Melatonin, a major hormone of pineal gland, was recently shown to attenuate acute gastric lesions induced by strong irritants because of the scavenging of free radicals but its role in ulcer healing has been little investigated. In this study we compared the effects of intragastric (i.g.) administration of melatonin and its precursor, L-tryptophan, with or without concurrent treatment with luzindole, a selective antagonist of melatonin MT2 receptors, on healing of chronic gastric ulcers induced by serosal application of acetic acid (ulcer area 28 mm2). The involvement of endogenous prostaglandins (PG), nitric oxide (NO) and sensory nerves in ulcer healing action of melatonin and L-tryptophan was studied in rats treated with indomethacin and NG-nitro-L-arginine (L-NNA) to suppress, respectively, cyclo-oxygenases (COX) and NO synthases or in those with functionally deactivated sensory nerves with capsaicin. The influence of melatonin on gastric secretion during ulcer healing was tested in separate group of rats with gastric ulcer equipped with gastric fistulas (GF). At day 8 and 15 upon the ulcer induction, the area of gastric ulcers was measured by planimetry, the mucosal blood flow (GBF) was determined by H2-gas clearance technique and gastric luminal NO2-/NO3- levels was assessed by Griess reaction. Plasma melatonin and gastrin levels were measured by specific radioimmunoassay (RIA). Biopsy mucosal samples were taken for expression of constitutive NO-synthase (cNOS) and inducible NOS (iNOS) by reverse transcriptase-polymerase chain reaction (RT-PCR). Melatonin (2.5-20 mg/kg-d i.g.) and L-tryptophan (25-100 mg/kg-d i.g.) dose-dependently accelerated ulcer healing, the dose inhibiting by 50% (ED50) of ulcer area being 10 and 115 mg/kg, respectively. This inhibitory effect of melatonin (10 mg/kg-d i.g.) and L-tryptophan (100 mg/kg-d i.g.) on ulcer healing was accompanied by a significant rise in the GBF at ulcer margin and an increase of plasma melatonin. luminal NO2-/NO3- and plasma gastrin levels. Gastric acid and pepsin outputs were significantly inhibited during the ulcer healing in melatonin-treated gastric mucosa as compared with those in vehicle-treated animals. Luzindole abolished completely the healing effects of melatonin and L-tryptophan and attenuated significantly the rise in plasma gastrin evoked by the hormone and its precursor. Indomethacin (5 mg/kg-d i.p). that blocked PG biosynthesis by 90% or L-NAME (20 mg/kg i.v), inhibitor of NOS. that suppressed luminal NO release, attenuated significantly melatonin and L-tryptophan-induced acceleration of ulcer healing and accompanying rise in GBF at ulcer margin and luminal NO release. The melatonin-induced acceleration of ulcer healing, hyperemia at ulcer margin and increase in the release of NO were enhanced when L-arginine but not D-arginine was added to L-NAME. The ulcer healing and the GBF effects of melatonin and L-tryptophan were significantly impaired in rats with capsaicin-induced denervation of sensory nerves and both, ulcer healing and the hyperem...

BackgroundAlendronate is an inhibitor of osteoclast-mediated bone resorption, but its clinical utility is limited due to gastrointestinal complications including bleeding erosions.AimsWe studied whether potent vasodilators hydrogen sulfide (H2S) and carbon monoxide (CO) can protect against alendronate-induced gastric lesions in rats exposed to mild stress.MethodsThree series (A, B, and C) of Wistar rats received alendronate (150–700 mg/kg i.g., series A) with or without NaHS (5 mg/kg), H2S donor or CORM-2 (5 mg/kg) releasing CO administered i.g. 30 min before alendronate administration (series B) in rats exposed for 3 days before alendronate administration to mild stress (series C). The area of gastric lesions was assessed by planimetry, the gastric blood flow (GBF) was determined by H2-gas clearance technique, and H2S production via CSE/CBS/3-MST activity and the gastric expression of HO-1, HO-2, HIF-1α, NF-κB, iNOS, COX-2, IL-1β, TNF-α, GPx-1 and SOD-2 were analyzed by qPCR or Western blot.ResultsAlendronate dose-dependently produced gastric mucosal lesions and significantly decreased GBF, and these effects were exacerbated by mild stress. NaHS and CORM-2 significantly reduced the alendronate-induced gastric lesions in non-stressed and stressed animals, but only NaHS but not CORM-2 raised H2S production. NaHS and CORM-2 inhibited gastric expression of HIF-1α protein and HO-1, HIF-1α, NF-κB, COX-2, iNOS, IL-1β, TNF-α mRNAs but failed to affect those of HO-2, GPx-1, and SOD-2.ConclusionBoth H2S and CO released from their donors, NaHS and CORM-2, protect gastric mucosa compromised by stress against alendronate-induced gastric damage via mechanism involving downregulation of HIF-1α, NF-κB and proinflammatory factors COX-2, iNOS, IL-1β, and TNF-α.

SUMMARYBackground: NSAIDs, such as aspirin (ASA), cause widespread mucosal damage, but repeated ASA insults appear to induce mucosal tolerance (adaptation) to this injury. The mechanism of the gastric adaptation to the damage induced by ASA has not been fully explained. Aim: To determine the role of the mucosal gene expression for spasmolitic peptide (SP) (a member of trefoil peptides) and transforming growth factor alpha (TGFa) as well as for cyclooxygenase (COX)-1 and COX-2 during gastric adaptation to ASA in rats. Methods: Gastric lesions were produced by ASA (100 mg/kg in 1.5 mL of 0.2 M HCl) applied intragastrically (i.g.) as a single dose, every day for 5 days. Control rats were given 1.5 mL of vehicle (0.2 M HCl i.g.) as a single dose, during 5 consecutive days. Gastric blood¯ow (GBF) was measured by H 2 -gas clearance technique and gastric mucosal specimens were taken for the assessment of cell proliferation rate in gastric mucosa by bromodeoxyuridine (BrdU) uptake, mucosal generation of prostaglandin E 2 measured by radioimmunoassay, and for expression of SP, TGFa COX-1 and COX-2 mRNA as determined by RT-PCR. To quantify the relative amounts of mRNA for SP and TGFa, southern blotting analysis of the PCR products was

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1) Persistent colonization with Candida could be achieved in rats treated with antisecretory agents or non-steroidal anti-inflammatory drugs (NSAIDs) such as ASA; 2) candidiasis reduces gastric acid secretion, while delaying ulcer healing possibly due to the impairment in GBF in the ulcer area and enhanced expression and release of IL-1beta and TNFalpha and 3) probiotic therapy could be useful in the treatment against the deleterious action of fungal infection on the healing of pre-existing gastric ulcers.

BACKGROUND AND PURPOSECarbon monoxide (CO), a gaseous mediator produced by haem oxygenases (HOs), has been shown to prevent stress-, ethanol-, aspirin-and alendronate-induced gastric damage; however, its role in gastric ulcer healing has not been fully elucidated. We investigated whether CO released from tricarbonyldichlororuthenium (II) dimer (CORM-2) can affect gastric ulcer healing and determined the mechanisms involved in this healing action. EXPERIMENTAL APPROACHGastric ulcers were induced in Wistar rats by serosal application of acetic acid. Animals received 9 days of treatment with RuCl 3 [2.5 mg·kg À1 intragastrically (i.g.)], haemin (5 mg·kg À1 i.g.), CORM-2 (0.1-10 mg·kg À1 i.g.) administered alone or with zinc protoporphyrin IX (ZnPP, 10 mg·kgGastric ulcer area and gastric blood flow (GBF) were assessed planimetrically, microscopically and by laser flowmeter respectively. Gastric mRNA/protein expressions of EGF, EGF receptors, VEGFA, HOs, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), COX-2, hypoxia-inducible factor (HIF)-1α and pro-inflammatory iNOS, IL-1β and TNF-α were determined by real-time PCR or Western blots. KEY RESULTSCORM-2 and haemin but not RuCl 3 or ZnPP decreased ulcer size while increasing GBF. These effects were reduced by ODQ, indomethacin, L-NNA and glibenclamide. CORM-2 significantly decreased the expression of pro-inflammatory markers, Nrf2/HO1 and HIF-1α, and up-regulated EGF. CONCLUSIONS AND IMPLICATIONSCO released from CORM-2 or endogenously produced by the HO1/Nrf2 pathway accelerates gastric ulcer healing via an increase in GBF, an up-regulation in EGF expression and down-regulation of the inflammatory response.

Duodenal fat such as oleate is known to influence gut functions by release of cholecystokinin (CCK), but the contribution of CCK endogenously released by duodenal fat or by diversion of pancreatic juice from the duodenum in the mechanism of mucosal integrity and gastroprotection has been little studied. This study was designed to compare the effect of CCK-8 and intraduodenal (i.d.) instillation of sodium oleate, or diversion of the pancreatic biliary secretions that are known to release CCK, on the gastric mucosal lesions induced by topical application of 100% ethanol or acidified aspirin (ASA) in rats with or without the pretreatment with a CCK-A receptor antagonist, loxiglumide, or with L-365,260 to block CCK-B receptors. In addition, the effect of suppression of prostaglandin (PG) biosynthesis by indomethacin (5 mg/kg i.p.), inhibition of nitric oxide (NO)-synthase by L-NAME (5 mg/kg i.v.), or blockade of sensory nerves by capsaicin (125 mg/kg s.c.) on the protective activity of sodium oleate was determined. Sodium oleate (50-200 mM i.d.), or diversion of pancreatic juice from the duodenum for 3 h that produced significant rise in plasma CCK levels, significantly reduced gastric lesions induced by 100% ethanol to an extent similar to that induced by exogenous CCK-8 (5 nmol/kg s.c.). The protective effect of oleate or diversion of pancreatic juice was accompanied by an increase in gastric blood flow (GBF). Both protection and accompanying hyperemia were completely abolished by blockade of CCK-A receptors with loxiglumide, whereas L-365,260, an antagonist of CCK-B receptors, had no effect. Oleate given i.d. significantly attenuated acidified ASA-induced gastric lesions and gastric secretion while increasing the luminal concentration of somatostatin. These effects were significantly reduced by loxiglumide but not by L-365,260. In contrast, CCK-8, which stimulated gastric acid secretion, failed to affect the lesions induced by acidified ASA and the decrease in the GBF produced by this ulcerogen. Indomethacin, which suppressed PG generation by approximately 90%, failed to influence the protective activity of oleate or CCK-8 against ethanol-induced lesions, whereas L-NAME, vagotomy, or sensory denervation significantly attenuated this protection and accompanying hyperemia. Addition to L-NAME of L-arginine, but not D-arginine, restored the protective and hyperemic effects of CCK-8 and duodenal oleate against gastric lesions induced by ethanol or acidified ASA. We conclude that endogenous CCK released by oleate or diversion of pancreatic secretion exerts a potent gastroprotective action on the stomach involving predominantly CCK-A receptors and depending on vagal activity, and hyperemia mediated by NO and sensory nerves but unrelated to acid secretory effects and endogenous PG.

Background: Leptin, a product of the ob gene controlling food intake, has recently been detected in the stomach and shown to be released by cholecystokinin (CCK) and to induce gastroprotection against various noxious agents, but it is not known whether centrally applied leptin influences gastric secretion and mucosal integrity. Aims: In this study we compared the effects of leptin and CCK-8 applied intracerebroventricularly (i.c.v.) on gastric secretion and gastric mucosal lesions induced by topical application of 75% ethanol. Methods: Several major series of Wistar rats were used in this study. The effects of leptin or CCK applied i.c.v. on gastric secretion were examined using conscious rats with gastric fistulas. For the studies on gastroprotection the following series of rats were used to determine the effects of: (A) leptin and CCK applied centrally on this protection and the blockade of CCK_A with loxiglumide (30 mg/kg i.p.) and CCK_B receptors with RPR 102681 (30 mg/kg i.p.); (B) cutting of vagal nerves; (C) inactivation of sensory nerves by capsaicin (125 mg/kg s.c.); (D) inhibition of calcitonin gene-related peptide (CGRP) receptors with CGRP_8–37 (100 μg/kg i.p.), and (E) suppression of nitric oxide synthase (NOS) with N^G-nitro-L-arginine methyl ester (L-NAME) (5 mg/kg i.v.) on ethanol-induced gastric lesions in rats with or without the i.c.v. pretreatment with leptin or CCK-8. Rats were anesthetized 1 h after ethanol administration to measure the gastric blood flow (GBF) and then to determine the area of gastric lesions by planimetry. Blood was withdrawn for the measurement of plasma leptin and gastrin levels by radioimmunoassay and gastric biopsy samples were collected for the determination of cNOS and iNOS mRNA by RT-PCR. Results: Leptin and CCK-8 (0.01–5 μg/kg i.c.v.) dose dependently attenuated gastric lesions induced by 75% ethanol; the doses reducing these lesions by 50% (ED₅₀) were 0.8 and 1.2 μg/kg, respectively. The protective effects of leptin and CCK-8 applied i.c.v. were accompanied by a significant rise in plasma leptin level and an increase in GBF. Blockade of CCK_A receptors with loxiglumide abolished the protective and hyperemic effects of CCK but not those of leptin, while RPR 10268, a specific antagonist of CCK_B receptors, counteracted leptin-induced protection and the rise in the GBF but failed to influence those afforded by CCK-8. For comparison, pretreatment with peripheral CCK-8 or leptin (10 μg/kg i.p.) causing a similar rise in the plasma leptin level also significantly reduced gastric lesions induced by 75% ethanol. The protective and hyperemic effects of centrally administered leptin were abolished by vagotomy, producing a fall in plasma leptin levels, and significantly attenuated by sensory denervation with capsaicin, by pretreatment with the CGRP antagonist, CGRP_8–37, or with L-NAME. A strong signal for iNOS mRNA was recorded in the gastric mucosa of leptin- and CCK-8-treated animals, whereas...