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Gastric ulcer is a very common disease that represent an economic burden. Non-steroidal anti-inflammatory drugs induce ulcer in old patients and in patients with comorbidities. Indomethacin is widely used to induce gastric ulcer in animal models. Diabetic patients are highly susceptible to develop gastric ulcer. Metformin, the first line medication for the treatment of type II diabetes melilites that have many off label uses in non-diabetic patients, has been recently reported to have anti-inflammatory activities. Therefore, this research was conducted to assess the possible healing effects of metformin on gastric ulcers induced by indomethacin in rats. Indomethacin (48 mg/kg) single dose increased stomach acidity, ulcer index and induced histopathological changes. Indomethacin also decreased mucin levels and increased the activity of tumor necrosis factor-α (TNF-α), nuclear factor kappa-B (NF-κB), Rho-associated protein kinas-1 (ROCK-1) and decreased the levels of the protective nitric oxide (NO). After the induction of ulcer, rats were treated by omeprazole (30 mg/kg) or metformin (50, 100 or 200 mg/kg). Omeprazole and metformin were found to decrease stomach acidity and ulcer index, restored the histological features and increased mucin levels. Both also decreased the levels of NF-κB, TNF-α, ROCK-1 and increased NO. Metformin exerted ulcer healing effects comparable to that of omeprazole. This can be attributed, at least partly, to its anti-inflammatory activity and increasing NO levels., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Multiple kinds of monoamine-based antidepressants have been shown prophylactic effects in experimentally induced gastric ulcer. The loss of redox homeostasis plays a principle role in the development of peptic mucosal damage. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases are one of the most important sources of reactive oxygen species within the gastrointestinal tract. It is unclear whether there are some common NADPH oxidases modulated by monoamine-based antidepressants in different gastric mucosal damage models. We explored the effects of selective serotonin-norepinephrine reuptake inhibitor (SNRI) duloxetine on the reactive oxygen species production and antioxidant capacity in the gastric mucosa of water immersion restraint (WIRS) or indomethacin treated rats, and examined the role of NADPH oxidases in the protective effects. Pretreated duloxetine prevented the increase of gastric mucosal NADPH oxidase activity and NADPH oxidase inhibitor apocynin dose-dependently protected gastric mucosa from damage by the two factors. Furthermore, dual oxidase 2 (DUOX2) and NADPH oxidase4 (NOX4) are involved in the protective effects of duloxetine in both models. We then examined NADPH oxidases expression modulated by the other monoamine-based antidepressants including selective serotonin reuptake inhibitor (SSRIs) fluoxetine, tricyclic agent (TCAs) amitriptyline and monoamine oxidase inhibitor (MAOs) moclobemide in the two models, and all the three antidepressants reduced the DUOX2 expression in the gastric mucosa. So DUOX2 was a common modulator in the preventive effects of all the monoamine-based antidepressants on WIRS- and indomethacin-induced gastric lesion. Our work provided a peripheral joint molecular target for monoamine modulatory antidepressants, which may be helpful to reveal the mechanisms of this kind of drugs more than monoamine regulation., Competing Interests: Declaration of competing interest There are no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Methylsulfonylmethane (MSM) is a natural organosulfur compound has been widely used as a dietary supplement. MSM has protective effects against various disorders through its anti-inflammatory and antioxidant properties however the effect of MSM on gastric mucosal injury remains unclear. The aim of the present study is to determine whether MSM has beneficial effects on ethanol/HCl-induced gastric ulcer in mice. Macroscopic and histopathological evaluation of gastric mucosa revealed that ethanol/HCl administration produced apparent mucosal injuries, while pretreatment with MSM (200 and 400mg/kg, orally) could effectively protect gastric mucosa against the injuries caused by acidified ethanol. MSM significantly increased the levels of glutathione (GSH), catalase (CAT) and prostaglandin E 2 (PGE 2 ), and decreased the levels of malondialdehyde (MDA), myeloperoxidase (MPO), carbonyl protein, and nitric oxide (NO) in gastric tissues compared with those in the ethanol group. MSM suppressed gastric inflammation by reducing the levels of proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, monocyte chemoattractant protein (MCP)-1 and matrix metalloproteinase (MMP)-9. Moreover, pretreatment of mice with MSM decreased the expression of nuclear factor kappa B (NF-κB) as a key regulator of inflammation in gastric mucosa. Taken together, these data suggest that MSM is able to decrease the severity of ethanol/HCl-induced gastric mucosal injury through inhibition of oxidative stress and inflammation., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objectives: The purpose of this study was to assess the gastroprotective properties of alpha-boswellic acid (α-BA), a pentacyclic triterpene compound from extracts of Frankincense., Methods: The gastroprotection of α-BA was assessed with ethanol-induced gastric lesions model, by histopathological assessment and measuring gastric juice acidity (pH), gastric wall mucus (GWM), prostaglandins E2 (PGE-2), membrane lipids peroxidation (MDA), superoxide dismutase (SOD) activity, catalase (CAT) activity and amount of nitric oxide (NO). The gastroprotective effects of α-BA through the nuclear factor erythroid-2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) anti-oxidative pathway were presented and measured by immunohistochemistry and Western blot., Key Findings: The results showed that α-BA reduced injuries associated with the administration of ethanol, gastric juice acidity and the formation of MDA and increased CAT activity and SOD activity and the level of NO and PGE-2 in a dose-depended manner. The expression of both Nrf2 and HO-1 was significantly increased in the group treated with 200 mg/kg α-BA, which suggested that activation of the Nrf2/HO-1 pathway might be critical in α-BA's prevention of gastric ulcers., Conclusions: These findings demonstrate that α-BA decreases oxidative stress and that the Nrf2/HO-1 pathway might play a role in the gastroprotective action of α-BA in ethanol-induced gastric injury in rats., (© 2016 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology.)

Context: Spondias mombin Linn (Anacardiaceae) and Ficus exasperata Valh (Moraceae) are botanicals with known phytotherapeutic potentials in the traditional system of medicine in the world., Objective: The objective of this study is to investigate the quantitative polyphenolic constituents and gastroprotective effects of aqueous leaf extracts of Spondias mombin and Ficus exasperata against indomethacin-induced gastric ulcer in rats., Materials and Methods: Ulceration was induced by a single oral administration of indomethacin (30 mg/kg body weight (b.w.)). Ulcerated rats were orally administered with esomeprazole (a reference drug) at a dose of 20 mg/kg body weight, and Spondias mombin and Ficus exasperata at a dose of 100 and 200 mg/kg b.w. once daily for 21 d after ulcer induction. Gastric secretions and antioxidant parameters were thereafter evaluated., Results: The significantly increased (p < 0.05) ulcer index, gastric volume, malondialdehyde level, and pepsin activity by indomethacin were effectively reduced by 65.40, 36.47, 45.71, and 53.79%, respectively, following treatment with F. exasperata at 200 mg/kg b.w. S. mombin at this regimen also attenuated these parameters by 71.70, 46.62, 50.16, and 55.73%. Moreover, the extracts significantly increase the reduced activity of superoxide dismutase as well as pH and mucin content in the ulcerated rats., Discussion and Conclusion: These findings are indicative of gastroprotective and antioxidative potentials of the extracts which is also evident in the degree of % inhibition against ulceration. The available data in this study suggest that the extracts proved to be capable of ameliorating indomethacin-induced gastric ulceration and the probable mechanisms are via antioxidative and proton pump inhibition.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to cause gastric mucosal damage as a side effect. Acetaminophen, widely used as an analgesic and antipyretic drug, has gastroprotective effects against gastric lesions induced by absolute ethanol and certain NSAIDs. However, the mechanisms that underlie the gastroprotective effects of acetaminophen have not yet been clarified. In the present study, we examined the role and protective mechanism of acetaminophen on ibuprofen-induced gastric damage in rats. Ibuprofen and acetaminophen were administered orally, and the gastric mucosa was macroscopically examined 4 hours later. Acetaminophen decreased ibuprofen-induced gastric damage in a dose-dependent manner. To investigate the mechanisms involved, transcriptome analyses of the ibuprofen-damaged gastric mucosa were performed in the presence and absence of acetaminophen. Ingenuity pathway analysis (IPA) software revealed that acetaminophen suppressed the pathways related to cellular assembly and inflammation, whereas they were highly activated by ibuprofen. On the basis of gene classifications from the IPA Knowledge Base, we identified the following five genes that were related to gastric damage and showed significant changes in gene expression: interleukin-1β (IL-1β), chemokine (C-C motif) ligand 2 (CCL2), matrix metalloproteinase-10 (MMP-10), MMP-13, and FBJ osteosarcoma oncogene (FOS). Expression of these salient genes was confirmed using real-time polymerase chain reaction. The expression of MMP-13 was the most reactive to the treatments, showing strong induction by ibuprofen and suppression by acetaminophen. Moreover, MMP-13 inhibitors decreased ibuprofen-induced gastric damage. In conclusion, these results suggest that acetaminophen decreases ibuprofen-induced gastric mucosal damage and that the suppression of MMP-13 may play an important role in the gastroprotective effects of acetaminophen.

Aim: To compare matrix metalloproteinase (MMP)-9 and tissue inhibitor of metalloproteinase (TIMP)-1 in gastric ulcer (GU) and chronic superficial gastritis (CSG)., Methods: This study enrolled 63 patients with GU and 25 patients with CSG. During upper gastroduodenal endoscopy, we took samples of gastric mucosa from the antrum and ulcer site from patients with GU, and samples of antral mucosa from patients with CSG. Mucosal biopsy tissues were cultured for 24 h, and the culture supernatant was measured for levels of MMP-9 and TIMP-1. After receiving eradication therapy for Helicobacter pylori (H. pylori) and 8 wk proton-pump inhibitor therapy for GU, follow-up endoscopy examination was performed after 6 mo and whenever severe symptoms occurred., Results: Levels of MMP-9 and TIMP-1 at the ulcer site or in the antrum were significantly higher in GU than CSG patients. MMP-9 levels at the ulcer site were significantly higher than in the antrum in GU patients, and had a significantly positive correlation with TIMP-1. MMP-9 levels were significantly higher in H. pylori-positive than H. pylori-negative GU and CSG patients. Levels of MMP-9 or TIMP-1 at the ulcer site were associated with the histological severity of activity and inflammation. About 57 GU patients were followed up, and seven had GU recurrence. H. pyloriinfection and MMP-9 levels were risk factors for the recurrence of GU adjusted for age and sex by multiple logistic regression analysis., Conclusion: MMP-9 may perform an important function in gastric ulcer formation and recurrence.

Background and Objective: Some short peptides have recently been reported to exhibit gastroprotective properties but the role of NO-synthase system in these mechanisms still leaves much to be elucidated. That is why the purpose of our study was to explore the gastroprotective effect of the hexapeptide Arg-α-Asp-Lys-Val-Tyr-Arg (thymohexin) under conditions of the modeling of iNOS activity., Materials and Methods: The studies were performed on 80 outbred male rats. Gastric lesions were induced with epinephrine (2 mg/kg) or indomethacin (30 mg/kg). Fifteen minutes before the exposure to ulcerogens rats were pretreated with thymohexin alone and combined with l-arginine or aminoguanidine. Twenty-four hours later gastric mucosa damage, L-arginine/NOS/NO system, processes of lipoperoxidation, superoxide dismutase and catalase activity were assessed., Results: Thymohexin markedly attenuated both epinephrine- and indomethacin-induced gastric ulceration in rats, decreasing the area and score of mucosal lesions (p<0.05), iNOS activity (p<0.05) and malonic dialdehyde content (p<0.05) in gastric mucosa. The cytoprotective effect of thymohexin was significantly enhanced by L-arginine and aminoguanidine. The combination of thymohexin and l-arginine was superior to that with aminoguanidine., Conclusions: Thymohexin protects gastric mucosa against epinephrine- and indomethacin-induced gastric lesions in rats. Thymohexin-induced gastroprotection is probably mediated by inhibition of iNOS and decrease of the oxidative damage in gastric mucosa., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Ample of evidence proved the gastroprotective effect of thymoquinone (TQ), the main constituent of Nigella sativa oil; however, the full mechanistic cassette on the gastric ulcer etiopathogenesis is not fully elucidated. The aim of the present work is to unveil some of the possible mechanisms. Animals were injected with vehicle, TQ (10 & 20mg/kg), omeprazole (10 & 20mg/kg) or their combination (10mg/kg). Thirty minutes later, pyloric ligation was carried out and followed consequently with ischemia for another 30min, abided by reperfusion for 120min. The ischemia/reperfusion insult increased the gastric acid secretion, acid output, and pepsin, as well as the gastric mucosal content/activity of lipid peroxide, proton pump and myeloperoxidase, along with ulcer index. However, content/activity of gastric mucin, reduced glutathione, total nitric oxide, and superoxide dismutase were decreased. TQ, especially the high dose level, corrected the altered parameters in a comparable manner to that of the reference drug used, omeprazole. In addition, when the low doses were combined they add to each other to reach the effect of the high dose of either drug. These results showed that apart from its known antioxidant properties, TQ has novel gastroprotective mechanisms via inhibiting proton pump, acid secretion and neutrophil infiltration, while enhancing mucin secretion, and nitric oxide production., (Copyright © 2012 Elsevier B.V. All rights reserved.)

This article reviews the pathogenic mechanism of non-steroidal anti-inflammatory drug (NSAID)-induced gastric damage, focusing on the relation between cyclooxygenase (COX) inhibition and various functional events. NSAIDs, such as indomethacin, at a dose that inhibits prostaglandin (PG) production, enhance gastric motility, resulting in an increase in mucosal permeability, neutrophil infiltration and oxyradical production, and eventually producing gastric lesions. These lesions are prevented by pretreatment with PGE₂ and antisecretory drugs, and also via an atropine-sensitive mechanism, not related to antisecretory action. Although neither rofecoxib (a selective COX-2 inhibitor) nor SC-560 (a selective COX-1 inhibitor) alone damages the stomach, the combined administration of these drugs provokes gastric lesions. SC-560, but not rofecoxib, decreases prostaglandin E₂ (PGE₂) production and causes gastric hypermotility and an increase in mucosal permeability. COX-2 mRNA is expressed in the stomach after administration of indomethacin and SC-560 but not rofecoxib. The up-regulation of indomethacin-induced COX-2 expression is prevented by atropine at a dose that inhibits gastric hypermotility. In addition, selective COX-2 inhibitors have deleterious influences on the stomach when COX-2 is overexpressed under various conditions, including adrenalectomy, arthritis, and Helicobacter pylori-infection. In summary, gastric hypermotility plays a primary role in the pathogenesis of NSAID-induced gastric damage, and the response, causally related with PG deficiency due to COX-1 inhibition, occurs prior to other pathogenic events such as increased mucosal permeability; and the ulcerogenic properties of NSAIDs require the inhibition of both COX-1 and COX-2, the inhibition of COX-1 upregulates COX-2 expression in association with gastric hypermotility, and PGs produced by COX-2 counteract the deleterious effect of COX-1 inhibition.

Current anti-gastric ulcer agents have side effects, despite the progression and expansion of advances in treatment. This study aimed to investigate the gastroprotective mechanisms of Pithecellobium jiringa ethanol extract against ethanol-induced gastric mucosal ulcers in rats. For this purpose, Sprague Dawley rats were randomly divided into five groups: Group 1 (normal control) rats were orally administered with vehicle (carboxymethyl cellulose), Group 2 (ulcer control) rats were also orally administered with vehicle. Group 3 (positive control) rats were orally administered with 20 mg/kg omeprazole, Groups 4 and 5 (experimental groups) received ethanol extract of Pithecellobium jiringa ethanol extract at a concentration of 250 and 500 mg/kg, respectively. Sixty minutes later, vehicle was given orally to the normal control group, and absolute ethanol was given orally to the ulcer control, positive control and experimental groups to generate gastric mucosal injury. The rats were sacrificed an hour later. The effect of oral administration of plant extract on ethanol-induced gastric mucosal injury was studied grossly and histology. The level of lipid peroxidation (malondialdehyde-MDA), superoxide dismutase (SOD) and gastric wall mucus were measured from gastric mucosal homogenate. The ulcer control group exhibited severe gastric mucosal injury, and this finding was also confirmed by histology of gastric mucosa which showed severe damage to the gastric mucosa with edema and leucocyte infiltration of the submucosal layer. Pre-treatment with plant extract significantly reduced the formation of ethanol-induced gastric lesions, and gastric wall mucus was significantly preserved. The study also indicated a significant increase in SOD activity in gastric mucosal homogenate, whereas a significant decrease in MDA was observed. Acute toxicity tests did not show any signs of toxicity and mortality up to 5 g/kg. The ulcer protective effect of this plant may possibly be due to its preservation of gastric wall mucus along with increased SOD activity and reduction of oxidative stress (MDA). The extract is non-toxic, even at relatively high concentrations.

For centuries, Aloe has been used as a herbal plant remedy against skin disorders, diabetes, and for its cardiac stimulatory activity. Here, we examined the gastroprotective effects of an Aloe vera polymer fraction (Avpf; molecular weight cut-off ≥50 kDa; 150 mg/kg body weight, p.o.) on an ethanol-induced gastric lesion mouse model. Mice pre-treated with Avpf had significantly fewer gastric lesions than their respective controls. To further examine the potential mechanism underlying this effect, we used reverse transcription-polymerase chain reaction to examine nitric oxide synthase and matrix metalloproteinase (MMP)mRNA expression on tissues from gastric lesions. Our results revealed that the mRNA expressions of inducible nitric oxide synthase (iNOS) and neuronal nitric oxide synthase (nNOS) were each reduced by ~50% in Avpf-treated mice vs. the controls, whereas, the mRNA expression levels of endothelial nitric oxide synthase remained unchanged. MMP-9, an index for gastric lesions, also alleviated the ethanol-treated gastric ulceration during Avpf treatment. These findings collectively suggest that Avpf significantly protects the gastric mucosa against ethanol-induced gastric damage, at least in part, by decreasing mRNA expression levels of not only iNOS and nNOS, but also MMP-9.

We investigated the effect of Vitamin C (Vit C) on the changes of activity of the enzymes of NO-synthase system, nitric oxide content, lipoperoxidation processes, activity of SOD and catalase in gastric mucosa (GM), and concentrations of L-arginine, Vit C and Vit E in the blood of rats under conditions of experimental ulcer of the stomach caused by adrenaline injection. Vit C displayed a pronounced antioxidant action, reduced the degree of destructive affections, diminished the activity of iNOS and lipoperoxidation processes, decreased the NO content and SOD activity. Furthermore, the concentration of L-arginine and Vit C in the blood was increased. Combined action of Vit C with L-arginine reduced the degree of GM lesions, activity of eNOS and the content of NO in GM whereas the concentration of L-arginine in blood was increased. Under conditions of Vit C action and iNOS and COX-2 blockage, the activity of NO-synthases and lipoperoxidation processes were slightly decreased, indicating on dominant action of Vit C.

Objective: To measure the expression of cyclooxygenase-2 (COX-2) mRNA in gastric biopsy specimens serially obtained from horses before, during, and after an 8-day intermittent feed-deprivation trial and to investigate the mucosal location of COX-2., Animals: 9 mixed-breed horses for retrieval of gastric biopsy specimens and 16 additional horses for immunohistochemical analysis., Procedures: Gastric biopsy specimens were obtained from 6 horses; 3 of these horses and 3 more participated in an intermittent feed-deprivation trial 9 weeks later. A quantitative PCR assay was used to determine the amount of COX-2 mRNA in biopsy specimens from nonulcerated and ulcerated gastric mucosa. Immunohistochemical staining of specimens by use of a polyclonal anti-COX-2 antibody was performed on full-thickness postmortem gastric biopsy specimens., Results: COX-2 mRNA was expressed in all glandular gastric mucosal specimens but was only detectable in nonglandular mucosal specimens when ulceration was present or during ulcer healing. Positive staining for COX-2 was present in 12 of 14 nonulcerated glandular mucosal sections. Although such staining was weak or absent in nonulcerated nonglandular sections, stronger staining was evident in regenerating epithelium at the rims of erosions and ulcers., Conclusions and Clinical Relevance: COX-2 was constitutively present in equine glandular gastric mucosa, although its contribution to mucosal protection remains unclear. Our finding of COX-2 mRNA expression in ulcer margins during healing may support a role for the products of this enzyme in mucosal repair. The potential roles of COX-2 should be considered when COX-2-selective inhibitors are prescribed for horses with gastric ulcers.

Matrix metalloproteinase (MMP)-2 is considered as a crucial regulator of angiogenesis, a process of new blood vessel formation. We reported previously that melatonin (N-acetyl-5-methoxy tryptamine), an antioxidant and anti-inflammatory agent, prevents indomethacin-induced gastric ulcers. Herein, we investigated the effect of melatonin on MMP-2-mediated angiogenesis during gastroprotection. Angiogenic properties of melatonin were tested in both rat corneal micropocket assay and in mouse model of indomethacin-induced gastric lesions. Melatonin augmented angiogenesis that was associated with amelioration of MMP-2 expression and activity and, upregulation of vascular endothelial growth factor (VEGF) in rat cornea. Melatonin prevented gastric lesions by promoting angiogenesis via upregulation of VEGF followed by over-expression of MMP-2. Similarly, healing of gastric lesions was associated with early expression of VEGF followed by MMP-2. In addition, upregulation of MMP-2 was parallel to MMP-14 and inverse to tissue inhibitor of metalloprotease (TIMP)-2 expression during gastroprotection. Our data demonstrated that melatonin exerts angiogenesis through MMP-2 and VEGF over-expression during protection and healing of gastric ulcers. This study highlights for the first time a phase-associated regulation of MMP-2 activity in gastric mucosa and an angiogenic action of melatonin to rescue indomethacin-induced gastropathy.

Objective: To characterize the expression of the cyclooxygenase (COX)-1 and COX-2 isoforms in naturally occurring ulcers of the nonglandular portion of the stomach in horses. SPECIMEN POPULATION: 38 specimens from ulcerated stomachs and 10 specimens from healthy stomachs., Procedures: Specimens were collected at an abbatoir; for each specimen of squamous gastric mucosa, 1 portion was fixed in neutral-buffered 10% formalin for immunohistochemical analysis and another was frozen at -70 degrees C for immunoblotting analysis. Immunoreactivity to 2 antibodies, MF241 (selective for COX-1) and MF243 (selective for COX-2), was evaluated by a veterinary pathologist using a scoring system. Expression of COX-1 and COX-2 was confirmed by use of immunoblotting analyses., Results: All specimens from healthy stomachs strongly expressed COX-1, whereas only 2 of 10 expressed COX-2. The expression of both isoforms varied greatly in the ulcerated mucosal specimens. Expression of COX-1 was significantly lower and expression of COX-2 was significantly higher in ulcerated versus healthy specimens., Conclusions and Clinical Relevance: Increased expression of COX-2 in gastric ulcers of the squamous portion of the stomach in horses suggested a role for this enzyme in gastric ulcer healing.

Background and Purpose: Hydrogen sulphide is an important mediator of gastric mucosal defence. The use of non-steroidal anti-inflammatory drugs continues to be limited by their toxicity, particularly in the upper gastrointestinal tract. We evaluated the gastrointestinal safety and anti-inflammatory efficacy of a novel hydrogen sulphide-releasing derivative of naproxen, ATB-346 [2-(6-methoxy-napthalen-2-yl)-propionic acid 4-thiocarbamoyl-phenyl ester]., Experimental Approach: The ability of ATB-346 versus naproxen to cause gastric damage was evaluated in healthy rats and in rats with compromised gastric mucosal defence. Effects on the small intestine and on the healing of ulcers were also assessed. The ability of ATB-346 to inhibit cyclooxygenase-1 and 2 and to reduce inflammation in vivo was also evaluated., Key Results: ATB-346 suppressed gastric prostaglandin E(2) synthesis as effectively as naproxen, but produced negligible damage in the stomach and intestine. In situations in which the gastric mucosa was rendered significantly more susceptible to naproxen-induced damage (e.g. ablation of sensory afferent nerves, inhibition of endogenous nitric oxide or hydrogen sulphide synthesis, co-administration with aspirin, antagonism of K(IR)6.x channels), ATB-346 did not cause significant damage. Unlike naproxen and celecoxib, ATB-346 accelerated healing of pre-existing gastric ulcers. In a mouse airpouch model, ATB-346 suppressed cyclooxygenase-2 activity and inhibited leukocyte infiltration more effectively than naproxen. ATB-346 was as effective as naproxen in adjuvant-induced arthritis in rats, with a more rapid onset of activity. Unlike naproxen, ATB-346 did not elevate blood pressure in hypertensive rats., Conclusions and Implications: ATB-346 exhibits anti-inflammatory properties similar to naproxen, but with substantially reduced gastrointestinal toxicity.

Unlabelled: Reactive oxygen species (ROS) play critical roles in Helicobacter pylori (H. pylori)-associated gastric ulceration and carcinogenesis. Inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) are involved in H. pylori-induced gastric diseases. Previously we demonstrated that H. pylori in Korean isolates induced the activation of mitogen-activated protein kinases (MAPK) and oxidant-sensitive transcription factors NF-kappaB and AP-1 which mediates the expression of iNOS and COX-2 in gastric epithelial AGS cells. beta-Carotene shows antioxidant activity and inhibits NF-kappaB-dependent gene expression in various cells. Present study aims to investigate whether beta-carotene inhibits H. pylori-induced expression of iNOS and COX-2 by suppressing the activation of MAPK, NF-kappaB, and AP-1 in gastric epithelial AGS cells. HP99 (H. pylori in Korean isolates) was added to AGS cells at the ratio of bacterium/cell, 300/1. beta-carotene inhibited H. pylori-induced increase in ROS level, the activation of MAPK (p38, the c-Jun NH2-terminal protein kinases, the extracellular signal-regulated kinases), NF-kappaB, and AP-1 and the expression of iNOS and COX-2 in AGS cells., Conclusion: beta-carotene inhibits oxidant-mediated activation of inflammatory signaling and suppresses the expression of iNOS and COX-2 in gastric epithelial AGS cells infected with H. pylori.

Cochinchina momordica seed extract (SKMS10), which is composed of the major compounds momordica saponins, has been evaluated for its gastroprotective effects in rat models of acute gastric mucosal damage. Ethanol and water immersion restraint stress (WRS) induced gastric damage, including hemorrhages and edema, was significantly attenuated by pretreatment with SK-MS10. In addition, SK-MS10 reduced increases of mucosal myeloperoxidase (MPO), IL-1β, and TNFα levels and the expression of cPLA(2), and 5-LOX induced by ethanol or WRS. SK-MS10 also increased hexosamine, adherent mucus, and the expression of MUC5AC. Furthermore, SK-MS10 enhanced the mucosal expression of the CGRP gene and its serum levels.N(G)-methyl L-arginine (L-NMMA) or capsaicin desensitization reversed the SK-MS10-induced gastroprotection effect. These results suggest that SK-MS10 is a gastroprotective agent against acute gastric mucosal damage by suppressing proinflammatory cytokines, downregulating cPLA(2), 5-LOX, and increasing the synthesis of mucus. Furthermore, CGRP-NO pathway was found to play an important role in these gastroprotective effects of SK-MS10., (© Springer Science+Business Media, LLC 2009)

The influence of components and some schemata of antiulcerous therapy on content and activity of monooxigenase system's enzymes in mucous membrane of stomach are studied on the model of experimental stomach ulcer in rats. It is established, that among components of antiulcerous therapy such as omeprazole, clarithromycin and metronidazole inhibit content and activity of MOS enzymes. Tinidazol, amoxicillin and azithromycin do not affect the function of MOS. Rifampicin and pantoprazole induce enzyme system of monooxigenase. In triple therapy with omeprazole, clarithromycin and metronidazole the inhibit effect of preparations to system of MOS is exponentiated and it leads to suppression of mucous cytoprotaction of gastro duodenal zone. Triple therapy of ulcerous disease with pantoprazole, rifampicin and azithromycin is effective planning to stimulate defense mechanisms of the organism.

The goal of the presented work was the research of signal transduction mechanism in the rat gastric parietal cells under stomach ulcer conditions. In these cells activation of adenylate cyclase (increase of cAMP level and proteinkinase A activity) and phosphoinositide (increases [Ca2+]i; cGMP and phoshatidylinocitole levels; proteinkinase C, proteinkinase G, and calmodulin-dependent-proteinkinase activity) of signals pathway was shown. An increase of plasma membrane phospholipids (PC, PS, PE, PI, LPC) level was shown. Under conditions of influence of the stress factor the membran enzymes activity (H+, K+ -ATPase, 5'-AMPase, Na+, K+ -ATPase, Ca2+, Mg2+ -ATPase and H+, K+ -ATPase) was considerably increased. The intensification of lipid peroxidation processes in rats was demonstrated.

Acute cold stress caused lesions of gastric mucosa as a result of its attack by active oxygen and nitrogen compounds. The tissue regeneration is regulated by a cascade of tyrosine protein kinases. Gastric ulceration leads to a decrease in activity of tyrosine protein kinases and phosphatases, following by fall in phosphotyrosine content in proteins of plasma membranes of gastric mucosa cells. No changes in superoxide dismutase activity, slight increase in catalase activity, inhibition of glutathione peroxydase, significant increase in OH* content and decrease in zinc level were observed in the gastric mucosa cells of stressed rats. That increased oxidative damage can lead to inactivation of protein tyrosine phosphatases. Nitric oxide synthase activity was three times higher in gastric mucosa cells after the cold stress. That can promote nitrosylation of tyrosine residues. During following days nitric oxide synthase activity remains high. Superoxide dismutase is activated on the 4 and 5th day after the stress. Catalase activity normalizes after second day. Tyrosine protein kinase activity increases in membranes with maximum on the 4th day, and remains inhibited in cytosole. Tyrosine protein phosphatases keep inhibited as well. Gluthatione peroxydase activity and zinc level decreased on the 5th day. Obtained results can be the evidence of violations in signal transduction through protein tyrosine kinase cascades, due to the reduction in tyrosine phosphorylation, as a result of increase in the content of active oxygen and nitrogen species.

Disturbance of the microcirculation and generation of reactive oxygen species are crucial in producing acute gastric mucosal lesions (AGML). To understand the protective mechanism against mucosal injury and oxidative stress in the stomach, we investigated sequential expression and localization of a product of lipid peroxidation and a chemical mediator of the oxidative response array, 4-hydroxynonenal (HNE), transcriptional factor, NF-E2-related factor (Nrf2), and the inducible heme oxygenase (HO-1) in the injured stomach. AGML was produced by intragastric administration of 0.6 N HCl in male rats. Expression and localization of HNE, Nrf2, and HO-1 were investigated by Western blotting, immunohistochemistry, real-time RT-PCR, and in situ hybridization histochemistry. Mucosal lesions and expression of HNE and HO-1 were assessed by prior treatment with the PGI2 analog beraprast or after sensory denervation by pretreatment with capsaicin. Mucosal lesions were assessed by prior treatment with a HO-1 inhibitor, zinc protoporphyrin (ZnPP). After AGML, increased generation of HNE was observed in the injured mucosa and the surrounding submucosa, followed by nuclear translocation of Nrf2 and upregulation of HO-1 in the macrophages located in the margin of the injured mucosa and in the submucosa. Pretreatment with beraprost attenuated AGML and downregulated the expression of HNE and HO-1, while sensory denervation aggravated AGML and upregulated the expression of HNE and HO-1. Pretreatment with ZnPP also aggravated AGML. The sequential HNE-Nrf2-HO-1 pathway in the gastric mucosal cells and the macrophages is involved in an adaptive mechanism against oxidative stress after AGML.

Levels were assayed and compared of metabolic enzymes--thymidine and adenosine--in gastric mucosa tissues and blood serum from patients with gastric ulcer disease and gastric cancer (age--30-60 yrs). Enzymatic levels matched to the highest degree in cases of ulcer disease aggravated by chronic atrophic gastritis and precancerous alterations (dysplasia, metaplasia). Elevated concentrations of thymidine kinase and phosphorylase and adenosine desaminase were identified both at foci of ulceration (p > 0.001, p > 0.05, respectively) and in blood serum in all age brackets. Moreover, blood serum assay confirmed the view that changes in serum enzyme levels are suggestive of those in tissue enzymatic profile. Our data established a direct correlation between accumulated effect of level changes, on the one hand, and risk of neoplastic transformation of gastric mucosa in ulcer patients, on the other.

Stress gastric ulcer is a serious complication, but the mechanism involved is not fully clarified. It is well known that mucosal cell apoptosis plays a crucial role in the pathogenesis of gastric ulceration. Recent studies have shown that endoplasmic reticulum (ER) stress is an important pathway leading to cellular apoptosis. To investigate the role of ER stress in the pathogenesis of stress gastric ulcer, we studied the alteration in the expression of ER stress markers GRP78 (glucose-regulated protein 78) and caspase-12 (an ER stress-specific proapoptotic molecule) and their relations with gastric mucosal apoptosis during development of stress gastric lesions in the water-immersion and restraint stress (WRS) model in rats. Rats developed severe gastric lesions after 6 h of WRS. Typical apoptosis was observed at the edge cells of WRS induced gastric lesions. Western blot analysis showed that GRP78 and activated caspase-12 were over-expressed in the gastric tissues of WRS rats. Immunohistochemical analysis demonstrated that increased GRP78 and caspase-12 were distributed only under the lesions. In addition, dithiothreitol and tunicamycin (ER stress inducers), which increased the expression of GRP78 and activated caspase-12, caused gastric mucosal injury and mucosal cell apoptosis in vitro. These findings suggest that ER stress might be involved in the development of stress gastric ulcer through an apoptotic mechanism.

1. No general consensus has been reached on the treatment of acute gastric lesions. The aims of the present study were to clarify the effects of sucralfate, cimetidine and rabeprazole monotherapies and combination therapies on acute gastric lesions from the viewpoint of connective tissue regeneration. 2. Gastric lesions were experimentally created by the oral administration of 50% ethanol-0.15 mol/L HCl to rats. After 30 min, the anti-ulcer agents sucralfate (100 mg/kg), cimetidine (20 mg/kg) and rabeprazole (2 mg/kg) were administered separately or in combination and the stomach was excised at different times to measure the level of hydroxyproline in the gastric mucosa and determine lesion index. Immunostaining against prolylhydroxylase was performed on some specimens. 3. In the control group, lesion index decreased linearly from 30 min after ethanol-HCl administration and the level of mucosal hydroxyproline peaked between 2 and 4 h later. Although sucralfate significantly promoted lesion healing, it had no effect on mucosal hydroxyproline level. Cimetidine suppressed increases in mucosal hydroxyproline and prolonged lesion healing, but these findings were reversed by combining cimetidine and sucralfate. Rabeprazole had no significant effect on lesion healing, but promoted lesion healing in combination with sucralfate. Immunohistochemical analysis showed that prolylhydroxylase was expressed in spindle cells that lined the glandular cells in a boundary area between normal and injured tissues. 4. Under conditions in which the effects of intragastric pH are minimal, sucralfate is superior to antisecretory agents in promoting the healing of acute gastric lesions.

Reactive oxygen species (ROS) have been implicated in the aetiology of HCl/ethanol- and indomethacin gastric mucosal damage. This study investigated the protective effects of kolaviron, a natural antioxidant from the seed of Garcinia kola, on oxidative gastric mucosal damage induced by HCl/ethanol, and indomethacin.A HCl/ethanol mixture (1.5 mL of 0.15 n HCl in 70% ethanol) and indomethacin (IND) caused severe gastric damage with an ulcer index of 2.90 +/- 0.8 and 2.5 +/- 0.4, respectively, and significant reductions in the gastric mucosal content of catalase (CAT), superoxide dismutase (SOD) and glutathione (GSH) (p < 0.001).Pre-treatment of animals with kolaviron (100 mg/kg) orally 1 h and once daily for 3 days prior to ulcer induction significantly reduced the formation of ulcers induced by HCl/ethanol with preventive ratios of 65 and 72, respectively, while rats treated with kolaviron 1 day and for 7 days prior to IND treatment attenuated ulcer formation by 59% and 77%. Pre-treatment with ranitidine 1 h prior to ulcer induction (50 mg/kg) elicited preventive ulcer ratio of 55. Kolaviron pre-treatment 1 h before ulcer induction attenuated the HCl/ethanol reduction in CAT, SOD and GSH by 43%, 42% and 30%, respectively, and 67%, 68% and 64% following 72 h treatment with kolaviron. Ranitidine elicited 24%, 41% and 29% protective effects, respectively.Similarly, kolaviron administered to rats 1 day and for 7 days before IND treatment attenuated the drug-induced inhibition of CAT by 44% and 70%; SOD by 23% and 43% and GSH by 32% and 55%, respectively. In a 1 h and 3-day treatment with kolaviron before HCl/ethanol administration, MDA was reduced by 35% and 55%, respectively, while kolaviron administration 1 day and for 7 days before IND elicited a 39% and 58% reduction in MDA. Ranitidine elicited 39% and 50% reduction in MDA following HCl/ethanol and IND treatment. The results indicate the gastroprotective activity of kolaviron, which may be linked to its intrinsic antioxidant properties., (Copyright 2006 John Wiley & Sons, Ltd.)

Aims: To test the hypothesis that both COX-1 and COX-2 expression in human gastric mucosa is up-regulated in the presence of inflammation as seen in patients with gastritis and gastric ulcers., Methods and Results: We performed immunohistochemistry using COX-1 and COX-2 monoclonal antibodies on gastric biopsies from 59 patients with normal mucosa, gastritis and gastric ulcers. Expression of COX-1 and COX-2 was quantified using an intensity proportion scoring system. Expression of COX-1 was primarily seen in the lamina propria mononuclear cells with some expression in deep gastric glands in the ulcer group. Expression of COX-2 was primarily seen in the deep gastric glands with focal expression in the lamina propria mononuclear cells. We found a stepwise increase in the expression of both COX-1 and COX-2 as mucosal damage progressed from normal to gastritis to gastric ulcer., Conclusions: We conclude that both COX-1 and COX-2 expression in the gastric mucosa are increased in the setting of gastritis and gastric ulceration. Although this increased expression may be due, at least in part, to an increase in inflammatory cell numbers, this study raises the possibility that both COX-1 and COX-2 are inducible, contrary to the traditionally held view of only COX-2 being inducible.

The rationale for the development of selective inhibitors of cyclooxygenase-2 (COX-2) was the proposal that this enzyme plays an important role in inflammation but does not contribute to the resistance of the gastrointestinal mucosa against injury. However, studies from several groups have established that both COX-1 and COX-2 have important functions in the maintenance of gastrointestinal mucosal integrity. Thus, in the normal rat stomach lesions only develop when both COX-1 and COX-2 are inhibited. On the other hand, in specific pathophysiological situations the isolated inhibition of either COX-1 or COX-2 without simultaneous suppression of the other COX isoenzyme is ulcerogenic. Furthermore, COX-2 plays an important role in the healing of gastric ulcers and inhibition of COX-2 delays ulcer healing. From these findings the initial concept that only inhibition of COX-1 interferes with gastrointestinal defense has to be re-evaluated.

Nonsteroidal anti-inflammatory drugs (NSAID) are well known to induce gastric mucosal damage including bleeding, ulceration and perforation in humans and animals too. These effects are related with the inhibition of the enzyme cyclooxygenase, which is the main established mechanism of action for these drugs. Fasted rats were given piroxicam, preferential COX-1 inhibitor (10-20 mg/kg) or meloxicam, preferential COX-2 inhibitor (7.5-15 mg/kg) orally. Six or nine hours (h) later, respectively, the stomach was excised, the severity of the damage assessed and myeloperoxidase (MPO) activity measured, as well as prostaglandin PGE(2) content. Furthermore, in order to assess the effects of these oxicams over previously damaged gastric mucosa, 1 ml of 0.6 N HCl was administered p.o. followed, 1 h after, of the correspondent dose of each NSAID, and the same parameters were determined. Oral administration of both drugs dose-dependently caused acute gastric haemorrhage erosions. Myeloperoxidase activity was significantly increased by piroxicam administration. In addition, PGE(2) content was significantly reduced. The association between the administration of the acid and NSAID caused a worsening of the damage and, while myeloperoxidase activity did not modify by both piroxicam and meloxicam, PGE(2) levels were reduced. These results suggest that the PG derived from both COX-1 and COX-2 pathway plays a beneficial role in the gastroprotection, and thus caution should be exercise in the clinical use of preferential COX-2 inhibitors.

Although the ulcerogenic action of corticosteroids in the stomach is controversial, its action on ulcer healing has not been defined. In this study, we used non-ulcerogenic doses of dexamethasone (0.1 or 0.2 mg/kg/day) to explore the adverse effect on ulcer healing as well as its pathological mechanisms in rat stomach. In this regard, we measured ulcer size, mucus thickness, epithelial cell proliferation and apoptosis, and angiogenesis at the ulcer site at different time points after ulcer induction. Protein expressions of cyclooxygenase-1 and -2 (COX-1 and COX-2) and cytosolic phospholipase A2 (cPLA2) over the ulcer margin were evaluated, and the mucosal prostaglandin E2 (PGE2) level was also determined. Dexamethasone treatment in the current doses did not produce mucosal damage in intact animals. However, the drug dose-dependently delayed gastric ulcer healing. It also decreased mucus content and epithelial cell proliferation at the ulcer margin as well as angiogenesis at the ulcer margin and base. These were associated with a significant decrease of COX-2 expression and PGE2 level but not COX-1 at the ulcer margin. The drug only marginally reduced the cPLA2 expression without affecting the apoptosis at the ulcer margin. PGE2 treatment reversed the adverse effects of dexamethasone on ulcer healing. It is concluded that nonulcerogenic doses of dexamethasone can delay ulcer repair via depression of COX-2 expression and PGE2 formation in the gastric mucosa.

Cyclooxygenase-1 (COX-1) derived eicosanoids promote gastroprotective mucosal defenses and induce platelet aggregation. By sparing COX-1, COX-2 specific inhibitors provide effective anti-inflammatory and analgesic activity while substantially reducing the risk of peptic ulcer disease and GI bleeding compared to dual COX inhibitors (traditional NSAIDs). Clinical studies of the COX-2-selective inhibitors have demonstrated efficacy equivalent to nonselective NSAIDs with significantly lower rates of GI toxicity. The incidence of endoscopic ulcers in some studies with coxibs has approximated placebo. However, as the detection of endoscopic lesions is not always correlated with symptomatic ulcers and ulcer complications, outcome studies of GI safety were performed. The results of large outcome studies have evaluated rofecoxib and celecoxib in over 39,000 patients with osteoarthritis or rheumatoid arthritis. Results of these studies showed that patients taking a supratherapeutic dose of rofecoxib or celecoxib had significantly lower rates of GI-related adverse events than those taking a nonselective NSAID. The GI safety of coxibs for patients using low dose aspirin concomitantly with a coxib appears to be reduced, particularly with regard to ulcer complications. Such data provide support for the COX-2 hypothesis and demonstrate that coxibs provide effective treatment of pain and inflammation with a reduced risk of gastropathy.

The healing of gastric ulcer is a complicated process that involves the proliferation of epithelial and endothelial cells and the concerted actions of a wide range of growth factors. Prostaglandins play an important role in ulcer healing. Expression of cyclooxygenase-2 (COX-2) is markedly upregulated around the margins of gastric ulcers and its inhibition leads to a delay of ulcer healing. Several of the growth factors that promote ulcer healing may work in part through COX-2-dependent mechanisms. Angiogenesis, which is crucial to ulcer healing, is tightly regulated by growth factors. Treatment with selective COX-2 inhibitors appears to alter the balance of serum levels of growth factors, favoring an inhibition of angiogenesis. Given the importance of COX-2 in regulating ulcer healing, caution should be taken in the use of selective inhibitors of COX-2 by patients at risk of ulcer disease.

Proton pump inhibitors (PPIs) are antiulcer agents that have both gastric antisecretory and mucosal protective actions. The mechanisms of PPI-induced gastric mucosal protection are not known. The present study was designed to examine the mechanism for lansoprazole-induced gastric mucosal protection in rats. Rats were given 0.5, 5, and 50 mg/kg/day lansoprazole alone or both lansoprazole (50 mg/kg/day) and a specific gastrin receptor antagonist 3R-1-(2,2-diethoxyethyl)-((4-methylphenyl)amino-carbonyl methyl)-3-((4-methylphenyl)ureidoindoline-2- one) (AG-041R) (3, 10, and 30 mg/kg/day) for 14 days. Serum gastrin concentrations were measured. The expression of cyclooxygenases (COX-1 and COX-2) in the gastric mucosa was analyzed using Western blotting and immunohistochemical staining. Another series of rats was used to examine the 1) levels of prostaglandin (PG) E2 in gastric mucosa, 2) influences of the drugs on gastric damage caused by absolute ethanol, and 3) effects of a COX-2-specific inhibitor on PGE2 in the gastric mucosa and the mucosal protection afforded by lansoprazole. Lansoprazole dose dependently increased the serum gastrin concentration and enhanced the mucosal expression of COX-2 but not that of COX-1. Lansoprazole increased gastric mucosal PGE2 and reduced gastric damage caused by ethanol. Concomitant administration of AG-041R abolished the lansoprazole-induced COX-2 expression, and increased mucosal PGE2 and mucosal protection. A specific COX-2 inhibitor blocked the lansoprazole-induced increase in mucosal PGE2 and mucosal protection. Activation of gastrin receptors by endogenous gastrin has a pivotal role in the effects of lansoprazole on COX-2 up-regulation and mucosal protection in the rat stomach.

Two isoenzymes of cyclooxygenase (COX), the key enzyme in prostaglandin (PG) biosynthesis, COX-1 and COX-2, have been identified. COX-1 was proposed to regulate physiological functions, COX-2 to mediate pathophysiological reactions such as inflammation. In particular, it was suggested that maintenance of gastric mucosal integrity relies exclusively on COX-1. Recently, it was shown that a selective COX-1 inhibitor does not damage the mucosa in the healthy rat stomach, although mucosal prostaglandin formation is near-maximally suppressed. However, concurrent treatment with a COX-1 and a COX-2 inhibitor induces severe gastric damage. This indicates that in normal mucosa both COX-1 and COX-2 have to be inhibited to evoke ulcerogenic effects. In the acid-challenged rat stomach inhibition of COX-1 alone is associated with dose-dependent injury which is aggravated by additional inhibition of COX-2 activity or prevention of acid-induced up-regulation of COX-2 expression by dexamethasone. After acid exposure, COX-2 inhibitors cause substantial gastric injury when nitric oxide formation is suppressed or afferent nerves are defunctionalized. Ischemia-reperfusion of the gastric artery increases levels of COX-2 but not COX-1 mRNA. COX-2 inhibitors or dexamethasone aggravate ischemia-reperfusion-induced mucosal damage up to 4-fold, an effect abolished by concurrent administration of 16,16-dimethyl-PGE2. Furthermore, the protective effects elicited by a mild irritant or intragastric peptone perfusion are antagonized by COX-2 inhibitors. Finally, COX-2 expression is increased in experimental ulcers. COX-2 inhibitors delay the healing of chronic gastric ulcers in experimental animals and decrease epithelial cell proliferation, angiogenesis and maturation of the granulation tissue to the same extent as non-steroidal anti-inflammatory drugs. These observations indicate that, in contrast to the initial concept, COX-2 plays an important role in gastric mucosal defense.

Background/aims: Ulcer healing involves expression of various growth factors such as epidermal growth factor (EGF), hepatocyte growth factor (HGF) and basic fibroblast growth factor (bFGF) at the ulcer margin, but the influence of EGF, HGF and bFGF applied locally with or without neutralizing anti-EGF, HGF and bFGF antibodies or cyclooxygenase (COX)-1 and COX-2 inhibitors on ulcer healing and the expression of COX-1 and COX-2 during ulcer healing have only been studied a little., Methods: Rats with gastric ulcers induced by serosal application of acetic acid (ulcer area 28 mm2 received a submucosal injection of either (1) vehicle (saline), (2) EGF, (3) HGF, and (4) bFGF with or without antibodies against EGF, HGF and bFGF or indomethacin (2 mg/kg/day i.p.), a nonspecific inhibitor of COX, or NS-398 (10 mg/kg/day i.g.) and Vioxx (5 mg/kg/day i.g.), both highly specific COX-2 inhibitors. A separate group of animals with chronic gastric fistulas was also used to assess gastric secretion during ulcer healing with and without growth factors. Each growth factor and specific antibody against EGF, HGF and bFGF (100 ng/100 microl each) were injected just around the ulcer immediately after ulcer induction and this local injection was repeated on day 2 following anesthesia and laparotomy. On days 13 and 21, the ulcer area was determined by planimetry, gastric blood flow (GBF) at the ulcer margin was examined by the H2-gas clearance technique, and mucosal generation of PGE2 and the gene expression of COX-1 and COX-2 in the non-ulcerated and ulcerated gastric mucosa were assessed. Gastric ulcers healed progressively within 21 days after induction and this effect was accompanied by a significant increase in GBF at the ulcer margin and in the expression of COX-2 in the ulcer area. Local treatment with EGF, HGF and bFGF produced a significant decrease in gastric acid secretion and significantly accelerated the rate of ulcer healing and raised GBF at the ulcer margin causing further significant upregulation of COX-2 but not COX-1 expression in the ulcerated mucosa. The acceleration of ulcer healing and hyperemia at the ulcer margin exhibited by locally applied EGF, HGF and bFGF were similar to those obtained with systemic administration of these growth factors. HGF applied submucosally, upregulated COX-2 expression and this was significantly attenuated by concurrent treatment with antibody against this peptide. Anti-EGF and anti-bFGF antibodies completely abolished the acceleration of the ulcer healing and hyperemia at the ulcer margin induced by these growth factors. Indomethacin and both COX-2 inhibitors significantly prolonged ulcer healing, while suppressing the generation of PGE2 in non-ulcerated and ulcerated gastric mucosa and GBF at the ulcer margin. The acceleration of ulcer healing by EGF, HGF and bFGF and the accompanying rise in GBF at the ulcer margin were significantly attenuated by the concurrent treatment with indomethacin or NS-398 and Vioxx., Conclusions: (1) Growth factors accelerate ulcer healing due to enhancement in the microcirculation around the ulcer and these effects are specific because they can be abolished by neutralization with antibodies; (2) COX-2-derived prostaglandins and suppression of gastric secretion may play an important role in the acceleration of ulcer healing by various growth factors, and (3) the local effects of EGF, HGF and bFGF on ulcer healing can be reproduced by their systemic application indicating the high efficacy of growth factors to accelerate this healing., (Copyright 2001 S. Karger AG, Basel)

Centella asiatica is a herbal medicine widely used in China and India for wound healing. The aim of this study was to examine its effects on the prevention of ethanol induced gastric lesions in rats. Gastric transmucosal potential difference (PD) was reduced by the application of 50% ethanol in the gastric ex-vivo chamber model and Centella extract (CE) accelerated its recovery. Oral administration of CE (0.05 g/kg, 0.25 g/kg and 0.50 g/kg) before ethanol administration significantly inhibited gastric lesions formation (58% to 82% reduction) and decreased mucosal myeloperoxidase (MPO) activity in a dose dependent manner. These results suggested that CE prevented ethanol induced gastric mucosal lesions by strengthening the mucosal barrier and reducing the damaging effects of free radicals.

Prostaglandins play a critical role in gastric mucosal cytoprotection and decrease progressively with age. Cyclooxygenase (COX), the rate-limiting enzyme for prostaglandin synthesis, exists in two isoforms, COX-1 and COX-2. The rat COX-1 gene expresses an alternatively spliced mRNA COX-1 splice variant (SV) that may, at best, code for a truncated COX-1 protein. With the use of competitive PCR, we determined whether COX gene expression was altered in the stomach with increasing age and after gastric ulcer induction. COX-1 mRNA was significantly reduced in the aged, and COX-1SV mRNA was significantly higher in the adults compared with the young and aged stomach. Levels of COX-1 and COX-2 were similarly expressed in the normal stomach. In acute gastric ulcers, only COX-2 mRNA levels were significantly elevated. When ulcers were undergoing healing and repair, COX-1 and COX-2 mRNA levels were significantly elevated. Age-related changes in COX-1 and COX-1SV but not COX-2 mRNA may alter gastric mucosal cytoprotection. Furthermore, COX-1 and COX-2 may both contribute to the healing of a gastric ulcer.

Background: Matrix metalloproteinases (MMPs), enzymes capable of degrading collagens and other extracellular matrix components, have been implicated in gastric ulcer formation. However, the effect on MMP expression of Helicobacter pylori, also implicated in these lesions, has not been studied to our knowledge., Aim: To seek links between H. pylori and MMP expression likely to affect gastric ulcer formation. After fibroblasts from human gastric wall were cocultured with H. pylori. concentrations of MMP-1 and -2 in the medium were determined by enzyme-linked immunosorbent assays., Results: Whereas MMP-1 was not detected in media from fibroblasts or H. pylori culture alone, MMP-1 was detected in cocultures (P<0.01). Similar amounts of MMP-2 were detected in medium from fibroblasts cultured alone and with H. pylori. No MMP-2 production by H. pylori cultured alone was detected., Conclusions: MMP-1 appears to be important in gastric ulcer pathogenesis, and MMP-1 induction by H. pylori may impede gastric ulcer healing.

Although it is established that growth factors and prostaglandins function in the maintenance of gastric mucosal integrity and in the healing of gastric mucosal injury and ulceration, the regulatory relationship between growth factors and prostaglandins in the gastric mucosa is not well characterized. Therefore, we investigated whether hepatocyte growth factor (HGF) affects expression of COX-2 (the inducible form of the prostaglandin synthesizing enzyme, cyclooxygenase) in gastric epithelial cells and whether this action is mediated through the MAP (ERK) kinase signaling pathway. In RGM1 cells (an epithelial cell line derived from normal rat gastric mucosa), HGF caused an increase in COX-2 mRNA and protein by 236% and 175%, respectively (both P<0.05). This induction of COX-2 expression was abolished by pretreatment with the MAPK kinase (MEK) inhibitor PD98059. HGF also triggered a 13-fold increase in c-Met/HGF receptor phosphorylation (P<0.005) and increased ERK2 activity by 684% (P<0.01). Pretreatment with PD98059 abolished the HGF-induced increase in ERK2 activity, but not c-Met/HGF receptor phosphorylation. The specific inhibitor of p38 MAP kinase, SB203580, had no effect on HGF-induced COX-2 expression. Thus, HGF triggers activation of the COX-2 gene in gastric epithelial cells through phosphorylation of c-Met/HGF receptor and activation of the ERK2 signaling pathway.-Jones, M. K., Sasaki, E., Halter, F., Pai, R., Nakamura, T., Arakawa, T., Kuroki, T., Tarnawski, A. S. HGF triggers activation of the COX-2 gene in rat gastric epithelial cells: action mediated through the ERK2 signaling pathway.

In this study, ischemia-reperfusion produced in rats by clamping the celiac artery for 0.5 h followed by 1 h of reperfusion was used to develop a new model of superficial gastric erosions progressing to deeper ulcers. Ischemia alone resulted in an immediate fall in gastric blood flow but no gross mucosal lesions were observed. When ischemia was followed by reperfusion, gastric erosive lesions occurred, reached a maximum at 12 h and then declined after 24 h. These acute erosions progressed into deeper lesions 24 h after ischemia-reperfusion and reached a peak after 3 days. Gastric blood flow and the mucosal generation of prostaglandin E(2) were significantly suppressed immediately following ischemia-reperfusion, but with the healing of deeper gastric ulcers, both gastric blood flow and prostaglandin E(2) generation were gradually restored. Cyclooxygenase-1 mRNA was detected by reverse transcription-polymerase chain reaction in intact gastric mucosa and throughout the recovery of the mucosa from acute ischemia-reperfusion lesions, whereas cyclooxygenase-2 mRNA, was recorded only after ischemia-reperfusion. NS-398 and rofecoxib, selective inhibitors of cyclooxyganase-2, failed to affect prostaglandin E(2) generation in the non-ulcerated gastric mucosa but inhibited it significantly in the ulcer area. The two cyclooxygenase-2 inhibitors as well as resveratrol, a specific cyclooxygenase-1 inhibitor and indomethacin and meloxicam, non-specific inhibitors of cyclooxygenase, augmented acute gastric erosions induced by ischemia-reperfusion and delayed significantly the progression of these lesions into deeper ulcers at each time interval after ischemia-reperfusion. We conclude that prostaglandins generated by both cyclooxygenase-1 and cyclooxygenase-2 contribute to the healing of gastric lesions induced by ischemia-reperfusion.

Objective: Recent reports have shown that patients infected with Helicobacter pylori (H. pylori) have a higher risk of gastric cancer. However, the mechanism of this increased risk is still unclear. In the gastric mucosa, the size of a continuously renewed population of cells is determined by the rates of cell production and of cell loss. Ornithine decarboxylase (ODC) activity is elevated in various gastrointestinal cancers and serves as a marker of mucosal proliferative activity. Apoptosis occurs throughout the gut and is associated with cell loss. Both cell proliferation and cell loss have important roles in H. pylori-associated gastric carcinogenesis. Therefore, we investigated the effect of H. pylori eradication on ODC activity and apoptosis in the gastric mucosa of patients with atrophic gastritis and gastric ulcers., Methods: Biopsy specimens of the gastric antrum were obtained at endoscopy from 17 H. pylori-positive gastric ulcers patients and 15 H. pylori-positive gastritis patients before and 4 wk after eradication therapy with amoxicillin, omeprazole, and a new anti-ulcer agent, ecabet sodium, and from 10 gastric ulcer patients in whom ulcer healed but H. pylori was left untreated. ODC activity and induction of apoptosis were determined immunohistochemically., Results: H. pylori was successfully eradicated with the triple therapy in 12 (80%) of 15 gastritis patients and 13 (76%) of 17 gastric ulcer patients. ODC activity was present in the gastric mucosa in 21 (84%) patients before eradication but in only four (16%) patients after successful eradication (p = 0.0005). The apoptotic index increased significantly (p = 0.0006) from 4.2% +/- 0.4% before treatment to 7.4% +/- 0.5% after successful eradication., Conclusions: Successful eradication of H. pylori decreases mucosal ODC activity and increases apoptosis in the gastric mucosa. These findings indicate that by decreasing mucosal cell proliferation and increasing epithelial cell loss, H. pylori eradication may help decrease the subsequent risk of gastric cancer.

Aim: To assess activity of superoxide dismutase and catalase in acute ulcer and in the end of its treatment with antisecretory (omeprasole and zaran), anti-Helicobacter (metronidasole) and antioxidant (alpha-tocopherol) drugs in patients with duodenal ulcer., Materials and Methods: 126 patients with duodenal ulcer were divided into 6 groups: group 1 patients had Helicobacter pylori (HP+) and were given omeprasole; group 2 patients had HP and were given omeprasole + metronizarole; group 3 patients were free of HP and received metronidasole + alpha-tocopherol; group 4 HP+ patients received zaran; group 5 HP+ patients got zaran = metronidasole; group 6 free of HP received zaran + alpha-tocopherol. The patients were examined using esophagogastroduodenoscopy, roentgenoscopy of the stomach, tests of the gastric juice., Results: An acute phase of ulcer was accompanied with enhanced activity of superoxide dismutase and low activity of catalase in mucosal biopsies from ulcer lesion and periulcer zone. In remission, antioxidant system resumed normal activity depending on the kind of the combined therapy. The combination omeprasole + metronidasole was more effective in HP eradication than zaran + metronidasole. Effect of alpha-tocopherol was poor., Conclusion: It is suggested that HP stimulates lipid peroxidation and thus maintains inflammation in gastric and duodenal mucosa.

It has been reported that cyclooxygenase-2 (COX-2) may play a crucial role in gastric ulcer healing. We examined the localization of COX-2 and the regulation of COX-2 mRNA expression in acetic acid ulcers in rats. PGE2 production was elevated in ulcerated tissue but not in intact tissue. COX-2 mRNA expression was induced in only the ulcerated tissue, and COX-2 protein was found in fibroblasts, monocytes/macrophages, and granulocytes. A selective COX-2 inhibitor inhibited increased PGE2 production by the ulcerated tissue. Interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and transforming growth factor-beta1 (TGF-beta1) mRNAs were also expressed only in the ulcerated tissue. In a culture of isolated ulcer base, blockade of IL-1beta and TNF-alpha reduced COX-2 mRNA expression and PGE2 production. In contrast, COX-2 mRNA expression and PGE2 production were promoted by prevention of TGF-beta1 action. These results indicate that COX-2 protein is highly localized in the base of gastric ulcers in rats and that COX-2 mRNA expression might be regulated positively by IL-1beta and TNF-alpha and negatively by TGF-beta1.

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.

Polyamines such as spermine or putrescine, resulting from increased activity of ornithine decarboxylase (ODC), are known for gastroprotective and mucosal growth-promoting effects. EGF exhibits similar effects, but little is known about the involvement of polyamines in acceleration of the healing of stress-induced gastric lesions by epidermal growth factor (EGF). In this study, rats with intact or suppressed ODC activity by alpha-difluoromethy-ornithine (DFMO, 400 mg/kg i.p.) were subjected to 3.5 h of water immersion and restraint stress (WRS) without or with addition of spermine or EGF. At 0, 2, 6, 12, or 24 h after stress, rats were sacrificed. The number of gastric lesions was determined and gastric blood flow (GBF) was recorded by the H2 gas clearance technique. Stress produced gastric lesions (mean number 18+/-2 per stomach) and decreased GBF (by approximately 43%), but at 2, 6, 12, and 24 h after stress, these lesions and the decrease in GBF were gradually attenuated. Pretreatment with DFMO or removal of an endogenous source of EGF by salivectomy resulted in a marked decrease in mucosal DNA synthesis and significantly delayed the healing of stress lesions. EGF or spermine significantly accelerated ulcer healing and increased the GBF in rats with intact or removed salivary glands. DFMO significantly reduced the enhancement of healing and the increase in GBF induced by EGF, but failed to influence those induced by exogenous spermine. We conclude that polyamines play an important role in mucosal recovery from stress lesions due to acceleration of mucosal repair and increase in gastric microcirculation and that increased ODC activity and resulting excessive polyamine release appear to act as primary mediators of EGF-induced acceleration of the healing of stress lesions.

The role of chloroform fraction of Calotropis procera root extract on different experimental ulcer models in rats was investigated. The extract demonstrated significant anti-ulcer activity against aspirin, indomethacin, ethanol, indomethacin + ethanol, or stress-induced ulcerations. Significant inhibition of gastric secretory volume and total acidity in pylorus ligated rats were observed to occur with the extract. It was also observed that the root extract significantly inhibited arachidonic acid metabolism induced by soyabean lipoxygenase. The results suggest that the anti-ulcer activity of the extract might be attributable to the inhibition of 5-lipoxygenase (5-LO).

1. We examined the effects of selective and nonselective cyclo-oxygenase (COX) inhibitors on various functional changes in the rat stomach induced by topical application of taurocholate (TC) and investigated the preferential role of COX isozymes in these responses. 2. Rat stomachs mounted in ex vivo chambers were perfused with 50 mM HCl and transmucosal potential difference (p.d.), mucosal blood flow (GMBF), luminal acid loss and luminal levels of prostaglandin E2 (PGE2) were measured before, during and after exposure to 20 mM TC. 3. Mucosal application of TC in control rats caused a reduction in p.d., followed by an increase of luminal acid loss and GMBF, and produced only minimal damage in the mucosa 2 h later. Pretreatment with indomethacin (10 mg kg[-1], s.c.), a nonselective COX-1 and COX-2 inhibitor, attenuated the gastric hyperaemic response caused by TC without affecting p.d. and acid loss, resulting in haemorrhagic lesions in the mucosa. In contrast, selective COX-2 inhibitors, such as NS-398 and nimesulide (10 mg kg[-1], s.c.), had no effect on any of the responses induced by TC and did not cause gross damage in the mucosa. 4. Luminal PGE2 levels were markedly increased during and after exposure to TC and this response was significantly inhibited by indomethacin but not by either NS-398 or nimesulide. The expression of COX-1-mRNA was consistently detected in the gastric mucosa before and after TC treatment, while a faint expression of COX-2-mRNA was detected only 2 h after TC treatment. 5. Both NS-398 and nimesulide significantly suppressed carrageenan-induced rat paw oedema, similar to indomethacin. 6. These results confirmed a mediator role for prostaglandins in the gastric hyperaemic response following TC-induced barrier disruption, and suggest that COX-1 but not COX-2 is a key enzyme in maintaining 'housekeeping' functions in the gastric mucosa under both normal and adverse conditions.

We isolated, by the subtraction cloning method, a pepsinogen C (PGC) gene fragment (the sequence between the 968th and 1179th base pairs) from a rat gastric mucosal cDNA library as a cDNA clone encoding a substance that promotes growth of the normal rat gastric mucosal cell line RGM1. Northern blot analysis revealed that PGC gene expression was enhanced not only in acetic acid-induced chronic gastric ulcers but also in indomethacin-induced gastric mucosal lesions. PGC gene expression was also increased in the Helicobacter felis-infected stomachs. Thus, the PGC gene may play a role in gastric epithelial cell growth during gastric mucosal healing.