Indomethacin-induced Gastric Mucosal Lesions Research Articles

Tormentic acid, a triterpenoid isolated from the fruits of Chaenomeles speciose, protected indomethacin-induced gastric mucosal lesion via modulating miR-139 and the CXCR4/CXCL12/PLC/PKC/Rho a/MLC pathway

Context Tormentic acid (TA), an effective triterpenoid isolated from Chaenomeles speciosa (Sweet) Nakai (Rosaceae) fruits, exerts an effective treatment for gastric damage. Objective To investigate the gastroprotective effect of TA on indomethacin (IND) damaged GES-1 cells and rats, and explore potential mechanisms. Materials and methods TA concentrations of 1.563–25 µM were used. Cell proliferation, apoptosis and migration were performed using MTT, colony formation, wound healing, migration, Hoechst staining assays. SD rats were divided into control, IND, TA (1, 2 and 4 mg/kg) + IND groups, once a day for 21 continuous days. Twenty-four hours after the last administration, all groups except the control group were given IND (100 mg/kg) by gavage. Gastric juice parameters, gastric ulcer, gastric blood flow (GBF), blood biochemical parameters and cytokine analysis and gastric mucosal histopathology were detected for 2 h and 6 h after IND oral administration. The mRNA and protein expression of miR-139 and the CXCR4/CXCL12/PLC/PKC/Rho A/MLC pathway were analyzed in the IND-damaged GES-1 cells and gastric tissue of rats. Results TA might ameliorate the gastric mucosal injury by accelerating the IND-damaged GES-1 cell proliferation and migration, ameliorating GBF, ulcer area and pathologic changes, the redox system and cytokine levels, the gastric juice parameters, elevating the gastric pH in IND damaged rats; suppressed miR-139 mRNA expression, elevated CXCR4 and CXCL12 mRNA and protein expression, p-PLC, p-PKC, Rho A, MLCK and p-MLC protein expression. Discussion and conclusions TA may have potential use as a clinical drug candidate for gastric mucosal lesion treatment.

Effect of Cuttlebone on Healing of Indomethacin-Induced Acute Gastric Mucosal Lesions in Rats.

The continuing use of nonsteroidal anti-inflammatory drugs (NSAIDs) usually increases the side effects such as peptic ulcer and acute gastric lesions in the gastrointestinal tract. Cuttlebone (CB), isolated from Sepiella maindroni de Rochebrune, was reported to have antioxidant activities, but its role in the treatment of indomethacin-induced gastric lesions has not yet been confirmed. In this research, we investigate the protective effect of cuttlebone on indomethacin-related ulcers in rats and possible mechanisms. Here, gastric ulcers were induced by oral administration of indomethacin, and then the rats were treated with omeprazole (4 mg/kg) or different doses (750, 1500, and 3000 mg/kg of body weight) of cuttlebone. We evaluated lesion index, inflammation score, and a series of oxidant/antioxidant parameters. The data demonstrated that cuttlebone could protect against gastric ulcers induced by indomethacin in a dose-dependent manner (positive correlation). Also, these effects were associated with attenuating the expression of malonaldehyde (MDA) and increasing the levels of some protective ingredients like epidermal growth factor (EGF), prostaglandin E2 (PGE2), and superoxide dismutase (SOD). Thus, considering its ability to protect indomethacin-induced acute gastric mucosal lesions and the underlying mechanisms, CB might be a potential candidate for treating gastric damage caused by NSAIDs.

커규민의 인도메타신 유도 위점막 손상에 대한 치료 효과

In the present study, the curative effect of curcumin on indomethacin-induced gastric mucosal lesions in rats was investigated. Indomethacin is a nonsteroidal anti-inflammatory drug (NSAID), with serious side effects, including erosion, ulcerative lesions, and petechial bleeding in the mucosa of the stomach. Gastric mucosal lesions were caused by oral administration of 25 ㎎/㎏ of indomethacin. Various doses (10, 50, and 100 ㎎/㎏) of curcumin were treated for 3 days by oral gavage. Indomethacin clearly increased the gastric ulcer area in the stomach, and curcumin significantly decreased the gastric ulcer area in a dose-dependent manner. Curcumin also markedly inhibited lipid peroxidation in the gastric mucosa and activated radical scavenging enzymes, such as superoxide dismutase (SOD), catalase, and glutathione peroxidase, in a dose-dependent manner. These results suggest that curcumin can induce recovery from indomethacin-induced gastric mucosal lesions through inhibition of lipid peroxidation and activation of radical scavenging enzymes, such as SOD, catalase, and glutathione peroxidase. Curcumin appears to be a powerful free radical quencher, and it may offer an attractive strategy for healing gastric mucosal lesions in humans.

Attenuation of gastric mucosal inflammation induced by indomethacin through activation of the A2A adenosine receptor in rats

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin induce gastric mucosal lesions in part by the activation of inflammatory cells and the production of proinflammatory cytokines. The activation of adenosine A(2A) receptors inhibits inflammation by increasing cyclic AMP in leukocytes and reducing both the production of various proinflammatory cytokines and neutrophil chemotaxis. The aim of present study was to determine whether administration of an orally active adenosine A(2A) receptor agonist (4-[3-[6-amino-9-(5-cyclopropylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl]-piperidine-1-carboxylic acid methyl ester; ATL-313) ameliorated indomethacin-induced gastric mucosal lesions in rats. Gastric lesions were produced by oral gavage of indomethacin (30 mg/kg). ATL-313 (1-10 microg/kg) was given orally just before the indomethacin administration. The ulcer index induced by indomethacin was significantly (>50%) reduced by pretreatment with ATL-313 and this effect was blocked completely by the addition of equimolar ZM241385, a selective A(2A) receptor antagonist. The gastric content of myeloperoxidase (MPO) and proinflammatory cytokines was significantly reduced by 10 microg/kg ATL-313, but gastric mucosal prostaglandin 2 (PGE2) was not affected. We conclude that ATL-313 does not inhibit the mucosal damaging effect of indomethacin, but it does block secondary injury due to stomach inflammation. A(2A) agonists may represent a class of new therapeutic drugs for NSAID-induced gastric ulcers.

Mitigation of indomethacin-induced gastric mucosal lesions by a potent specific type V phosphodiesterase inhibitor

To investigate the gastroprotective effect of vardenafil against indomethacin-induced gastric damage. Forty-eight female Wistar albino rats were randomly divided into 6 groups. Group 1 received saline only. Group 2 (indomethacin) received indomethacin. Rats in group 3 and 4 were pretreated with different doses of famotidine. Group 5 and 6 were pretreated with different doses of vardenafil. Rats in groups 3 to 6 received 25 mg/kg indomethacin 30 min after pretreatment. The animals were sacrificed 6 h later and their stomachs were opened. Gastric lesions were counted and measured. The stomach of each animal was divided in two parts for histopathological examinations and nitric oxide (NO) and malondialdehyde (MDA) assays, respectively. There were no gastric mucosal lesion in the saline group but all rats in the indomethacin group had gastric mucosal ulcerations (ulcer count; 6.25 +/- 3.49, and mean ulcer area; 21.00 +/- 12.35). Ulcer counts were diminished with famotidine 5 mg/kg (4.12 +/- 2.47, P > 0.05), 20 mg/kg (2.37 +/- 4.43, P < 0.05), vardenafil 2 mg/kg (4.37 +/- 3.06), and vardenafil 10 mg/kg (1.25 +/- 1.38, P < 0.05) compared to the indomethacin group. Gastric mucosal lesion areas were diminished with famotidine 5 mg/kg (8.62 +/- 2.97, P < 0.001) , famotidine 20 mg/kg (0.94 +/- 2.06, P < 0.001), vardenafil 2 mg/kg (6.62 +/- 5.87, P < 0.001), and vardenafil 10 mg/kg (0.75 +/- 0.88, P < 0.001) compared to the indomethacin group. MDA levels were significantly higher in indomethacin group (28.48 +/- 14.51), compared to the famotidine 5 mg/kg (6,21 +/- 1.88, P < 0.05), famotidine 20 mg/kg (5.88 +/- 1.60. P < 0.05), vardenafil 2 mg/kg (15.87 +/- 3.93, P < 0.05), and vardenafil 10 mg/kg (10.97 +/- 4.50, P < 0.05). NO concentration in gastric tissues of the famotidine groups were significantly increased (P < 0.05), but the NO increases in the vardenafil groups were not statistically significant. Histopathology revealed diminished gastric damage for pretreatment groups compared to the indomethacin group (P < 0.05). Vardenafil affords a significant dose-dependent protection against indomethacin induced gastric mucosal lesions in rats.

Medicinal Flowers. XXVI. Structures of Acylated Oleanane-Type Triterpene Oligoglycosides, Yuchasaponins A, B, C, and D, from the Flower Buds of &lt;i&gt;Camellia oleifera&lt;/i&gt;&amp;mdash;Gastroprotective, Aldose Reductase Inhibitory, and Radical Scavenging Effects&amp;mdash;

The methanolic extract and its 1-butanol-soluble fraction from the flower buds of Camellia oleifera ABEL were found to exhibit inhibitory effects on ethanol- and indomethacin-induced gastric mucosal lesions in rats. The ethyl acetate- and 1-butanol-soluble fractions also showed inhibitory effects on rat lens aldose reductase and scavenging effects on 1,1-diphenylpicryl-2-hydrazyl radical and superoxide. From the 1-butanol-soluble fraction, four new acylated oleanane-type triterpene oligoglycosides, yuchasaponins A, B, C, and D, were isolated and their structures were elucidated on the basis of chemical and physicochemical evidence. On the other hand, quercetin 3-O-alpha-L-rhamnopyranoside and kaempferol 3-O-alpha-L-rhamnopyranoside were isolated from the ethyl acetate- and 1-butanol-soluble fractions as the principal constituents, and their gastroprotective effects were examined.

Functional Saponins in Tea Flower (Flower Buds of &lt;i&gt;Camellia sinensis&lt;/i&gt;): Gastroprotective and Hypoglycemic Effects of Floratheasaponins and Qualitative and Quantitative Analysis Using HPLC

As a part of our characterization studies on the bioactive saponin constituents of tea flowers (Camellia sinensis, flower buds), the methanolic extract and 1-butanol-soluble portion (the saponin fraction) from the flower buds were found to exhibit potent inhibitory effects on ethanol- and indomethacin-induced gastric mucosal lesions in rats and on serum glucose elevation in sucrose-loaded rats. Among the constituents of the 1-butanol-soluble portion, floratheasaponins A, B, and C showed gastroprotective and hypoglycemic activities. Furthermore, we have developed qualitative and quantitative methods using HPLC for the principle saponins, floratheasaponins A-F, in tea flowers, which were previously found to show antiallergic and antiobesity effects. Using those methods, the saponin composition of Indian tea flowers were found to be similar to those of Chinese (Anhui) but not of Japanese tea flowers. On the other hand, it was found that the floratheasaponin contents in tea flowers varied markedly during the blooming period, and they were abundant at half-bloom. Additionally, the contents of caffeine in the tea flowers were examined using HPLC.

Medicinal Foodstuffs. XXXIII. Gastroprotective Principles from Boesenbergia rotunda (Zingiberaceae) - Absolute Stereostructures of Diels-Alder Type Addition Prenylchalcones

-The methanolic extract from the rhizomes of Boesenbergia rotunda (Zingiberaceae) was found to exhibit potent inhibitory activities on ethanol- or indomethacin-induced gastric mucosal lesions in rats. Through the bioassay-guided separation, six new optically active Diels-Alder type addition prenylcalcones, (+)-panduratin A (la), (-)-panduratin A (1b), (+)-4-hydroxypanduratin A (2a), (-)-4-hydroxypanduratin A (2b), (+)-isopanduratin A (3a), and (-)-isopanduratin A (3b) were isolated together with 12 known compounds [(4-14) and geraniol]. The absolute stereostrucutures of six new compounds were elucidated on the basis of physicochemical evidence including CD spectra. Among them, the enantiomeric mixtures of panduratin A (la, 1b) and 4-hydroxypanduratin A (2a, 2b), and pinocembrin (4) showed gastroprotective effects on ethanol- or indomethacin-induced gastric mucosal in rats.

Medicinal Flowers. XV. The Structures of Noroleanane- and Oleanane-Type Triterpene Oligoglycosides with Gastroprotective and Platelet Aggregation Activities from Flower Buds of Camellia japonica

The methanolic extract from the flowers buds of Camellia japonica L. (Theaceae) were found to exhibit potent inhibitory activities on ethanol- or indomethacin-induced gastric mucosal lesions in rats. Through bioassay-guided separation, 28-noroleanane-type triterpene oligoglycosides, camelliosides A, B, and C, and an oleanane-type triterpene oligoglycoside, camellioside D, were isolated from the methanolic extract together with five known compounds. The absolute stereostructures of camelliosides were determined on the basis of chemical and physicochemical evidence, which included the structure revision of the nortriterpene aglycons (camellenodiol and camelledionol). The principal oligoglycosides, camelliosides A and B, showed platelet aggregation activity in addition to the gastroprotective effects on ethanol- or indomethacin-induced gastric mucosal lesions in rats.

Medicinal Flowers. XVI. New Dammarane-Type Triterpene Tetraglycosides and Gastroprotective Principles from Flower Buds of Panax ginseng

The oligoglycoside fraction from the flower buds of Panax ginseng C. A. MEYER (Araliaceae) was found to show protective effects on ethanol-induced gastric mucosal lesions in rats. From the oligoglycoside fraction, new dammarane-type triterpene tetraglycosides, floralginsenosides M, N, O, and P, were isolated together with the major oligoglycosides ginsenoside Rd and Re. The structures of the new floralginsenosides were elucidated on the basis of chemical and physicochemical evidence. Ginsenoside Rd (protopanaxadiol 3,20-O-bisdesmoside) exhibited inhibitory effects on ethanol- and indomethacin-induced gastric mucosal lesions in rats.

Bioactive Saponins and Glycosides. XXIII. Triterpene Saponins with Gastroprotective Effect from the Seeds of Camellia sinensis-Theasaponins E3, E4, E5, E6, and E7-

The saponin fraction from the seeds of the tea plant [Camellia sinensis (L.) O. KUNTZE (Theaceae)] was found to exhibit potent protective effects on ethanol- and indomethacin-induced gastric mucosal lesions in rats. Five new triterpene saponins, theasaponins E3 (1), E4 (2), E5 (3), E6 (4), and E7 (5), were isolated together with 11 known saponins from the saponin fraction. The chemical structures of 1-5 were elucidated on the basis of chemical and physicochemical evidence. Among the isolated saponins, theasaponins E1 (6), E2 (7), and E5 (3) and assamsaponin C (10) showed an inhibitory effect on ethanol-induced gastric mucosal lesions at a dose of 5.0 mg/kg, p.o. and their activities were stronger than that of omeplazole. With regard to the structure-activity relationships of theasaponins, the following structural requirements for a protective effect on ethanol-induced gastric lesions were suggested; 1) the 21- and/or 22-acyl groups are essential for the activity, 2) acetylation of the 16-hydroxyl group reduce the activity.

Anti-Inflammatory, Antinociceptive, and Gastric Effects ofHypericum perforatumin Rats

The pharmacological activity of Hypericum perforatum was assessed using models of inflammation, nociception, and gastric mucosal injury in rats. H. perforatum was given systemically as well as orally. When administered systemically, H. perforatum (50–300 mg/kg, s.c.) produced a dose-related and significant inhibition of the edematogenic response to s.p. injection of carrageenan. The percentages of maximal inhibition by the above doses were 53.7, 61.3, and 75.3%, respectively (compared to 90% after 50 mg/kg fluoxetine and 60.7% after 72 mg/kg etodolac). In tests of nociception, H. perforatum, administered orally, displayed antinociceptive activity in the tail electric stimulation and hot plate tests. The antinociceptive activity was observed with 25 mg/kg and a maximal increase in hot plate latency by 50% (compared to 73.2 and 77.8% increases by 5 or 10 mg/kg fluoxetine, respectively). In contrast, the acetic acid–induced (0.6%, i.p.) writhing was significantly reduced by fluoxetine or etodolac, but not H. perforatum. Also, the nociceptive response caused by i.p. injection of capsaicin (1.6 μg/paw) was unaffected by H. perforatum, but reduced by fluoxetine. Injection of H. perforatum (50, 125, or 250 mg/kg, s.c.) to pylorus-ligated rats, decreased gastric acid secretion, but increased indomethacin-induced gastric mucosal lesions dose dependently. These results demonstrate that H. perforatum exhibits antiedematogenic and antinociceptive properties, which may be of value for the management of inflammatory painful conditions. The agent, however, causes gastric irritation and may aggravate that of NSAIDs.

Ganoderma lucidumPolysaccharide Fractions Accelerate Healing of Acetic Acid-Induced Ulcers in Rats

The polysaccharide (PS) fractions from several medicinal herbs have been reported to have anti-ulcer effects against experimental ulcers in the rat. The water-soluble PS fractions from Ganoderma lucidum (Reishi mushroom) have been shown to inhibit indomethacin-induced gastric mucosal lesions in rats. This study aimed to investigate the effect of the PS fraction from G. lucidum on the healing of gastric ulcers induced by acetic acid in the rat and to elucidate the underlying mechanisms involved. The abdomen of rats was incised, and the stomach was treated with 10 M acetic acid (100 microL) for 1 minute, and then treated with G. lucidum PS (0.1, 0.5, or 1.0 g/kg) intragastrically, once a day for 14 consecutive days. The results indicated that the oral administration of G. lucidum PS at 0.5 and 1.0 g/kg for 2 weeks caused a significant acceleration of ulcer healing by 40.1% and 55.9%, respectively. In the mechanistic studies, additional rats were treated with 10 M acetic acid to induce acute ulcers, and then treated with G. lucidum PS (1.0 g/kg) for 3, 7, 10, or 14 days. Exposure of the rat stomach to acetic acid led to decreased mucus and increased prostaglandin levels. Treatment with G. lucidum PS at 1.0 g/kg significantly (P < .05) suppressed or restored the decreased gastric mucus levels and increased gastric prostaglandin concentrations compared with the control group. These results indicates that G. lucidum PS is an active component with healing efficacy on acetic acid-induced ulcers in the rat, which may represent a useful herbal preparation for the prevention and treatment of peptic ulcers.

Protective effects of steroid saponins from paris polyphylla var. yunnanensis on ethanol- or indomethacin-induced gastric mucosal lesions in rats: structural requirement for activity and mode of action

The methanolic extract from the rhizomes of Paris polyphylla S m. var . yunnanensis (F r.) H-M. was found to potently inhibit ethanol-induced gastric lesions in rats. Through bioassay-guided separation, four known spirostanol-type steroid saponins, pennogenin 3- O-α- l-rhamnopyranosyl(1→2)-[α- l-arabinofuranosyl(1→4)]-β- d-glucopyranoside ( 1), pennogenin 3- O-α- l-rhamnopyranosyl(1→4)-α- l-rhamnopyranosyl(1→4)-[α- l-rhamnopyranosyl(1→2)]-β- d-glucopyranoside ( 2), diosgenin 3- O-α- l-rhamnopyranosyl(1→2)-[α- l-arabinofuranosyl(1→4)]-β- d-glucopyranoside ( 3), and diosgenin 3- O-α- l-rhamnopyranosyl(1→4)-α- l-rhamnopyranosyl(1→4)-[α- l-rhamnopyranosyl(1→2)]-β- d-glucopyranoside ( 4), and a new furostanol-type steroid saponin, parisaponin I ( 5), together with two known furostanol-type steroid saponins, trigofoenoside A ( 6) and protogracillin ( 7), were isolated from the active fraction. Compounds 1– 4 (1.25–10 mg/kg, po) strongly inhibited gastric lesions induced by ethanol and indomethacin. With regard to structural requirement of steroid saponins, the 3- O-glycoside moiety and spirostanol structure were found to be essential for the activity and the 17-hydroxyl group in the aglycon part enhanced the protective effects against ethanol-induced gastric lesions. The protective effects of 1 and 3 against ethanol-induced gastric lesions were attenuated by pretreatment with indomethacin and N-ethylmaleimide. Compounds 1 and 3 weakly inhibited acid secretions in pylorus-ligated rats. These findings suggested that endogenous prostaglandins and sulfhydryl compounds were involved in the protective activity.

Anti-oxidative herbs and indomethacin-induced rat gastric mucosal lesions: protection by GamiHyangsa-Yukgunja.

This study investigates the protective effects of GamiHyangsa-Yukgunja (GHY, a popular herbal medicine formula) on indomethacin-induced gastric mucosal lesions and morphological change in rats. Subcutaneous injection of indomethacin (25 mg/kg) produced the following gastric morphological alterations: mucosa hemorrhagic infarct, mucosa cell necrosis, leukocyte infiltration, mucosa hemorrhagic erosion, and gastric pit disappearance. Tissue damages were accompanied by increased oxidative stress, lipid peroxidation, and decreases in superoxide dismutase (SOD), and catalase (CAT) activities, and glutathione (GSH) concentrations. Our results show that pretreatment of the rats with orally administered GHY extract (3.3 ml/kg/day) significantly reduced gastric lesion formation and caused the amelioration of several pathological changes in the above-mentioned gastric mucosal lesions. Concomitantly, GHY-pretreatment increased gastric mucosal SOD and CAT activities and GSH concentrations. We therefore propose that GHY exerts a prophylactic effect on the indomethacin-induced gastric mucosal lesions by enhancing antioxidant defense systems.

Activation of central opioid receptors may induce gastric mucosal defence in the rat

The effect of different opioid peptides on acidified ethanol- and indomethacin-induced gastric mucosal lesions was studied following intracerebroventricular (i.c.v.) administration. It was found that both the selective δ opioid receptor agonists—deltorphin II, [D-Ala 2, D-Leu 5]-enkephalin (DADLE), [D-Pen 2, D-Pen 5]-enkephalin (DPDPE)-, μ-opioid receptor agonist — [D-Ala 2, Phe 4, GlyT-ol]-enkephalin (DAGO) — as well as β-endorphin inhibited the mucosal damage induced by both ethanol and indomethacin in pmolar dose range. In contrast, the gastric acid secretion was not influenced by DADLE in the dose of 16 nmol/rat and only a slight reduction (40%) was induced by DAGO in the dose of 1.9 nmol/rat. The protective effect was abolished in both ulcer models by bilateral cervical vagotomy. N G-nitro-L-arginine, an inhibitor of NO synthase, reduced the protective action in ethanol-induced, but not in indomethacin-induced gastric damage. The results suggest that activation of supraspinal δ and μ-opioid receptors resulted in inhibition of gastric mucosal lesions elicited by ethanol or indomethacin. The gastroprotective action is independent from the effect of opioids on acid secretion. Vagal nerve is involved in conveying the central action to the periphery. The mechanism of the gastroprotective effect of opioids is different in ethanol- and indomethacin-ulcer models: prostaglandins and nitric oxide are likely to be involved in the protective action of opioid peptides in ethanol-, but not in the indomethacin-ulcer model.

Potentiating effect of passive cigarette smoking on gastrointestinal damage induced by indomethacin in rats.

Cigarette smoking and nonsteroidal antiinflammatory drugs (NSAIDs) have been associated with gastroduodenal ulcers. The present study aimed to clarify the ulcerogenic mechanisms of passive cigarette smoking on gastrointestinal damage induced by indomethacin in fasted or in fasted and refed rats. Rats were exposed to cigarette smoke (0%, 1%, 2%, or 4%, v/v) before and/or after indomethacin administration. Cigarette smoke dose-dependently potentiated indomethacin-induced gastric mucosal lesions in the fasted animals and further lowered gastric blood flow. The gastric myeloperoxidase activity (a marker enzyme for neutrophils) was also potentiated. In addition, passive cigarette smoking increased the mortality and aggravated duodenal ulceration and also the reduction of duodenal blood flow in the fasted and refed rats after indomethacin treatment. The results indicated that the potentiating effect of passive cigarette smoking on indomethacin-induced gastroduodenal lesions is probably due to the depression of blood flow in the gastroduodenal mucosa and to the aggravation of neutrophil infiltration in the gastric mucosa.

Protective effects of oleanolic acid oligoglycosides on ethanol- or indomethacin-induced gastric mucosal lesions in rats

We examined the effects of various oleanolic acid oligoglycosides obtained from traditional herbs on ethanol- or indomethacin-induced gastric mucosal lesions in rats and on gastric secretion in pylorus-ligated rats. Test samples were given orally to fasted rats 1 h before absolute ethanol (1.5 ml rat , p.o.) or indomethacin (30 mg kg , s.c.) treatment, or ligation of the pylorus. Oleanolic acid 3- O-monodesmosides [oleanolic acid 3- O-glucuronide ( 1, 20–50 mg kg ), momordin Ic ( 2, 5–50 mg kg ), and 28- O-deglucosyl-chikusetsusaponins IV ( 5, 10–50 mg kg ) and V ( 7, 10–50 mg kg )] were found to show protective effects on ethanol-induced gastric mucosal lesions, whereas oleanolic acid 3,28- O-bisdesmosides [momordin IIc (3), chikusetsusaponins IV (4) and V (6)], oleanolic acid 28- O-monodesmoside [compound O (8)], and their common aglycon [oleanolic acid ( 9)] showed no such effects. Oleanolic acid 3- O-monodesmosides ( 1, 2, and 5) also showed protective effects on indomethacin-induced gastric mucosal lesions. 28- O-Deglucosyl-chikusetsu-saponin V ( 7) did not inhibit the indomethacin-induced lesions, while chikusetsusaponins V ( 6, 50 mg kg ) had the gastroprotective effect. These active saponins ( 1, 2, 4–7, 10–50 mg kg ) did not decrease the gastric secretion by oral administration in pylorus-ligated rats.

Rat gastric mucosal cells express ICAM-1 and proinflammatory cytokines during indomethacininduced mucosal injury

Adhesion molecules and cytokines are known to be involved in the formation of acute gastric mucosal injury. However, it is not clear whether the gastric mucosal cells express these molecules and modulate the inflammation. To clarify whether gastric mucosal cells express intercellular adhesion molecule-1 (ICAM-1) and proinflammatory cytokines (tumor necrosis factor-α (TNF-α), interleukin-1-α (IL-1α), and cytokine-induced neutrophil chemoattractant-2-β (CINC-2β)) in the formation of gastric mucosal injury, we have used rat indomethacin-induced gastric mucosal lesions as an in vivo model. The gene expression of all cytokines and ICAM-1 increases at the early stages of indomethacin-induced gastritis (TNF-α and IL-1-α gene expression began to increase earlier than that of ICAM-1 and CINC-2-β) and can mainly be detected in the gastric epithelial layer. To further identify the source of those molecules, the epithelial cells were separated into seven fractions according to their sizes by a counterflow elution. ICAM-1 and CINC-2-β gene expressions are particularly enhanced in the middle-sized cell fractions that are rich in gastric mucous-producing cells. The effect of TNF-α or IL-1-α on the gene expression of ICAM-1 and cytokines was examined by using RGM-1 cells as a model for gastric mucosal cells. RGM-1 cells show an augmented ICAM-1 and proinflammatory cytokine expression in response to TNF-α or IL-1-α stimulation. Moreover, immunohistochemical staining also reveals an increase in ICAM-1 and CINC protein production in RGM-1 cells in response to TNF-α stimulation. We conclude that gastric mucosal cells express various cytokines and an adhesion molecule during the formation of acute gastric mucosal injury and that they may modulate the inflammation.

Increased Hepatocyte Growth Factor Content in Rat Stomach during Omeprazole Treatment

Background and Aims: Hepatocyte growth factor (HGF) is a potent mitogen of gastric epithelial cells, and its production is stimulated during the healing of gastric mucosal lesions. In this study, the effect of a proton pump inhibitor, omeprazole, on the production and degradation of HGF in the stomach was examined to elucidate the mechanism of the omeprazole-induced acceleration of gastric mucosal healing. Methods: Indomethacin-induced gastric mucosal lesions were induced in rats with or without omeprazole pretreatment. HGF gene expression and the content of HGF was investigated in the rat stomach. HGF degradation by gastric juice was also tested. Results: In omeprazole-treated rats, the healing of gastric mucosal lesions was accelerated in comparison with those of untreated rats. Although omeprazole treatment did not enhance the indomethacin-induced increase in HGF gene expression, it significantly augmented the gastric HGF content. Furthermore, omeprazole increased the gastric content not only of the inactive but also of the active heterodimeric form of HGF, and this appeared to be due to the inhibition of the HGF degradation by gastric juice. Conclusion: Omeprazole-induced acceleration of gastric mucosal healing may be mediated at least in part by the reduced degradation of HGF in the stomach.