1,211,312 research outputs found

    The glucocorticoid receptor in inflammatory processes : transrepression is not enough

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    Glucocorticoids (GCs) are the most commonly used anti-inflammatory agents to treat inflammatory and immune diseases. However, steroid therapies are accompanied by severe side-effects during long-term treatment. The dogma that transrepression of genes, by tethering of the glucocorticoid receptor (GR) to DNA-bound pro-inflammatory transcription factors, is the main anti-inflammatory mechanism, is now challenged. Recent discoveries using conditional GR mutant mice and genomic approaches reveal that transactivation of anti-inflammatory acting genes is essential to suppress many inflammatory disease models. This novel view radically changes the concept to design selective acting GR ligands with a reduced side-effect profile

    Fetal skin as a pro-inflammatory organ: Evidence from a primate model of chorioamnionitis.

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    BackgroundIntrauterine infection is a primary cause of preterm birth and fetal injury. The pro-inflammatory role of the fetal skin in the setting of intrauterine infection remains poorly characterized. Whether or not inflammation of the fetal skin occurs in primates remains unstudied. Accordingly, we hypothesized that: i) the fetal primate skin would mount a pro-inflammatory response to preterm birth associated pro-inflammatory agents (lipopolysaccharides from Escherichia coli, live Ureaplasma parvum, interleukin-1β) and; ii) that inhibiting interleukin-1 signaling would decrease the skin inflammatory response.MethodsRhesus macaques with singleton pregnancies received intraamniotic injections of either sterile saline (control) or one of three pro-inflammatory agonists: E. coli lipopolysaccharides, interluekin-1β or live U. parvum under ultrasound guidance. A fourth group of animals received both E. coli lipopolysaccharide and interleukin-1 signaling inhibitor interleukin-1 receptor antagonist (Anakinra) prior to delivery. Animals were surgically delivered at approximately 130 days' gestational age.ResultsIntraamniotic lipopolysaccharide caused an inflammatory skin response characterized by increases in interluekin-1β,-6 and -8 mRNA at 16 hours. There was a modest inflammatory response to U. parvum, but interleukin-1β alone caused no inflammatory response in the fetal skin. Intraamniotic Anakinra treatment of lipopolysaccharide-exposed animals significantly reduced skin inflammation.ConclusionsIntraamniotic lipopolysaccharide and U. parvum were associated with modest increases in the expression of inflammatory mediators in primate fetal skin. Although administration of Interleukin-1β alone did not elicit an inflammatory response, lipopolysaccharide-driven skin inflammation was decreased following intraamniotic Anakinra therapy. These findings provide support for the role of the fetal skin in the development of the fetal inflammatory response

    The influence of surface morphology and wettability on the inflammatory response against poly(L-lactic acid): A semi-quantitative study with monoclonal antibodies

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    In this study, the influence of surface morphology and wettability of both degradable and nondegradable polymer films on the inflammatory response after subcutaneous implantation in the rat was investigated. Degradable nonporous, porous, and combi (porous with a nonporous layer on one side) poly(L-lactic acid) (PLLA) films and nondegradable polytetrafluoroethylene (PTFE) and (porous) expanded PTFE (e-PTFE) were used. Contact angles measurements indicate that PLLA is more hydrophillic than PTFE. Assessment of the inflammatory response was performed after various periods of implantation (up till 180 days), with both conventional light microscopy and immunohistochemistry using monoclonal antibodies (mAbs). The inflammatory response observed initially can largely be considered as part of the wound healing reaction, and up till day 40 the inflammatory response against PLLA was minimally more intense than against PTFE (porous as well as nonporous). From day 40 on, the PLLA films provoke a more intense inflammatory response as compared to the PTFE films. Both porous PLLA and the porous side of the combi PLLA film provoke a more intense inflammatory response than nonporous PLLA and the nonporous side of the combi PLLA film, respectively. In general, PTFE and e-PTFE films provoke an inflammatory response which is minimally more intense than the one provoked by the sham operation. Almost no ingrowth of tissue was observed in the porous e-PTFE films. In contrast, there was abundant tissue ingrowth in and an inflammatory response against porous PLLA. It can be concluded that biodegradable PLLA films provoke a more intense inflammatory response than nondegradable PTFE films. Also, porosity enhances the inflammatory response. However, porosity enhances the inflammatory response only when the wettability of a biomaterial permits cellular ingrowth

    Microbial imbalance in inflammatory bowel disease patients at different taxonomic levels

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    Background Inflammatory bowel disease (IBD), is a debilitating group of chronic diseases including Crohn’s Disease (CD) and ulcerative colitis (UC), which causes inflammation of the gut and affects millions of people worldwide. At different taxonomic levels, the structure of the gut microbiota is significantly altered in IBD patients compared to that of healthy individuals. However, it is unclear how these IBD-affected bacterial groups are related to other common bacteria in the gut, and how they are connected across different disease conditions at the global scale. Results In this study, using faecal samples from patients with IBD, we show through diversity analysis of the microbial community structure based on the 16S rRNA gene that the gut microbiome of IBD patients is less diverse compared to healthy individuals. Furthermore, we have identified which bacterial groups change in abundance in both CD and UC compared to healthy controls. A substantial imbalance was observed across four major bacterial phyla including Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria, which together constitute >98% of the gut microbiota. Next, we reconstructed a bacterial family co-abundance network based on the correlation of abundance profiles obtained from the public gut microbiome data of >22000 samples of faecal and gut biopsies taken from both diseased and healthy individuals. The data was compiled using the EBI metagenomics database [1]. By mapping IBD-altered bacterial families to the network, we show that the bacterial families which exhibit an increased abundance in IBD conditions are not well connected to other groups, implying that these families generally do not coexist together with common gut organisms. Whereas, the bacterial families whose abundance is reduced or did not change in IBD conditions compared to healthy conditions are very well connected to other bacterial groups, suggesting they are highly important groups of bacteria in the gut that can coexist with other bacteria across a range of conditions. Conclusions IBD patients exhibited a less diverse gut microbiome compared to healthy individuals. Bacterial groups which changed in IBD patients were found to be groups which do not co-exist well with common commensal gut bacteria, whereas bacterial groups which did not change in patients with IBD were found to commonly co-exist with commensal gut microbiota. This gives a potential insight into the dynamics of the gut microbiota in patients with IBD

    Dairy products and inflammation: a review of the clinical evidence

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    Inflammation is a major biological process regulating the interaction between organisms and the environment, including the diet. Because of the increase in chronic inflammatory diseases, and in light of the immune-regulatory properties of breastfeeding, the ability of dairy products to modulate inflammatory processes in humans is an important but unresolved issue. Here, we report a systematic review of 52 clinical trials investigating inflammatory markers in relation to the consumption of dairy products. An inflammatory score (IS) was defined to quantitatively evaluate this interaction. The IS was significantly positive for the entire data set, indicating an anti-inflammatory activity in humans. When the subjects were stratified according to their health status, the IS was strongly indicative of an anti-inflammatory activity in subjects with metabolic disorders and of a pro-inflammatory activity in subjects allergic to bovine milk. Stratifying the data by product categories associated both low-fat and high-fat products, as well as fermented products, with an anti-inflammatory activity. Remarkably, the literature is characterized by a large gap in knowledge on bioavailability of bioactive nutrients. Future research should thus better combine food and nutritional sciences to adequately follow the fate of these nutrients along the gastrointestinal and metabolic axes.info:eu-repo/semantics/publishedVersio

    Understanding the role of P2X7 in affective disorders—are glial cells the major players?

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    Pathophysiology associated with several psychiatric disorders has been linked to inflammatory biomarkers. This has generated a theory of major depressive disorders as an inflammatory disease. The idea of pro-inflammatory cytokines altering behavior is now well accepted however many questions remain. Microglia can produce a plethora of inflammatory cytokines and these cells appear to be critical in the link between inflammatory changes and depressive disorders. Microglia play a known role in sickness behavior which has many components of depressive-like behavior such as social withdrawal, sleep alterations, and anorexia. Numerous candidate genes have been identified for psychiatric disorders in the last decade. Single nucleotide polymorphisms (SNPs) in the human P2X7 gene have been linked to bipolar disorder, depression, and to the severity of depressive symptoms. P2X7 is a ligand-gated cation channel expressed on microglia with lower levels found on astrocytes and on some neuronal populations. In microglia P2X7 is a major regulator of pro-inflammatory cytokines of the interleukin-1 family. Genetic deletion of P2X7 in mice is protective for depressive behavior in addition to inflammatory responses. P2X7−/− mice have been shown to demonstrate anti-depressive-like behavior in forced swim and tail suspension behavioral tests and stressor-induced behavioral responses were blunted. Both neurochemical (norepinephrine, serotonin, and dopamine) and inflammatory changes have been observed in the brains of P2X7−/− mice. This review will discuss the recent evidence for involvement of P2X7 in the pathophysiology of depressive disorders and propose mechanisms by which altered signaling through this ion channel may affect the inflammatory state of the brain

    Microarray analyses demonstrate the involvement of type i interferons in psoriasiform pathology development in D6-deficient mice

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    The inflammatory response is normally limited by mechanisms regulating its resolution. In the absence of resolution, inflammatory pathologies can emerge, resulting in substantial morbidity and mortality. We have been studying the D6 chemokine scavenging receptor, which played an indispensable role in the resolution phase of inflammatory responses and does so by facilitating removal of inflammatory CC chemokines. In D6-deficient mice, otherwise innocuous cutaneous inflammatory stimuli induce a grossly exaggerated inflammatory response that bears many similarities to human psoriasis. In the present study, we have used transcriptomic approaches to define the molecular make up of this response. The data presented highlight potential roles for a number of cytokines in initiating and maintaining the psoriasis-like pathology. Most compellingly, we provide data indicating a key role for the type I interferon pathway in the emergence of this pathology. Neutralizing antibodies to type I interferons are able to ameliorate the psoriasis-like pathology, confirming a role in its development. Comparison of transcriptional data generated from this mouse model with equivalent data obtained from human psoriasis further demonstrates the strong similarities between the experimental and clinical systems. As such, the transcriptional data obtained in this preclinical model provide insights into the cytokine network active in exaggerated inflammatory responses and offer an excellent tool to evaluate the efficacy of compounds designed to therapeutically interfere with inflammatory processes

    Impact of contraception and IVF hormones on metabolic, endocrine, and inflammatory status

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    Assisted reproductive technologies (ART) represent commonly utilized management strategies for infertility with multifactorial causes (including genetically predisposed diseases). Amongst ART, in vitro fertilization (IVF) is the most popular. IVF treatment may predispose the mother to increased risks and complications during pregnancy, and there may be adverse fetal outcomes. Hormonal therapies, including oral contraceptives, may impair glucose and lipid metabolism, and promote insulin resistance and inflammation. IVF treatment involves administration of reproductive hormones, similar in composition but in much higher doses than those used for oral contraception. The provision of IVF reproductive hormones to mice associates with glucose intolerance. In addition, the physiological and hormonal changes of pregnancy can trigger an inflammatory response, and metabolic and endocrine changes. There is controversy regarding the potential effects of IVF hormonal therapies in the promotion of diabetogenic and inflammatory states, additional to those that occur during pregnancy, and which may therefore predispose women with IVF-conceived pregnancies to adverse obstetric outcomes compared with women with spontaneously conceived pregnancies. This review summarizes the limited published evidence regarding the effect of IVF-based fertility therapies on glucose homeostasis, insulin resistance, cardio-metabolic profile, and markers of inflammation

    Inflammatory Markers in Pediatric Obesity: Health and Physical Activity Implications

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    The prevalence of childhood obesity has recently peaked in the USA with ~17% of children considered obese. With the increase in adiposity that occurs with weight gain, a persistent low-grade inflammatory state is created. The most commonly studied inflammatory markers associated with obesity are the cytokines, tumor necrosis factor α and interleukin-6, and the acute-phase reactant, C-reactive protein. Understanding the relation between adiposity and inflammation is an important concept because these inflammatory markers influence insulin sensitivity, glucose metabolism, and atherosclerosis, ultimately leading to impaired health. In addition to obesity, physical inactivity is associated with elevated inflammatory markers. The literature, however, is inconsistent as to whether the association between physical activity and inflammation is independent of adiposity. In some obese children, physical fitness appears to circumvent the increase in inflammatory markers that are associated with obesity. The purpose of this review is to examine the relation between adiposity and inflammatory markers, including potential health implications and the impact of physical activity. We exposed a dearth of literature in understanding the interaction between obesity and physical activity on inflammatory markers, especially in children because their anthropometrics change. This review highlights the necessity for further research to better understand the complexity of the chronic inflammatory state associated with obesity
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