Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038358 (gastric ulcer)
 5,179 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The possession of the cytotoxin-associated gene (cagA) of Helicobacter pylori is thought to be highly associated with peptic ulcer disease. However, the pathogenic role of cagA is still unknown. We have emphasized the importance of the interrelationship between H. pylori-derived ammonia and oxygen radicals from infiltrated leucocytes. The aim of the present study was to explore the relationship between oxygen radical production and H. pylori strain diversity based on cagA possession. An endoscopic examination and gastric mucosal biopsy were performed in 30 H. pylori-infected patients with gastric ulcer. Myeloperoxidase (MPO) content and the luminol-dependent chemiluminescence value in the biopsied gastric specimens were measured as an index for leucocyte infiltration and oxygen radical production. From the precipitates of cultured bacterial isolates of biopsied specimens, bacterial DNA was purified and analysed by polymerase chain reaction to characterize the possession of cagA. While all patients had ureC-positive strains, 22 had cagA-positive and eight had cagA-negative strains. In patients with cagA-positive strains, MPO contents as well as chemiluminescence values in the gastric corpus were significantly higher than those in patients with cagA-negative strains. Gastric mucosal leucocyte recruitment and activation are suggested to be enhanced by cagA gene-positive H. pylori infection.
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PMID:Augmented levels of gastric mucosal leucocyte activation by infection with cagA gene-positive Helicobacter pylori. 957 Feb 43

Rebamipide, a gastroprotective drug, is a compound selected from over 500 amino acid analogs of 2(1H)-quinolinone tested for gastroprotective action and for efficacy to heal experimental gastric ulcers. This drug stimulates prostaglandin generation in gastric mucosa and improves not only the speed but also the quality of ulcer healing. In addition, it protects the gastric mucosa against acute injury caused by various noxious and ulcerogenic factors. Based on these experimental results, rebamipide had been subsequently tested in several clinical trials and approved in Japan for therapeutic use in patients with gastric ulcers and patients with acute gastritis. The main purpose of developing this type of drug was to improve the quality of ulcer healing, especially in that antisecretory drugs lack this advantage. In a preliminary clinical study, rebamipide improved the quality of gastric ulcer healing and reduced future ulcer recurrence. A number of basic research studies have been performed to clarify the mechanisms of rebamipide's action. These studies demonstrated unique properties of rebamipide and convincingly showed that it increases gastric mucus glycoprotein components, stimulates migration and proliferation of wounded epithelial cell monolayers, increases expression of epidermal growth factor and its receptor in normal and ulcerated gastric mucosa, and scavenges active oxygen radicals. The drug also attenuates the activity of neutrophils and the production of inflammatory cytokines stimulated by NSAIDs and/or H. pylori. Therefore, rebamipide can contribute to the management of patients who are taking NSAIDs or are infected with H. pylori. The inhibition of immunoinflammatory responses by rebamipide in H. pylori-infected patients may prevent development of gastritis, peptic ulcer disease, its recurrence, and possibly gastric cancer. Moreover, rebamipide may enhance eradication of H. pylori-infection using standard eradication therapy. Further studies are needed to clarify these possible advantages of rebamipide.
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PMID:Rebamipide: overview of its mechanisms of action and efficacy in mucosal protection and ulcer healing. 975 20

Rebamipide is the first anti-gastric ulcer and antigastritis drug that not only increases endogenous prostaglandin in gastric mucosa but also scavenges oxygen-derived free radicals and inhibits their production. In the present paper, we have reviewed the antioxidative and antiinflammatory properties of rebamipide mainly demonstrated by in vitro studies. The study, using the electron paramagnetic resonance (EPR) spin trapping technique, showed that superoxide production was inhibited by rebamipide when isolated human neutrophils were stimulated with opsonized zymosan or Helicobacter pylori water extract in a dose-dependent manner. Chemiluminescence generated from neutrophils activated by H. pylori or formyl-methionyl-leucyl-phenylalanine was also decreased by the treatment with rebamipide. Rebamipide, at concentrations of 10(-5) and 10(-6) M, reduced the adherence of neutrophils to endothelial cells as well as the CD18 expression on neutrophils induced by H. pylori water extract. The EPR study also demonstrated the direct hydroxyl radical scavenging activity of rebamipide, and a kinetic study showed that the second-order rate constant for the reaction between rebamipide and hydroxyl radical was 2.24 x 10(10) M(-1)/s(-1). The inhibitory effect of rebamipide on lipid peroxidation induced by a free radical initiator was also demonstrated by the in vitro system using rat gastric mucosal homogenates. These data indicate that rebamipide offers a potential for protection against reactive oxygen- and activated neutrophil-associated gastric mucosal injury by scavenging hydroxyl radical and inhibiting neutrophil activation or lipid peroxidation.
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PMID:In vitro studies indicating antioxidative properties of rebamipide. 975 24

Helicobacter pylori (HP), undoubtedly, the most common world-wide infection plays an important role in pathogenesis of peptic ulcer. Proof for a causal role for HP in peptic ulcer rests in two major points; 1) the majority of ulcer patients are HP infected and the prevalence of this infection for both gastric ulcer (GU) and duodenal ulcer (DU) is much higher than for gender- and age-adjusted controls and 2) the cure of HP infection dramatically reduces ulcer recurrence. Conclusions regarding the mechanisms by which HP induces peptic ulcer are restricted mainly to studies observing the consequences of its eradication by antibiotics combined with gastric inhibitors or bismuth agents. Several specific virulence factors such as cytotoxin-associated gene A (CagA) and vacuolating cytotoxin A (VacA) as well as other noxious substances including ammonia, lipopolysaccharide (endotoxin), platelet activating factor (PAF), nitric oxide (NO) and others have been implicated in gastritis and were found to be significantly more frequent in gastric cancer than in gender- and age-matched controls, especially in younger generation. Chronic inflammation, atrophic gastritis, intestinal metaplasia, impaired defense mechanisms combined with hypergastrinemia, deficiency of vitamin C in the stomach , excessive oxygen metabolites and epithelial cell proliferation have been associated with gastric cancer. This multi-step pathway originally proposed by Correa and his colleagues, long before the HP was discovered in the stomach, leads to cancer but may be reversed by eradication of HP. This is, however, a controversial issue because gastric atrophy and intestinal metaplasia may be also caused by other factors such as bile reflux, dietary irritants, and autoimmunity. The implication of HP in MALT-lymphoma is based on the observations that eradication of HP in early stage of low-grade of this tumor leads to complete remission. The significance of HP in non-ulcer dyspepsia remains questionable and requires further studies.
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PMID:Helicobacter pylori associated gastric pathology. 1069 52

Highly reactive oxygen-free radicals are implicated in the pathogenic process of various diseases. Using an animal model of diabetes (alloxan-induced hyperglycaemia in mice), a model of gastric ulcer (indomethacin-induced gastric lesion in rats), and a model of bronchial asthma (ovalbumin-induced allergic bronchospasm in guinea pigs), a potential therapeutic effect was tested in known antioxidant drugs (alpha-tocopherol, ubiquinone), the thio-compound mesna, and drugs with a possible antioxidant effect (substances derived from the ergoline structure: 6-hydroxynicotinic acid and 4-hydroxypyridine). The pre-treatment with ubiquinone and 6-hydroxynicotinic acid almost completely prevented alloxan-induced hyperglycaemia (94 and 93% inhibition of hyperglycaemia, respectively). A weaker effect was shown by alpha-tocopherol and 4-hydroxypyridine (31 and 27% inhibition of hyperglycaemia, respectively). Mesna negligibly increased hyperglycaemia. 32% and 21% inhibitions of the number of gastric lesions were shown after administration of 6-hydroxynicotinic acid and alpha-tocopherol, respectively. Other drugs, most markedly mesna, aggravated gastric lesions. The most marked protective effect on ovalbumin-induced bronchospasm was exerted by 6-hydroxynicotinic acid (the pulmonary ventilation was increased by 84% in comparison with control group), while mesna and (alpha-tocopherol had a weaker effect (amelioration by 50 and 51 %, respectively). Ubiquinone and 4-hydroxypyridine aggravated pulmonary ventilation. The most marked protective effect in the animal models used was shown by 6-hydroxynicotinic acid.
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PMID:Effects of known and potential antioxidants on animal models of pathological processes (diabetes, gastric lesions, allergic bronchospasm). 1108 99

We investigated the role of xanthine oxidase-derived oxygen radicals in the development of endothelin-1-induced gastric ulcer. Mucosal lipid peroxidation showed a peak 24 h after injection, while gastric mucosal haemodynamics were fully restored 26 h after endothelin-1 injection. Allopurinol and oxypurinol, but not superoxide dismutase or catalase, protected the gastric mucosa 24 h after endothelin-1 injection. Oxypurinol antagonized both the vasoconstrictor effect of endothelin-1 and the decrease in gastric ATP. All treatments on the second day after endothelin-1 injection significantly reduced gastric mucosal damage. Xanthine oxidase-derived oxygen radicals contributed largely to the exacerbation but they did not mediate the onset of endothelin-1-induced gastric ulcer. Pretreatment with probucol (500 mg/kg, p.o.) also protected the gastric mucosa from endothelin-1-induced mucosal injury by its antioxidant activity. Oxypurinol was gastroprotective through its vasoactive and energy saving actions. The haemodynamic background of endothelin-1-induced gastric ulcer consists of long lasting ischaemia and subsequent "reperfusion" which may be responsible for the late burst of oxygen radicals.
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PMID:Oxygen radicals mediate the final exacerbation of endothelin-1-induced gastric ulcer in rat. 1117 71

Dimethylglycine is an anti-stress nutrient with antioxidant properties. Recently, studies have implicated the generation of oxygen-derived free radicals and lipid peroxidation as one of the mechanisms in the pathogenesis of gastric ulcer. Hence, we evaluated the antiulcer activity of dimethylglycine in various rat models of ulcer and also investigated the probable antioxidant mechanism of the anti-ulcer effect. Dimethylglycine at a dose of 25 and 35 mg kg(-1) significantly reduced ulcer number, ulcer size and ulcer index in pyloric-ligation-, ibuprofen- and stress-induced ulcers. The 35 mg kg(-1) dose was more effective than 25 mg kg(-1) and was comparable to famotidine. Dimethylglycine did not produce any significant change in acid secretion, unlike famotidine. There was a significant increase in plasma and tissue malondialdehyde levels in pyloric-ligated rats but these levels fell following dimethylglycine treatment. Also, there was a significant reduction in glutathione levels after dimethylglycine treatment. The results suggest that the gastroprotective effect of dimethylglycine could be mediated by its free radical scavenging activity and cytoprotection of gastric mucosa.
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PMID:Effect of dimethylglycine on gastric ulcers in rats. 1119 81

In a rat model of the ischemia-reperfusion with pylorus ligation, gastric ulcer was formed, although gastric acid secretion was reduced. When the polymorphonuclear leukocytes were inactivated in advance, gastric ulcer was not formed, but acid secretion was increased, indicating that gastric acid is not a cause of the ulcer formation in this model. The mechanism of gastric acid suppression accompanied by ischemia-reperfusion was examined in relation to the role of oxygen-free radicals in this rat model. Prior administration of superoxide dismutase did not modulate acid secretion, but N-nitro-L-arginine methyl ester (L-NAME) increased acid secretion. The action of L-NAME was antagonized specifically by L-arginine, but not by D-arginine. S-nitroso-N-acetylpenicillamine did not inhibit basal acid secretion but antagonized the action of L-NAME. Aminoguanidine increased significantly the gastric acid output that was suppressed by ischemia-reperfusion. When polymorphonuclear leukocytes were inactivated by treatment with their antibody, the gastric acid output recovered to the level in the pylorus-ligated rat without ischemia-reperfusion. These results suggested that nitric oxide (NO) produced by the infiltrated polymorphonuclear leukocytes plays an important role in the suppression of acid secretion induced by ischemia-reperfusion.
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PMID:The role of nitric oxide in the gastric acid secretion induced by ischemia-reperfusion in the pylorus-ligated rat. 1147 Feb 62

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, indomethacin (IND), ibuprofen and newer cyclooxygenase-2 selective NSAIDs (e.g. celecoxib) delay gastric ulcer healing partly through the inhibition of angiogenesis, but the molecular mechanisms involved are not fully elucidated. Effective angiogenesis is required for ulcer healing to supply oxygen and nutrients to the healing site. The early growth response factor (Egr-1) is a transcription factor, which is rapidly activated by a variety of extracellular signals or tissue injury and is important for angiogenesis to occur. This study aimed to determine whether indomethacin (IND) and/or the selective COX-2 inhibitor, NS-398, interfere with egr-1 gene expression in human microvascular endothelial cells (HMVEC) in response to vascular endothelial growth factor (VEGF) stimulation. HMVEC were treated with 0.5 mM IND or 100 microM NS-398 for 16 h, and then VEGF (10 ng/ml) or vehicle was added. Egr-1 mRNA and protein expression levels were determined by RT-PCR and Western-blotting, respectively. VEGF treatment caused a significant elevation of Egr-1 mRNA (261+/-21%, P<0.001) and protein expression (174+/-15%, P<0.01) vs. vehicle. IND pre-treatment significantly inhibited VEGF-induced Egr-1 mRNA expression by 29+/-4% (P<0.01) and protein expression by 41+/-8% (P<0.05). NS-398 inhibited VEGF-induced Egr-1 mRNA and protein expression by 23+/-3% and 35+/-4%, respectively (both P<0.01). Since transcriptional activation of egr-1 is responsible for expression of proteins involved in proliferation of endothelial cells essential for angiogenesis, these results provide a new mechanism for NSAIDs' interference with angiogenesis.
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PMID:NSAIDs inhibit the activation of egr-1 gene in microvascular endothelial cells. A key to inhibition of angiogenesis? 1159 63

The objective of the present study is to delineate the mechanism of oxidative damage in human gastric ulcerated mucosa despite the presence of some antioxidant enzymes. We report for the first time the critical role of an endogenous peroxidase, a major H(2)O(2) metabolizing enzyme, in controlling oxidative damage in gastric mucosa. Human gastric mucosa contains a highly active peroxidase in addition to the myeloperoxidase contributed by neutrophil. In both non-Helicobacter pylori (H. pylori)- and H. pylori-mediated gastric ulcer, when myeloperoxidase level increases due to neutrophil accumulation, gastric peroxidase (GPO) level decreases significantly. Moreover, gastric ulcer is associated with oxidative damage of the mucosa as evidenced by significant increase in lipid peroxidation, protein oxidation, and thiol depletion indicating accumulation of reactive oxygen metabolites (ROM). Mucosal total superoxide dismutase (Mn and Cu-Zn SOD) level also decreases significantly leading to increased accumulation of O(2)(*-). To investigate the plausible ROM-mediated inactivation of the GPO during ulceration, the enzyme was partially purified from the mucosa. When exposed to an in vitro ROM generating system, using Cu(2+), ascorbate, and H(2)O(2,) the enzyme gets inactivated, which is dependent on Cu(2+), ascorbate, or H(2)O(2). Insensitivity to SOD excludes inactivation by O(2)(*-). However, complete protection by catalase indicates that H(2)O(2) is essential for inactivation. Sensitivity to EDTA and hydroxyl radical *OH) scavengers indicates that GPO is inactivated most probably by *OH generated from H(2)O(2). We propose that GPO is inactivated in vivo by ROM generated by activated neutrophil. This leads to further accumulation of endogenous H(2)O(2) to cause more oxidative damage to aggravate the ulcer.
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PMID:Critical role of an endogenous gastric peroxidase in controlling oxidative damage in H. pylori-mediated and nonmediated gastric ulcer. 1193 99


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