Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021390 (inflammatory bowel disease)
 23,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitric oxide (NO.) plays a central role in the physiology of the gastrointestinal tract and its response to critical illness. Potential sources of NO. in the gut include: intrinsic intestinal tissue (mast cells, epithelium, smooth muscle, neural plexus), resident and/or infiltrating leukocytes (neutrophils, monocytes), reduction of luminal gastric nitrate, and denitrification by commensal anaerobes. The brain and endothelial isoforms of nitric oxide synthase are expressed under resting conditions, whereas inflammatory stimuli are required for the induction of the inducible type. Under resting conditions, mucosal perfusion is regulated by NO. derived from the vascular endothelium of the mesenteric bed. During inflammation, excessive NO. production from the inducible synthase may contribute to mucosal hyperemia. Coordination of peristalsis and sphincteric action is mediated by the release of NO., which acts as the principal neurotransmitter of the nonadrenergic, noncholinergic enteric nervous system. Alterations in bowel motility, such as ileus, result from excessive concentrations of NO. generated during endotoxicosis and inflammatory bowel disease. The role of NO. in the regulation of salt and water secretion is poorly understood. Endotoxin-induced inhibition of gastric acid secretion appears to be mediated by the action of NO. on parietal cells. NO. may protect the gastrointestinal mucosa from a variety of stimuli (caustic ingestion, ischemia, ischemia/reperfusion injury, early endotoxic shock) by maintaining mucosal perfusion, inhibiting neutrophil adhesion to mesenteric endothelium, blocking platelet adhesion, and preventing mast cell activation. Excessive NO., however, may directly injure the mucosa. Barrier function of the intestinal mucosa is protected by NO. in the early stages of injury, when neutrophil adhesion, ischemia, and mast cell activation are relevant. Inhibition of NO. synthesis ameliorates barrier dysfunction during more advanced stages of inflammation, when activation of inducible NOS yields toxic concentrations of NO.. At high concentrations, NO. disrupts the actin cytoskeleton, inhibits ATP formation, dilates cellular tight junctions, and produces a hyperpermeable state. Selective inhibition of the inducible isoform of NOS and maintenance of the constitutive types may be therapeutic.
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PMID:Nitric oxide in the gut. 758 76

Nitric oxide (NO.) plays a central role in the Physioliology of the gastrointestinal tract and its response to critical illness. Potential sources of NO. in the gut include: intrinsic intestinal tissue (mast cells, epithelium, smooth muscle, neural plexus), resident and/or infiltrating leukocytes (neutrophils, monocytes), reduction of luminal gastric nitrate, and denitrification by commensal anaerobes. The brain and endothelial isoforms of nitric oxide synthase are expressed under resting conditions, whereas inflammatory stimuli are required for the induction of the inducible type. Under resting conditions, mucosal perfusion is regulated by NO. derived from the vascular endothelium of the mesenteric bed. During inflammation, excessive NO. production from the inducible synthase may contribute to mucosal hyperemia. Coordination of peristalsis and sphincteric action is mediated by the release of NO., which acts as the principal neurotransmitter of the nonadrenergic, noncholinergic enteric nervous system. Alterations in bowel motility, such as ileus, result from excessive concentrations of NO. generated during endotoxicosis and inflammatory bowel disease. The role of NO. in the regulation of salt and water secretion is poorly understood. Endotoxin-induced inhibition of gastric acid secretion appears to be mediated by the action of NO. on parietal cells. NO. may protect the gastrointestinal mucosa from a variety of stimuli (caustic ingestion, ischemia, ischemia/reperfusion injury, early endotoxic shock) by maintaining mucosal perfusion, inhibiting neutrophil adhesion to mesenteric endothelium, blocking platelet adhesion, and preventing mast cell activation. Excessive NO., however, may directly injure the mucosa. Barrier function of the intestinal mucosa is protected by NO. in the early stages of injury, when neutrophil adhesion, ischemia, and mast cell activation are relevant. Inhibition of NO. synthesis ameliorates barrier dysfunction during more advanced stages of inflammation, when activation of inducible NOS yields toxic concentrations of NO.. At high concentrations, NO. disrupts the actin cytoskeleton, inhibits ATP formation, dilates cellular tight junctions, and produces a hyperpermeable state. Selective inhibition of the inducible isoform of NOS and maintenance of the constitutive types may be therapeutic.
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PMID:Nitric oxide in the gut. 770 93

Urinary nitrate is known to be a measure of environmental exposure. Only recently an endogenous metabolic pathway resulting in nitrate synthesis was described. We have determined the concentration of nitrate expressed as nitrate/creatinine ratio in the urine of patients in whom a significant environmental nitrate load was presumed to be absent. A significant elevation of nitrates in patients with inflammatory bowel disease compared with patients with non-inflammatory disorders was observed (0.173 +/- 0.155 vs. 0.037 +/- 0.016 mol/mol creatinine, P < 0.01). Increased nitrate excretion in the urine of patients with inflammatory bowel disease may reflect the endogenous nitrate synthesis induced by the immune activation.
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PMID:Increased urinary nitrate excretion in inflammatory bowel disease. 816 91

The objective of this study was to quantitatively characterize the effects FK506 on the pathophysiology observed in a model of chronic granulomatous colitis in rats and compare these effects to those obtained with cyclosporin A (CyA). Chronic granulomatous colitis was induced in female Lewis rats via intramural (subserosal) injections of peptidoglycan/polysaccharide (PG/PS) into the distal colon. Rats then received daily injections (i.m.) of either vehicle for CyA (0.5 ml/kg cremophor), CyA in vehicle (25 mg/kg), saline (0.5 ml/kg) or FK506 (1 mg/kg in saline), beginning 7 days after PG/PS injection and continuing for an additional 2 weeks. On day 21, we found that the intramural injection of PG/PS produced a chronic colitis that was associated with hepatic and splenic granulomatous inflammation. Daily treatment with CyA or FK506 beginning 7 days after the induction of colitis resulted in significant inhibition in colonic mucosal permeability, colonic myeloperoxidase activity and plasma nitrate/nitrite levels when compared with their vehicle or untreated controls. In some instances, we noticed a significant vehicle-dependent anti-inflammatory activity. The incidence of peritoneal adhesions as well as the presence of hepatic and splenic granulomas induced by PG/PS were also significantly reduced in both the CyA- and FK506-treated groups. Taken together, these data suggest that immunosuppressive therapy is effective at attenuating both the colitis as well as the extraintestinal inflammation induced by PG/PS. We conclude that FK506 may be useful in the treatment of certain types of inflammatory bowel disease.
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PMID:Effects of cyclosporine or FK506 in chronic colitis. 902 26

Ursodeoxycholate (UDCA) has anti-inflammatory and chemoprotective effects in animal models of inflammatory bowel disease and colon cancer. Because overproduction of nitric oxide (NO) by the inducible isoform of NO synthase (iNOS) is implicated in the pathogenesis of these conditions, we investigated the ability of UDCA to inhibit NO production in transformed human intestinal epithelial (DLD-1) cells. Nitrite/nitrate production was measured by the Griess reaction, enzymatic activity of iNOS was assessed by conversion of L-arginine to L-citrulline, and protein and mRNA were measured by Western and Northern blotting. Dose-dependent inhibition of interleukin-1 beta- and interferon-gamma-stimulated nitrite/nitrate production was observed when cells were preincubated for 6 h with UDCA (0-800 microM), and a substantial inhibition (81 +/- 3.2%) was seen at 500 microM. In cytokine-stimulated cells, UDCA reduced iNOS mRNA, protein, and enzyme activity without exerting cytotoxicity. UDCA had a minimal direct inhibitory effect on iNOS enzyme activity. UDCA pretreatment also reduced the expression of iNOS in the colonic epithelium of rats treated with bacterial lipopolysaccharide. Thus UDCA inhibits the induction of epithelial iNOS in vitro and in vivo, and this effect may contribute to the anti-inflammatory and chemoprotective actions of UDCA.
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PMID:Ursodeoxycholate inhibits induction of NOS in human intestinal epithelial cells and in vivo. 925 19

An attractive approach to the treatment of inflammatory conditions such as osteo- and rheumatoid arthritis, inflammatory bowel disease, and sepsis is through the selective inhibition of human inducible nitric oxide synthase (hiNOS) since localized excess nitric oxide (NO) release has been implicated in the pathology of these diseases. A series of monosubstituted iminohomopiperidinium salts possessing lipophilic functionality at ring positions 3, 5, 6, and 7 has been synthesized, and series members have demonstrated the ability to inhibit the hiNOS isoform with an IC50 as low as 160 nM (7). Compounds were found that selectively inhibit hiNOS over the human endothelial constitutive enzyme (heNOS) with a heNOS/hiNOS IC50 ratio in excess of 100 and as high as 314 (9). Potencies for inhibition of hiNOS and the human neuronal constitutive enzyme (hnNOS) are comparable. Substitution in the 3 and 7 positions provides compounds that exhibit the greatest degree of selectivity for hiNOS and hnNOS over heNOS. Submicromolar potencies for 6 and 7 in a mouse RAW cell assay demonstrated the ability of these compounds to inhibit iNOS in a cellular environment. These latter compounds were also found to be orally bioavailable and efficacious due to their ability to inhibit the increase in plasma nitrite/nitrate levels in a rat LPS model.
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PMID:2-Iminohomopiperidinium salts as selective inhibitors of inducible nitric oxide synthase (iNOS). 955 68

A disease similar to ulcerative colitis in humans has been identified in cotton-top tamarins (CTTs) in captivity. The clinical signs include weight loss, diarrhea, and rectal bleeding with the pathological features and biochemical abnormalities of ulcerative colitis. Approximately 25 to 40% of these animals develop colon cancer after 2 to 5 years of captivity. An infectious etiology has been proposed; however, no microbial agent to date has been identified. Helicobacter spp. have been associated with enterocolitis and inflammatory bowel disease (IBD) in humans and animals. Infection with Helicobacter pylori or Helicobacter mustelae is associated with an increased risk of gastric adenocarcinoma and lymphoma of the mucosa-associated lymphoid tissue. Helicobacter hepaticus causes hepatitis, hepatic adenomas, and hepatocellular carcinomas in susceptible strains of mice. The aim of this study was to assess a colony of CTTs with a high incidence of IBD and colon cancer for the presence of colonic Helicobacter spp. A fusiform, gram-negative bacterium with bipolar flagella and periplasmic fibers was isolated from the feces of CTTs. The bacterium grew under microaerobic conditions at 37 and 42 degrees C but not at 25 degrees C, did not hydrolyze urea, was positive for catalase and oxidase, did not reduce nitrate to nitrite, did not hydrolyze indoxyl acetate or alkaline phosphatase, and was resistant to nalidixic acid, cephalothin, and trimethoprim-sulfamethoxazole. On the basis of 16S rRNA gene sequence analysis, the organism was classified as a novel Helicobacter species. This is the first Helicobacter isolated from CTTs. Further studies are needed to elucidate the role of this novel Helicobacter sp. in the pathogenesis of ulcerative colitis and colonic adenocarcinoma in CTTs.
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PMID:Novel intestinal Helicobacter species isolated from cotton-top tamarins (Saguinus oedipus) with chronic colitis. 985 80

Induction of colitis by 2,4,6-Trinitrobenzenesulphonic acid (TNB) in the rat is a widely used experimental model of inflammatory bowel disease. Action of TNB as a hapten, induces colitis involving infiltration of colonic mucosa by neutrophils and macrophages and increased production of inflammatory mediators. The aim of the present study was to measure nitric oxide synthase (NOS) activity and characterize relations between inducible NOS (iNOS) activity and other signs of inflammation in TNB-induced colitis. A profound and sustained increase in the activity of iNOS was found in the colon. The activity of NOS in the spleen was also increased, but remained at low levels as compared to those in colon. No increases in plasma nitrite + nitrate concentrations were found suggesting local rather than systemic induction of iNOS. The increase in iNOS activity in the colon was preceded by macroscopic inflammatory lesions, like hyperemia, ulcerations and edema formation as well as neutrophil accumulation in the gastric mucosa and increased circulating concentrations of PGE2 metabolite (PGEM). Concentrations of PGEM in the plasma and myeloperoxidase activity (MPO; marker of neutrophil infiltration) in the gut declined in 48h whereas increased iNOS activity and the macroscopic inflammatory lesions remained over the 72h follow-up period. The results demonstrate increased local iNOS activity in TNB-Induced colitis mimicking the situation in human inflammatory bowel disease.
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PMID:Induction of iNOS in a rat model of acute colitis. 1021 70

1. The inducible isoform of nitric oxide synthase (iNOS) may be involved in the pathogenesis of inflammatory bowel disease. Using the human intestinal epithelial cell line, Caco-2, iNOS expression, regulation and sensitivity to the glucocorticoid, dexamethasone after cytokine exposure and its relationship to the degree of differentiation has been studied. 2. NOS activity, assessed by NO2- and NO3- release, was time-dependently increased after exposure to interferon gamma alone or in combination with interleukin-1beta and tumour necrosis factor alpha. 3. Cytokine-induced iNOS activity was increased with days in culture over 20 days and number of passages, suggesting iNOS up-regulation during enterocyte-like differentiation. This activity was inhibited by the selective iNOS inhibitor 1400 W (0.1 - 100 microM). In addition, iNOS protein induction was confirmed by Western blot. 4. Actinomycin D (5 microg ml(-1) inhibited cytokine-induced iNOS activity, protein expression and mRNA level. Pyrrolidine dithiocarbamate (PDTC: 10 - 200 microM) and 3,4 dichloroisocoumarin (0.1 - 100 microM) reduced cytokine-induced iNOS activity and protein expression at both day 10 and 15 after confluence. PDTC also decreased iNOS mRNA levels, suggesting NF-kappaB involvement in its transcription at these times. 5. The tyrphostins A25 and B42 reduced cytokine-induced iNOS activity at both day 10 and 15 after confluence, indicating the JAK-2 kinase is also involved at these times. The tyrphostins also reduced the iNOS protein expression. 6. Dexamethasone (0.1 - 10 microM, for 24 h) reduced cytokine-induced iNOS activity at day 15 and 20 after cell confluence, but not at day 5 or 10. 7. Dexamethasone (5 microM) decreased cytokine-induced iNOS protein expression at day 10 as well as at day 15 after confluence. 8. These findings indicate that iNOS induction and its inhibition by dexamethasone in this human intestinal epithelial cell line is dependent on the degree of differentiation.
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PMID:Regulation of induction of nitric oxide synthase and the inhibitory actions of dexamethasone in the human intestinal epithelial cell line, Caco-2: influence of cell differentiation. 1051 52

Endogenously formed nitrogen and oxygen free radicals are believed to be involved in human cancer etiology. Plasma nitrate/nitrite originates from endogenous nitric oxide production in fasting humans, decrease in superoxide scavenger activity (SSA), and free sulfhydryl groups (SH) reflects the amount of superoxide anion generated, and nitrotyrosine is believed to be formed by the interaction of tyrosine and peroxynitrite in vivo. The aim of the current study was to measure plasma nitrate/ nitrite, SSA, and SH in 69 patients (mean age +/- standard deviation, 66 +/- 11 years) with colorectal carcinoma. Nitrotyrosine was measured from both the plasma and tumor tissues in 32 patients. All patients had adenocarcinoma of the colon or rectum. Twenty-five patients were classified as stage B according to Dukes classification as modified by Astler-Coller, 13 were classified as stage C, and 31 patients were classified as stage D. To determine whether the changes are specific for colorectal cancer, 20 patients with active inflammatory bowel disease (IBD; mean age, 52 +/- 18 years) and 30 healthy volunteers, who served as control subjects (mean age, 48 +/- 11 years), were studied. Plasma nitrate/nitrite was measured by the modified Griess method, SSA was measured by an electron/spin resonance spin trapping method, free SH was measured by Ellman's method, and the presence of nitrotyrosine in the plasma and tumor tissue was detected by high performance liquid chromatography (HPLC) using C- 18-derivatized silica (5 microm) column (C18S, Crestpaque, New York, NY, USA) and at a wavelength of 274 nm. Patients with colorectal carcinoma and with active IBD had a significantly higher plasma nitrate/ nitrite level (51.2 +/- 26.2 microm and 56.0 +/- 14.6 microm versus. 29.6 +/- 6.3 microm; p < 0.01), and a lower SSA level (39 +/- 11.5 U/g protein and 52.0 +/- 18.9 U/g protein versus. 88 +/- 25.1 U/g protein; p < 0.05) and SH level (7.7 +/- 3.89 microm protein and 6.4
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PMID:Evidence of in vivo peroxynitrite formation in patients with colorectal carcinoma, higher plasma nitrate/nitrite levels, and lower protection against oxygen free radicals. 1063 9


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