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)

We have investigated the mechanism of indomethacin-induced gastric ulcer caused by reactive oxygen species (ROS) and the gastroprotective effect of curcumin thereon. Curcumin dose-dependently blocks indomethacin-induced gastric lesions, showing 82% protection at 25 mg/kg. Indomethacin-induced oxidative damage by ROS as shown by increased lipid peroxidation and thiol depletion is almost completely blocked by curcumin. Indomethacin causes nearly fivefold increase in hydroxyl radical (()OH) and significant inactivation of gastric mucosal peroxidase to elevate endogenous H(2)O(2) and H(2)O(2)-derived ()OH, which is prevented by curcumin. In vitro studies indicate that indomethacin inactivates peroxidase irreversibly only in presence of H(2)O(2) by acting as a suicidal substrate. 5,5-Dimethyl-pyrroline-N-oxide (DMPO) protects the peroxidase, indicating involvement of indomethacin radical in the inactivation. Indomethacin radical was also detected in the peroxidase-indomethacin-H(2)O(2) system as DMPO adduct (a(N) = 15 G, a(beta)(H) = 16 G) by electron spin resonance spectroscopy. Curcumin protects the peroxidase in a concentration-dependent manner and consumes H(2)O(2) for its oxidation as a suitable substrate of the peroxidase, thereby blocking indomethacin oxidation. Curcumin can also scavenge ()OH in vitro. We suggest that curcumin protects gastric damage by efficient removal of H(2)O(2) and H(2)O(2) -derived ()OH by preventing peroxidase inactivation by indomethacin.
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PMID:Indomethacin inactivates gastric peroxidase to induce reactive-oxygen-mediated gastric mucosal injury and curcumin protects it by preventing peroxidase inactivation and scavenging reactive oxygen. 1663 30

The first patient with chronic paroxysmal hemicrania has been followed for 45 years, and for 33 years with indomethacin treatment. The headache became less severe with time; there was no indomethacin tachyphylaxis. The first patient with SUNCT was followed for 28 years, until his demise at 89. Pain became worse with time. No adequate therapy was found. The first patient with Hemicrania continua was followed for 19 years, until her demise at 81. She was treated with indomethacin during the whole observation time. There was no tachyphylaxis. Both patients treated with indomethacin developed gastric ulcer. And both had gastric surgery. Indomethacin therapy may be a life-long affair. The risk of gastric complications may be substantial.
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PMID:Chronic paroxysmal hemicrania, hemicrania continua and SUNCT: the fate of the three first described cases. 1681 54

Gastric mucosal damage is directly associated with extracellular matrix degradation in which matrix metalloproteinases (MMPs) play a crucial role. Remodeling of connective tissues and loss of tissue integrity due to the action of MMPs are reported in several inflammatory diseases, including gastric ulcer. Indomethacin-induced gastric ulceration involves the generation of reactive oxygen species (ROS) and a reduction in MMP-2 transcription and translation. Our aim was to identify the mechanism for suppression of MMP-2 activity by ROS during acute ulceration and further to examine the possible actions of antioxidants, especially melatonin, during healing. Melatonin (N-acetyl-5-methoxytryptamine) blocked hydroxyl radical and nitrite anion generation, protein oxidation, mucosal cell disruption, and MMP-2 downregulation. In addition, suppression of MMP-2 activity by H2O2 in a dose- and time-dependent manner in vitro is blocked by melatonin, omeprazole, and curcumin. We observed that melatonin and other antioxidants (e.g., curcumin and omeprazole) offered gastroprotection in vivo by upregulation of suppressed MMP-2 expression and activity at the level of secretion and synthesis. Moreover, antioxidants reversed the suppression of MMP-2 expression by upregulation of MT1-MMP and downregulation of TIMP-2. Hence, we hypothesize that antioxidants exerted protection against H2O2-mediated inactivation and downregulation of MMP-2 expression during onset of indomethacin-induced ulceration.
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PMID:Hydrogen peroxide-mediated downregulation of matrix metalloprotease-2 in indomethacin-induced acute gastric ulceration is blocked by melatonin and other antioxidants. 1693 74

Indomethacin is one of non-steroidal anti-inflammatory drugs that are commonly used clinically and often cause gastric mucosal injury as a side effect. Generation of reactive oxygen species (ROS) and activation of apoptotic signaling are involved in the pathogenesis of indomethacin-induced gastric mucosal injury. Thioredoxin-1 (Trx-1) is a small redox-active protein with anti-oxidative activity and redox-regulating functions. The aim of this study was to investigate the protective effect of Trx-1 against indomethacin-induced gastric mucosal injury. Trx-1 transgenic mice displayed less gastric mucosal damage than wild type (WT) C57BL/6 mice after intraperitoneal administration of indomethacin. Administration of recombinant human Trx-1 (rhTrx-1) or transfection of the Trx-1 gene reduced indomethacin-induced cytotoxicity in rat gastric epithelial RGM-1 cells. Pretreatment with rhTrx-1 suppressed indomethacininduced ROS production and downregulation of phosphorylated Akt in RGM-1 cells. Survivin, a member of inhibitors of apoptosis proteins family, was downregulated by indomethacin, which was suppressed in Trx-1 transgenic mice or by administration of rhTrx-1 in RGM-1 cells. Trx-1 inhibits indomethacin-induced apoptotic signaling and gastric ulcer formation, suggesting that it may have a preventive and therapeutic potential against indomethacin-induced gastric injury.
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PMID:Thioredoxin-1 attenuates indomethacin-induced gastric mucosal injury in mice. 1765 42

This study investigated the involvement of neutrophil infiltration, disturbances in nitric oxide (NO) generation and oxidative stress in indomethacin-induced gastric ulcer, and the possible gastroprotective potentials of leptin, known for its angiogenic effect. Male Wistar albino rats (180-220 g) were allocated into a normal control group, ulcer control group (received a single dose of indomethacin 40 mg/kg p.o.) and an ulcer group pretreated with leptin (10 microg/kg i.p. 30 min before ulcer induction). The animals were killed 6 h after indomethacin administration and their gastric juice, serum and mucosal tissue were used for gastric injury evaluation. Indomethacin produced multiple lesions in glandular mucosa, evidenced by marked increase in gastric ulcer index (GUI) accompanied by significant increases in gastric juice acidity, tissue myeloperoxidase (MPO) activity, serum NO and tissue conjugated diene (CD), and marked decreases in tissue NO and glutathione (GSH) as well as glutathione reductase (GR) and superoxide dismutase (SOD) activities, while gastric juice mucin and tissue glutathione peroxidase (GPx) were not affected. Leptin exerted significant gastroprotection as evidenced by significantly decreased GUI and attenuated neutrophil infiltration. Leptin significantly increased mucin and tissue NO, restored GR and SOD activities and up-regulated GPx activity. It failed to affect acidity, serum NO, GSH and CD. These results suggest that leptin confers significant gastroprotection against indomethacin-induced injury through interfering with neutrophil infiltration, NO production and oxidative stress.
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PMID:Gastroprotective effect of leptin in indomethacin-induced gastric injury. 1818 Oct 30

Nonsteroidal anti-inflammatory drugs delay gastric ulcer healing, and the ability of proton pump inhibitors to counteract this detrimental effect is debated. This study evaluates the effects of pantoprazole on experimental gastric ulcer healing in the presence of indomethacin. Rats with acetic-acid-induced gastric ulcers were orally treated for 3 or 7 days with pantoprazole (15 micromol/kg/day) or famotidine (20 micromol/kg/day), alone or in combination with indomethacin (3 micromol/kg/day). Ulcerated tissues were processed to assess ulcer area, malondialdehyde, proliferating cell nuclear antigen (PCNA) and cleaved caspase-3. Experiments on pylorus-ligated rats indicated that pantoprazole and famotidine were employed at equivalent inhibitory doses on gastric acid secretion (-67.9% and -64.5%, respectively). Indomethacin delayed ulcer healing both at days 3 and 7 (+22 and +35 mm(2) vs control ulcer, respectively). At day 3, pantoprazole was more effective than famotidine in promoting ulcer healing in indomethacin-treated animals (-53.6 and -31.6 mm(2) vs indomethacin, respectively). Malondialdehyde levels and caspase-3 activation in ulcers were increased by indomethacin (+79% and +3.7 folds vs control ulcer, respectively), and these effects were counteracted by pantoprazole (-77.9% and -3.5 folds vs indomethacin, respectively), but not famotidine. Increments of ulcer PCNA expression (+2.5 folds vs normal) were enhanced further by pantoprazole or famotidine, alone or in combination with indomethacin (+8.6 and +10.3 folds vs normal, respectively). Similar results were obtained after 7-day treatments of ulcerated animals with test drugs. It is concluded that, along with acid suppression, pantoprazole exerts acid-independent effects on ulcer healing, which can be ascribed to a decrease in tissue oxidation and apoptosis.
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PMID:Effects of pantoprazole on ulcer healing delay associated with NSAID treatment. 1885 45

Nicotinamide, a precursor of nicotinamide adenine dinucleotide (NAD(+)), is an essential nutrient for cell growth that participates in DNA repair and energy production. Nonsteroidal anti-inflammatory drugs (NSAIDs)-induced gastropathy is an intricate process involving gastric mucus depletion, increased microvascular permeability, nitric oxide imbalance, as well as free radical production. The present study was conducted to test for the possible gastroprotective effect of nicotinamide utilizing an acute indomethacin-induced gastric ulcer model. Sucralfate possesses antiulcer/antioxidant properties; hence it was used as the reference drug. Indomethacin resulted in hemorrhagic mucosal lesions, increased microvascular permeability, and reduced the gastric mucosal contents of nitric oxide and mucus. Moreover, it produced an imbalance in the mucosal redox state as indicated by a decline of glutathione and glutathione peroxidase, which were associated with increased lipid peroxides. Comparable to sucralfate, nicotinamide markedly decreased the severity of indomethacin-induced gastric lesions and restored the levels of altered biochemical parameters. Gastroprotection afforded by nicotinamide is possibly mediated by conservation of gastric mucus, as well as nitric oxide contents, enhanced gastric microvascular permeability, and its antioxidant properties.
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PMID:Nicotinamide alleviates indomethacin-induced gastric ulcers: a novel antiulcer agent. 1985 87

Several reports have indicated that indomethacin-induced gastropathy is mediated through generation of free radicals, neutrophil infiltration and disturbance in nitric oxide production. Rutin is a potent antioxidant flavonoid. Recently, rutin was reported to inhibit neutrophil infiltration and to modulate nitric oxide production in gastric mucosa. Therefore, the aim of this study was to investigate the protective effect of rutin against indomethacin-induced gastric injury. Accordingly, four groups of rats were used. The first three groups were injected orally with vehicle, rutin (200 mg/kg) and indomethacin (48 mg/kg) respectively. The fourth group was injected with rutin 1 hr before indomethacin. Animals were killed after 6 hr of indomethacin administration. Gastric juice acidity and gastric injury were evaluated directly. Moreover, the activities of myeloperoxidase, superoxide dismutase and the contents of reduced glutathione, thiobarbituric acid reactive substance and total nitrite/nitrate (as a marker of nitric oxide production) were determined in mucosal tissues. Indomethacin increased gastric ulcer index, gastric myeloperoxidase activity, gastric acidity and thiobarbituric acid reactive substance contents compared with control. On the other hand, indomethacin decreased glutathione, nitrite/nitrate contents and superoxide dismutase activity. Histopathological examination of the stomachs of indomethacin-treated rats revealed degenerative changes in gastric tissues. Pre-treatment with rutin protected gastric tissues against indomethacin-induced gastropathy as demonstrated from reduction in the ulcer index, attenuation of histopathological changes and amelioration of the altered oxidative stress and biochemical parameters. These results indicate that rutin has a protective effect against indomethacin-induced gastropathy probably through inhibiting neutrophil infiltration, suppression of oxidative stress generation and replenishing nitrite/nitrate levels regardless of gastric acidity.
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PMID:Gastroprotective effect of rutin against indomethacin-induced ulcers in rats. 2037 37

Indomethacin is a nonsteroid anti-inflammatory agent that is known to induce severe gastric mucosal lesions. In this study, we investigated the effect of selenium on gastric mucosal lesions in rats. To confirm the curative effect of selenium against indomethacin-induced gastric ulcers, gastric ulcers were induced by oral administration of 25 mg/kg indomethacin, and then different doses (10, 50, and 100 microgram/kg of body weight) of selenium or vehicle were treated by oral gavage for 3 days. Oral administration of indomethacin clearly increased the gastric ulcer area in the stomach, whereas selenium applied for 3 days significantly decreased the gastric ulcer area in a dose-dependent manner. In addition, selenium markedly reduced the increase of lipid peroxidation induced by indomethacin in the gastric mucosa and increased activities of radical scavenging enzymes such as superoxide dismutase, catalase, and glutathione peroxidase in a dose-dependent manner. These results reveal that selenium can heal indomethacininduced gastric ulcers through elimination of the lipid peroxides and activation of radical scavenging enzymes.
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PMID:Curative effect of selenium against indomethacin-induced gastric ulcers in rats. 2153 24

The Bartter syndrome is a rare hereditary salt-wasting tubulopathy, characterized by metabolic alkalosis, hypokalemia, hyperreninemia and hyperaldosteronemia of varying severity. Indomethacin and high doses of oral potassium have been until now the therapeutic strategies used, with high risk of gastrointestinal injury. Since April 2009, aliskiren--renin inhibitor--has been used in individual cases of Bartter syndrome in adults, by ignoring its use in pediatrics. The authors present the case of an eight year old child with Bartter syndrome, treated with oral potassium chloride and oral indomethacin, whom has been diagnosed a giant gastric ulcer. To enable the reduction of the amount of potassium administered, we chose to start the aliskiren.
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PMID:[Bartter syndrome: a new therapeutic approach]. 2285 10


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