal children ages 6-12 years, 223 normal-weight and 223 obese children were recruited. Blood pressure, waist circumference, weight, and height were measured. In addition to MPO, glucose, insulin, metabolic lipid parameters, oxidized low-density lipoproteins, adiponectin, leptin, resistin, C-reactive protein (CRP), interleukin 6, tumor necrosis factor α, matrix metalloproteinase-9 (MMP-9), and plasminogen activator inhibitor 1 were determined.. We found that MPO was elevated in prepubertal obese children and that this enzyme was associated with such proinflammatory and cardiovascular risk biomarkers as CRP, MMP-9, and resistin. Insulin resistance calculated by the homeostatic assessment model was the best predictor of MPO.. MPO is an early biomarker of inflammation associated with CVD risk in obese children at the prepubertal age.

Topics: Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Case-Control Studies; Child; Female; Humans; Inflammation; Male; Obesity; Peroxidase; Prospective Studies; Resistin; Risk Factors

Moutan cortex radicis (MCR) is a Chinese herbal medicine that was widely used over a long period as an analgesic, antipyretic, and anti-inflammatory agent in China. Lipopolysaccharide (LPS)-induced acute lung injury (ALI) in rat models is considered similar to adult respiratory distress syndrome (ARDS) in humans. Therefore, the present study investigates the effect of MCR on ALI. The ALI model was developed through the intra-tracheal (IT) administration of LPS (16mg/kg) to Sprague-Dawley (SD) rats, which formed the LPS group. MCR was orally administered before and after LPS was introduced into rats (MCR-LPS group and LPS-MCR group, respectively). In the MCR-LPS group, rats received MCR 2g/kg/times 3 times before LPS challenge; the LPS-MCR group received MCR 2g/kg/times 3 times after LPS challenge. The results of this experiment indicate that the number of total cells and neutrophils and the concentration of protein exudation in bronchoalveolar lavage fluid (BALF) significantly decreased in the MCR-LPS group. Cytokine levels, including levels of interleukin (IL)-1β, macrophage-inflammatory peptide (MIP)-2, IL-6, and IL-10, in BALF were also significantly inhibited at 16h after LPS administration in the MCR-LPS group. Myeloperoxidase (MPO) activity in lung tissue was reduced in the MCR-LPS and LPS-MCR groups at 16h after LPS administration. Furthermore, leukocyte infiltration and protein exudation in the alveolar space were less severe in the MCR-LPS group than in the LPS group. Therefore, the findings of this study suggest that the administration of MCR prior to LPS improves ALI, possibly mediating ALI through anti-inflammation.

Topics: Acute Lung Injury; Animals; Antithrombin III; Body Temperature; Bronchoalveolar Lavage Fluid; Cytokines; Drugs, Chinese Herbal; Inflammation; Leukocytes; Lipopolysaccharides; Lung; Paeonia; Peptide Hydrolases; Peroxidase; Phytotherapy; Plasminogen Activator Inhibitor 1; Rats; Rats, Sprague-Dawley

The consequence of inflammatory bowel diseases (IBD) is cytokine-mediated severe local tissue damage. Our aim was to determine the extent of inflammatory response and to influence the morphologic changes during the subacute phase of trinitro-benzene sulfonic acid (TNBS)-induced experimental colitis by oral phosphatidylcholine (PC) and N-methyl-D-aspartate (NMDA) receptor antagonist kynurenic acid therapy.. Sprague-Dawley rats were randomized to control, untreated colitis (ic TNBS), colitis fed with 2% PC-containing diet (3 days pre-treatment +3 days treatment after TNBS induction), colitis with kynurenic acid treatment (on day 6, n = 7) groups. The colitis was characterized by tissue myeloperoxidase and plasma TNF-alpha levels, the extent of tissue damage, structural changes in microvasculature (FITC-dextran staining) and mucosal injury (acridine orange staining) were determined by in vivo confocal laser scanning endomicroscopy (Optiscan Five1, Australia) and conventional histology (hematoxyilin-eosin staining).. Significant elevation in myeloperoxidase and TNF-alpha levels with remarkable damage in epithelial structure was detected in the colitis group. Both treatment regimens significantly decreased the level of inflammatory activation but only PC pretreatment could preserve the number of goblet cells and the epithelial structure. Treatment with kynurenic acid did not alter the morphology changes.. Oral PC pretreatment is a promising possibility in the therapy of IBDs through decreasing inflammatory reaction and increasing the number of goblet cells.

Topics: Administration, Oral; Animals; Biomarkers; Colitis; Disease Models, Animal; Excitatory Amino Acid Antagonists; Inflammation; Inflammatory Bowel Diseases; Intestinal Mucosa; Kynurenic Acid; Microcirculation; Microscopy, Confocal; Peroxidase; Phosphatidylcholines; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

Gastrointestinal methane generation has been demonstrated in various conditions, but it is not known whether it has any impact on the mammalian physiology or pathophysiology. Our aim was to characterize the effects of exogenous methane on the process of inflammatory events induced by reoxygenation in a canine model of ischemia-reperfusion.. Sodium pentobarbital-anesthetized inbred beagle dogs (n = 18) were randomly assigned to sham-operated or ischemia-reperfusion (I/R) groups. I/R was induced by occluding the superior mesenteric artery for 1 h, and the subsequent reperfusion was monitored for 3 h. For 5 min before reperfusion, the animals were mechanically ventilated with normoxic artificial air with or without 2.5% methane. The macrohemodynamics and small intestinal pCO2 gap changes were recorded and tissue superoxide and nitrotyrosine levels and myeloperoxidase activity changes were determined in intestinal biopsy samples. Structural mucosal damage was measured via light microscopy and HE staining.. Methane inhalation positively influenced the macrohemodynamic changes, significantly reduced the intestinal pCO2 gap changes and the magnitude of the tissue damage after reperfusion. Further, the intestinal myeloperoxidase activity, the superoxide and nitrotyrosine levels were reduced.. These data demonstrate the anti-inflammatory profile of methane. The study provides evidence that exogenous methane modulates leukocyte activation and affects key events of I/R-induced oxidative and nitrosative stress.

Topics: Administration, Inhalation; Animals; Anti-Inflammatory Agents; Biomarkers; Carbon Dioxide; Disease Models, Animal; Dogs; Hemodynamics; Inflammation; Intestine, Small; Leukocytes; Methane; Peroxidase; Random Allocation; Reperfusion Injury; Superoxides; Tyrosine

Inflammation and angiogenesis, key components of fibrovascular tissue growth, exhibit considerable variability among species and strains. We investigated whether the response of inbred and outbred mice strains to dipyridamole (DP) on these processes would present similar variability. The effects of the drug on blood vessel formation, inflammatory cell recruitment, collagen deposition and cytokine production were determined on the fibroproliferative tissue induced by sponge implants in Swiss and Balb/c mice. Angiogenesis as assessed by hemoglobin (Hb) and vascular endothelial growth factor (VEGF) concentrations differed between the strains. Swiss implants had the highest Hb content but the lowest VEGF concentrations. Systemic DP treatment exerted an antiangiogenic effect on Balb/c implants but an proangiogenic effect on Swiss implants. The inflammatory enzyme activities myeloperoxidase (six-fold higher in Balb/c implants) and N-acetyl-β-D-glucosaminidase were reduced by the treatment in Balb/c implants only. Nitrite concentrations were also higher in Balb/c implants by 40% after DP treatment. Tumor necrosis factor-alpha levels were similar in the implants of both strains and were not reduced by DP. Transforming growth factor β-1 levels and collagen deposition also varied between the strains. The inbred strain had similar levels of the cytokine but implants of Swiss mice presented more collagen. DP treatment reduced collagen deposition in Balb/c implants only. Our data showing the influence of the genetic background on marked heterogeneity of inflammatory angiogenesis components and differential sensitivity to DP may provide some answers to clinical evidence for resistance to angiogenic therapy.

Topics: Acetylglucosaminidase; Animals; Blood Flow Velocity; Collagen; Dipyridamole; Hemoglobins; Inflammation; Mice; Mice, Inbred BALB C; Neovascularization, Pathologic; Nitric Oxide; Nitrites; Peroxidase; Phosphodiesterase Inhibitors; Species Specificity; Surgical Sponges; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factors

Inflammation has classically been defined histopathologically, especially by the presence of immune cell infiltrates. However, more recent studies suggest a role for "low-grade" inflammation in a variety of disorders ranging from metabolic syndrome to cancer, which is defined by modest elevations in pro-inflammatory gene expression. Consequently, there is a need for cost-effective, non-invasive biomarkers that, ideally, would have the sensitivity to detect low-grade inflammation and have a dynamic range broad enough to reflect classic robust intestinal inflammation. Herein, we report that, for assessment of intestinal inflammation, fecal lipocalin 2 (Lcn-2), measured by ELISA, serves this purpose. Specifically, using a well-characterized mouse model of DSS colitis, we observed that fecal Lcn-2 and intestinal expression of pro-inflammatory cytokines (IL-1β, CXCL1, TNFα) are modestly but significantly induced by very low concentrations of DSS (0.25 and 0.5%), and become markedly elevated at higher concentrations of DSS (1.0 and 4.0%). As expected, careful histopathologic analysis noted only modest immune infiltrates at low DSS concentration and robust colitis at higher DSS concentrations. In accordance, increased levels of the neutrophil product myeloperoxidase (MPO) was only detected in mice given 1.0 and 4.0% DSS. In addition, fecal Lcn-2 marks the severity of spontaneous colitis development in IL-10 deficient mice. Unlike histopathology, MPO, and q-RT-PCR, the assay of fecal Lcn-2 requires only a stool sample, permits measurement over time, and can detect inflammation as early as 1 day following DSS administration. Thus, assay of fecal Lcn-2 by ELISA can function as a non-invasive, sensitive, dynamic, stable and cost-effective means to monitor intestinal inflammation in mice.

Topics: Acute-Phase Proteins; Animals; Biomarkers; Chemokine CXCL1; Enzyme-Linked Immunosorbent Assay; Feces; Female; Inflammation; Interleukin-10; Interleukin-1beta; Intestinal Mucosa; Lipocalin-2; Lipocalins; Male; Mice; Mice, Inbred C57BL; Neoplasms; Oncogene Proteins; Peroxidase; Tumor Necrosis Factor-alpha

Haptoglobin (Hp) protein is responsible for hemoglobin clearance after intra-plaque hemorrhage. Hp gene exists as Hp-1 and Hp-2 alleles and the phenotypes show important molecular heterogeneity. We tested the hypothesis that hemoglobin clearance may be deficient in diabetic atheroma from patients with Hp2-2, triggering increased oxidative, inflammatory, and angiogenic patterns compared with controls.. Forty patients with diabetes mellitus were genotyped and their peripheral plaques compared after atherectomy. Plaque hemorrhage, iron content, hemoglobin-binding protein CD163, and heme-oxygenase-1 were quantified. Oxidative, inflammatory, and angiogenic patterns were evaluated by measuring myeloperoxidase, interleukin-10, macrophages, vascular cell adhesion molecule-1, smooth muscle actin, and plaque neovascularization (CD34/CD31). Plaques with Hp2-2 (n=7) had increased hemorrhage (P<0.005), iron content (P<0.001), and reduced CD163 expression (P<0.002) compared with controls (n=14). Hp2-2 plaques had increased heme-oxygenase-1 protein (P<0.02), myeloperoxidase gene (P<0.05), and protein (P<0.0001). Anti-inflammatory interleukin-10 gene (P<0.04), and protein expressions (P<0.0001) were decreased in Hp2-2. Finally, macrophage (P<0.0001), vascular cell adhesion molecule-1 (P=0.001), smooth muscle actin (P=0.002) scores, and neovessels density (P<0.0001) were increased in Hp2-2.. Genotype-dependent impairment of hemoglobin clearance after intra-plaque hemorrhage is associated with increased oxidative, inflammatory, and angiogenic response in human diabetic atherosclerosis.

Topics: Actins; Aged; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Atherosclerosis; Biomarkers; Case-Control Studies; Diabetes Mellitus; Diabetic Angiopathies; Female; Genotype; Haptoglobins; Heme Oxygenase-1; Hemoglobins; Humans; Inflammation; Interleukin-10; Iron; Male; Middle Aged; Neovascularization, Pathologic; Oxidative Stress; Peroxidase; Phenotype; Prospective Studies; Receptors, Cell Surface; Vascular Cell Adhesion Molecule-1

Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl) and other cyclic nitroxides have been shown to inhibit the chlorinating activity of myeloperoxidase (MPO) in vitro and in cells. To examine whether nitroxides inhibit MPO activity in vivo we selected acute carrageenan-induced inflammation on the rat paw as a model. Tempol and three more hydrophobic 4-substituted derivatives (4-azido, 4-benzenesulfonyl, and 4-(4-phenyl-1H-1,2,3-triazol-1-yl)) were synthesized, and their ability to inhibit the in vitro chlorinating activity of MPO and carrageenan-induced inflammation in rat paws was evaluated. All of the tested nitroxides inhibited the chlorinating activity of MPO in vitro with similar IC(50) values (between 1.5 and 1.8 μM). In vivo, the attenuation of carrageenan-induced inflammation showed some correlation with the lipophilicity of the nitroxide at early time points but the differences in the effects were small (<2-fold) compared with the differences in lipophilicity (>200-fold). No inhibition of MPO activity in vivo was evident because the levels of MPO activity in rat paws correlated with the levels of MPO protein. Likewise, paw edema, levels of nitrated and oxidized proteins, and levels of plasma exudation correlated with the levels of MPO protein in the paws of the animals that were untreated or treated with the nitroxides. The effects of the nitroxides in vivo were compared with those of 4-aminobenzoic hydrazide and of colchicine. Taken together, the results indicate that nitroxides attenuate carrageenan-induced inflammation mainly by reducing neutrophil migration and the resulting MPO-mediated damage. Accordingly, tempol was shown to inhibit rat neutrophil migration in vitro.

Topics: Aniline Compounds; Animals; Antioxidants; Carrageenan; Chemotaxis; Colchicine; Cyclic N-Oxides; Edema; Halogenation; Inflammation; Male; Neutrophil Infiltration; Neutrophils; Nitrogen Oxides; Oxidation-Reduction; Peroxidase; Rats; Rats, Wistar; Spin Labels

Inflammation contributes to the pathophysiology of many diseases. In this report, we present noninvasive bioluminescence imaging methods that distinguish acute and chronic inflammation in mouse models. Systemic delivery of luminol (5-amino-2,3-dihydro-1,4-phthalazinedione) enables detection of acute inflammation largely mediated by tissue-infiltrating neutrophils, whose myeloperoxidase (MPO) activity is required for luminol bioluminescence. In contrast, bioluminescence from injection of lucigenin (bis-N-methylacridinium nitrate) closely correlates with late phase and chronic inflammation. Lucigenin bioluminescence is independent of MPO and, instead, requires phagocyte NADPH oxidase (Phox) activity in macrophages. We are able to visualize tissue inflammation resulting from wound healing, bacterial infection, foreign substance implantation, and antitumor immune responses. Given the central role of inflammation in a variety of disorders, we believe these noninvasive imaging methods can help dissect the differential roles of neutrophils and macrophages in a variety of pathological conditions.

Topics: Acridines; Animals; Disease Models, Animal; Fluorescent Dyes; Inflammation; Luminescent Measurements; Luminol; Macrophages; Mice; NADPH Oxidases; Neutrophils; Peroxidase; Phagocytes

Acute pancreatitis (AP) is a common inflammatory disease mediated by damage to acinar cells and subsequent pancreatic inflammation with infiltration of leukocytes. The neuronal guidance protein, netrin-1, has been shown to control leukocyte trafficking and modulate inflammatory responses in several inflammation-based diseases. The present study was aimed toward investigating the effects of netrin-1 in an in vivo model of AP in mice. AP was induced in C57BL/6 mice by administration of two intraperitoneal injections of L-Arginine (4 g/kg). Mice were treated with recombinant mouse netrin-1 at a dose of 1 µg/mouse or vehicle (0.1% BSA) intravenously through the tail vein immediately after the second injection of L-Arginine, and every 24 h thereafter. Mice were sacrificed at several time intervals from 0 to 96 h after the induction of pancreatitis. Blood and tissue samples of pancreas and lung were collected and processed to determine the severity of pancreatitis biochemically and histologically. Immunohistochemical staining demonstrated that netrin-1 was mainly expressed in the islet cells of the normal pancreas and the AP model pancreas, and the pancreatic expression of netrin-1 was down-regulated at both the mRNA and protein levels during the course of AP. Exogenous netrin-1 administration significantly reduced plasma amylase levels, myeloperoxidase activity, pro-inflammatory cytokine production, and pancreas and lung tissue damages. Furthermore, netrin-1 administration did not cause significant inhibition of nuclear factor-kappa B activation in the pancreas of L-Arginine-induced AP. In conclusion, our novel data suggest that netrin-1 is capable of improving damage of pancreas and lung, and exerting anti-inflammatory effects in mice with severe acute pancreatitis. Thus, our results indicate that netrin-1 may constitute a novel target in the management of AP.

Topics: Acinar Cells; Amylases; Animals; Arginine; Cytokines; Disease Models, Animal; Gene Expression; Inflammation; Injections, Intraperitoneal; Injections, Intravenous; Islets of Langerhans; Lung; Male; Mice; Mice, Inbred C57BL; Nerve Growth Factors; Netrin-1; NF-kappa B; Pancreas; Pancreatitis, Acute Necrotizing; Peroxidase; Tumor Suppressor Proteins

Chemokines and their receptors play a role in the innate immune response as well as in the disruption of the balance between pro-inflammatory Th17 cells and regulatory T cells (Treg), underlying the pathogenesis of coronary vasculitis in Kawasaki disease (KD).. Here we show that genetic inactivation of chemokine receptor (CCR)-2 is protective against the induction of aortic and coronary vasculitis following injection of Candida albicans water-soluble cell wall extracts (CAWS). Mechanistically, both T and B cells were required for the induction of vasculitis, a role that was directly modulated by CCR2. CAWS administration promoted mobilization of CCR2-dependent inflammatory monocytes (iMo) from the bone marrow (BM) to the periphery as well as production of IL-6. IL-6 was likely to contribute to the depletion of Treg and expansion of Th17 cells in CAWS-injected Ccr2(+/+) mice, processes that were ameliorated following the genetic inactivation of CCR2.. Collectively, our findings provide novel insights into the role of CCR2 in the pathogenesis of vasculitis as seen in KD and highlight novel therapeutic targets, specifically for individuals resistant to first-line treatments.

Topics: Animals; Aorta; B-Lymphocytes; Bone Marrow Cells; Candida albicans; Cell Movement; Cell Proliferation; Cell Wall; Coronary Vessels; Disease Models, Animal; Immunity; Inflammation; Interleukin-6; Lymphocyte Depletion; Macrophages; Mice; Mice, Inbred C57BL; Monocytes; Peroxidase; Receptors, CCR2; Receptors, CCR5; T-Lymphocytes; T-Lymphocytes, Regulatory; Th17 Cells; Vasculitis

Inflammation and oxidative stress play fundamental roles in the pathogenesis of atherosclerosis. Myeloperoxidase has been extensively implicated as a key mediator of inflammatory and redox-dependent processes in atherosclerosis. However, the effect of synthetic myeloperoxidase inhibitors on atherosclerosis has been insufficiently studied. In this study, ApoE(-/-) mice were randomized to low- and high-dose INV-315 groups for 16 weeks on high-fat diet. INV-315 resulted in reduced plaque burden and improved endothelial function in response to acetylcholine. These effects occurred without adverse events or changes in body weight or blood pressure. INV-315 treatment resulted in a decrease in iNOS gene expression, superoxide production and nitrotyrosine content in the aorta. Circulating IL-6 and inflammatory CD11b(+)/Ly6G(low)/7/4(hi) monocytes were significantly decreased in response to INV-315 treatment. Acute pretreatment with INV-315 blocked TNFα-mediated leukocyte adhesion in cremasteric venules and inhibited myeloperoxidase activity. Cholesterol efflux was significantly increased by high-dose INV-315 via ex-vivo reverse cholesterol transport assays. Our results suggest that myeloperoxidase inhibition may exert anti-atherosclerotic effects via inhibition of oxidative stress and enhancement of cholesterol efflux. These findings demonstrate a role for pharmacologic modulation of myeloperoxidase in atherosclerosis.

Topics: Animals; Aorta; Apolipoproteins E; Atherosclerosis; Blood Pressure; Disease Models, Animal; Endothelium, Vascular; Enzyme Inhibitors; Inflammation; Interleukin-6; Male; Mice; Mice, Knockout; Oxidative Stress; Peroxidase; Plaque, Atherosclerotic

Chronic inflammation and oxidative stress play fundamental roles in the pathogenesis of non-alcoholic steatohepatitis (NASH). Previously, we reported that myeloperoxidase (MPO), an aggressive oxidant-generating neutrophil enzyme, is associated with NASH severity in man. We now investigated the hypothesis that MPO contributes to the development and progression of NASH.. Low-density lipoprotein receptor-deficient mice with an MPO-deficient hematopoietic system (LDLR(-/-/)MPO(-/-tp) mice) were generated and compared with LDLR(-/-/)MPO(+/+tp) mice after induction of NASH by high-fat feeding.. High-fat feeding caused a ~4-fold induction of liver MPO in LDLR(-/-/)MPO(+/+) mice which was associated with hepatic sequestration of MPO-positive neutrophils and high levels of nitrotyrosine, a marker of MPO activity. Importantly, LDLR(-/-/)MPO(-/-tp) mice displayed markedly reduced hepatic neutrophil and T-lymphocyte infiltration (p<0.05), and strong down regulation of pro-inflammatory genes such as TNF-α and IL-6 (p<0.05, p<0.01) in comparison with LDLR(-/-/)MPO(+/+tp) mice. Next to the generalized reduction of inflammation, liver cholesterol accumulation was significantly diminished in LDLR(-/-/)MPO(-/-tp) mice (p = 0.01). Moreover, MPO deficiency appeared to attenuate the development of hepatic fibrosis as evident from reduced hydroxyproline levels (p<0.01). Interestingly, visceral adipose tissue inflammation was markedly reduced in LDLR(-/-/)MPO(-/-tp) mice, with a complete lack of macrophage crown-like structures. In conclusion, MPO deficiency attenuates the development of NASH and diminishes adipose tissue inflammation in response to a high fat diet, supporting an important role for neutrophils in the pathogenesis of metabolic disease.

Topics: Adipose Tissue; Animals; Cholesterol; Diet, High-Fat; Enzyme Induction; Fatty Liver; Feeding Behavior; Humans; Inflammation; Liver; Liver Cirrhosis; Mice; Mice, Inbred C57BL; Neutrophils; Non-alcoholic Fatty Liver Disease; Peroxidase; Receptors, LDL; Triglycerides

Red seaweeds synthesize a great variety of sulfated galactans. Sulfated polysaccharides (PLSs) from seaweed are comprised of substances with pharmaceutical and biomedical potential. The aim of the present study was to evaluate the protective effect of the PLS fraction extracted from the seaweed Gracilaria birdiae in rats with naproxen-induced gastrointestinal damage. Male Wistar rats were pretreated with 0.5% carboxymethylcellulose (control group-vehicle) or PLS (10, 30, and 90 mg/kg, p.o.) twice daily (at 09:00 and 21:00) for 2 days. After 1 h, naproxen (80 mg/kg, p.o.) was administered. The rats were killed on day two, 4 h after naproxen treatment. The stomachs were promptly excised, opened along the greater curvature, and measured using digital calipers. Furthermore, the guts of the animals were removed, and a 5-cm portion of the small intestine (jejunum and ileum) was used for the evaluation of macroscopic scores. Samples of the stomach and the small intestine were used for histological evaluation, morphometric analysis and in assays for glutathione (GSH) levels, malonyldialdehyde (MDA) concentration, and myeloperoxidase (MPO) activity. PLS treatment reduced the macroscopic and microscopic naproxen-induced gastrointestinal damage in a dose-dependent manner. Our results suggest that the PLS fraction has a protective effect against gastrointestinal damage through mechanisms that involve the inhibition of inflammatory cell infiltration and lipid peroxidation.

Topics: Animals; Dose-Response Relationship, Drug; Gastrointestinal Diseases; Glutathione; Gracilaria; Inflammation; Lipid Peroxidation; Male; Malondialdehyde; Naproxen; Peroxidase; Polysaccharides; Rats; Rats, Wistar

It is reported that defects exist in the small intestinal epithelial barrier of inflammatory bowel disease, which might be associated with increased intestinal permeability at a very early stage. Our study aims to investigate the role of Lactobacillus plantarum on the decrease of epithelial permeability and the further protective effects on the intestinal epithelial barrier using the IL-10-deficient mouse model. Our study showed that tight junction associated proteins were increased after the pre-treatment of L. plantarum by fluorescence staining, western blot, real-time PCR and transmission electron microscope. Oral gavage of milk containing L. plantarum was effective in decreasing small intestinal permeability using methods of Ussing chamber assay and sugar probe. Assay of pro-inflammatory cytokines IFN-γ, TNF-α, MPO, and colonic histology by ELISA showed protective effects of L. plantarum on the intestinal epithelial barrier. Therefore, L. plantarum may prevent the development of colitis in IL-10-deficient mice by blocking changes in the expression of TJ proteins, TJ structure and intestinal permeability.

Topics: Animals; Colitis; Cytokines; Inflammation; Interleukin-10; Intestinal Mucosa; Intestines; Lactobacillus plantarum; Mice; Mice, Transgenic; Milk; Permeability; Peroxidase; Tight Junctions

High inflammatory AIRmax mice homozygous for Slc11a1 R and S alleles were produced. AIRmax(SS) mice showed faster ear tissue regeneration than AIRmax(RR) mice, suggesting that the S allele favored tissue restoration. Here, we investigated the gene expression profiles and the inflammatory reactions of AIRmax(RR) and AIRmax(SS) mice during the initial phase of ear tissue regeneration. We observed superior levels of analysis of wound myeloperoxidase and edema in AIRmax(SS) mice, although similar cell influx was verified in both lines. Of the genes, 794 were up- and 674 down-regulated in AIRmax(RR), while 735 genes were found to be up- and 1616 down-regulated in AIRmax(SS) mice 48 h after punch. Both mouse lines showed significant over-represented genes related to cell proliferation; however AIRmax(SS) displayed up-regulation of inflammatory response genes. Quantitative PCR experiments showed higher expressions of Tgfb1, Dap12 and Trem1 genes in AIRmax(SS) mice. These results indicate that Slc11a1 gene modulated the early inflammatory events of ear tissue regeneration.

Topics: Alleles; Animals; Base Sequence; Cation Transport Proteins; DNA Primers; Ear, External; Female; Gene Expression; Inflammation; Male; Mice; Mice, Inbred Strains; Peroxidase; Quantitative Trait Loci; Real-Time Polymerase Chain Reaction; Regeneration; Wound Healing

Understanding the interactions between sleep and the immune system may offer insight into why short sleep duration has been linked to negative health outcomes. We, therefore, investigated the effects of napping and extended recovery sleep after sleep restriction on the immune and inflammatory systems and sleepiness. After a baseline night, healthy young men slept for a 2-h night followed by either a standard 8-h recovery night (n=12), a 30-min nap (at 1 p.m.) in addition to an 8-h recovery night (n=10), or a 10-h extended recovery night (n=9). A control group slept 3 consecutive 8-h nights (n=9). Subjects underwent continuous electroencephalogram polysomnography and blood was sampled every day at 7 a.m. Leukocytes, inflammatory and atherogenesis biomarkers (high-sensitivity C-reactive protein, interleukin-8, myeloperoxidase, fibrinogen and apolipoproteins ApoB/ApoA), sleep patterns and sleepiness were investigated. All parameters remained unchanged in the control group. After sleep restriction, leukocyte and - among leukocyte subsets - neutrophil counts were increased, an effect that persisted after the 8-h recovery sleep, but, in subjects who had a nap or a 10-h recovery sleep, these values returned nearly to baseline. Inflammatory and atherogenesis biomarkers were unchanged except for higher myeloperoxidase levels after sleep restriction. The increased sleepiness after sleep restriction was reversed better in the nap and extended sleep recovery conditions. Saliva cortisol decreased immediately after the nap. Our results indicate that additional recovery sleep after sleep restriction provided by a midday nap prior to recovery sleep or a sleep extended night can improve alertness and return leukocyte counts to baseline values.

Topics: Adult; Atherosclerosis; Attention; Data Interpretation, Statistical; Female; Humans; Hydrocortisone; Immunity, Cellular; Inflammation; Leukocyte Count; Male; Neutrophils; Peroxidase; Polysomnography; Saliva; Sleep; Sleep Deprivation; Software; Young Adult

Research on dietary modulation of inflammatory bowel disease is in its infancy. Dietary heme, mimicking red meat, is cytotoxic to colonic epithelium and thus may aggravate colitis. Alternatively, heme-induced colonic stress might also result in potential protective heat-shock proteins (HSPs). Therefore, we investigated the effect of dietary heme on trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats.. Rats were fed a high-fat control diet or a similar diet supplemented with heme. After dietary adaptation, rats were rectally infused with TNBS for colitis induction or saline for sham treatment. Colitis severity was evaluated and several markers were quantified in colonic mucosa isolated 1 wk after colitis induction. Furthermore, cytotoxicity of fecal water and serum α-1-acid glycoprotein were measured.. Dietary heme increased cytotoxicity of the fecal water. Heme-fed sham-treated rats had higher colonic HSP-25 and heme-oxygenase-1 mRNA levels, which was confirmed by immunohistochemistry. HSP induction by heme was associated with decreased protein levels of myeloperoxidase and interleukin-1β after subsequent TNBS infusion. However, no dietary effects were observed on histologic colitis score. Furthermore, body weight gain, colon length, and food intake were lower and α-1-acid glycoprotein concentrations were higher in heme-fed colitic rats. In addition, somatostatin, involved in mucosal repair, was not changed with TNBS infusion in heme-fed rats.. Dietary heme adversely affects colitis, despite HSP induction. We speculate that the irritating influence of dietary heme, being continuously present in the colon, impairs recovery after colitis induction. A diet high in red meat might be a risk factor for inflammatory bowel disease development.

Topics: Animals; Biomarkers; Colitis; Colon; Enterobacter; Heat-Shock Proteins; Heme; Heme Oxygenase-1; Inflammation; Interleukin-1beta; Intestinal Mucosa; Lactobacillaceae; Male; Peroxidase; Rats; Rats, Wistar; Trinitrobenzenesulfonic Acid

The pathogenesis of stroke involves inflammation, apoptosis, and excitotoxicity, which is mediated in part by neuronal NO synthase (nNOS) activation. Ghrelin, an endogenous 28-amino acid peptide, is shown to exert antiapoptotic and anti-inflammatory properties. However, the effect of ghrelin in permanent focal cerebral ischemia and the role of the vagus nerve in its action remain unknown. To study this, male adult Sprague-Dawley rats underwent right-sided permanent middle cerebral artery occlusion (MCAO) with or without prior bilateral truncal vagotomy. This was followed by infusion of 4 nmol human ghrelin as treatment or saline as vehicle. Neurological deficit was assessed at 24 h after MCAO. Rats were killed thereafter, and brains were rapidly removed and analyzed for infarct size, markers of inflammation, excitotoxicity, and apoptosis. Compared with vehicle treatment, human ghrelin treatment in vagus nerve-intact rats after MCAO showed marked reduction in neurological deficit by 57% and infarct size by 25%. Middle cerebral artery occlusion resulted in increases in cerebral TNF-α, IL-6, neutrophil trafficking, matrix metalloproteinase 9 and nNOS gene expression, nitrotyrosine, and apoptosis. Human ghrelin treatment in vagus nerve-intact rats significantly decreased the above measurements. Human ghrelin treatment also improved 7-day survival and significantly decreased neurological deficit over the entire 7 days after MCAO in vagus nerve-intact rats compared with vehicle. Prior vagotomy, however, blunted human ghrelin's neuroprotective effects on neurological deficit, infarct size, TNF-α, neutrophil trafficking, nitrotyrosine, and apoptosis. Human ghrelin is thus a neuroprotective agent that inhibits inflammation, nNOS activity, and apoptosis in focal cerebral ischemia through a vagal pathway.

Topics: Animals; Apoptosis; Brain Ischemia; Ghrelin; Humans; Immunohistochemistry; Inflammation; Interleukin-6; Male; Matrix Metalloproteinase 9; Neutrophils; Nitric Oxide Synthase Type I; Peroxidase; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Tumor Necrosis Factor-alpha; Tyrosine; Vagotomy; Vagus Nerve

We wanted to assess to what extent concentrations of circulating proteins appear to be developmentally regulated, and to what extent such regulation is influenced by intra-uterine inflammation.. We measured 22 proteins in blood obtained on postnatal days 1, 7, and 14 from 818 children born before the 28th week of gestation for whom we also had information about placenta morphology.. Within the narrow gestational age range of this sample, some protein concentrations increase in blood with increasing gestational age. More commonly, the concentrations of inflammation-related proteins decrease with increasing gestational age. We observed this inverse pattern both in children whose placenta was and was not inflamed. CONCLUSIONS/INFERENCES: Regardless of whether or not the placenta is inflamed, the concentrations of inflammation-related proteins in early blood specimens appear to be developmentally regulated with the most common pattern being a decrease with increasing gestational age.

Topics: Acute-Phase Proteins; Blood Proteins; Cell Adhesion Molecules; Chemokines; Gene Expression Regulation, Developmental; Gestational Age; Humans; Infant, Newborn; Inflammation; Matrix Metalloproteinases; Peroxidase; Receptors, Cytokine; Receptors, Vascular Endothelial Growth Factor; Vascular Endothelial Growth Factor A

Neutrophil-dependent reactions catalysed by myeloperoxidase (MPO) are thought to play important roles in the pulmonary pathobiology of cystic fibrosis (CF). Aerosolized thiol antioxidants such as glutathione (GSH) and N-acetylcysteine (NAC) are currently being utilized as therapeutics to modify CF respiratory tract oxidative processes. This study hypothesized that MPO in CF airway lining fluids may be a target of such therapeutics. MPO activity in sputum from 21 adult CF patients was found to be inversely associated with lung function (FEV(1)). In contrast, systemic inflammation (assessed by plasma C-reactive protein) was not correlated with lung function. Ex vivo studies revealed that GSH and NAC effectively scavenged N-chloramines in sputum and inhibited sputum MPO activity with potency exquisitely dependent upon MPO activity levels. Detailed kinetic analyses revealed that NAC and GSH inhibit MPO by distinct mechanisms. Activation of the key pro-inflammatory transcription factor NF-κB in cultured HBE1 cells was inhibited by GSH. The findings reveal that MPO activity and its reactive products represent useful predictors of the doses of inhaled thiol antioxidants required to ameliorate airway oxidative stress and inflammation in CF patients and provide mechanistic insight into the antioxidative/anti-inflammatory mechanisms of action of GSH and NAC when administered into the CF lung.

Topics: Acetylcysteine; Adult; C-Reactive Protein; Cells, Cultured; Chloramines; Cystic Fibrosis; Female; Glutathione; Humans; Inflammation; Lung; Male; Middle Aged; Neutrophils; NF-kappa B; Oxidation-Reduction; Oxidative Stress; Peroxidase; Sputum; Young Adult

1. It has been shown that phloroglucinol has anti-inflammatory and anti-oxidant properties. Both inflammatory cell infiltration and myeloperoxidase (MPO) activation play an important role in myocardial reperfusion injury. The aim of the present study was to explore the effect of phloroglucinol on myocardial reperfusion injury and the mechanisms involved. 2. Anaesthetized rats were pretreated with phloroglucinol (15 or 30 mg/kg, i.g.) or vehicle (5 mmol/L carboxymethyl cellulose sodium) 30 min prior to experimentation. The left main coronary artery was subjected to 1 h occlusion followed by 3 h reperfusion. Infarct size, the release of creatine kinase (CK), inflammatory cell infiltration, MPO activity and protein content, catalase in the blood and myocardium, and myocardial apoptosis were measured. 3. Following myocardial ischaemia and reperfusion in vehicle-treated rats, infarct size was 43.5 ± 3.7% (relative to the area at risk). Accompanying detrimental changes included elevated CK, enhanced inflammatory cell infiltration, high numbers of myocardial apoptotic cells, elevated caspase 3 activity, increased MPO activity and content in the plasma and myocardium and reduced catalase activity. These effects were attenuated by pretreatment with both doses of phloroglucinol (15 and 30 mg/kg, i.g.). 4. The results of the present study suggest that phloroglucinol protects the myocardium against ischaemia-reperfusion injury in rats and that its beneficial effects are related to inhibition of MPO activity and inflammatory cell infiltration.

Topics: Animals; Apoptosis; Cardiotonic Agents; Drug Evaluation, Preclinical; Enzyme Inhibitors; Inflammation; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Neutrophil Infiltration; Peroxidase; Phloroglucinol; Rats; Rats, Sprague-Dawley

Betulinic acid (BA) is a naturally occurring triterpenoid widely distributed throughout the plant kingdom. We previously reported that BA inhibits lipopolysaccharide (LPS)-induced interleukin-6 production through modulation of nuclear factor κB (NF-κB) in human peripheral blood mononuclear cells (hPBMCs). This study attempted to identify other mechanisms through which BA modulates LPS signalling in mononuclear cells. The effects of BA on signalling pathways downstream were focused on in this study.. We determined the ability of BA to interfere with p38 and extracellular regulated kinase (ERK) phosphorylation as well as Akt phosphorylation and nuclear factor-κB activation using LPS-activated hPBMCs as an in vitro model. LPS-induced endotoxin shock in mice was the in vivo model employed.. BA inhibited LPS-induced COX-2 protein expression and prostaglandin E(2) production and also attenuated LPS-induced ERK and Akt phosphorylation, but not p38 in hPBMCs. BA abolished LPS-induced IκBα phosphorylation and thus normalized the levels of IκBα in cytosol. BA also inhibited LPS-induced reactive oxygen species formation and lactate dehydrogenase release. Interestingly, BA improved the life span of mice in endotoxin shock and also inhibited PGE(2) production and myeloperoxidase activity in vivo.. BA modulates LPS-induced COX-2 expression in hPBMCs by inhibiting ERK and Akt pathways as well as by modulating IκBα phosphorylation. At the same time, no cell toxicity was observed. The effect of the drug was confirmed through in vivo experiments. The study gives an insight into the molecular mechanisms of BA.

Topics: Animals; Betulinic Acid; Disease Models, Animal; Electrophoretic Mobility Shift Assay; Endotoxins; Humans; Inflammation; Leukocytes, Mononuclear; Male; Mice; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; NF-kappa B; Pentacyclic Triterpenes; Peroxidase; Phosphorylation; Prostaglandins E; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Sepsis; Shock, Septic; Triterpenes

Advanced oxidation protein products (AOPP) is widely used as a uremic biomarker, especially for cardiovascular disease. However, it has not been determined whether it is better to measure AOPP in plasma or serum. In this cross-sectional study, which included 102 patients undergoing maintenance hemodialysis, fibrinogen-free serum and defibrinated plasma samples were prepared. AOPP levels from fibrinogen-free samples displayed a stronger correlation with myeloperoxidase activity and levels of C-reactive protein, interleukin-6 and tumor necrosis factor-alpha, as well as prevalent cardiovascular disease, than AOPP levels obtained from plasma samples. These results demonstrated that fibrinogen interferes with the measurement of AOPP.

Topics: Biomarkers; Blood Specimen Collection; C-Reactive Protein; Cardiovascular Diseases; Cross-Sectional Studies; Female; Fibrinogen; Humans; Inflammation; Interleukin-6; Male; Middle Aged; Oxidation-Reduction; Oxidative Stress; Peroxidase; Renal Dialysis; Tumor Necrosis Factor-alpha

The initial mechanical tissue disruption of spinal cord injury (SCI) is followed by a period of secondary injury that increases the size of the lesion. Secondary injuries are associated with edema, inflammation, excessive cytokine release, excitotoxicity and cell apoptosis. 3,4-dihydroxyphenyl lactic acid (DLA) is one of the major water-soluble components of chemical constituents from Salvia miltiorrhiza (SM). To investigate the inhibition effects of DLA on secondary injury of SCI, focusing especially on suppression of inflammatory responses and the mechanism of this effect, the following studies were performed: Basso, Beattie, and Bresnahan (BBB) scores to assess motor functions till 10 days after SCI; Nissl and Fast Blue histological staining and immunohistochemistry of inhibitory-kappa B-alpha (IκB-α) and nuclear factor-kappa B (NF-κB) p65 subunit protein; levels of myeloperoxidase (MPO) activity analysis as an indicator of polymorphonuclear infiltration; IL-6 production in plasma 10 days after SCI; Western blot analysis to determine cytoplasm levels of IκB-α and NF-κB p65 subunit proteins in the nuclear fractions 10 days after SCI. DLA significantly attenuated the motor function and tissue damage following SCI in rats, significant reduced polymorphonuclear cell infiltration and IL-6 production, as well as reduced cytoplasm IκB-α degradation and the nuclear translocation of NF-κB p65 subunit protein after SCI. In conclusion, the results clearly demonstrate that DLA inhibit the inflammation responses induced by SCI via inhibiting effect of production of IL-6 and nuclear translocation of NF-κB.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Anti-Inflammatory Agents; Disease Models, Animal; I-kappa B Kinase; Inflammation; Interleukin-6; Male; Myelin Sheath; NF-kappa B; Peroxidase; Rats; Rats, Wistar; Spinal Cord Injuries; Time Factors

Terminalia paniculata Roxb. (Family-Combretaceae) is a wild tree commonly used in traditional ayurvedic medicine for the treatment of inflammation of parotid glands and in menstrual disorders.. To explore the folk use of Terminalia paniculata on pharmacological grounds to evaluate the scientific basis of anti-inflammatory activity.. The anti-inflammatory activity of Terminalia paniculata was studied against carrageenan-induced hind paw edema, air pouch inflammation and complete Freund's adjuvant (CFA)-induced arthritis in rats. The aqueous extract of Terminalia paniculata bark (TPW) was administered at the concentrations of 100, 200 and 400mg/kg body weight.. TPW showed significant (p<0.05) anti-inflammatory activity by reducing the edema volume in carrageenan-induced paw edema in rats. Further, TPW (400mg/kg) also reduced the carrageenan-induced leukocyte migration (50.92 ± 5.71%) and myeloperoxidase activity (49.31 ± 5.24%) in air pouch exudates. TPW (200mg/kg) exhibits anti-rheumatic and analgesic activities by improving the altered haematological milieu (ESR, CRP, RF, WBC, RBC and Hb) and also by inhibiting the flexion scores and radiographic changes in CFA-induced arthritis. This extract also had significant (p<0.05) effects on the occurrence of secondary lesions compared to CFA control.. Terminalia paniculata bark may be a potential preventive or therapeutic candidate for the treatment of chronic inflammation and arthritis.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Antirheumatic Agents; Arthritis, Experimental; Carrageenan; Edema; Freund's Adjuvant; Hematologic Tests; Inflammation; Leukocytes; Male; Medicine, Ayurvedic; Peroxidase; Phytotherapy; Plant Bark; Plant Extracts; Radiography; Range of Motion, Articular; Rats; Rats, Wistar; Terminalia

Bradykinin-related vasoactive peptides (kinins) are important mediators of local and systemic inflammatory reactions. However, at local inflammatory foci, the production of kinins from proteinaceous precursors (kininogens) can be affected by reactive oxygen species released by phagocyte cells. One of the predominant oxidants at these places is hypochlorous acid which is formed from hydrogen peroxide and chloride ions by neutrophil myeloperoxidase. In this study, inactivation of human kininogens after oxidation with the myeloperoxidase-H₂O₂-chloride system was observed and analyzed by protein chemistry methods. The kinin release from oxidized kininogens by major kinin-producing enzymes, plasma and tissue kallikreins, proceed with a very low rate. This effect was assigned to apparent inability of kallikreins to process the kinin N-terminus owing to the conversion of the adjacent Met-361 residue to methionine sulfoxide. Additionally, the oxidized high-molecular mass kininogen lost its natural ability to bind plasma prekallikrein. This effect was assigned to the oxidation of Trp-569 residue within the prekallikrein-binding region which is subsequently destructed owing to cleavage of the peptide bond after that residue. One possible pathophysiological consequence of the described effects on kininogens could be the impairment of the normal assembly and triggering of the kinin-forming system on defense cell surfaces.

Topics: Amino Acid Sequence; Bradykinin; Humans; Inflammation; Kininogens; Kinins; Methionine; Molecular Sequence Data; Peroxidase; Phagocytes; Prekallikrein; Reactive Oxygen Species; Tryptophan

We investigated anti-inflammatory properties of a novel 5-lipoxygenase (5-LO) inhibitor, KRH-102140, in vitro and in vivo. 5-LO enzyme activity was assayed using insect cell lysates overexpressing rat 5-LO. The leukotriene B(4) (LTB(4)) level was assayed in rat basophilic leukemia (RBL-1) cell line. ICR (Institute of Cancer Research) mice were used for in vivo assays. Mouse ear edema was induced by topical application of arachidonic acid. An air pouch was induced by subcutaneous injection of sterile air into mice, followed by zymosan treatment. Sprague-Dawley rats were used for pharmacokinetic studies.. KRH-102140 inhibited 5-LO activity with an IC(50) value of 160 ± 23 nmol/l in parallel with LTB(4) inhibition in RBL-1 cells. Oral administration of KRH-102140 (10-100 mg/kg) reduced ear edema, myeloperoxidase activity and LTB(4) production in murine inflammation models. Oral bioavailability as determined in rats was 66%.. Our results show that KRH-102140, a new 5-LO inhibitor, exhibits potent anti-inflammatory activities in vitro as well as in vivo.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonate 5-Lipoxygenase; Benzopyrans; Benzylamines; Cell Line; Drug Discovery; Edema; Half-Life; Inflammation; Leukocytes; Leukotriene B4; Lipoxygenase Inhibitors; Male; Metabolic Clearance Rate; Mice; Mice, Inbred ICR; Peroxidase; Rats; Rats, Sprague-Dawley; Recombinant Proteins

Experiments were designed to investigate the effects of ethyl pyruvate (EP) in a murine model of hind-limb ischemia-reperfusion (IR) injury.. C57BL6 mice underwent 90 minutes of unilateral ischemia followed by 24 hours of reperfusion using two treatment protocols. For the preischemic treatment (pre-I) protocol, mice (n=6) were given 300 mg/kg EP before ischemia, followed by 150 mg/kg of EP just before reperfusion and at 6 hours and 12 hours after reperfusion. In a postischemic treatment (post-I) protocol, mice (n=7) were treated with 300 mg/kg EP at the end of the ischemic period, then 15 minutes later, and 2 hours after reperfusion and 150 mg/kg of EP at 4 hours, 6 hours, 10 hours, 16 hours, and 22 hours after reperfusion. Controls mice for both protocols were treated with lactated Ringers alone at time intervals identical to EP. Skeletal muscle levels of adenosine triphosphate (ATP), interleukin-1β, keratinocyte chemoattractant protein, and thrombin antithrombin-3 complex were measured. Skeletal muscle architectural integrity was assessed microscopically.. ATP levels were higher in mice treated with EP compared with controls under the both treatment protocols (p=0.02). Interleukin-1β, keratinocyte chemoattractant protein, thrombin antithrombin-3 complex (p<0.05), and the percentage of injured fibers (p<0.0001) were significantly decreased in treated versus control mice under the both protocols.. Muscle fiber injury and markers of tissue thrombosis and inflammation were reduced, and ATP was preserved with EP in pre-I and post-I protocols. Further investigation of the efficacy of EP to modulate IR injury in a larger animal model of IR injury is warranted.

Topics: Adenosine Triphosphate; Animals; Antithrombin III; Disease Models, Animal; Inflammation; Interleukin-1; Lactates; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Peptide Hydrolases; Peroxidase; Pyruvates; Reperfusion Injury; Thrombosis

Topics: Animals; Anti-Inflammatory Agents; Cyclohexanols; Disease Models, Animal; Eucalyptol; Guinea Pigs; Inflammation; Mice; Monoterpenes; Peroxidase; Reactive Oxygen Species

Urate and myeloperoxidase (MPO) are associated with adverse outcomes in cardiovascular disease. In this study, we assessed whether urate is a likely physiological substrate for MPO and if the products of their interaction have the potential to exacerbate inflammation. Urate was readily oxidized by MPO and hydrogen peroxide to 5-hydroxyisourate, which decayed to predominantly allantoin. The redox intermediates of MPO were reduced by urate with rate constants of 4.6 × 10(5) M(-1) s(-1) for compound I and 1.7 × 10(4) M(-1) s(-1) for compound II. Urate competed with chloride for oxidation by MPO and at hyperuricemic levels is expected to be a substantive substrate for the enzyme. Oxidation of urate promoted super-stoichiometric consumption of glutathione, which indicates that it is converted to a free radical intermediate. In combination with superoxide and hydrogen peroxide, MPO oxidized urate to a reactive hydroperoxide. This would form by addition of superoxide to the urate radical. Urate also enhanced MPO-dependent consumption of nitric oxide. In human plasma, stimulated neutrophils produced allantoin in a reaction dependent on the NADPH oxidase, MPO and superoxide. We propose that urate is a physiological substrate for MPO that is oxidized to the urate radical. The reactions of this radical with superoxide and nitric oxide provide a plausible link between urate and MPO in cardiovascular disease.

Topics: Allantoin; Cardiovascular Diseases; Humans; Hydrogen Peroxide; Hyperuricemia; Inflammation; NADPH Oxidases; Neutrophils; Oxidation-Reduction; Peroxidase; Substrate Specificity; Superoxides; Uric Acid

Implants are defined as controlled sustained release delivery systems of therapeutic agents incorporated or dispersed into a polymeric carrier. These systems can be implanted in specific organs and delivered by the therapeutic agents at the target site to treat various pathological processes. In the present study, the effects of dexamethasone-loaded polyurethane implants [PU ACT (dexamethasone acetate) implants] on inflammatory angiogenesis in a murine sponge model were investigated. PU ACT implants were inserted into nonbiocompatible sponges, used as a framework for fibrovascular tissue growth, and implanted into subcutaneous tissue located on the back of mice. After 7 days of implantation, the implant system was collected and processed for the assessment of hemoglobin (Hb; vascular index), myeloperoxidase (MPO), and N-acetyl-β-D-glucosaminidase (NAG; inflammatory enzymes activities) and collagen content. ACT released from the polymeric implants provided a significant decrease in the neovascularization in the sponge (Hb content). PU ACT implants provided no effects on neutrophil infiltration (MPO activity) but macrophage recruitment was affected by the glucocorticoid delivered by implants (NAG activity). ACT released from implants was able to reduce the collagen deposition. The qualitative histological findings corroborated with the measured biochemical parameters. These local drug delivery systems derived from polyurethane efficiently modulated the key components of inflammation, angiogenesis, and fibrosis induced by sponge discs in an experimental animal model.

Topics: Acetylglucosamine; Angiogenesis Inhibitors; Animals; Anti-Inflammatory Agents; Biomarkers; Chemistry, Pharmaceutical; Collagen; Dexamethasone; Disease Models, Animal; Drug Carriers; Drug Compounding; Drug Implants; Female; Fibrosis; Hemoglobins; Inflammation; Macrophages; Mice; Neovascularization, Pathologic; Neutrophils; Peroxidase; Polyurethanes; Surgical Sponges; Technology, Pharmaceutical; Time Factors

Several lines of evidence have shown that helminthiasis can significantly reduce disease severity in animal models of intestinal inflammation, airway inflammation/hyperreactivity, diabetes, and multiple sclerosis. Identification and characterization of helminth-derived immunomodulatory molecules that contribute to anticolitis effects could lead to new therapeutic approaches in inflammatory bowel diseases (IBDs) without the need for helminth infection. We evaluated the therapeutic potential of adult human hookworm, Ancylostoma ceylanicum, crude (Aw) and excreted/secreted (ES) products on dextran sulfate sodium (DSS)-induced colitis in BALB/c mice.. Colitis was induced by 5% DSS oral administration for 7 days. Clinical disease severity was monitored daily during concomitant intraperitoneal treatment with helminth-derived products. Additionally, several pathways of immunological modulation induced by A. ceylanicum products (MPO, EPO, Th1, Th2, and Th17 cytokine responses) in the inflamed intestinal microenvironment were assessed. Finally, the histopathological profile of the colon was characterized.. Hookworm products are able to modulate the potent proinflammatory response induced by DSS, mainly through the downregulation of Th1 and Th17 cytokines. These proteins also reduce clinical and colonic microscopic inflammation scores as well as EPO and MPO activity.. Ancylostoma ceylanicum Aw and ES mediators have an important therapeutic potential in experimental colitis in mice, which may provide a more socially acceptable form of therapy for patients with IBDs as opposed to using living worms. Our results support the urgency of further isolation and recombinant expression of active hookworm products responsible for the beneficial effects on colitis.

Topics: Adult; Ancylostoma; Ancylostomiasis; Animals; Colitis; Cricetinae; Cytokines; Dextran Sulfate; Disease Models, Animal; Helminth Proteins; Humans; Inflammation; Male; Mesocricetus; Mice; Mice, Inbred BALB C; Peroxidase

The sympathetic nervous system regulates visceral function through the release of catecholamines and cotransmitters from postganglionic sympathetic neurons and adrenal chromaffin cells (ACCs). Previous studies have shown that norepinephrine secretion is decreased during experimental colitis due to the inhibition of voltage-gated Ca(2+) current (I(Ca)) in postganglionic sympathetic neurons. The present study examined whether colonic inflammation causes a similar impairment in depolarization-induced Ca(2+) influx in ACCs using the dextran sulfate sodium (DSS) model of acute colitis in mice. Alterations in ACC function during colitis were assessed using fura 2-acetoxymethyl ester Ca(2+) imaging techniques and perforated patch-clamp electrophysiology. In ACCs isolated from mice with DSS-induced acute colitis, the high-K(+)-stimulated increase in intracellular Ca(2+) concentration ([Ca(2+)](i)) was significantly reduced to 74% of the response of ACCs from control mice. Acute colitis caused a 10-mV hyperpolarization of ACC resting membrane potential, without a significant effect on cellular excitability. Delayed-rectifier K(+) and voltage-gated Na(+) current densities were significantly enhanced in ACCs from mice with DSS-induced acute colitis, with peak current densities of 154 and 144% that of controls, respectively. Importantly, acute colitis significantly inhibited I(Ca) in ACCs between -25 and +20 mV. Peak I(Ca) density in ACCs from mice with DSS-induced acute colitis was 61% that of controls. High-K(+)-induced increases in [Ca(2+)](i) were also reduced in ACCs from mice with 2,4,6-trinitrobenzene sulfonic acid-induced acute colitis and DSS-induced chronic colitis to 68 and 78% of the control responses, respectively. Our results suggest that, during colitis, voltage-dependent Ca(2+) influx is impaired in ACCs. Given the importance of Ca(2+) signaling in exocytosis, these alterations may decrease systemic catecholamine levels, which could play an important role in inflammatory bowel disease. This is the first demonstration of aberrant ACC function during experimental colitis.

Topics: Analysis of Variance; Animals; Calcium; Calcium Channels; Chromaffin Cells; Colitis; Dextran Sulfate; Electrophysiology; Inflammation; Male; Mice; Mice, Inbred C57BL; Peroxidase; Reverse Transcriptase Polymerase Chain Reaction

Tumor necrosis factor alpha (TNF-α) has been implicated in the pathogenesis of Crohn's disease. TNF antagonists are effectively used to treat these patients, although the efficiency of different antagonists varies. In the present study we combined TNF-α binding cyclic peptide (TBCP) and TNFR1 binding cyclic peptide (TRBCP) to treat TNBS-induced colitis in rats for one week. The symptoms of colitis including bloody diarrhea, rectal prolapse, and a profound and sustained weight loss were significantly ameliorated and the colon inflammatory damage, both macroscopic and histological scores, MPO activity, and NO production were markedly decreased in rats by neutralization of TNF-α and blocking TNFR1, as compared with those in rats treated with irrelevant peptide or normal saline (P<0.05). The transcripts of IL-1β and IL-8, and the protein expression of TNF-α in rats treated with both TBCP and TRBCP were also down-regulated (P<0.05), while these proinflammatory cytokines remained unchanged in rats treated with irrelevant peptide or normal saline. These findings suggest that the combination of TNF-α- and TNFR1-binding peptide effectively improves the symptoms of TNBS-induced colitis and alleviates colonic pathological damages in rats. This combination may be a potent candidate for clinical treatment of the inflammatory bowel disease.

Topics: Animals; Colitis; Colon; Gene Expression Regulation; Humans; Inflammation; Interleukin-1beta; Interleukin-8; Leukocytes; Male; Nitric Oxide; Peptide Library; Peptides, Cyclic; Peroxidase; Rats; Rats, Wistar; Receptors, Tumor Necrosis Factor, Type I; Transcription, Genetic; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

Brain damage from neonatal hypoxia-ischemia (HI) plays a major role in neonatal mortality and morbidity. Using the Rice-Vannucci model of HI in rats, we verified that 8 days after HI injury, adenosine deaminase (ADA), N-acetyl-glucosaminidase (NAG) and myeloperoxidase (MPO) activities increased in the left hemisphere hippocampus (HI group); however, the activity of 5'-nucleotidase (5'NT) remained unchanged. In the hematoxylin-eosin analysis (HE), we detected selective and delayed degeneration of hippocampal pyramidal neurons and astroglial reaction accompanied by glial fibrillary acidic protein (GFAP)-positive and vimentin-positive in the immunohistochemistry analysis in the HI group compared with the control group. We observed the selective necrosis of neurons, vascular endothelial proliferation and inflammatory response accompanied by the increase of the key enzyme of adenosine metabolism in the HI group. The increase of ADA activity, despite the 5'NT activity was not altered, indicates the predominance of ADA activity in the postischemic homeostasis of extra cellular adenosine. The presence of leukocytes into the ischemic areas displays the possible importance of the neutrophil-macrophages associated with the increase of MPO and NAG activities 8 days after HI. These findings may contribute to the evaluation of some consequences of the damage caused by neonatal HI.

Topics: Animals; Animals, Newborn; Astrocytes; Hexosaminidases; Hippocampus; Hypoxia-Ischemia, Brain; Immunohistochemistry; Inflammation; Male; Neurons; Peroxidase; Rats; Rats, Wistar

Inflammation is associated with a reduced availability of NO in the vasculature. We investigated the possible involvement of altered levels of the substrate (arginine) and the inhibitor [ADMA (asymmetric ω-NG,NG-dimethylarginine)] of NOS (NO synthase). Plasma concentrations of arginine and ADMA, the inflammatory markers CRP (C-reactive protein) and MPO (myeloperoxidase), and oxLDL [oxidized LDL (low-density lipoprotein)] were measured in 369 male and 377 female participants (aged 50-87 years) of a population-based cohort study. The arginine/ADMA ratio decreased significantly across increasing tertiles of CRP and MPO. These negative associations remained significant in a linear regression model with both MPO (P = 0.002) and CRP (P < 0.001) as independent variables and adjusted for age, sex and cardiovascular risk factors. In a fully adjusted regression model, MPO was positively associated with ADMA {5.4 [95% CI (confidence interval), 1.3-9.4] nmol/l change of ADMA per S.D. increase in MPO; P = 0.010}, whereas CRP was not (P = 0.36). Conversely, in a fully adjusted model, CRP was negatively associated with arginine [-2.8 (95% CI, -4.0 to -1.6) μmol/l arginine per S.D. of CRP; P < 0.001], without a significant contribution of MPO (P = 0.23). The relationship between MPO and ADMA became stronger with increasing levels of oxLDL (1.8, 5.2 and 8.7 nmol/l ADMA per S.D. of MPO for increasing tertiles of oxLDL), consistent with the ability of MPO to amplify oxidative stress. In contrast, the relationship between CRP and arginine was not modified by levels of oxLDL. In conclusion, an unfavourable NOS substrate/inhibitor ratio may contribute to the reduced NO bioavailability associated with inflammation.

Topics: Aged; Aged, 80 and over; Arginine; Biomarkers; C-Reactive Protein; Cohort Studies; Female; Humans; Inflammation; Lipoproteins, LDL; Male; Middle Aged; Nitric Oxide Synthase; Oxidative Stress; Peroxidase

Minocycline (Mino) and doxycycline (Dox) are second generation tetracyclines known to present several other effects, which are independent from their antimicrobial activities. We studied in a comparative way the anti-inflammatory effects of Mino and Dox, on acute models of peripheral inflammation in rodents (formalin test and peritonitis in mice, and carrageenan-induced paw oedema in rats). Immunohistochemical assays for TNF-alpha and iNOS in rat paws of carrageenan-induced oedema were also carried out as well as in vitro assays for myeloperoxidase (MPO) and lactate dehydrogenase (LDH). Furthermore, antioxidant activities were evaluated by the DPPH assay.. In the formalin test although Mino and Dox (1, 5, 10 and 25 mg/kg, i.p.) inhibited the first phase, they acted predominantly on the second phase of the test, where inhibition of the licking time close to 80% were observed. Mino and Dox were very efficacious in reducing the carrageenan-induced paw oedema in rats (10, 25 and 50 mg/kg, i.p.) and carrageenan-induced leucocyte migration (1 and 5 mg/kg, i.p.) to mice peritoneal cavities. Besides, they also significantly inhibited MPO and LDH releases at doses ranging from 0.001 to 1 μg/ml. Thus, in general, the anti-inflammatory activity of Dox was higher as compared to that of Mino, although the radical scavenging activity of Mino was of a magnitude 10 times higher.. Our data indicate that anti-inflammatory and antioxidant effects, involve the inhibition of iNOS and TNF-alpha, among other properties, and these encourage clinical studies of these compounds for new therapeutic applications, especially those were inflammation plays a role.

Topics: alpha-Tocopherol; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Biphenyl Compounds; Carrageenan; Cell Movement; Doxycycline; Edema; Formaldehyde; Inflammation; L-Lactate Dehydrogenase; Male; Mice; Mice, Inbred Strains; Minocycline; Neutrophils; Nitric Oxide Synthase Type II; Oxidation-Reduction; Pain; Pain Measurement; Peritonitis; Peroxidase; Picrates; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

Epidemiologic studies have associated higher dietary consumption of soy isoflavones with decreased self-report of cough and allergic respiratory symptoms, but the pharmacodynamic effects of soy isoflavone on asthmatic model have not been well-described. Here, we hypothesized that soy isoflavone may have potential effects on airway hyperresponsiveness, inflammation and airway remodeling in a murine of asthma. Mice sensitized and challenged with ovalbumin developed airway inflammation. Bronchoalveolar lavage fluid was assessed for inflammatory cell counts, and for cytokine levels. Lung tissues were examined for cell infiltration, mucus hypersecretion and airway remodeling, and for the expression of inflammatory biomarkers. Airway hyperresponsiveness was monitored by direct airway resistance analysis. Oral administration of soy isoflavone significantly reduced ovalbumin-induced airway hyperresponsiveness to intravenous methacholine, and inhibited ovalbumin-induced increases in eosinophil counts. RT-PCR analysis of whole lung lysates revealed that soy isoflavone markedly suppressed ovalbumin-induced mRNA expression of eotaxin, interleukin(IL)-5, IL-4 and matrix metalloproteinase-9, and increased mRNA expression of interferon (IFN)-γ and tissue inhibitor of metalloproteinase-1 in a dose-dependent manner. Soy isoflavone also substantially recovered IFN-γ/IL-4 (Th1/Th2) levels in bronchoalveolar lavage fluid. In addition, histologic studies showed that soy isoflavone dramatically inhibited ovalbumin-induced lung tissue eosinophil infiltration, airway mucus production and collagen deposition in lung tissues. Our findings suggest that soy isoflavone as nutritional supplement may provide a novel means for the treatment of airway inflammatory disease.

Topics: Airway Remodeling; Animals; Asthma; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Chemokine CCL11; Collagen; Eosinophils; Female; Glycine max; Hypersensitivity; Inflammation; Interferon-gamma; Interleukin-4; Interleukin-5; Isoflavones; Lung; Matrix Metalloproteinase 9; Methacholine Chloride; Mice; Mice, Inbred ICR; Mucus; Ovalbumin; Peroxidase; Respiratory System; Superoxide Dismutase; Tissue Inhibitor of Metalloproteinase-1

Garcinia gardneriana is popularly used in skin disorders; therefore, this article investigated the effect of G. gardneriana extracts from leaves, bark and seeds and two isolated compounds in ear oedema and leucocytes migration caused by croton oil. The topical application of the extract of G. gardneriana leaves was able to reduce (70 ± 3%, and ID(50) 0.33 mg/ear) ear oedema, while the seeds (51 ± 5%) and the wood (60 ± 12%) extracts were less effective. In a time-course evaluation, the leaf extract (1 mg/ear) was effective when applied 2 hr before and until 3 hr after the stimulation, presenting a higher effectiveness when applied right after croton oil (83 ± 7% inhibition). In addition, the leaf extract was able to diminish the myeloperoxidase (MPO) activity in 64 ± 13%, which suggests the inhibition of leucocyte infiltration that was confirmed by histological analysis. Also, both biflavonoids isolated from the leaves of G. gardneriana, fukugetin (or morelloflavone) and 13-naringenin-II 8-eriodictyol (GB-2a), were able to reduce ear oedema, with ID(50) values of 0.18 (0.10-0.28) and 0.22 (0.15-0.31) mg/ear, respectively, besides the inhibition of MPO activity of 52 ± 6% and 64 ± 5%, respectively. Using the fluorescent probe 2',7'-dichlorodihydrofluorescein diacetate, the leaf extract, fukugetin and GB-2a topically applied to the ear treated with croton oil reduced 52 ± 15%, 63 ± 17% and 83 ± 4%, respectively, the production of reactive oxygen species of the skin. Thus, these results reveal the anti-inflammatory effect of G. gardneriana leaves for topical usage, and both biflavonoids are responsible for this effect.

Topics: Administration, Cutaneous; Animals; Anti-Inflammatory Agents; Cell Movement; Disease Models, Animal; Garcinia; Inflammation; Inhibitory Concentration 50; Leukocytes; Male; Mice; Peroxidase; Plant Extracts; Reactive Oxygen Species; Skin Diseases; Time Factors

Oxidized low-density lipoproteins (oxLDL) play a critical role in the initiation of atherosclerosis through activation of inflammatory signaling. In the present work we investigated the role of antioxidant and signal modulation properties of plant polyphenols in controlling vascular inflammation. Significant decrease in intracellular NO level and superoxide overproduction was found in human umbilical vein endothelial cells (HUVEC) treated with oxLDL, but not with LDL. The redox imbalance was prevented by the addition of quercetin or resveratrol. Expression analysis of 14 genes associated with oxidative stress and inflammation revealed oxLDL-mediated up-regulation of genes specifically involved in leukocyte recruitment and adhesion. This up-regulation could be partially avoided by the addition of verbascoside or resveratrol, while treatment with quercetin resulted in a further increase in the expression of these genes. Lipopolysaccharide (LPS)-treated HUVEC were also used for the evaluation of anti-inflammatory potency of plant polyphenols. Significant differences between HUVEC treaded with oxLDL and LPS were found in both the expression pattern of inflammation-related genes and the effects of plant polyphenols on cellular responses. The present data indicate that plant polyphenols may affect vascular inflammation not only as antioxidants but also as modulators of inflammatory redox signaling pathways.

Topics: Antioxidants; Blood Vessels; Cell Adhesion; Cell Line; Cell Proliferation; Chemotaxis, Leukocyte; Endothelial Cells; Flavonoids; Humans; Inflammation; Lipopolysaccharides; Lipoproteins, LDL; Nitric Oxide; Nitrites; Oxidation-Reduction; Peroxidase; Phenols; Plants; Polyphenols; RNA, Messenger; Signal Transduction; Up-Regulation

Colitis induced by trinitrobenzene sulfonic acid (TNBS) with reactivation is a good experimental model for studying inflammatory bowel disease pathogenesis and appropriate therapeutics. This experimental model allows the induction of colitis relapse and remission periods and the establishment of chronic disease features, such as the mesenteric adipose tissue alterations observed in Crohn's disease. Lymph node activation and the role of perinodal adipose tissue (PAT) have been poorly studied in this model. Thus, a study of the interactions of lymph nodes and PAT could help to elucidate the mechanisms behind IBD pathogenesis.. The purpose of this study was to examine lymph nodes and PAT alterations during reactivated TNBS-colitis in Wistar rats.. In this study, the alterations of PAT and lymph node cells during experimental colitis, induced by repeated intracolonic TNBS instillations, were evaluated, focusing on fatty acid and adipocytokine profile analysis and cytokines production, respectively.. Fatty acid analysis of PAT reveals an increase of ω-6 polyunsaturated fatty acids during colits, such as linoleic acid, gamma-linolenic acid and arachidonic acid. ω-6 arachidonic acid was not increased in lymph node cells or serum. PAT also produces elevated levels of pro- and anti-inflammatory adipokines during colitis. Lymph node cells release high levels of IFN-γ and TNF-α but not IL-10, characterizing the predominant Th-1 response associated with this disease. Nevertheless, T cells from animals with colitis demonstrated increased IFN-γ production via a COX-2-dependent mechanism after supplementation with ω-6 arachidonic acid, suggesting that PAT modification could contribute to the lymph node cell activation observed during colitis.

Topics: Adipokines; Adipose Tissue; Animals; Arachidonic Acid; bcl-2-Associated X Protein; Colitis; Cyclooxygenase 2; Gene Expression Regulation; Inflammation; Interferon-gamma; Lymph Nodes; Male; Mesentery; Peroxidase; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Wistar; Trinitrobenzenesulfonic Acid

There is substantial evidence that inflammation within the central nervous system contributes to stroke risk and recovery. Inflammatory conditions increase stroke risk, and the inflammatory response is of major importance in recovery and healing processes after stroke. We investigated the role of inflammatory genes IL1B, IL6, MPO, and TNF in stroke susceptibility and recovery in a population sample of 672 patients and 530 controls, adjusting for demographic, clinical and lifestyle risk factors, and stroke severity parameters. We also considered the likely complexity of inflammatory mechanisms in stroke, by assessing the combined effects of multiple genes. Two interleukin 6 (IL6) and one myeloperoxidase (MPO) single-nucleotide polymorphisms were significantly associated with stroke risk (0.022<(corrected)P<0.042), highlighting gene variants of low to moderate effect in stroke risk. An epistatic interaction between the IL6 and MPO genes was also identified in association with stroke susceptibility (P=0.031 after 1,000 permutations). In a subset of 546 patients, one IL6 haplotype was associated with stroke outcome at 3 months ((corrected)P=0.024), an intriguing finding warranting further validation. Our findings support the association of the IL6 gene and present novel evidence for the involvement of MPO in stroke susceptibility, suggesting a modulation of stroke risk by main gene effects, clinical and lifestyle factors, and gene-gene interactions.

Topics: Aged; Case-Control Studies; Epistasis, Genetic; Female; Genetic Predisposition to Disease; Humans; Inflammation; Interleukin-6; Male; Middle Aged; Peroxidase; Polymorphism, Single Nucleotide; Recovery of Function; Risk Factors; Stroke

The regulator of cytokine signaling known as protein inhibitor of activated STAT-1 (PIAS1) is increasingly understood to have diverse regulatory functions for inflammation, but its effect in inflammatory conditions such as severe acute pancreatitis (SAP) has not previously been reported. The aim of this study was to investigate the effect of upregulation of PIAS1 on SAP associated with acute lung injury (ALI), and its subsequent effect on disease severity. Sprague-Dawley rats were given an IV injection of adenovirus serotype 5 (Ad5)/F35-PIAS1, Ad5/F35-vector or saline before induction of SAP. The control group received only a sham operation. Lung and pancreas samples were harvested 16h after induction. The protein levels of PIAS1 in tissue were investigated. The severity of pancreatic injury was determined by a histological score of pancreatic injury, serum amylase, and pancreatic water content. The lung injury was evaluated by measurement of pulmonary microvascular permeability, lung myeloperoxidase activity and malondialdehyde levels. The survival rates of rats were also analyzed. The results found that in Ad5/F35-PIAS1 treated rats, serum tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 levels were decreased but showed no influence on the levels of IL-10, and the severity of pancreatic tissue injury was less compared with either untreated SAP or Ad5/F35-vector treated rats (P<0.01). The administration of Ad5/F35-PIAS1 in SAP-induced rats downregulated the activity of the signal transducer and activator of transcription-1 (STAT1) pathway and the expressions of matrix metalloproteinase-9 (MMP-9) and intercellular adhesion molecule (ICAM)-1 protein in lung. Thus, compared with the untreated SAP rats, the inflammatory response and the severity of ALI decreased, and the survival rates increased (P<0.01). These findings suggest that PIAS1 could augment anti-inflammatory activity by inhibiting STAT1, thus attenuating the severity of SAP associated with ALI.

Topics: Acute Lung Injury; Animals; Down-Regulation; Inflammation; Interleukin-1beta; Interleukin-6; Male; Pancreatitis; Peroxidase; Protein Inhibitors of Activated STAT; Rats; Rats, Sprague-Dawley; STAT1 Transcription Factor; Taurocholic Acid; Time Factors; Tumor Necrosis Factor-alpha; Up-Regulation

Obesity (Ob) and type 1 diabetes (T1DM) are associated with increased inflammation and oxidative stress, which are major pathogenetic pathways toward higher cardiovascular risks. Although long-term exercise protects against systemic inflammation and oxidation, acute exercise actually exerts pro-inflammatory and oxidative effects, prompting the necessity for better defining these molecular processes in at-risk patients; in particular, very little is known regarding obese and T1DM children. We therefore examined key inflammatory and oxidative stress variables during exercise in 138 peripubertal children (47 Ob, 12.7 ± 0.4 yr, 22 F, BMI% 97.6 ± 0.2; 49 T1DM, 13.9 ± 0.2 yr, 20 F, body mass index% [BMI] 63.0 ± 3.6; 42 healthy, CL, 13.5 ± 0.5 yr, 24 F, BMI% 57.0 ± 3.6), who performed 10 bouts of 2-min cycling ~80% VO(2max) , separated by 1-min rest intervals. Blood samples were drawn at baseline and peak exercise. Ob displayed elevated baseline interleukin-6 (IL-6, 2.1 ± 0.2 pg/mL, p < 0.005) vs. CL (1.5 ± 0.3), whereas T1DM displayed the greatest maximum exercise-induced change in IL-6 (1.2 ± 0.3) than in both Ob (0.7 ± 0.1, p < 0.001) and CL (0.6 ± 0.1, p < 0.0167). Myeloperoxidase (MPO) was elevated in T1DM (143 ± 30 ng/mL, p < 0.0167) vs. CL (89 ± 10) and Ob (76 ± 6), whereas increases in exercise only occurred in Ob and CL. Disparate baseline and exercise responses were also observed for 8-hydroxy-2'-deoxyguanosine, glutathione, and F(2) -isoprostane. This data show distinct patterns of dysregulation in baseline and adaptive immunologic and oxidative responses to exercise in Ob and T1DM. A full understanding of these alterations is required so that developing exercise regimens aimed at maximizing health benefits for specific dysmetabolic states can be achieved based on complete scientific characterization rather than empirical implementation.

Topics: Adolescent; Blood Glucose; Child; Diabetes Mellitus, Type 1; Exercise; Exercise Test; Female; Humans; Inflammation; Interleukin-6; Leukocyte Count; Lipid Metabolism; Male; Neutrophils; Obesity; Oxidation-Reduction; Oxidative Stress; Peroxidase

Endotoxin induced chorioamnionitis increases IL-1 and provokes an inflammatory response in the fetal ileum that interferes with intestinal maturation. In the present study, we tested in an ovine chorioamnionitis model whether IL-1 is a major cytokine driving the inflammatory response in the fetal ileum.. Sheep bearing singleton fetuses received a single intraamniotic injection of recombinant ovine IL-1α at 7, 3 or 1 d before caesarian delivery at 125 days gestational age (term = 150 days).. 3 and 7 d after IL-1α administration, intestinal mRNA levels for IL-4, IL-10, IFN-γ and TNF-α were strongly elevated. Numbers of CD3+ and CD4+ T-lymphocytes and myeloidperoxidase+ cells were increased whereas FoxP3+ T-cells were detected at low frequency. This increased proinflammatory state was associated with ileal mucosal barrier loss as demonstrated by decreased levels of the intestinal fatty acid binding protein and disruption of the tight junctional protein ZO-1.. Intraamniotic IL-1α causes an acute detrimental inflammatory response in the ileum, suggesting that induction of IL-1 is a critical element in the pathophysiological effects of endotoxin induced chorioamnionitis. A disturbed balance between T-effector and FoxP3+ cells may contribute to this process.

Topics: Animals; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Chorioamnionitis; Fatty Acid-Binding Proteins; Female; Fetus; Forkhead Transcription Factors; Ileum; Inflammation; Interleukin-1alpha; Membrane Proteins; Peroxidase; Phosphoproteins; Pregnancy; Reverse Transcriptase Polymerase Chain Reaction; Sheep, Domestic; Zonula Occludens-1 Protein

Vitamin C supplementation has been suggested to reduce cardiovascular disease risk. However, no studies have examined the relationship between vitamin C status and vascular dysfunction in lean and obese individuals in the absence of supplementation. We examined whether vascular function is interrelated with vitamin C status and inflammation in healthy, college-aged lean and obese men with no history of dietary supplementation. A cross-sectional study was conducted during winter 2008 in lean and obese men aged 21±3 years (n=8/group). Brachial artery flow-mediated dilation (FMD) was measured to determine vascular endothelial function. Plasma antioxidants (vitamin C, vitamin E, and thiols), inflammatory proteins (C-reactive protein [CRP], myeloperoxidase [MPO], and cytokines), and cellular adhesion molecules were measured. Participants also completed 3-day food records on the days preceding their vascular testing. Group differences were evaluated by t tests, and correlation coefficients were determined by linear regression. FMD was 21% lower (P<0.05) in obese men. They also had 51% lower vitamin C intakes and 38% lower plasma vitamin C concentrations. Obese men had greater plasma concentrations of CRP, MPO, inflammatory cytokines, and cellular adhesion molecules. Participants' CRP and MPO were each inversely related (P<0.05) to FMD (r=-0.528 and -0.625) and plasma vitamin C (r=-0.646 and -0.701). These data suggest that low vitamin C status is associated with proinflammatory responses and impaired vascular function in lean and obese men. Additional study is warranted to determine whether improving dietary vitamin C intakes from food attenuate vascular dysfunction.

Topics: Antioxidants; Ascorbic Acid; Blood Flow Velocity; Brachial Artery; C-Reactive Protein; Cell Adhesion Molecules; Cross-Sectional Studies; Cytokines; Endothelium, Vascular; Humans; Inflammation; Male; Nutritional Status; Obesity; Peroxidase; Thinness; Ultrasonography; Vitamin E; Young Adult

Accumulative evidences have showed that some coumarin derivatives have significantly anti-inflammatory effects. To investigate the potential anti-inflammatory effect of compound IMMLG5521, a novel coumarin derivative, carrageenan-induced pleurisy model in rats was employed. The results showed that IMMLG5521 (5, 10 and 20 mg/kg) exhibited anti-inflammatory effects, reducing pleural exudate formation, decreasing total number of inflammation cells and polymorphonuclear leukocytes infiltration, attenuating histological injury and reducing TNF-α, IL-1β, MIP-2 and IL-8 release. Further investigation revealed that the compound may exert its anti-inflammatory effect via inhibiting nuclear translocation of NF-кB in inflammatory cells collected from pleural exudates. Taken together, the present results suggested that IMMLG5521 inhibited acute inflammation in carrageenan-induced pleurisy model that could be, in part, related to a reduction of release of inflammatory factors, another part may be related to an inhibition of NF-кB activation.

Topics: Animals; Anti-Inflammatory Agents; Carrageenan; Coumarins; Cytokines; Inflammation; Lung; Male; NF-kappa B; Peroxidase; Pleural Cavity; Pleurisy; Rats; Rats, Sprague-Dawley; Signal Transduction

Heme oxygenase (HO)-2 is highly expressed in the corneal epithelium and is a component of the heme oxygenase system that represents an intrinsic cytoprotective and anti-inflammatory system based on its ability to modulate leukocyte migration and to inhibit expression of inflammatory cytokines and proteins via its products biliverdin/bilirubin and carbon monoxide (CO). We have shown that in HO-2 null mice epithelial injury leads to unresolved corneal inflammation and chronic inflammatory complications including ulceration, perforation and neovascularization. In this study, we explore whether a localized corneal suppression of HO-2 is sufficient for disrupting the innate anti-inflammatory and repair capability of the cornea.. Silencing hairpin RNA (shRNA) against HO-2 was administered subconjunctivally (100 ng/eye) as well as topically (100 ng/eye) starting one day before corneal epithelial debridement and once daily, thereafter. The corneal epithelium was removed using an Alger Brush in anesthetized mice. Re-epithelialization was assessed by fluorescein staining using a dissecting microscope and image analysis. Inflammatory response was quantified by myeloperoxidase activity. Levels of mRNA were measured by RT-PCR.. Local injection of HO-2-specific shRNA led to a 50% reduction in corneal HO-2 mRNA. Administration of HO-2-specific shRNA delayed corneal re-epithelialization when compared with the control shRNA-treated group by 14%, 20%, and 12% at days 3, 4, and 7 after injury, respectively (n=18-24). The observed delay in the wound repair process in HO-2 shRNA treated mice was accompanied by a threefold and 3.5 fold increase in the neovascular response at days 4 and 7 after injury. Further, local knockdown of HO-2 lead to an aberrant chronic inflammatory response, as shown by presence of high numbers of inflammatory cells still present in the cornea at day 7 after injury; 1.04±0.45×10(6) in HO-2 knockdown mice versus 0.14±0.03×10(6) inflammatory cells in control mice. Matrix metalloproteinase-2 (MMP-2) but not MMP-9 increased following injury and remained elevated in the injured corneas of the HO-2 shRNA-treated eyes.. Corneal knockdown of HO-2 via local administration of HO-2-specific shRNA leads to delayed re-epithelialization, increased neovascularization and an aberrant inflammatory response similar to what is observed in the HO-2 null mouse. The elevated MMP-2 expression may contribute to the increase in neovascularization in corneas in which HO-2 expression is suppressed.

Topics: Administration, Topical; Animals; Cornea; Corneal Injuries; Epithelium, Corneal; Fluorescein; Gene Expression; Heme Oxygenase (Decyclizing); Inflammation; Injections, Intraocular; Matrix Metalloproteinase 2; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; Peroxidase; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; RNA, Messenger; RNA, Small Interfering; Up-Regulation; Wound Healing

Acute lung injury or acute respiratory distress syndrome is a serious clinical problem with high mortality. Oxidative stress was found to play a major role in mediating lung injury and antioxidants have been shown to be effective in attenuating acute lung injury. In this study, we determine the effects of tempol, a membrane-permeable radical scavenger, in lipopolysaccharide (LPS)-induced acute lung injury and the underlying mechanism. Acute lung injury was induced by intraperitoneal injection of LPS (1mg/kg) and mice were treated with tempol 30min before injection of LPS. One hour later, bronchoalveolar lavage fluid was collected and subjected to estimation of total and differential cell counts as well as the proinflammatory cytokines; tumor necrosis factor-alpha(TNF-α), interleukin-1beta(IL-1β) and interferon-gamma (IFN-γ). Lung tissue damage was confirmed by histopathological changes and by immunohistochemical analysis of myeloperoxidase (MPO). Moreover, lipid peroxidation, reduced glutathione (GSH) and nitric oxide (NO) were investigated in the lung tissue. Pretreatment with tempol produced significant attenuation of LPS-induced lung injury as well as inhibition of LPS mediated increase in MPO immunostaining, MDA and NO levels in lung tissue. Elevated cytokines levels in both bronchoalveolar lavage fluid and lung tissue homogenates of acute lung injury mice were significantly decreased after administration of tempol. These findings confirmed significant protection by tempol against LPS-induced acute lung injury and that superoxide anion scavenging appears to be a potential target for new potential therapy in pulmonary disorders.

Topics: Acute Lung Injury; Animals; Bronchoalveolar Lavage Fluid; Cell Count; Cell Membrane Permeability; Cyclic N-Oxides; Cytokines; Free Radical Scavengers; Glutathione; Inflammation; Lipid Peroxidation; Lipopolysaccharides; Lung; Male; Malondialdehyde; Mice; Nitric Oxide; Oxidative Stress; Peroxidase; Spin Labels; Superoxides

TNBS-induced colitis has characteristics resembling human Crohn's disease including transmural inflammation, ulceration, and fibrosis. Current treatments target acute symptoms but do not necessarily prevent fibrotic complications of the disease. The aim of this study was to determine the effect of pentoxifylline and its primary metabolite (M-1) on fibrosis in the TNBS-induced colitis model. Myeloperoxidase activity and interleukin-18 are indicators of inflammation and were elevated in the TNBS model. The morphology damage score assesses colon damage and was also elevated in the TNBS model. Collagen as the indicator of fibrosis was quantified and visualized by the Sirius Red/Fast Green staining technique and collagen type I was assessed by Western analysis. Collagen was elevated in the TNBS-induced model. Pentoxifylline and M-1 treatment significantly attenuated colon damage and inflammation in TNBS-colitis (P<0.05). M-1 treatment significantly reduced the TNBS-induced increase in colon weight, colon thickness and total collagen content (P<0.05). Results suggest that pentoxifylline and M-1 inhibit intestinal fibrosis in this experimental model and may prove beneficial in the treatment of intestinal fibrosis associated with human Crohn's disease with the added benefit of inhibiting inflammation and ulceration. This is the first study to examine the effects of racemic M-1 in vivo and one of the few studies to examine the effect of drugs on both inflammation and fibrosis in an experimental model of colitis.

Topics: Animals; Colitis; Collagen Type I; Colon; Disease Models, Animal; Female; Fibrosis; Inflammation; Interleukin-18; Intestinal Mucosa; Intestines; Organ Size; Pentoxifylline; Peroxidase; Rats; Rats, Sprague-Dawley; Stereoisomerism; Time Factors; Trinitrobenzenesulfonic Acid

Inflammation occurs routinely when managing gliomas and is not easily distinguishable from tumor regrowth by current MRI methods. The lack of noninvasive technologies that monitor inflammation prevents us to understand whether it is beneficial or detrimental for the patient, and current therapies do not take this host response in consideration. We aim to establish whether a gadolinium (Gd)-based agent targeting the inflammatory enzyme myeloperoxidase (MPO) can selectively detect intra- and peritumoral inflammation as well as glioma response to treatment by MRI.. We carried out serial Gd-bis-5-HT-DTPA (MPO-Gd) MRI before and after treating rodent gliomas with different doses of oncolytic virus (OV) and analyzed animal survival. The imaging results were compared with histopathologic and molecular analyses of the tumors for macrophage/microglia infiltration, virus persistence, and MPO levels.. Elevated MPO activity was observed by MRI inside the tumor and in the peritumoral cerebrum at day 1 post-OV injection, which corresponded with activation/infiltration of myeloid cells inhibiting OV intratumoral persistence. MPO activity decreased, whereas tumor size increased, as the virus and the immune cells were cleared (days 1-7 post-OV injection). A 10-fold increase in viral dose temporally decreased tumor size, but augmented MPO activity, thus preventing extension of viral intratumoral persistence.. MPO-Gd MRI can distinguish enhancement patterns that reflect treatment-induced spatiotemporal changes of intratumoral and intracerebral inflammation from those indicating tumor and peritumoral edema. This technology improves the posttreatment diagnosis of gliomas and will increase our understanding of the role of inflammation in cancer therapy.

Topics: Animals; Brain Neoplasms; Cell Line, Tumor; Edema; Genetic Vectors; Inflammation; Kinetics; Macrophages; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C57BL; Oncolytic Virotherapy; Peroxidase; Rats; Rats, Inbred F344

Vitamin deficiencies are common in patients with inflammatory bowel disease (IBD). Homocysteine (Hcys) is a thrombogenic amino acid produced from methionine (Met), and its increase in patients with IBD indicates a disruption of Met metabolism; however, the role of Hcys and Met metabolism in IBD is not well understood. We hypothesized that disrupted Met metabolism from a B-vitamin-deficient diet would exacerbate experimental colitis. Mice were fed a B(6)-B(12)-deficient or control diet for 2 wk and then treated with dextran sodium sulfate (DSS) to induce colitis. We monitored disease activity during DSS treatment and collected plasma and tissue for analysis of inflammatory tissue injury and Met metabolites. We also quantified Met cycle activity by measurements of in vivo Met kinetics using [1-(13)C-methyl-(2)H(3)]methionine infusion in similarly treated mice. Unexpectedly, we found that mice given the B-vitamin-deficient diet had improved clinical outcomes, including increased survival, weight maintenance, and reduced disease scores. We also found lower histological disease activity and proinflammatory gene expression (TNF-α and inducible nitric oxide synthase) in the colon in deficient-diet mice. Metabolomic analysis showed evidence that these effects were associated with deficient B(6), as markers of B(12) function were only mildly altered. In vivo methionine kinetics corroborated these results, showing that the deficient diet suppressed transsulfuration but increased remethylation. Our findings suggest that disrupted Met metabolism attributable to B(6) deficiency reduces the inflammatory response and disease activity in DSS-challenged mice. These results warrant further human clinical studies to determine whether B(6) deficiency and elevated Hcys in patients with IBD contribute to disease pathobiology.

Topics: Analysis of Variance; Animals; Body Weight; Colitis; Dextran Sulfate; Gene Expression; Glutathione; Homocysteine; Inflammation; Interleukin-10; Kaplan-Meier Estimate; Male; Metabolomics; Methionine; Methylmalonic Acid; Mice; Mice, Inbred C57BL; Nitric Oxide Synthase Type II; Peroxidase; Pyridoxal Phosphate; S-Adenosylhomocysteine; Severity of Illness Index; Tumor Necrosis Factor-alpha; Vitamin B 12 Deficiency; Vitamin B 6 Deficiency

The presence of pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptors in capsaicin-sensitive peptidergic sensory nerves, inflammatory and immune cells suggest its involvement in inflammation. However, data on its role in different inflammatory processes are contradictory and there is little known about its functions in the airways. Therefore, our aim was to examine intranasal endotoxin-induced subacute airway inflammation in PACAP gene-deficient (PACAP⁻/⁻) and wild-type (PACAP⁺/⁺) mice. Airway responsiveness to inhaled carbachol was determined in unrestrained mice with whole body plethysmography 6 h and 24 h after LPS. Myeloperoxidase (MPO) activity referring to the number of accumulated neutrophils and macrophages was measured with spectrophotometry and interleukin-1β (IL-1β) concentration with ELISA from the lung homogenates. Histological evaluation and semiquantitative scoring were also performed. Bronchial responsiveness, as well as IL-1β concentration and MPO activity markedly increased at both timepoints. Perivascular edema dominated the histological picture at 6 h, while remarkable peribronchial granulocyte accumulation, macrophage infiltration and goblet cell hyperplasia were seen at 24h. In PACAP⁻/⁻ mice, airway hyperreactivity was significantly higher 24 h after LPS and inflammatory histopathological changes were more severe at both timepoints. MPO increase was almost double in PACAP⁻/⁻ mice compared to the wild-types at 6 h. In contrast, there was no difference between the IL-1β concentrations of the PACAP⁺/⁺ and PACAP⁻/⁻ mice. These results provide evidence for a protective role for PACAP in endotoxin-induced airway inflammation and hyperreactivity.

Topics: Animals; Bronchi; Bronchial Hyperreactivity; Carbachol; Cholinergic Agonists; Enzyme-Linked Immunosorbent Assay; Female; Granulocytes; Histocytochemistry; Inflammation; Interleukin-1beta; Lipopolysaccharides; Lung; Macrophages; Mice; Mice, Knockout; Peroxidase; Pituitary Adenylate Cyclase-Activating Polypeptide; Plethysmography, Whole Body

In this study, we report that α,β-amyrin, a plant-derived pentacyclic triterpene, reduced persistent inflammatory and neuropathic hyperalgesia in mice by a direct activation of the CB(1) and CB(2) cannabinoid receptors (CB(1)R and CB(2)R). The oral treatment with α,β-amyrin (30 mg/kg) significantly reduced mechanical and thermal hyperalgesia and inflammation induced by complete Freund's adjuvant (CFA) and by partial sciatic nerve ligation (PSNL). The pretreatment with either CB(1)R or CB(2)R antagonists and the knockdown gene of the receptors significantly reverted the antinociceptive effect of α,β-amyrin. Of note, binding studies showed that α,β-amyrin directly bound with very high affinity to CB(1)R (K(i)=0.133 nM) and with a lower affinity to CB(2)R (K(i)=1989 nM). Interestingly, α,β-amyrin, ACEA (CB(1)R agonist), or JWH-133 (CB(2)R agonist), at doses that caused antinociception, failed to provoke any behavioral disturbance, as measured in the tetrad assay. In addition, α,β-amyrin largely decreased interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α), keratinocyte-derived chemokine (KC) and interleukin 6 (IL-6) levels, and myeloperoxidase activity. Likewise, α,β-amyrin prevented the activation of the transcriptional factors: nuclear factor κB (NF-κB) and cyclic adenosine monophosphate response element binding (CREB) and the expression of cyclooxygenase 2 in mice footpads and spinal cords. The present results demonstrated that α,β-amyrin exhibits long-lasting antinociceptive and anti-inflammatory properties in 2 models of persistent nociception via activation of cannabinoid receptors and by inhibiting the production of cytokines and expression of NF-κB, CREB and cyclooxygenase 2.

Topics: Analysis of Variance; Animals; Anti-Inflammatory Agents; Area Under Curve; Body Weight; Cyclohexanols; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Edema; Enzyme-Linked Immunosorbent Assay; Freezing Reaction, Cataleptic; Hyperalgesia; Inflammation; Locomotion; Male; Mice; Neuralgia; Oleanolic Acid; Oligodeoxyribonucleotides, Antisense; Pain Threshold; Pentacyclic Triterpenes; Peroxidase; Protein Binding; Rats; Rats, Wistar; Receptors, Cannabinoid; Tritium

Hydroquinone impairs several leucocyte cell functions, which alter the immune response. Although endothelial cell functions are important for the development of immune responses, hydroquinone actions on endothelial cell have not been shown. Therefore, the effect of hydroquinone exposure (10 or 100 μM for 2 hr) on primary culture of microvascular endothelial cells (PMECs) obtained from the cremaster muscle of Wistar rats incubated in the presence or absence of lipopolysaccharide (LPS, 2 μg/mL) was investigated. Hydroquinone treatment induced the membrane expression of cell adhesion molecules (CAMs) from the immunoglobulin superfamilies ICAM-1 (intercellular), VCAM-1(vascular) and PECAM-1 (platelet endothelial) and induced the secretion of cytokines interleukin-1β (IL-1β) and tumour necrosis factor-α (TNF-α). The effects were dependent on transcriptional modifications because enhanced CAM mRNA expression as well as both cytokines and nuclear factor κB (NF-κB) nuclear activation was found. These effects may be due to the direct action of hydroquinone rather than its quinone metabolites, because endothelial cells do not present myeloperoxidase enzyme and hydroquinone incubation did not induce the expression of cytochrome P450 2E1 (CYP2E1) or prostaglandin H synthase 1. In addition, the incubation of endothelial cells with benzoquinone (10 μM, 2 hr) impaired PECAM-1 expression and did not modify NF-κB nuclear activation. Taken together, the data herein presented reveal that hydroquinone evokes pro-inflammatory properties in endothelial cells that are triggered by the enhancement of NF-κB nuclear translocation-dependent gene transcription.

Topics: Animals; Benzoquinones; Cell Adhesion Molecules; Cells, Cultured; Cytochrome P-450 CYP2E1; Endothelial Cells; Hydroquinones; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-1beta; Leukocytes; Lipopolysaccharides; NF-kappa B; Peroxidase; Platelet Endothelial Cell Adhesion Molecule-1; Rats; Rats, Wistar; RNA, Messenger; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

Anti-inflammatory effects of antidepressants have been reported in some studies, but the mechanisms underlying these effects remain unknown. Amitriptyline, a tricyclic antidepressant, is widely used in the management of psychological disorders and various types of pain, including neuropathic pain or fibromyalgia. In our previous work, we found the role of supraspinal mechanisms in the anti-inflammatory effect of amitriptyline. In the line of the indicated study, we sought to evaluate the effects of intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) application of amitriptyline in the carrageenan-induced paw edema in rats in more details. Our findings confirmed that i.p. (40 and 80 mg/kg) and i.c.v. (100 μg/rat) injection of amitriptyline inhibited carrageenan-induced inflammation at different times. We also found that both i.p. and i.c.v. amitriptyline significantly decreased migration of polymorphonuclear (PMN) leucocytes into the site of inflammation, according to pathological evidence and the activity of myeloperoxidase (MPO). Furthermore, i.p. amitriptyline at the applied doses markedly reduced interleukin (IL)-1β and tumor necrosis factor (TNF)-α levels in the paw treated with carrageenan. Our results also showed that i.c.v. amitriptyline noticeably decreased the concentration of IL-1β in the inflamed paws. The TNF-α levels reduced in the i.c.v. group, even though these reductions were not statistically significant. These results confirmed the anti-inflammatory effects of systemic and central amitriptyline in the carrageenan-induced paw edema in rats, and demonstrated that these effects mediated mostly through the inhibition of PMN cells migration and release of IL-1β and TNF-α into the site of inflammation.

Topics: Amitriptyline; Animals; Anti-Inflammatory Agents; Carrageenan; Edema; Extremities; Inflammation; Infusions, Intraventricular; Injections, Intraperitoneal; Interleukin-1beta; Male; Neutrophils; Peroxidase; Rats; Rats, Wistar; Skin; Tumor Necrosis Factor-alpha

The present study was designed to evaluate the antinociceptive profile of caffeic acid in mice and rats. Caffeic acid (5-100 mg/kg, p.o.), in a dose dependent manner inhibited acetic acid-induced writhing and late phase of formalin-induced pain in mice, with an ED(50) of 22.38 and 10.92 mg/kg, respectively. However, caffeic acid was ineffective in the hot plate and tail flick tests. Analgesic activity was also examined in carrageenan and lipopolysaccharide (LPS)-induced mechanical hyperalgesia in rats, where locally induced myeloperoxidase (MPO), malondialdehyde (MDA) and nitrite levels in foot pad were estimated by colorimetric assay. Oral administration of caffeic acid (200mg/kg, p.o.) showed analgesic activity similar to nimesulide (4 mg/kg, p.o.) and inhibited MPO, MDA and nitrite generation in the inflamed paw. Histological examination revealed reduction in neutrophil infiltration and protection of tissue damage by caffeic acid. These results suggest that caffeic acid exhibits peripheral analgesic effect in mice and rats and could be further examined for the treatment of chronic painful episodes.

Topics: Acetates; Animals; Behavior, Animal; Caffeic Acids; Carrageenan; Formaldehyde; Inflammation; Lipopolysaccharides; Male; Malondialdehyde; Mice; Nitrites; Pain; Peroxidase; Rats

The aim of the study was to determine the effects of fucoidan on rat myocardial ischemia-reperfusion (I/R) model and elucidate the potential mechanisms. Myocardial I/R injury was induced by the occlusion of left anterior descending coronary artery for 30 min followed by reperfusion for 2h. After 2h reperfusion, hemodynamics parameters were detected. Blood samples were collected to determine serum levels of tumor necrosis factor-α (TNF-α) and interleukin 6, 10 (IL-6, 10). Hearts were harvested to assess histopathological changes, infarct size (IS), and the content of myeloperoxidase (MPO). The expression of high-mobility group box 1 (HMGB1), phosphor-IκB-α and phosphor-nuclear factor kappa B (NF-κB) were assayed by western blot. Compared with control group, treatment with fucoidan improved left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP) and the contractility index (P<0.05, P<0.01). Fucoidan reduced the myocardial IS, the levels of TNF-α and IL-6, and the activity of MPO (P<0.05, P<0.01). Fucoidan down-regulated the expression of HMGB1, phosphor-IκB-α and NF-κB, but increased the content of IL-10 when compared with control (P<0.05, P<0.01). Besides, the infiltration of polymorph nuclear leukocytes (PMNs) and histopathological damages in myocardium were decreased in fucoidan treated groups (PMNs, P<0.05, P<0.01). These findings revealed that the administration of fucoidan could regulate the inflammation response via HMGB1 and NF-κB inactivation in I/R-induced myocardial damage.

Topics: Animals; Blotting, Western; Cytokines; Hemodynamics; HMGB1 Protein; Inflammation; Myocardial Reperfusion Injury; NF-kappa B; Peroxidase; Phaeophyceae; Polysaccharides; Rats; Rats, Sprague-Dawley

Renal ischemia-reperfusion injury causes acute renal failure, and the hallmarks of renal ischemia-reperfusion injury are inflammation, apoptosis, necrosis, and capillary dysfunction. Milk fat globule-epidermal growth factor-factor VIII (MFG-E8), a membrane-associated secretory glycoprotein, is produced by immune cells and reported to participate in multiple physiologic processes associated with tissue remodeling. We have recently shown that MFG-E8 treatment attenuates organ injury, inflammatory responses, and survival after sepsis through the enhancement of phagocytosis of apoptotic cells. The purpose of this study was to determine whether administration of MFG-E8 attenuates renal ischemia-reperfusion injury.. Prospective, controlled, and randomized animal study.. : A research institute laboratory.. Male C57BL/6J mice (20-25 g).. : Renal ischemia-reperfusion injury with bilateral renal pedicle clamping for 45 mins, followed by reperfusion. A recombinant murine MFG-E8 (0.4 μg/20 g) was given intraperitoneally at the beginning of reperfusion.. MFG-E8 levels, organ injury variables, inflammatory responses, histology, apoptosis, and capillary functions were assessed at 1.5 and 20 hrs after reperfusion. A 60-hr survival study was conducted in MFG-E8 and recombinant murine MFG-E8-treated wild-type mice. After renal ischemia-reperfusion injury, MFG-E8 mRNA and protein expressions were significantly decreased in the kidneys and spleen. Treatment with recombinant murine MFG-E8 recovered renal dysfunction, significantly suppressed inflammatory responses, apoptosis, necrosis, and improved capillary functions in the kidneys. In the survival study, MFG-E8 mice showed a significant deterioration and, in contrast, recombinant murine MFG-E8-treated wild-type mice showed a significant improvement of survival compared with vehicle-treated wild-type mice.. MFG-E8 can be developed as novel treatment for renal ischemia-reperfusion injury. This protective effect appears to be mediated through the enhancement of apoptotic cell clearance and improvement of capillary functions in the kidneys.

Topics: Animals; Antigens, Surface; Apoptosis; Blotting, Western; Disease Models, Animal; In Situ Nick-End Labeling; Inflammation; Ischemia; Kidney; Liver; Male; Mice; Mice, Inbred C57BL; Milk Proteins; Peroxidase; Recombinant Proteins; Reperfusion Injury; Reverse Transcriptase Polymerase Chain Reaction; Spleen

Tumour necrosis factor (TNF)-α plays a critical role in the pathogenesis of T helper type 1-mediated colitis such as Crohn's disease. However, the roles of its two receptors in mediating pathology remain largely unknown. In this study, trinitrobenzene sulphonic acid (TNBS) was used to induce colitis in TNF-receptor single or double knock-out (DKO) BALB/c mice and in wild-type counterparts. TNF-R1(-/-) mice had significantly less weight loss, reduced mortality, colon shortening and oedema, colon histological damage and lower levels of colon myeloperoxidase compared with wild-type (WT) BALB/c mice. A similar manifestation was also observed in TNF-R2(-/-) and TNF-R1(-/-) TNF-R2(-/-) (TNF-R DKO) mice. Strikingly, systemic inflammatory response (including splenomegaly and monocyte expansion) was found in WT and TNF-R1(-/-) mice after TNBS, instead of TNF-R2(-/-) and TNF-R DKO mice. Attenuated pathology of colitis in TNF-R1(-/-) or TNF-R2(-/-) mice correlated with lower amounts of interleukin (IL)-6, IL-1β, monocyte chemotactic protein (MCP)-1, IL-12p70 and interferon (IFN)-γ production in the colons. Importantly, ablation of TNF-R1 or TNF-R2 reduced the number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labelling (TUNEL)-positive apoptotic epithelial cells in the affected colons compared with WT TNBS-instilled controls, which might be due to the heightened ratio of Bcl-2/Bax and reduced activity of nuclear factor (NF)-κB. These findings suggest that either TNF-R1 or TNF-R2 plays a pathogenic role in the pathology of colitis and TNF signalling via TNF-R1 or TNF-R2 alone is not sufficient for inducing mucosal damage.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Body Weight; Chemokines; Colitis, Ulcerative; Colon; Cytokines; Edema; Gene Expression; Granulocytes; I-kappa B Proteins; Inflammation; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Monocytes; Neutrophils; NF-KappaB Inhibitor alpha; Organ Size; Peroxidase; Proto-Oncogene Proteins c-bcl-2; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; Spleen; Survival Analysis; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

Sulfur mustard (SM, bis(2-chloroethyl)sulfide) is a bifunctional alkylating agent that causes dermal inflammation, edema and blistering. To investigate the pathogenesis of SM-induced injury, we used a vapor cup model which provides an occlusive environment in which SM is in constant contact with the skin. The dorsal skin of SKH-1 hairless mice was exposed to saturated SM vapor or air control. Histopathological changes, inflammatory markers and DNA damage were analyzed 1-14 days later. After 1 day, SM caused epidermal thinning, stratum corneum shedding, basal cell karyolysis, hemorrhage and macrophage and neutrophil accumulation in the dermis. Cleaved caspase-3 and phosphorylated histone 2A.X (phospho-H2A.X), markers of apoptosis and DNA damage, respectively, were increased whereas proliferating cell nuclear antigen (PCNA) was down-regulated after SM exposure. By 3 days, epithelial cell hypertrophy, edema, parakeratosis and loss of epidermal structures were noted. Enzymes generating pro-inflammatory mediators including myeloperoxidase and cyclooxygenase-2 were upregulated. After 7 days, keratin-10, a differentiation marker, was evident in the stratum corneum. This was associated with an underlying eschar, as neoepidermis began to migrate at the wound edges. Trichrome staining revealed increased collagen deposition in the dermis. PCNA expression in the epidermis was correlated with hyperplasia, hyperkeratosis, and parakeratosis. By 14 days, there was epidermal regeneration with extensive hyperplasia, and reduced expression of cleaved caspase-3, cyclooxygenase-2 and phospho-H2A.X. These findings are consistent with the pathophysiology of SM-induced skin injury in humans suggesting that the hairless mouse can be used to investigate the dermatoxicity of vesicants and the potential efficacy of countermeasures.

Topics: Animals; Apoptosis; Biomarkers; Caspase 3; Cell Degranulation; Cell Differentiation; Cyclooxygenase 2; DNA Damage; Histones; Inflammation; Keratinocytes; Keratins; Male; Mast Cells; Mice; Mice, Hairless; Mustard Gas; Peroxidase; Proliferating Cell Nuclear Antigen; Skin; Staining and Labeling; Wound Healing

Although adrenomedullin (AM) is known to ameliorate inflammatory processes, few data exist regarding the effect of AM on inflammatory colitis. Therefore, we examined the effect of AM on inflammatory response in vitro and in vivo colitis model.. In mice experimental colitis induced by 3% dextran sulfate sodium (DSS) in drinking water for 7 days, AM with 225-900 μg/kg in 0.5 ml of saline or saline alone were given intraperitoneally once a day. In the in vitro experiment, we determined the cytokine response in THP-1 cell activated by lipopolysaccharide with or without AM of 10 nM. Additionally, we performed wound healing assay in Caco-2 cell interfered by DSS with or without AM of 100 nM.. In the colitis model, AM significantly reduced the disease activity index, histological score, and local production of inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in accordance with reduction of serum amyloid A levels. Secretion of TNF-α in lipopolysaccharide-stimulated THP-1 cells was significantly reduced in the presence of AM. The distance of wound healing interfered by 0.25% DSS was significantly improved in the presence of AM of 100 nM.. These results demonstrate that AM could ameliorate DSS-induced experimental colitis possibly through suppression of systemic and local production of cytokines such as TNF-α, associated with acceleration of ulcer reepithelialization and colon tissue regeneration.

Topics: Adrenomedullin; Animals; Body Weight; Cell Line; Cell Movement; Colitis; Colon; Cytokines; Dextran Sulfate; Epithelium; Humans; Inflammation; Inflammation Mediators; Male; Mice; Mice, Inbred BALB C; Peroxidase; Serum Amyloid A Protein; Ulcer; Up-Regulation

We previously reported an increase in matrix metalloproteinase-9 (MMP-9) levels in the olfactory bulb immediately after nerve transection; however, its role remains unknown. In this study, we determined the source of MMP-9 by monitoring the infiltration of inflammatory leukocytes in the olfactory bulb after nerve transection. We used myeloperoxidase to identify neutrophils and CD68 to identify macrophages at days 1, 7, and 10. MMP-9 colocalized with neutrophils at all three time points but was not contained in macrophages. This is the first study to demonstrate that MMP-9 is associated with early inflammatory response after olfactory injury, and provides insight into mechanisms underlying olfactory injury and recovery processes.

Topics: Animals; Biomarkers; Cell Migration Assays, Macrophage; Immunohistochemistry; Inflammation; Macrophages; Matrix Metalloproteinase 9; Mice; Microscopy, Confocal; Neutrophils; Olfactory Bulb; Olfactory Nerve; Olfactory Nerve Injuries; Peroxidase

Eosinophilic inflammation in chronic obstructive pulmonary disease (COPD) is predictive for responses to inhaled steroids. We hypothesised that the inflammatory subtype in mild and moderate COPD can be assessed by exhaled breath metabolomics. Exhaled compounds were analysed using gas chromatography and mass spectrometry (GC-MS) and electronic nose (eNose) in 28 COPD patients (12/16 Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I/II, respectively). Differential cell counts, eosinophil cationic protein (ECP) and myeloperoxidase (MPO) were measured in induced sputum. Relationships between exhaled compounds, eNose breathprints and sputum inflammatory markers were analysed and receiver operating characteristic (ROC) curves were constructed. Exhaled compounds were highly associated with sputum cell counts (eight compounds with eosinophils, 17 with neutrophils; p < 0.01). Only one compound (alkylated benzene) overlapped between eosinophilic and neutrophilic profiles. GC-MS and eNose breathprints were associated with markers of inflammatory activity in GOLD stage I (ECP: 19 compounds, p < 0.01; eNose breathprint r = 0.84, p = 0.002) (MPO: four compounds, p < 0.01; eNose r = 0.72, p = 0.008). ROC analysis for eNose showed high sensitivity and specificity for inflammatory activity in mild COPD (ECP: area under the curve (AUC) 1.00; MPO: AUC 0.96) but not for moderate COPD. Exhaled molecular profiles are closely associated with the type of inflammatory cell and their activation status in mild and moderate COPD. This suggests that breath analysis may be used for assessment and monitoring of airway inflammation in COPD.

Topics: Aged; Asthma; Biomarkers; Breath Tests; Cell Count; Eosinophil Cationic Protein; Exhalation; Female; Humans; Inflammation; Male; Metabolomics; Middle Aged; Peroxidase; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; ROC Curve; Sensitivity and Specificity; Severity of Illness Index; Sputum

Because imperatorin (IPT), the furanocoumarins exhibits anti-inflammatory activity, we reasoned that IPT might modulate the allergic rhinitis (AR). The aim of this study was to analyze the regulation of AR by IPT. Here, we show the effect and mechanism of IPT in an ovalbumin (OVA)-induced AR model. The number of rubs after the OVA challenge in the OVA-sensitized mice was significantly higher than that in the OVA-unsensitized mice. The increased number of rubs was inhibited by the oral administration of IPT. The increased levels of IgE and histamine in the OVA-sensitized mice were reduced by IPT administration. The levels of interferon-γ were enhanced, whereas the levels of interleukin (IL)-4 were reduced on the spleen tissue of the IPT-administered AR mice. Protein levels of IL-1β, macrophage inflammatory protein-2, intercellular adhesion molecule-1, and cyclooxygenase-2 were reduced by IPT administration in the nasal mucosa of the OVA-sensitized mice. In the IPT-administered mice, the number of eosinophils and mast cells infiltration increased by OVA-sensitization were also decreased. In addition, IPT inhibited caspase-1 activity in the same nasal mucosa tissue. In activated human mast cells, the receptor-interacting protein 2 (RIP2), IκB kinase (IKK)-β, nuclear factor-κB (NF-κB)/RelA, and caspase-1 activation were increased, but increased RIP2, IKK-β, NF-κB/RelA, and caspase-1 activation were inhibited by the treatment of IPT. In addition, IPT inhibited caspase-1 activity and IL-1β production in IgE-stimulated bone marrow-derived mast cells. We can conclude that IPT exerts significant effects by regulating of caspase-1 activation in AR animal and in vitro models.

Topics: Animals; Blotting, Western; Bone Marrow Cells; Caspase 1; Caspase Inhibitors; Cell Line; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Furocoumarins; Histamine; Histamine Release; Humans; I-kappa B Proteins; Inflammation; Mast Cells; Mice; Mice, Inbred BALB C; Nasal Mucosa; Ovalbumin; Peroxidase; Receptor-Interacting Protein Serine-Threonine Kinase 2; Receptor-Interacting Protein Serine-Threonine Kinases; Reverse Transcriptase Polymerase Chain Reaction; Rhinitis, Allergic, Perennial

The purpose of this study is to demonstrate that NADPH oxidase mediating the ROS production is the major pathway for ROS generation in neutrophils during exercise. NADPH oxidase, as a target can modulate oxidative damage induced by overtraining, which can be value to the prevention of exercise-induced immunosuppression.. Thirty male Wistar rats were randomly divided into three groups: a negative control group (C, n = 10), an overtraining group (E, n = 10) and an overtraining + DPI intervention group (D, n =10). Groups E and D were trained on a standard treadmill with progressive load for 11 weeks. After 36-40 h from the last training, eight rats were randomly selected from each group, and blood was sampled from the orbital vein. ELISAs were used to measure serum cytokine levels and lipid peroxidation in blood plasma. Flow cytometry with Annexin V/PI double staining was used to measure neutrophil apoptosis and necrosis. DNA damage in lymphocytes was tested using single cell gel electrophoresis (SCGE). The co-localization between gp91(phox) and p47(phox) of the NADPH-oxidase was detected using immunocytochemistry and confocal microscopy.. 1) Compared with group C, the concentrations of IL-1β, IL-8, and TNF-α were significantly increased and MCP-1, and CINC were significantly decreased in blood plasma from group E (P < 0.01 and P < 0.05, respectively). Concentrations of IL-1β and MCP-1 were decreased (P < 0.05), and IL-8 and TNF-α were significantly increased (P <0.05) in blood plasma from group D. MDA and MPO were elevated in plasma from groups E and D (P < 0.01 and P < 0.05, respectively). 2) Compared with group C, the percentage of neutrophils apoptosis were significantly elevated (P < 0.01) in both groups E and D, and the percentage of cell death was raised in group E (P < 0.05). No significant change was observed in group D. 3) Compared with group C, the number of comet cells, an indicator of DNA damage, was significantly increased (P < 0.01), and the width and tail length of comet cells were notably increased in group E, while no significant increase was observed in group D. 4) The p47(phox )protein translocated to the cell membrane and co-localized with the gp91(phox) subunit of NADPH oxidase in neutrophils activated by overtraining.. 1) Excessive exercise led to an increased secretion of inflammatory cytokines and chemokines in peripheral blood, and it may have induced tissue inflammation 2) Overtraining can activate the NADPH oxidase-mediated overproduction of ROS, leading to increased lipid peroxidation. 3) NADPHoxidase in neutrophils as a target, was responsible for ROS, oxidative damage to phagocytes and lymphocytes and changes to inflammatory cytokines and immune regulatory factors all affect cellular immune functions and may be causative factors for exercise-induced immunosuppression.

Topics: Animals; Apoptosis; Comet Assay; Cytokines; Immune Tolerance; Immunohistochemistry; Inflammation; Male; Membrane Glycoproteins; Microscopy, Confocal; NADPH Oxidase 2; NADPH Oxidases; Neutrophils; Peroxidase; Physical Conditioning, Animal; Rats; Rats, Wistar; Reactive Oxygen Species

Mineral trioxide aggregate (MTA) and calcium hydroxide [Ca(OH)(2)] are promising biomaterials for stimulating dentinogenesis and cementogenesis. This research was undertaken to understand how MTA and CA(OH)(2) participate in the inflammatory, healing, and biomineralization processes. In this part of the study, we evaluated inflammatory signaling molecules promoted by in vivo host interaction with MTA and Ca(OH)(2).. Human dentin tubes were filled with ProRoot MTA (Dentsply Tulsa Dental, Tulsa, OK), Ca(OH)(2), or kept empty. After 12 hours and 1, 3, 7, 15, 30, and 60 days of implantation in subcutaneous tissues in the backs of mice, the tubes and surrounding tissues were retrieved for cytokine level quantification and histological and immunohistochemical analysis.. MTA and Ca(OH)(2) induced proinflammatory cytokine up-regulation for up to 3 days. Moreover, interleukin-10 overexpression was noted on the tissue in contact with the biomaterials during the acute phase of the inflammatory reaction. Immunohistochemical analyses showed an increased expression of myeloperoxidase, nuclear factor kappa B (NF-κB), cyclooxygenase-2, inducible nitric oxide synthase enzymes, and vascular endothelial growth factor on day 1 for all groups.. MTA and Ca(OH)(2) increased the activation of the NF-κB signaling system on day 1 for all groups. This finding can be associated with a proinflammatory and pro-wound healing environment, which was promoted earlier by MTA.

Topics: Aluminum Compounds; Animals; Calcification, Physiologic; Calcium Compounds; Calcium Hydroxide; Cyclooxygenase 2; Drug Combinations; Humans; Inflammation; Interleukin-10; Interleukin-1beta; Mice; NF-kappa B; Nitric Oxide Synthase Type II; Oxides; Peroxidase; Root Canal Filling Materials; Signal Transduction; Silicates; Up-Regulation; Vascular Endothelial Growth Factor A; Wound Healing

Myeloperoxidase (MPO) is an important enzyme that catalyzes the reaction between hydrogen peroxide and chloride to generate hypochlorous acid, which oxidizes a range of biomolecules and has been associated with inflammatory diseases. The synthetic compounds N-phenylmaleimide (NFM) and 4-methyl-N-phenylmaleimide (Me-NFM) increased the MPO activity in vitro (of isolated enzyme and in isolated cells after animal treatment) and in vivo assays. MPO-induction may represent a good model system to investigate the molecular and cellular mechanisms of oxidative cell injury induced by activated neutrophils, and the interactions between damaging species involved in the respiratory burst.

Topics: Animals; Disease Models, Animal; Enzyme Activation; Inflammation; Male; Maleimides; Mice; Neutrophils; Oxidative Stress; Peroxidase; Rats; Rats, Wistar

This study investigated the effect of Urtica dioica, known as stinging nettle, seed oil (UDO) treatment on colonic tissue and blood parameters of trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats. Experimental colitis was induced with 1 mL of TNBS in 40% ethanol by intracolonic administration with a 8-cm-long cannula with rats under ether anesthesia, assigned to a colitis group and a colitis+UDO group. Rats in the control group were given saline at the same volume by intracolonic administration. UDO (2.5 mL/kg) was given to the colitis+UDO group by oral administration throughout a 3-day interval, 5 minutes later than colitis induction. Saline (2.5 mL/kg) was given to the control and colitis groups at the same volume by oral administration. At the end of the experiment macroscopic lesions were scored, and the degree of oxidant damage was evaluated by colonic total protein, sialic acid, malondialdehyde (MDA), and glutathione levels, collagen content, tissue factor activity, and superoxide dismutase and myeloperoxidase activities. Colonic tissues were also examined by histological and cytological analysis. Pro-inflammatory cytokines (tumor necrosis factor-α, interleukin-1β, and interleukin-6), lactate dehydrogenase activity, and triglyceride and cholesterol levels were analyzed in blood samples. We found that UDO decreased levels of pro-inflammatory cytokines, lactate dehydrogenase, triglyceride, and cholesterol, which were increased in colitis. UDO administration ameliorated the TNBS-induced disturbances in colonic tissue except for MDA. In conclusion, UDO, through its anti-inflammatory and antioxidant actions, merits consideration as a potential agent in ameliorating colonic inflammation.

Topics: Administration, Oral; Animals; Antioxidants; Cholesterol; Colitis; Colon; Disease Models, Animal; Female; Glutathione; Inflammation; Interleukin-6; L-Lactate Dehydrogenase; Male; Malondialdehyde; N-Acetylneuraminic Acid; Oxidative Stress; Peroxidase; Plant Oils; Rats; Rats, Wistar; Seeds; Superoxide Dismutase; Triglycerides; Trinitrobenzenesulfonic Acid; Urtica dioica

We conducted this study to evaluate the effects of thoracic epidural anesthesia (TEA) on inflammatory response, lipid peroxidation, and oxidative stress in a rat model of mesenteric ischemia/reperfusion (I/R).. Rats were divided into 4 groups: sham group (n=6; sham laparotomy), control group (n=6; I/R), bupivacaine group (n=6; mesenteric I/R and 20 μL/h 0.5% bupivacaine), and saline group (n=6, mesenteric I/R and 20 μL/h 0.9% saline). I/R injury was established by occluding the superior mesenteric artery for 1 hour followed by 12 hours reperfusion. Blood gas, tumor necrosis factor-α, interleukin-6, interleukin-1β, glutathione peroxidise, superoxide dismutase, catalese, myeloperoxidase concentrations, immunohistochemical examinations (intracellular adhesion molecule-1), apoptosis determination, and wet/dry ratio of intestinal edema were determined.. Bupivacaine significantly decreased the cytokine, malondialdehyde, and myeloperoxidase levels and increased the antioxidant enzyme levels. Wet/dry ratio comparison showed a significant decrease in the bupivacaine (2.88±0.17) group in comparison with control (5.45±0.67) and saline (5.87±0.17) groups. The intestinal injury score was significantly decreased in rats in the epidural bupivacaine (2 [1-2]) infusion group in comparison with rats in the control (3 [2-3]) and saline (3 [2-4]) groups. Bupivacaine (63%) caused a significant decrease in the percentage of apoptotic cells in comparison with control (85%) only. ICAM-1 levels in the bupivacaine (27.4±7.1) group decreased in comparison with control (12.3±7.4) and saline (24.9±3.2) groups.. This study demonstrated that epidural bupivacaine attenuates the mesenteric I/R-related inflammatory response and intestinal damage.

Topics: Anesthesia, Epidural; Anesthetics, Local; Animals; Apoptosis; Bupivacaine; Catalase; Catheterization; Cytokines; Glutathione Peroxidase; Immunohistochemistry; Inflammation; Intercellular Adhesion Molecule-1; Intestinal Mucosa; Intestines; Lipid Peroxidation; Male; Malondialdehyde; Mesenteric Artery, Superior; Oxidative Stress; Peroxidase; Rats; Rats, Wistar; Reperfusion Injury; Superoxide Dismutase; Thoracic Vertebrae

Myeloperoxidase (MPO) is a prime candidate for promoting oxidative stress during inflammation. This abundant enzyme of neutrophils uses hydrogen peroxide to oxidize chloride to highly reactive and toxic chlorine bleach. We have identified 2-thioxanthines as potent mechanism-based inactivators of MPO. Mass spectrometry and x-ray crystal structures revealed that these inhibitors become covalently attached to the heme prosthetic groups of the enzyme. We propose a mechanism whereby 2-thioxanthines are oxidized, and their incipient free radicals react with the heme groups of the enzyme before they can exit the active site. 2-Thioxanthines inhibited MPO in plasma and decreased protein chlorination in a mouse model of peritonitis. They slowed but did not prevent neutrophils from killing bacteria and were poor inhibitors of thyroid peroxidase. Our study shows that MPO is susceptible to the free radicals it generates, and this Achilles' heel of the enzyme can be exploited to block oxidative stress during inflammation.

Topics: Animals; Crystallography, X-Ray; Disease Models, Animal; Enzyme Inhibitors; Humans; Inflammation; Mice; Neutrophils; Oxidation-Reduction; Oxidative Stress; Peritonitis; Peroxidase; Xanthines

Inflammation and angiogenesis are key components of fibrovascular tissue growth, a biological event underlying both physiological (wound healing) and pathological conditions (tumor development, chronic inflammation). We investigated these components in three frequently used mouse strains (Swiss, Balb/c and C57BL/6J) to verify the influence of genetic background on the kinetics of inflammatory cell recruitment/activation, neovascularization, extracellular matrix deposition, and cytokine production in polyether-polyurethane sponge implanted subcutaneously in male mice of these strains. The kinetics of neutrophil recruitment/activation as assessed by myeloperoxidase (MPO) activity was 2- and 3-fold higher in Balb/c implants at day 1 compared with Swiss and C57BL/6J implants, respectively. Macrophage accumulation/activation as NAG (n-acetyl β-glucosaminidase) activity was higher in Swiss implants. The levels the monocyte chemoattractant protein 1 (CCL2(MCP-1)) peaked at day 10 in the three types of implants but was produced more by C57BL/6J mice. Angiogenesis (hemoglobin, vascular endothelial growth factor-VEGF, and number of vessels) differed among the strains. Swiss implants had the highest hemoglobin content but the lowest VEGF levels. In contrast, Balb/c implants had higher VEGF levels but lower hemoglobin. Collagen deposition and transforming growth factor β-1; TGFβ-1 levels also varied among the groups. Swiss and Balb/c implants had progressive increase in TGFβ-1 from 4 to 14 days, while C57BL/6J implants achieved the peak at day 10 and fell at day 14. These findings emphasize the major contribution of genetic background in the temporal pattern and intensity of inflammatory angiogenesis components that may have functional consequences in physiological and pathological conditions where these processes co-exist.

Topics: Acetylglucosaminidase; Animals; Chemokine CCL2; Collagen; Disease Models, Animal; Hemoglobins; Inflammation; Kinetics; Macrophages; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neovascularization, Pathologic; Neovascularization, Physiologic; Neutrophil Infiltration; Peroxidase; Regional Blood Flow; Skin; Species Specificity; Transforming Growth Factor beta1; Vascular Endothelial Growth Factor A

Our goal was to characterize the neuroprotective properties of orally administered phosphatidylcholine (PC) in a rodent model of systemic inflammation. Sprague-Dawley rats were killed at 3 h, 1 day, 3 days, or 7 days after i.p. administration of lipopolysaccharide (LPS) to determine the plasma levels of tumor necrosis factor α (TNF-α) and interleukin 6 cytokines. The control group and one group of LPS-treated animals were nourished with standard laboratory chow, whereas another LPS-treated group received a special diet enriched with 1% PC for 5 days before the administration of LPS and thereafter during the 7-day observation period. Immunohistochemistry was performed to visualize the bromodeoxyuridine and doublecortin-positive neuroprogenitor cells and Iba1-positive microglia in the hippocampus, whereas the degree of mucosal damage was evaluated on ileal and colon biopsy samples after hematoxylin-eosin staining. The activities of proinflammatory myeloperoxidase and xanthine-oxidoreductase and the tissue nitrite/nitrate (NOx) level were additionally determined, and the cognitive functions were monitored via Morris water maze testing. The inflammatory challenge transiently increased the hippocampal NOx level and led to microglia accumulation and decreased neurogenesis. The intestinal damage, mucosal myeloperoxidase, xanthine-oxidoreductase, and NOx changes were less pronounced, and long-lasting behavioral alterations were not observed. Phosphatidylcholine pretreatment reduced the plasma TNF-α and hippocampal NOx changes and prevented the decreased neurogenesis. These data demonstrated the relative susceptibility of the brain to the consequences of transient peripheral inflammatory stimuli. Phosphatidylcholine supplementation did not reduce the overall extent of peripheral inflammatory activation, but efficiently counteracted the disturbed hippocampal neurogenesis by lowering circulating TNF-α concentrations.

Topics: Animals; Doublecortin Protein; Hippocampus; Ileum; Immunohistochemistry; Inflammation; Lipopolysaccharides; Male; Microglia; Neurons; Peroxidase; Phosphatidylcholines; Rats; Rats, Sprague-Dawley; Stem Cells; Tumor Necrosis Factor-alpha; Xanthine Dehydrogenase

Systemic inflammatory mediators play an important role in the development of sepsis. In this study, we analyzed the role of Rho kinase in the activation of immune response and acute lung injury in a mouse model of sepsis.. C57BL/6J mice were randomly divided into three groups: control, LPS, and LPS+fasudil. We used a mouse model of endotoxemia that consists of intraperitoneal injection of a high dose of LPS (30 mg/kg); a Rho kinase inhibitor, fasudil (10 mg/kg), dissolved in sterile saline (1 μL/g body weight) was applied by intraperitoneal injection at 18 and 1 h before injection of LPS (LPS+fasudil group). The control mice received vehicle sterile saline only. Blood was collected and lungs were harvested at 3 and/or 6 h for analysis.. At 3 and 6 h, the increased TNF-α and IL-1β levels in plasma and MPO activity in lung tissue by LPS could be significantly inhibited by fasudil. In addition, LPS-induced histologic changes in the lungs at 6 h could be effectively reversed by fasudil pretreatment. Furthermore, pretreatment of mice with fasudil inhibited LPS-induced increasing of TNF-α, IL-1β mRNA expression (3 and 6 h) and AP-1/DNA binding activity (3 h) in blood cells. In survival studies, fasudil (10 mg/kg), which was administered 18 and 1 h before the application of LPS, conferred a protection against lethality induced by LPS (30 mg/kg).. These results suggest that Rho kinase may play a role in the pathology of systemic inflammation during early phase of sepsis, and the potential mechanism of action may be partly through the adjustment of AP-1 pathway.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Acute Lung Injury; Animals; Disease Models, Animal; Inflammation; Interleukin-1beta; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Peroxidase; Protein Kinase Inhibitors; rho-Associated Kinases; Survival Rate; Transcription Factor AP-1; Tumor Necrosis Factor-alpha

Dysregulation of TNF-α in lamina propria macrophages (LPM) is a feature of inflammatory bowel diseases (IBD). LPS-Induced-TNF-Alpha-Factor (LITAF) is a transcription factor that mediates TNF-α expression. To determine whether LITAF participates in the mediation of TNF-α expression in acutely inflamed colonic tissues, we first established the TNBS-induced colonic inflammation model in C57BL/6 mice. LPM were harvested from non-inflamed and inflamed colonic tissue and inflammatory parameters TNF-α and LITAF mRNA and protein levels were measured ex-vivo. LPM from TNBS-treated mice secreted significantly more TNF-α at basal state and in response to LPS than LPM from untreated mice (p<0.05). LITAF mRNA and protein levels were elevated in LPM from TNBS compared with untreated animals and LPS further increased LITAF protein levels in LPM from inflamed tissue (P<0.05). To further confirm the role of LITAF in acutely inflamed colonic tissues, TNBS-induced colonic inflammation was produced in LITAF macrophage specific knockout mice (LITAF mac -/- mice) and compared to wild type (WT) C57BL/6. Twenty four hours following TNBS administration, colonic tissue from LITAF mac -/- mice had less MPO activity and reduced colonic TNF-α mRNA then WT C57BL/6 mice (p<0.05). LPM harvested from LITAF mac -/- secreted significantly less TNF-α in response to LPS than wild type (WT) C57BL/6 (p<0.05). This study provides evidence that LITAF contributes to the regulation of TNF-α in LPM harvested following acute inflammation or LPS treatment paving the way for future work focusing on LITAF inhibitors in the treatment of TNF-α-mediated inflammatory conditions.

Topics: Animals; Blotting, Western; Colon; DNA-Binding Proteins; Enzyme-Linked Immunosorbent Assay; Inflammation; Lipopolysaccharides; Macrophages; Mice; Mice, Inbred C57BL; Mucous Membrane; Nuclear Proteins; Peroxidase; Reverse Transcriptase Polymerase Chain Reaction; Transcription Factors; Tumor Necrosis Factor-alpha

The inflammatory response is an active process in cervical cancer and may act in the progression and/or regression of the lesion. At the site of inflammation, macrophages and neutrophils are present as well as cytokines such as TNF-α and IFN-γ. This study aims to evaluate the inflammatory response levels in women with cervical intraepithelial lesions (CIN) and with squamous cell carcinoma (SCC) of the cervix. Serum samples obtained from women without evidence of disease (n=30), with CIN (n=30) and with SCC of the cervix (n=30) were analyzed for the activities of N-acetylglucosaminidase (NAG) and myeloperoxidase (MPO) by enzymatic assay and the serum levels of TNF-α and IFN-γ by ELISA assay. The activities of NAG and MPO and the level of TNF-α were higher in women with CIN compared to the women with SCC. The levels of IFN-γ were lower in the group of women with CIN compared to the group with SCC. There was not a significant association between the degree of the CIN and the staging of the SCC of the cervix and the degree of inflammation as assessed by the levels of inflammatory markers. The inflammatory response was inversely correlated with the progression of the carcinogenic process. In the three groups, the control group, women with CIN and women with invasive SCC, there was no association between the degree of preinvasive lesions and staging of the SCC of the cervix.

Topics: Acetylglucosaminidase; Adult; Aged; Biomarkers; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Disease Progression; Female; Humans; Immunologic Surveillance; Inflammation; Interferon-gamma; Macrophage Activation; Macrophages; Middle Aged; Neutrophils; Peroxidase; Tumor Necrosis Factor-alpha; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms

Resveratrol, a polyphenol compound with anti-inflammatory properties, has been previously evaluated for its beneficial effects in several ulcerative colitis models. However, the current study elucidates the effect of resveratrol on adhesion molecules, as well as its antioxidant efficacy in a trinitrobenzene sulfonic acid (TNBS)-induced ulcerative-colitis model. Colitis was induced by rectal instillation of TNBS, followed by daily per os administration of either sulphasalazine (300 mg/kg) or resveratrol (2 and 10 mg/kg) for 7 days. Administration of resveratrol decreased the ulcerative area and colon mass index; these effects were further supported by the reduction in colon inflammation grades, as well as histolopathological changes, and reflected by the stalling of body mass loss. The anti-inflammatory effects of resveratrol were indicated by lowered myeloperoxidase activity, and by suppressing ICAM-1 and VCAM-1 levels in the colon and serum. In addition, it restored a reduced colonic nitric oxide level and reinstated its redox balance, as evidenced by the suppression of lipid peroxides and prevention of glutathione depletion. The anti-ulcerative effect of the higher dose of resveratrol was comparable with those of sulphasalazine. The study confirms the anti-ulcerative effect of resveratrol in TNBS-induced experimental colitis via reduction of neutrophil infiltration, inhibition of adhesive molecules, and restoration of the nitric oxide level, as well as the redox status.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Body Weight; Cell Adhesion Molecules; Colitis, Ulcerative; Colon; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Glutathione; Inflammation; Intercellular Adhesion Molecule-1; Lipid Peroxidation; Male; Peroxidase; Rats; Rats, Wistar; Resveratrol; Stilbenes; Sulfasalazine; Trinitrobenzenesulfonic Acid; Vascular Cell Adhesion Molecule-1