Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0009319 (colitis)
 19,384 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Excessive intake of saturated fatty acids and/or linoleic acid favors the induction of an array of lipid mediators and cytokines enhancing inflammatory responses. Conversely, dietary supplementation with (n-3) fatty acids or vitamin D ameliorates inflammation and autoimmune diseases. Although it was well accepted that conjugated linoleic acid (CLA) prevented diseases with a common inflammatory pathogenesis (i.e., cancer and atherosclerosis), no studies were available on the roles of CLA in mucosal inflammation. The present study was designed to investigate the anti-inflammatory actions and molecular mechanisms underlying the regulation of colonic health by CLA. We hypothesized that colonic inflammation can be ameliorated by dietary CLA supplementation. To test this hypothesis, inflammation of the colonic mucosa was triggered by challenging pigs fed either soybean oil-supplemented or CLA-supplemented diets with an enteric bacterial pathogen (i.e., Brachyspira hyodysenteriae). Immunoregulatory cytokines and peroxisome proliferator-activated receptor-gamma (PPAR-gamma) mRNA expression were assayed in colonic lymph nodes and colon of pigs. Colonic mucosal lesions and lymphocyte subset distribution were evaluated by histology and immunohistochemistry. Supplementation of CLA in the diet before the induction of colitis decreased mucosal damage; maintained cytokine profiles (i.e., interferon-gamma and interleukin-10) and lymphocyte subset distributions (i.e., CD4+ and CD8+), resembling those of noninfected pigs; enhanced colonic expression of PPAR-gamma; and attenuated growth failure. Therefore, CLA fed preventively before the onset of enteric disease attenuated inflammatory lesion development and growth failure.
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PMID:Nutritional regulation of porcine bacterial-induced colitis by conjugated linoleic acid. 1209 86

Nuclear factor-kappaB-dependent up-regulation of inflammatory cytokines occurs in inflammatory bowel disease. We investigated the effect of pioglitazone, a peroxisome proliferator-activated receptor-gamma ligand, on dextran sulfate sodium-induced colonic mucosal injury and inflammation in mice. Acute colitis was induced in female mice receiving 0, 1, 3, and 10 mg/kg i.p. of pioglitazone daily. Colonic mucosal inflammation was evaluated chemically and histologically. Thiobarbituric acid-reactive substances and tissue-associated myeloperoxidase activity were measured in intestinal mucosa as indices of lipid peroxidation and neutrophil infiltration, respectively. Colonic mRNA expression of pro-inflammatory cytokines and inducible nitric oxide synthase was measured by reverse transcription-PCR and nuclear factor-kappaB activation was evaluated by electrophoretic mobility shift assay. Dextran sulfate sodium administration resulted in decreases in body weight and colon length and increases in lipid peroxide and neutrophil accumulation of the intestine. In contrast, co-administration with pioglitazone prevented these changes. Transcripts coding for pro-inflammatory cytokines and inducible nitric oxide were expressed in high levels after the development of colitis, and pioglitazone markedly reduced mRNA expression of these genes. DNA binding activity of nuclear factor-kappaB was markedly increased, whereas in pioglitazone co-treated intestines the effect was significantly reduced. These data suggest that peroxisome proliferator-activated receptor-gamma may be a novel therapeutic target for the therapy of inflammatory bowel disease.
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PMID:Pioglitazone, a PPAR-gamma ligand, provides protection from dextran sulfate sodium-induced colitis in mice in association with inhibition of the NF-kappaB-cytokine cascade. 1268 11

The peroxisome proliferator-activated receptor-alpha (PPAR-alpha) is a member of the nuclear receptor superfamily of ligand-dependent transcription factors related to retinoid, steroid and thyroid hormone receptors. The aim of the present study was to examine the effects of endogenous and exogenous PPAR-alpha ligand on the development of experimental colitis. To address this question, we used an experimental model of colitis, induced by dinitrobenzene sulfonic acid (DNBS). When compared to DNBS-treated PPAR-alpha wild-type (WT) mice, DNBS-treated PPAR-alpha knockout mice (PPAR-alphaKO) mice experienced a higher rate of the extent and severity of the histological signs of colon injury. After administration of DNBS PPAR-alphaWT mice experienced hemorrhagic diarrhea, weight loss and large areas of necrosis in the mucosa of the colon were also observed. Neutrophil infiltration was associated with upregulation of ICAM-1. Immunohistochemistry for nitrotyrosine showed an intense staining in the inflamed colon. Absence of a functional PPAR-alpha gene in PPAR-alphaKO mice resulted in a significant augmentation of all the above-described parameters. On the contrary, the treatment of PPAR-alphaWT with Wy-14643 (1 mg/kg daily i.p) significantly reduced: (i) the degree of hemorrhagic diarrhea and weight loss, (ii) the degree of colon injury, (iii) the rise in MPO activity (mucosa), (iv) the increase in staining (immunohistochemistry) for nitrotyrosine, as well as (v) the upregulation of ICAM-1 caused by DNBS in the colon. In order to elucidate whether the protective effects of Wy-14643 is related to activation of the PPAR-alpha receptor, we also investigated the effect the of Wy-14643 treatment on PPAR-alpha-deficient mice. The absence of the PPAR-alpha receptor significantly abolished the protective effect of the PPAR-alpha agonist against DNBS-induced colitis. Thus, endogenous and exogenous PPAR-alpha ligands reduce the degree of colitis caused by DNBS. We propose that PPAR-alpha ligand may be useful in the treatment of inflammatory bowel disease.
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PMID:Role of endogenous and exogenous ligands for the peroxisome proliferators activated receptors alpha (PPAR-alpha) in the development of inflammatory bowel disease in mice. 1549 55

Crohn's disease is associated with an excessive T helper (TH) type 1 inflammatory immune response. Reducing the influx of disease-associated CD4+ TH1 cells into the inflamed intestine is likely to be beneficial in preventing a disease flare-up and even possibly in reducing the effect of acute disease. Thiazolidenedione (TZD) ligands, which activate peroxisome proliferator-activated receptor-gamma (PPARgamma), have been shown to reduce TH1 inflammation in murine models of colitis, primarily in a preventative fashion. To determine whether PPARgamma ligands reduce this inflammation in part by reducing TH1 chemoattractant levels in vivo, the TZD pioglitazone was tested for its effects on a TH1 chemokine (CXCL10) in 2 models of colitis (i.e., dextran sodium sulfate and 2,4,6-dinitrobenzene sulfonic acid-mediated colitis). In both models, CXCL10 levels were significantly reduced by pioglitazone. Because TZDs can affect gene expression either directly, by regulating the binding of PPARgamma to consensus promoter elements, or indirectly, by modulating other signaling pathways that can affect gene transcription, the regulation of CXCL10 by TZDs was investigated in vitro in both HT-29 colon epithelial cells and THP-1 monocyte/macrophage cells. TZDs significantly reduced CXCL10 protein levels from activated HT-29 cells and THP-1-derived macrophages in a dose-dependent manner at nanomolar concentrations. However, TZDs did not affect messenger RNA levels or nuclear factor-kappaB activation at these concentrations in these cells. These findings imply the existence of a novel posttranscriptional regulatory antiinflammatory mechanism by TZDs that is not associated with reductions in nuclear factor-kappaB activation.
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PMID:Intestinal antiinflammatory effects of thiazolidenedione peroxisome proliferator-activated receptor-gamma ligands on T helper type 1 chemokine regulation include nontranscriptional control mechanisms. 1573 30

5-aminosalicylic acid (5-ASA) is an antiinflammatory drug widely used in the treatment of inflammatory bowel diseases. It is known to inhibit the production of cytokines and inflammatory mediators, but the mechanism underlying the intestinal effects of 5-ASA remains unknown. Based on the common activities of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands and 5-ASA, we hypothesized that this nuclear receptor mediates 5-ASA therapeutic action. To test this possibility, colitis was induced in heterozygous PPAR-gamma(+/-) mice and their wild-type littermates, which were then treated with 5-ASA. 5-ASA treatment had a beneficial effect on colitis only in wild-type and not in heterozygous mice. In epithelial cells, 5-ASA increased PPAR-gamma expression, promoted its translocation from the cytoplasm to the nucleus, and induced a modification of its conformation permitting the recruitment of coactivators and the activation of a peroxisome-proliferator response element-driven gene. Validation of these results was obtained with organ cultures of human colonic biopsies. These data identify PPAR-gamma as a target of 5-ASA underlying antiinflammatory effects in the colon.
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PMID:Intestinal antiinflammatory effect of 5-aminosalicylic acid is dependent on peroxisome proliferator-activated receptor-gamma. 1582 83

Colitis involves immune cell-mediated tissue injuries, but the contribution of epithelial cells remains largely unclear. Vanin-1 is an epithelial ectoenzyme with a pantetheinase activity that provides cysteamine/cystamine to tissue. Using the 2,4,6-trinitrobenzene sulfonic acid (TNBS)-colitis model we show here that Vanin-1 deficiency protects from colitis. This protection is reversible by administration of cystamine or bisphenol A diglycidyl ether, a peroxisome proliferator-activated receptor (PPAR)gamma antagonist. We further demonstrate that Vanin-1, by antagonizing PPARgamma, licenses the production of inflammatory mediators by intestinal epithelial cells. We propose that Vanin-1 is an epithelial sensor of stress that exerts a dominant control over innate immune responses in tissue. Thus, the Vanin-1/pantetheinase activity might be a new target for therapeutic intervention in inflammatory bowel disease.
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PMID:Vanin-1 licenses inflammatory mediator production by gut epithelial cells and controls colitis by antagonizing peroxisome proliferator-activated receptor gamma activity. 1714 56

Exogenous lysophosphatidic acid (LPA) has been shown to beneficial in renal ischemia/reperfusion injury, wound healing and colitis. LPA acts via specific G-protein-coupled receptors and also peroxisome proliferator-activated receptor-gamma (PPAR-gamma). However, activation of PPAR-gamma is dependent on the presence of an unsaturated acyl chain. Here we investigate the effects of saturated LPA (18:0) and unsaturated LPA (18:1) on the organ injury associated with endotoxemia and the receptors mediating LPA activity. Male Wistar rats received either lipopolysaccharide (LPS, 6 mg/kg i.v.) or vehicle. The PPAR-gamma antagonist GW9662 (1 mg/kg i.v.), the LPA receptor antagonist Ki16425 (0.5 mg/kg i.v.) or vehicle was administered 30 min after LPS. LPA 18:0 or LPA 18:1 (1 mg/kg i.v.) or vehicle was administered 1 h after injection of LPS. Endotoxemia for 6 h resulted in an increase in serum levels of aspartate aminotransferase, alanine aminotransferase and creatine kinase. Therapeutic administration of LPA 18:0 or 18:1 reduced the organ injury caused by LPS. LPA 18:0 also attenuated the increase in plasma IL-1beta caused by LPS. Ki16425, but not GW9662, attenuated the beneficial effects of LPA 18:0, however, Ki16425 and GW9662 attenuated the beneficial effects of 18:1. In conclusion, LPA reduces the organ injury caused by endotoxemia in the rat. Thus, LPA may be useful in the treatment of shock of various aetiologies. The mechanism of action is related to acyl chain saturation, with LPA 18:0 acting via G-protein-coupled receptors and LPA 18:1 acting via G-protein-coupled receptors and PPAR-gamma.
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PMID:Lysophosphatidic acid reduces the organ injury caused by endotoxemia-a role for G-protein-coupled receptors and peroxisome proliferator-activated receptor-gamma. 1717 80

Various animal models showed that peroxisome proliferator-activated receptor (PPAR)gamma agonists, when given as a gavage shortly preceding colitis induction, protect against inflammatory bowel disease (IBD). We have examined the effects of 16 days rosiglitazone treatment via the diet prior to dextran sodium sulphate (DSS)-induced colitis in mice. After 7 days DSS in the drinking water, rosiglitazone-fed mice had lost significantly more weight than control mice. Rosiglitazone-treated mice had more diarrhea, weight of colon and spleen were increased, and length of colon was decreased. Histology showed that rosiglitazone-treated mice had more severe colitis, mainly caused by more ulceration, crypt loss, and edema. Immunofluorescence showed a loss of tight junction structure Zonula Occludens protein 1 (ZO-1) in colons of rosiglitazone-treated mice as compared to control mice. Also, serum amyloid P component (SAP) concentrations in plasma were increased. However, concentrations of tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma in colon homogenates, and TNF-alpha in spleen homogenates were significantly decreased, whereas interleukin (IL)-10 in spleen homogenates was increased. Other cytokines (IL-2, IL-4, IL-6, IL-12p70 and monocyte chemotactic protein (MCP)-1) and myeloperoxidase (MPO) concentrations showed no differences. In conclusion, 16 days pretreatment with rosiglitazone impaired DSS-induced colitis in mice.
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PMID:The PPARgamma agonist rosiglitazone impairs colonic inflammation in mice with experimental colitis. 1751 Aug 6

The aim of the present study was to examine the role of endogenous peroxisome proliferator-activated receptor-alpha (PPAR-alpha) ligand on the permeability and structure of small intestine tight junctions (TJs) in an animal model of experimental colitis, induced by dinitrobenzene sulfuric acid (DNBS). Four days after colitis induction with DNBS, the ileal TJs were studied by means of transmission electron microscopy using lanthanum nitrate and immunohistochemistry of occludin, zonula occludens 1, and claudin 2. Administration of DNBS to wild-type mice induced colon injury associated with a significant increase of plasma and colon tumor necrosis factor-alpha levels and with a significant increase of ileal permeability. Distal colitis in mice induced an increase of TJ permeability throughout the entire small intestine, and the extent of alterations correlates with colonic damage. Small intestinal permeability was associated with the presence of apoptosis (evaluated by FAS ligand expression and terminal deoxynucleotidyltransferase-mediated UTP nick end labeling coloration), which was associated with a significantly increased expression of proapoptotic Bax and decreased ileum content of antiapoptotic Bcl-2. Absence of a functional PPAR-alpha gene in PPAR-alpha knockout mice resulted in a significant augmentation of all the above-described parameters. Taken together, our results clearly demonstrate that endogenous PPAR-alpha ligands reduced small intestinal permeability in experimental colitis through the regulation of apoptosis and TJ protein.
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PMID:Absence of functional peroxisome proliferator-activated receptor-alpha enhanced ileum permeability during experimental colitis. 1751 53

(5E,7Z,10Z,13Z,16Z,19Z)-4-Hydroxy-5,7,10,13,16,19-docosahexaenoic acid (4-OHDHA) is a potential agonist of peroxisome proliferator-activated receptor-gamma (PPARgamma) and antidiabetic agent as has been previously reported. As PPARgamma agonists may also have anti-inflammatory functions, in this study, we investigated whether 4-OHDHA has an inhibitory effect on expression of inflammatory genes in vitro and whether 4-OHDHA could relieve the symptoms of dextran sodium sulfate (DSS)-induced colitis in a murine model of inflammatory bowel disease. 4-OHDHA inhibited production of nitric oxide and expression of a subset of inflammatory genes including inducible nitric oxide synthase (Nos2/iNOS) and interleukin 6 (Il6) by lipopolysaccharide (LPS)-activated macrophages. In addition, 4-OHDHA-treated mice when compared to control mice not receiving treatment recovered better from the weight loss caused by DSS-induced colitis. Changes in disease activity index (DAI) of 4-OHDHA-treated mice were also more favorable than for control mice and were comparable with mice treated with a typical anti-inflammatory-drug, 5-aminosalichylic acid (5-ASA). These results suggest that 4-OHDHA has potentially clinically useful anti-inflammatory effects mediated by suppression of inflammatory gene expression.
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PMID:4-Hydroxydocosahexaenoic acid, a potent peroxisome proliferator-activated receptor gamma agonist alleviates the symptoms of DSS-induced colitis. 1819 Oct 38


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