Key Inflammatory Molecules Research Articles

Molecular Mechanisms and New Treatment Paradigm for Atrial Fibrillation.

Atrial fibrillation represents the most common arrhythmia leading to increased morbidity and mortality, yet, current treatment strategies have proven inadequate. Conventional treatment with antiarrhythmic drugs carries a high risk for proarrhythmias. The soluble epoxide hydrolase enzyme catalyzes the hydrolysis of anti-inflammatory epoxy fatty acids, including epoxyeicosatrienoic acids from arachidonic acid to the corresponding proinflammatory diols. Therefore, the goal of the study is to directly test the hypotheses that inhibition of the soluble epoxide hydrolase enzyme can result in an increase in the levels of epoxyeicosatrienoic acids, leading to the attenuation of atrial structural and electric remodeling and the prevention of atrial fibrillation. For the first time, we report findings that inhibition of soluble epoxide hydrolase reduces inflammation, oxidative stress, atrial structural, and electric remodeling. Treatment with soluble epoxide hydrolase inhibitor significantly reduces the activation of key inflammatory signaling molecules, including the transcription factor nuclear factor κ-light-chain-enhancer, mitogen-activated protein kinase, and transforming growth factor-β. This study provides insights into the underlying molecular mechanisms leading to atrial fibrillation by inflammation and represents a paradigm shift from conventional antiarrhythmic drugs, which block downstream events to a novel upstream therapeutic target by counteracting the inflammatory processes in atrial fibrillation.

An evidence-based review of the mechanism of action, efficacy, and safety of biologic therapies in the treatment of psoriasis and psoriatic arthritis.

Biologic agents have expanded the repertoire of efficacious and safe systemic therapies for the treatment of moderate-to-severe psoriasis and active psoriatic arthritis. The biologics act to inhibit key inflammatory molecules that are thought to be involved in the pathogenesis of these chronic inflammatory disorders as well as physiologic immune responses. In this paper, we discuss the proposed molecular mechanisms of action, efficacy, and safety of the two FDA-approved classes of biologics, the tumor necrosis factor inhibitors and the interleukin-12/23 inhibitor. The tumor necrosis factor inhibitors that are reviewed include etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol. The interleukin- 12/23 inhibitor that is discussed is ustekinumab. Specifically, we review the mechanism of action for each biologic agent and the FDA-approved indications and dosing for these therapeutics. We provide up-to-date evidence for the efficacy of these systemic medications using key phase 3 clinical trial data, we highlight important safety information for each biologic based on long-term open-label extension trials and safety registries, and we discuss studies that investigate off-label dosing with the biologics. Each biologic is reviewed in these specific areas of focus for their indicated treatment of psoriasis and/or psoriatic arthritis.

Inflammation: Therapeutic Targets for Diabetic Neuropathy

There are still no approved treatments for the prevention or of cure of diabetic neuropathy, and only symptomatic pain therapies of variable efficacy are available. Inflammation is a cardinal pathogenic mechanism of diabetic neuropathy. The relationships between inflammation and the development of diabetic neuropathy involve complex molecular networks and processes. Herein, we review the key inflammatory molecules (inflammatory cytokines, adhesion molecules, chemokines) and pathways (nuclear factor kappa B, JUN N-terminal kinase) implicated in the development and progression of diabetic neuropathy. Advances in the understanding of the roles of these key inflammatory molecules and pathways in diabetic neuropathy will facilitate the discovery of the potential of anti-inflammatory approaches for the inhibition of the development of neuropathy. Specifically, many anti-inflammatory drugs significantly inhibit the development of different aspects of diabetic neuropathy in animal models and clinical trials.

Baicalein Reduces Airway Injury in Allergen and IL-13 Induced Airway Inflammation

BackgroundBaicalein, a bioflavone present in the dry roots of Scutellaria baicalensis Georgi, is known to reduce eotaxin production in human fibroblasts. However, there are no reports of its anti-asthma activity or its effect on airway injury.Methodology/Principal FindingsIn a standard experimental asthma model, male Balb/c mice that were sensitized with ovalbumin (OVA), treated with baicalein (10 mg/kg, ip) or a vehicle control, either during (preventive use) or after OVA challenge (therapeutic use). In an alternate model, baicalein was administered to male Balb/c mice which were given either IL-4 or IL-13 intranasally. Features of asthma were determined by estimating airway hyperresponsiveness (AHR), histopathological changes and biochemical assays of key inflammatory molecules. Airway injury was determined with apoptotic assays, transmission electron microscopy and assessing key mitochondrial functions. Baicalein treatment reduced AHR and inflammation in both experimental models. TGF-β1, sub-epithelial fibrosis and goblet cell metaplasia, were also reduced. Furthermore, baicalein treatment significantly reduced 12/15-LOX activity, features of mitochondrial dysfunctions, and apoptosis of bronchial epithelia.Conclusion/SignificanceOur findings demonstrate that baicalein can attenuate important features of asthma, possibly through the reduction of airway injury and restoration of mitochondrial function.

Effects of Bariatric Surgery on Adipokine-Induced Inflammation and Insulin Resistance

Over a third of the US population is obese and at high risk for developing type 2 diabetes, insulin resistance, and other metabolic disorders. Obesity is considered a chronic low-grade inflammatory condition that is primarily attributed to expansion and inflammation of adipose tissues. Indeed, adipocytes produce and secrete numerous proinflammatory and anti-inflammatory cytokines known as adipokines. When the balance of these adipokines is shifted toward higher production of proinflammatory factors, local inflammation within adipose tissues and subsequently systemic inflammation occur. These adipokines including leptin, visfatin, resistin, apelin, vaspin, and retinol binding protein-4 can regulate inflammatory responses and contribute to the pathogenesis of diabetes. These effects are mediated by key inflammatory signaling molecules including activated serine kinases such as c-Jun N-terminal kinase and serine kinases inhibitor κB kinase and insulin signaling molecules including insulin receptor substrates, protein kinase B (PKB, also known as Akt), and nuclear factor kappa B. Bariatric surgery can decrease body weight and improve insulin resistance in morbidly obese subjects. However, despite reports suggesting reduced inflammation and weight-independent effects of bariatric surgery on glucose metabolism, mechanisms behind such improvements are not yet well understood. This review article focuses on some of these novel adipokines and discusses their changes after bariatric surgery and their relationship to insulin resistance, fat mass, inflammation, and glucose homeostasis.

Genetics of Cerebral Vasospasm

Cerebral vasospasm (CV) is a major source of morbidity and mortality in aneurysmal subarachnoid hemorrhage (aSAH). It is thought that an inflammatory cascade initiated by extravasated blood products precipitates CV, disrupting vascular smooth muscle cell function of major cerebral arteries, leading to vasoconstriction. Mechanisms of CV and modes of therapy are an active area of research. Understanding the genetic basis of CV holds promise for the recognition and treatment for this devastating neurovascular event. In our review, we summarize the most recent research involving key areas within the genetics and vasospasm discussion: (1) Prognostic role of genetics—risk stratification based on gene sequencing, biomarkers, and polymorphisms; (2) Signaling pathways—pinpointing key inflammatory molecules responsible for downstream cellular signaling and altering these mediators to provide therapeutic benefit; and (3) Gene therapy and gene delivery—using viral vectors or novel protein delivery methods to overexpress protective genes in the vasospasm cascade.

Molecular Signaling Involved in Oxysterol-Induced β1-Integrin Over-Expression in Human Macrophages

The hypercholesterolemia-atherosclerosis association is now established; hypercholesterolemia may induce vascular-cell activation, subsequently increasing expression of adhesion molecules, cytokines, chemokines, growth factors, and other key inflammatory molecules. Among inflammatory molecules expressed by vascular cells, integrins play a critical role in regulating macrophage activation and migration to the site of inflammation, by mediating cell-cell and cell-extracellular matrix interactions. The main lipid oxidation products present in oxidized LDL that may be responsible for inflammatory processes in atherogenesis, are cholesterol oxidation products, known as oxysterols. This study demonstrates the effect of an oxysterol mixture, compatible with that detectable in human hypercholesterolemic plasma, on the expression and synthesis of β1-integrin in cells of the macrophage lineage. The molecular signaling whereby oxysterols induce β1-integrin up-regulation is also comprehensively investigated. Over-expression of β1-integrin depends on activation of classic and novel members of protein kinase C and extracellular signal-regulated kinases 1 and 2, as well as of the up-stream G-protein (Gq and G13), c-Src, and phospholipase C. In addition, the localization of β1-integrin in advanced human carotid plaques is highlighted, marking its importance in atherosclerotic plaque progression.

Imidazolium salt attenuates thioacetamide-induced liver fibrosis in mice by modulating inflammation and oxidative stress

Background and aimOxidative stress contributes to liver fibrosis through the activation of hepatic stellate cells. In a cell-based screening study, a class of imidazolium salts demonstrates anti-fibrogenic properties. Little is known on imidazolium salt mechanistic effects. We investigated the anti-fibrogenic effect of one of the imidazolium salts, 1,3-bisbenzylimidazoliumbromide (DBZIM), in a chronic mouse model of liver fibrosis and evaluated the mechanism of this treatment. MethodsLiver fibrosis was induced in mice by oral feeding of thioacetamide for 16 weeks. DBZIM was administered weekly, starting on the first day or 12 weeks from the day of thioacetamide administration. Hepatic function, histology and oxidative stress were examined. Expression of key inflammatory molecules and the molecular mechanism of DBZIM were assessed in hepatic stellate cells. ResultsDBZIM decreased the fibrogenic response in thioacetamide-mice as measured by collagen deposition and α-smooth muscle actin expression (P<0.01). DBZIM improved liver function and reduced both oxidative damage and inflammation (P<0.01). Most importantly, our findings report the discovery that astrocyte elevated gene-1, involved in tumour progression, was up-regulated in thioacetamide-mice and DBZIM modulated astrocyte elevated gene-1 and NF-κB expression. ConclusionThese findings indicate DBZIM is a potent therapeutic agent for the treatment of liver fibrosis.

Mechanisms Behind the Anti-inflammatory Actions of Insulin

The epidemic of diabetes mellitus is worsening worldwide. Diabetes mellitus is a chronic metabolic disease characterized by inappropriate recurrent or persistent hyperglycemia. Numerous studies have demonstrated that hyperglycemia, the most significant predictor of poor clinical outcome in diabetes mellitus patients, can directly promote an inflammatory response and oxidative stress. Although there are various causes of DM, all eventually lead to absolute or relative insulin deficiency and death of pancreatic β-cells. Thus, insulin inevitably becomes the primary medication used to treat the disease and prevent diabetic complications in all DM patients. Interestingly, an emerging body of evidence suggests that insulin suppresses the inflammatory process, not only through preventing hyperglycemia but also by modulating key inflammatory molecules. In this review, we discuss the findings of studies done in vitro as well as clinical trials that have demonstrated an anti-inflammatory action of insulin and that have pointed to mechanisms responsible for this effect. Further, we discuss how the anti-inflammatory action of insulin bears on our current understanding of the pathophysiology and complications of both type 1 and type 2 diabetes.

α-Crystallin Downregulates the Expression of TNF-α and iNOS by Activated Rat Retinal Microglia in vitro and in vivo

Purpose: Inhibition of microglial activation has become an important strategy to attenuate neurotoxic damage to the central nervous system. We evaluated the effects of α-crystallin on the production of cytokines in lipopolysaccharides (LPS) and optic nerve injury-activated retinal microglia. Methods: Microglia were collected from retinas of newborn rats, cultured and treated with LPS in vitro. Microglia were also activated by an optic nerve crush in vivo. Pretreatments with and without α-crystallin were performed in cultured cells, and by intravitreal injection in adult rats. Expression of tumor necrosis factor-α (TNF-α), nitric oxide (NO) and inducible NOS synthase (iNOS) were measured by RT-PCR, ELISA, Western blot and the nitrate reductase method. Results: Activated microglia significantly upregulated TNF-α and iNOS mRNA expression and protein production in vitro. An optic nerve crush also increased expression of retinal iNOS and TNF-α protein. Treatment with α-crystallin in vitro and in vivo downregulated their expression. Conclusion: The protective effect of α-crystallin may be due to its effect on microglia via a downregulation in the expression and release of 2 key immune regulatory and inflammatory molecules: TNF-α and iNOS.

Adipose inflammation: cause or consequence of obesity-related insulin resistance

Obesity constitutes a critical risk factor for the development of many life threatening diseases, particularly insulin resistance and type 2 diabetes. Adipose tissue plays an important role in regulating whole body energy homeostatsis and obesity-related insulin resistance. Inflammation has been commonly linked to insulin resistance. Recent studies demonstrated that adipose tissue is an important source for producing inflammatory molecules in the obese state, primarily due to accumulation of macrophages. Animal models deficient in key inflammatory molecules or with reduced adipose macrophage infiltration are protected from development of obesity-related insulin resistance. Repression of adipose inflammation may be a useful approach to ameliorate obesity-associated metabolic disorders.

Altered gene expression in early atherosclerosis is blocked by low level apolipoprotein E.

BackgroundMice deficient in apolipoprotein E (apoE−/−) develop atherosclerosis. The possible linkage between expression of adhesion molecules/cofactors and atherosclerosis was probed at the level of mRNA and protein expression. The hypothesis of a linkage between changes of adhesion molecules/cofactors and atherosclerosis was tested further by suppression of aortic lesion formation in apoE−/− mice by expression of very low levels of transgenic apolipoprotein E.Methodology/Principal FindingsWe show that at 8.5 months of age, the apoE−/− mice display elevated expression of mRNA for LFA-1, MAC-1, VCAM-1, ICAM-1, and for CD44, as well as MCP-1, cathepsin B, and COX-2 (but not that for eNOS) in atherosclerotic aortic arches. At earlier age, (10–13 week old) apoE−/− mice already display elevated expression of mRNA of CD44, LFA-1, MAC-1, VCAM-1, ICAM-1, cathepsin, and of COX-2 in lesioned aortic arches. Expressing very low levels of transgenic apolipoprotein E suppresses both aortic lesions and the expression of mRNA of LFA-1, VCAM-1, MCP-1, cathepsin B, and of ICAM-1 in ApoE−/− mice. We tested at the level of protein, the observations obtained for mRNA expression. CD11a (a component of LFA-1), VCAM-1 and cathepsin B expression was found to be elevated in apoE−/− aortas at 8–9 months; low level expression of transgenic apolipoprotein E rectifies these changes.Conclusions/SignificanceAtherosclerotic lesions in apoE−/− mice are detected as early as 4 weeks of age. Expression of low levels of apoE is shown to be both atheroprotective and to suppress these changes in key adhesion and inflammatory molecules observed in early atherosclerotic lesions.

Targeting NOX, INOS and COX‐2 in inflammatory cells: Chemoprevention using food phytochemicals

Biological, biochemical and physical stimuli activate inflammatory leukocytes, such as macrophages, resulting in induction and synthesis of proinflammatory proteins and enzymes, together with free radicals, as innate immune responses. On the other hand, chronic and dysregulated activation of some inducible enzymes, including NADPH oxidase (NOX), inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, have been shown to play pivotal roles in the development of certain inflammatory diseases such as oncogenesis. While the use of synthetic agents, especially those targeting molecules, is an attractive and reasonable approach to prevent carcinogenesis, it should be noted that traditional herbs and spices also exist along with their active constituents, which have been demonstrated to disrupt inflammatory signal transduction pathways. In this mini-review, the molecular mechanisms of activation or induction of NOX, iNOS and COX-2, as well as some food phytochemicals with marked potential to regulate those key inflammatory molecules, are highlighted. For example, 1'-acetoxychavicol acetate, which occurs in the rhizomes of the subtropical Zingiberaceae plant, has been shown to attenuate NOX-derived superoxide generation in macrophages, as well as lipopolysaccharide-induced nitric oxide and prostaglandin E(2) production through the suppression of iNOS and COX-2 synthesis, respectively. Notably, this phytochemical has exhibited a wide range of cancer prevention activities in several rodent models of inflammation-associated carcinogenesis. Herein, the cancer preventive potentials of several food phytochemicals targeting the induction of NOX, iNOS and COX-2 are described.

The role of the purinergic P2X7 receptor in inflammation.

The inflammatory process, orchestrated against a variety of injurious stimuli, is composed of three inter-related phases; initiation, propagation and resolution. Understanding the interplay between these three phases and harnessing the beneficial properties of inflammation whilst preventing its damaging effects, will undoubtedly lead to the advent of much needed therapies, particularly in chronic disease states. The P2X7 receptor (P2X7R) is increasingly recognised as an important cell surface regulator of several key inflammatory molecules including IL-1β, IL-18, TNF-α and IL-6. Moreover, as P2X7R-dependent cytokine production is driven by activating the inflammasome, antagonists of this receptor are likely to have therapeutic potential as novel anti-inflammatory therapies. The function of the P2X7R in inflammation, immunity and its potential role in disease will be reviewed and discussed.

Age associated alterations in costimulatory and adhesion molecule expression in lupus-prone mice are attenuated by food restriction with n-6 and n-3 fatty acids.

Costimulatory and adhesion molecules are known to play a major role in the pathogenesis of systemic lupus erythematosus. Since fish oil and calorie restriction have been reported to attenuate the development of disease in lupus prone (NZBxNZW)F1 mice, the objective of this study was to assess the expression of these key inflammatory molecules in these mice fed diets differing in n-6 and n-3 fatty acid content and fed either food restricted or ad libitum. Age-associated increases in the expression of CD28, ICAM-1, and PGP-1 molecules that are involved in the recruitment of inflamed lymphocytes into the kidney were attenuated in mice restricted in food intake. The increase in costimulatory (CD80 and CD86) and adhesion (ICAM-1, PGP-1, LFA-1, and Mac-1) in peripheral blood mononuclear cells was also attenuated by food restriction and to a lesser extent by fish oil alone. Interestingly, amelioration of lupus (laminin expression and proteinuria) correlated with the above beneficial effects and could be seen even in 24-month-old mice. In summary, food restriction and fish oil delay the onset of lupus disease and increase life span in B/W mice by prolonging the maintenance of a youthful immune phenotype.

The Human Immunodeficiency Virus-1 Tat Protein Activates Human Umbilical Vein Endothelial Cell E-selectin Expression via an NF-κB-dependent Mechanism

Human immunodeficiency virus infection is associated with inflammation and endothelial cell activation that cannot be ascribed to direct infection by the virus or to the presence of opportunistic infections. Factors related to the virus itself, to the host and/or to environmental exposures probably account for these observations. The HIV protein Tat, a viral regulator required for efficient transcription of the viral genome in host cells is secreted from infected cells and taken up by uninfected by-stander cells. Tat can also act as a general transcriptional activator of key inflammatory molecules. We have examined whether Tat contributes to this endothelial cell activation by activating NF-kappaB. Human endothelial cells exposed to Tat in the culture medium activated E-selectin expression with delayed kinetics compared with tumor necrosis factor (TNF). Tat-mediated E-selectin up-regulation required the basic domain of Tat and was inhibited by a Tat antibody. Transfection of human E-selectin promoter-luciferase reporter constructs into Tat-bearing cells or into endothelial cells co-transfected with a Tat expression vector resulted in induction of luciferase expression. Either Tat or TNF activated p65 translocation and binding to an oligonucleotide containing the E-selectin kappaB site 3 sequence. Tat-mediated p65 translocation was also delayed compared with TNF. Neither agent induced new synthesis of p65. A super-repressor adenovirus (AdIkappaBalphaSR) that constitutively sequesters IkappaB in the cytoplasm as well as cycloheximide or actinomycin D inhibited Tat- or TNF-mediated kappaB translocation and E-selectin up-regulation.

Microglial activation by the small heat shock protein, alpha-crystallin.

Activated microglia regulate immune and inflammatory responses in the CNS under a variety of stresses due to infection, injury and disease. In this study, we show that a stress-inducible small heat shock protein, alpha-crystallin, induces in vitro activation of microglia cultured from newborn rat brain. Exposure of microglia to alpha-crystallin resulted in an increased production of nitric oxide (NO) and the expression of the inducible NO synthase (iNOS) as determined by Western blot and reverse transcriptase-polymerase chain reaction (RT-PCR) analyses. Alpha-crystallin also stimulated the synthesis of the pro-inflammatory cytokine, TNF alpha. The results presented showing microglial induction of the two key immune regulatory and inflammatory molecules, i.e., NO and TNF alpha, in response to a stress-inducible protein, suggest a link between environmental stress and the CNS immune response.