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)

Large numbers of polymorphonuclear leukocytes which generate reactive oxygen metabolites are found in mucosa and submucosa of the intestinal wall of subjects suffering from inflammatory bowel disease. We have, therefore, examined the relative influences of hydrogen peroxide (H2O2), hypochlorous acid (HOCl) and N-chloramines such as NH2Cl, on the neurally stimulated and nonstimulated guinea pig ileum. In separate experiments the oxidants were tested in the presence and absence of the cyclooxygenase inhibitor piroxicam and the antioxidant glutathione. All three oxidants, in concentrations produced by activated neutrophils, increased the muscle tone (concentration-dependent, peak at 0.3 mM for NH2Cl and H2O2 and 1 mM for HOCl). Tetrodotoxin (0.5 microM) inhibited the NH2Cl and H2O2 effects by 50% and 70%, respectively. Piroxicam (5 microM) partially blocked maximal contractions induced by all three oxidants. The contractile response to carbachol (10 microM) was blocked by 0.3 mM NH2Cl, but not by H2O2 and HOCl. In electrically stimulated ileum the oxidants produced a concentration-dependent biphasic response (transient enhancement of neurally mediated twitch contraction followed by marked inhibition). This response was not modified by piroxicam, hexamethonium, atropine and pyrilamine. The inhibition of twitch contraction was irreversible for NH2Cl and HOCl, in contrast to H2O2, which was reversed by repeated washing. Neither the contractile effect nor the effects on nerve stimulation-induced contraction were affected by preincubation of the tissue with glutathione, whereas prior combination of NH2Cl with glutathione prevented the effects of NH2Cl. Oxidant-induced contraction of guinea pig ileum appears to be via release of prostaglandins and one or more neurotransmitters. High concentrations of reactive oxygen metabolites may alter receptor function.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differential effects of reactive oxygen metabolites on neurally stimulated and nonstimulated guinea pig ileum. 167 Oct 95

Oxidative damage has been implicated in the pathogenesis of inflammatory bowel disease. In the present study sulphasalazine and mesalazine (5-aminosalicylic acid) in vitro were shown to possess scavenging activity and to attenuate the production of oxygen metabolites by neutrophils. In a double-blind randomized crossover study, with five patients with inflammatory bowel disease in remission and four healthy controls, we evaluated the influence of in vivo administration of sulphasalazine and mesalazine on the neutrophil oxygen metabolite production in vitro. Apart from a small but significant increase in the neutrophil H2O2 and O2 production by sulphasalazine, in particular in controls, in vivo administration of both drugs hardly affected the oxygen metabolite-producing capacity of the cells. This observation was confirmed by in vitro preincubation of neutrophils with the drugs and subsequent oxygen metabolite production analysis. It is concluded that sulphasalazine and mesalazine do not influence the oxidative capacity of neutrophils, but scavenge and attenuate the production of oxygen metabolites when present in the immediate surroundings of the cells. Thus, protection against oxidative damage is definitely one of the modes of action of these drugs.
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PMID:Influence of sulphasalazine and mesalazine on cellular and biochemical oxygen metabolite production. Effect of in vivo administration and an in vitro analysis. 168 Feb 47

Inflammatory phagocytic leukocytes produce superoxide and hydrogen peroxide and secrete myeloperoxidase (MPO) into the extracellular medium. MPO catalyzes the oxidation of Cl- by H2O2 to yield chlorinated oxidants (e.g. HOCl and NH2Cl), which have been shown to induce pathologic changes in mucosal function. We examined the ability of 5-aminosalicylic acid (5-ASA), a drug used to treat inflammatory bowel disease (IBD), to inhibit oxidation of L-cysteine by NH2Cl, HOCl and H2O2. NH2Cl and HOCl were especially strong oxidants against L-cysteine. 5-ASA prevented L-cysteine oxidation by NH2Cl and HOCl; an interaction associated with the formation of characteristic absorption spectra due to the oxidation of 5-ASA was observed. NH2Cl and HOCl evoked characteristic increases in short-circuit current (Isc), indicative of net electrolyte transport, when added to the serosal side of stripped rat colon mounted in Ussing chambers. Premixing of NH2Cl with 5-ASA 10 min before addition to the tissue markedly reduced the secretory response to NH2Cl. In contrast, 5-ASA immediately reduced the response to HOCl. The reduction in the functional response to NH2Cl and HOCl by 5-ASA may contribute to its mechanism of action in the treatment of the symptoms of IBD.
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PMID:Scavenging effect of 5-aminosalicylic acid on neutrophil-derived oxidants. Possible contribution to the mechanism of action in inflammatory bowel disease. 184 73

Neutrophil-derived oxidants may be involved in inflammatory bowel disease. Stable oxidants formed by halogenation of primary amines (e.g., monochloramine, NH2Cl) are extremely potent and may be of major importance in the pathophysiological response in inflammatory bowel disease. We tested the effects of NH2Cl relative to other oxidants on muscle-stripped rat colon under short-circuit conditions. Serosal addition of the oxidants evoked a concentration-dependent increase in short-circuit current (Isc). The EC50 values were 3.2 microM for NH2Cl, 6.5 microM for HOCl and 6.5 microM for H2O2. Responses to NH2Cl and H2O2 were abolished by removal of Cl- or Ca++. Unidirectional 36Cl- flux measurements showed that both oxidants (50 microM) evoked significant decreases in net chloride absorption. Tetrodotoxin (0.5 microM) and atropine (0.5 microM) partially inhibited the initial phase of the response to 50 microM NH2Cl; tetrodotoxin completely inhibited and atropine partially inhibited the response to 50 microM H2O2. Piroxicam (5 microM) inhibited the increase in Isc to 50 microM NH2Cl and H2O2 by 20-45% and 90%, respectively. Serosal prostaglandin E2 levels were significantly increased after the addition of 50 microM NH2Cl and H2O2. The morphological response to NH2Cl consisted of changes in mucosal depth and crypt architecture. In conclusion, at concentrations found in inflamed tissue, both NH2Cl and H2O2 increase Isc probably by stimulating release of arachidonate metabolites and neurotransmitter(s). NH2Cl also may act directly on the epithelial cell to stimulate Isc and evoke Cl- secretion.
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PMID:Monochloramine, a neutrophil-derived oxidant, stimulates rat colonic secretion. 203 26

The sample population in this initial case control study of the adenosine diphosphate ribosyl transferase (ADPRT) response of inflammatory bowel disease patients included: 23 patients with ulcerative colitis (UC)-active and inactive, 13 patients with Crohn's disease (CD)-active and inactive, 14 first degree relatives of UC and CD patients, and 19 age-matched controls. Adenosine diphosphate ribosyl transferase activity was determined after one hour incubation with 1% plasma (the constitutive value) or with 1% plasma and 100 microM H2O2 (the activated value) with the resulting difference designated as the induced value. Statistically significant decrease in ADPRT activity was found for the constitutive, activated and induced values in human mononuclear leucocytes of UC and CD patients, compared with controls. The values in the first degree relatives of UC and CD patients were not significantly different from either the control or disease populations, indicating an intermediate ADPRT response. These results may be related to the nature of the immunological response of IBD patients and comparable with similar findings in other diseases with known DNA repair deficiencies--for example, colon cancer.
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PMID:Hydrogen peroxide induced adenosine diphosphate ribosyl transferase (ADPRT) response in patients with inflammatory bowel disease. 314 30

The oxidative metabolism of circulating neutrophils was studied in patients with Crohn's disease and ulcerative colitis. The production of superoxide anion (02-.) in patients with ulcerative colitis was markedly decreased irrespective of whether soluble or particulate, non-chemotactic or chemotactic stimuli were used. Crohn's disease neutrophils showed a just marginally diminished 02-. production. Disease activity, as defined by the Crohn's disease activity index, was negatively correlated with the neutrophil O2-. production in both diseases. In both Crohn's disease and in ulcerative colitis neutrophil hydrogen peroxide (H2O2) production was normal. It is concluded that the neutrophil function, as-assessed by superoxide anion production, is impaired in patients with inflammatory bowel disease. It is therefore suggested that the suboptimal microbicidal function of these cells, as demonstrated in the present study, may contribute to the disease process.
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PMID:Impaired activation of the neutrophil oxidative metabolism in chronic inflammatory bowel disease. 381 12

Evidence of in vivo oxidant-induced injury in inflammatory bowel disease (IBD) is largely indirect. Colon epithelial crypt cells (CEC) from paired specimens of histologically normal and inflamed bowel from IBD patients with active disease were examined for altered protein thiol redox status as an indicator of oxidative damage. When CEC preparations from 22 IBD patients were labeled with the reduced-thiol-specific probe [14C]-iodoacetamide (IAM), there was decreased labeling of a number of proteins indicating oxidation of thiol groups in CEC from inflamed mucosa compared to paired normal mucosa, especially the loss of thiol labeling of a 37-kD protein which was almost completely lost. The loss of reduced protein thiol status for the 37-kD band was paralleled by loss of epithelial cell glyceraldehyde-3-phosphate dehydrogenase (GAPDH, EC 1.2.1.12) enzyme activity, an enzyme known to contain an essential reduced cysteine (Cys149) at the active site. The identity of the 37-kD protein as GADPH monomer was confirmed by NH2-terminal amino acid sequence analysis. To examine whether this type of in vivo injury could be attributed to biologically relevant oxidants produced by inflammatory cells, CEC prepared from normal mucosa were exposed to H2O2, OCl-, nitric oxide (NO), and a model chloramine molecule chloramine T (ChT) in vitro. Dose-dependent loss of IAM labeling and GAPDH enzyme activity was observed. The efficacy (IC50) against IAM labeling was OCl- >> ChT > H2O2 > NO (52 +/- 3, 250 +/- 17, 420 +/- 12, 779 +/- 120 microM oxidant) and OCl- >> ChT > NO > H2O2 (89 +/- 17, 256 +/- 11, 407 +/- 105, 457 +/- 75 microM oxidant), respectively, for GAPDH enzyme activity. This study provides direct evidence of in vivo oxidant injury in CEC from inflamed mucosa of IBD patients. Oxidation and inhibition of essential protein function by inflammatory cells is a potential mechanism of tissue injury that may contribute to the pathogenesis of the disease and supports the exploration of compounds with antioxidant activity as new therapies for IBD.
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PMID:Evidence of oxidant-induced injury to epithelial cells during inflammatory bowel disease. 869 Jul 84

Rebamipide (OPC-12759), a quinolone derivative, and OPC-6535, a thiazol-carboxylic acid derivative, are compounds with ability to protect gastrointestinal (GI) mucosal integrity against reactive oxygen metabolites (ROM). The underlying mechanism of OPC-mediated protection remains poorly understood. It is now established that ROM can injure the mucosa by disruption of the cytoskeletal network, a key component of mucosal barrier integrity. We, therefore, investigated whether OPC compounds prevent the oxidation, disassembly, and instability of the cytoskeletal protein actin and, in turn, protect intestinal barrier function against ROM. Human intestinal (Caco-2) cell monolayers were pretreated with OPC (-12759 or -6535) prior to incubation with ROM (H2O2) or HOCl). Effects on cell integrity (ethidium homodimer-1), epithelial barrier function (fluorescein sulfonic acid clearance), and actin cytoskeletal integrity (high-resolution laser confocal) were then determined. Cells were also processed for quantitative immunoblotting of G- and F-actin to measure oxidation (carbonylation) and disassembly of actin. In monolayers exposed to ROM, preincubation with OPC compounds prevented actin oxidation, decreased depolymerized G-actin, and enhanced the stable F-actin. Concomitantly, OPC agents abolished both actin cytoskeletal disruption and monolayer barrier dysfunction. Data suggest for the first time that OPC drugs prevent oxidation of actin and lead to the protection of actin cytoskeleton and intestinal barrier integrity against oxidant insult. Accordingly, these compounds may be used as novel therapeutic agents for the treatment of a variety of oxidative inflammatory intestinal disorders with an abnormal mucosal barrier such as inflammatory bowel disease.
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PMID:OPC-compounds prevent oxidant-induced carbonylation and depolymerization of the F-actin cytoskeleton and intestinal barrier hyperpermeability. 1116 75

Loss of intestinal barrier integrity is associated with oxidative inflammatory GI disorders including inflammatory bowel disease. Using monolayers of human intestinal epithelial (Caco-2) cells, we recently reported that epidermal growth factor (EGF) protects barrier integrity against oxidants by stabilizing the microtubule cytoskeleton, but the mechanism downstream of the EGF receptor (EGFR) is not established. We hypothesized that phospholipase C (PLC)-gamma is required. Caco-2 monolayers were exposed to oxidant (H2O2) with or without pretreatment with EGF or specific inhibitors of EGFR tyrosine kinase (AG-1478, tyrphostin 25) or of PLC (L-108, U-73122). Other Caco-2 cells were stably transfected with a dominant negative fragment for PLC-gamma (PLCz) to inhibit PLC-gamma activation. Doses of EGF that enhanced PLC activity also protected monolayers against oxidant-induced tubulin disassembly, disruption of the microtubule cytoskeleton, and barrier leakiness as assessed by radioimmunoassay, quantitative Western blots, high-resolution laser confocal microscopy, and fluorometry, respectively. Pretreatment with either type of inhibitor abolished EGF protection. Transfected cells also lost EGF protection and showed reduced PLC-gamma phosphorylation and activity. We conclude that EGF protection requires PLC-gamma signaling and that PLC-gamma may be a useful therapeutic target.
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PMID:Phospholipase C-gamma inhibition prevents EGF protection of intestinal cytoskeleton and barrier against oxidants. 1144 22

Induction of colitis by acetic acid (AA) in the rat is widely used experimental model of inflammatory bowel disease (IBD) and ulcerations. AA as an irritant induces colitis involving infiltration of colonic mucosa with neutrophils and increased production of inflammatory mediators, such as hydrogen peroxide (H2O2), nitric oxide (NO), myeloperoxidase activity (MPO), and tumor necrosis factor (TNF-alpha). Trimetazidine (TMZ), an antianginal compound, was administered to investigate if its cytoprotective features in cardiac tissue are also effective in AA colitis where ischemic injury contributes to colitis. Administration of TMZ intraperitoneally improved the macroscopic and microscopic score alterations produced by AA. AA administration significantly elevated colonic MPO activity; however, treatment with TMZ significantly lowered this enzyme activity compared to AA. AA administration significantly enhanced superoxide dismutase (SOD) activities, except for AA + TMZ given rectally. TMZ treatment significantly lowered nitrate levels, but AA increased these levels. AA administration markedly lowered TNF-alpha levels, but TMZ treatment elevated these levels to control. These findings indicate that overproduction of NO may be involved in the immunosuppression observed during acute AA-induced rat colitis. In conclusion, TMZ treatment was more effective via the intraperitoneal than rectal route, and may be beneficial in therapy of colitis.
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PMID:Effects of trimetazidine on acetic acid-induced colitis in female Swiss rats. 1265 21


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