Gastric Mucosal Cytoprotection Research Articles

Вплив інгібіторів циклооксигенази та ліпооксигенази на процеси ульцерогенезу та цитопротекції в слизовій оболонці шлунка щурів

Вплив інгібіторів циклооксигенази та ліпооксигенази на процеси ульцерогенезу та цитопротекції в слизовій оболонці шлунка щурів

Gastric mucosal cytoprotection in the rat by cysteine.

The free radical scavengers methyl-methionine sulphonium bromide and cysteine (5%) protected the rat gastric mucosa against ischaemic injury produced by reserpine (5 mg kg-1 i.p.). Pretreatment with 1 mL of 5% cysteine by gavage completely protected against injury rats with no ligation and 70% of rats with pyloric ligation after they had been given aspirin (200 mg kg-1 by gavage), a dose that produced gastric mucosal injury in 40% of rats with no ligation and 70% of rats with pyloric ligation after 4 h. Ethanol (1 mL of 40% solution by gavage) after 1 h produced gastric mucosal injury in all animals and pretreatment with 1 mL of 5% cysteine by gavage completely protected 80% of non-ligated and 70% of pyloric-ligated rats against this injury. This protection was not associated with any significant effect on H+ output. The data suggest that cysteine maintains gastric mucin by a mechanism independent of acid secretion.

Gastric mucosal cytoprotection in the rat by naftidrofuryl oxalate

Ischaemic gastric mucosal injury was assessed in the rat by measurement of the area of the injury produced after 6 h by reserpine (5 mg kg-1 i.p.) or 5-hydroxytryptamine (5-HT) (50 mg kg-1 i.p.). Pretreatment with naftidrofuryl 1 mL, 1% by gavage significantly (P less than 0.001) protected the rat stomach against the reserpine (24 +/- 2.7 mm2 vs 40 +/- 4.7 mm2, mean +/- s.e.m., n = 10) and 5-HT injury (11.4 +/- 1.7 mm2 vs 27 +/- 4.1 mm2, mean +/- s.e.m., n = 10). Naftidrofuryl 1 mL 2% by gavage was more effective (P less than 0.001) in this respect and mucosal injury only developed in 50% of rats injected with reserpine (9.4 +/- 1.1 mm2) and 30% of those injected with 5-HT (3.2 +/- 0.4 mm2). Administration of naftidrofuryl 1 mL 5% by gavage completely protected the rat against both the reserpine- and 5-HT-induced acute gastric mucosal injury. This protection was not associated with any significant influence on the H+ output.

Effect of dimethylglycine on gastric ulcers in rats.

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

Adaptive cytoprotection of gastric mucosa in rats after intragastric administration of edible alcohol

Adaptive cytoprotection of gastric mucosa in rats after intragastric administration of edible alcohol

Zinc L‐carnosine protects against mucosal injury in portal hypertensive gastropathy through induction of heat shock protein 72

Increased susceptibility to gastric mucosal injury is observed in portal hypertensive gastropathy (PHG). In this study, the effects of zinc L-carnosine, an anti-ulcer drug, were evaluated on expression of heat shock protein (hsp) 72 and cytoprotection in gastric mucosa in a rat model of PHG. Portal hypertensive gastropathy with liver cirrhosis was induced by bile duct ligation for 4 weeks in male Sprague-Dawley rats. Expression of gastric mucosal hsp72 was evaluated by Western blotting at 6 h after intragastric administration of L-carnosine, zinc sulfate, or zinc L-carnosine. Blood was also collected for determination of serum zinc level. Mucosal protective abilities against hydrochloric acid (HCl) (0.6N) followed by pretreatment with L-carnosine, zinc sulfate or zinc L-carnosine were also studied. L-carnosine, zinc sulfate, and zinc L-carnosine induced hsp72 in gastric mucosa of rats with bile duct ligation. Zinc sulfate and zinc L-carnosine suppressed HCl-induced mucosal injury. However, L-carnosine could not suppress HCl-induced mucosal injury. Serum zinc levels were significantly elevated after zinc L-carnosine administration. Furthermore, pretreatment with zinc L-carnosine (30-300 mg/kg) increased the expression of hsp72 in gastric mucosa and prevented HCl-induced mucosal injury in rats with bile duct ligation in a dose-dependent manner. Zinc derivatives, especially zinc L-carnosine, protected portal hypertensive gastric mucosa with increased hsp72 expression in cirrhotic rats. It is postulated that zinc L-carnosine may be beneficial to the mucosal protection in PHG as a 'chaperone inducer'.

American Gastroenterological Association Future Trends Committee Report: Effects of Aging of the Population on Gastroenterology Practice, Education, and Research

American Gastroenterological Association Future Trends Committee Report: Effects of Aging of the Population on Gastroenterology Practice, Education, and Research

Global Analysis of Gene Expression in Gastric Ischemia-Reperfusion: A Future Therapeutic Direction for Mucosal Protective Drugs

Gastric ischemia-reperfusion is a relatively common condition leading to mucosal injury and may affect mucosal repair via modulating the gene expression of growth factors. Therefore, precise understanding of the molecular mechanism of ischemia or ischemia-reperfusion may lead to the discovery of new mucosal protective drugs. DNA microarray analysis followed by powerful data analysis has the potential to uncover previously undescribed genes involved in gastric injury and lead to an increased understanding of gastric mucosal cytoprotection. We introduced the laser-assisted microdissection to obtain cell-specific RNA from gastric mucosa in vivo and obtained sufficient amounts of cRNA for GeneChip analysis. This comprehensive approach enabled the simultaneous analysis of many genes, including transcriptional factors, as well as the generation of novel hypothesis on the mechanism of action of gastro-protective agents.

Development of Agonists/Antagonists for Protease‐Activated Receptors (PARs) and the Possible Therapeutic Application to Gastrointestinal Diseases

AbstractFor Abstract see ChemInform Abstract in Full Text.

Development of Agonists/Antagonists for Protease-Activated Receptors (PARs) and the Possible Therapeutic Application to Gastrointestinal Diseases

Protease-activated receptors (PARs), a family of G-protein-coupled seven-transmembrane-domain receptors, are activated by proteolytic unmasking of the N-terminal cryptic tethered ligand by certain serine proteases. Among four PAR family members cloned to date, PAR-1, PAR-2, and PAR-4 can also be activated through a non-enzymatic mechanism, which is achieved by direct binding of exogenously applied synthetic peptides based on the tethered ligand sequence, known as PARs-activating peptides, to the body of the receptor. Various peptide mimetics have been synthesized as agonists for PARs with improved potency, selectivity, and stability. Some peptide mimetics and/or nonpeptide compounds have also been developed as antagonists for PAR-1 and PAR-4. PARs are widely distributed in the mammalian body, especially throughout the alimentary systems, and play various roles in physiological/pathophysiological conditions, i.e., modulation of salivary, gastric, or pancreatic glandular exocrine secretion, gastrointestinal smooth muscle motility, gastric mucosal cytoprotection, suppression/facilitation of visceral pain and inflammation, etc. Thus PARs are now considered novel therapeutic targets, and development of selective agonists and/or antagonists for PARs might provide a novel strategy for the treatment of various diseases that are resistant to current therapeutics.

Protease-Activated Receptors (PARs) as Therapeutic Targets: Development of Agonists / Antagonists and Modulation of Gastrointestinal Functions

Protease-activated receptors (PARs), a family of G-protein-coupled seven-transmembrane-domain receptors, are activated by proteolytic unmasking of the N-terminal cryptic tethered ligand by certain serine proteases. Among four PAR family members cloned to date, PAR-1, PAR-2 and PAR-4 can also be activated through a non-enzymatic mechanism, which is achieved by direct binding of exogenously applied synthetic peptides based on the tethered ligand sequence, namely PARs-activating peptides, to the body of the receptor. Various peptide mimetics have been synthesized as agonists and / or antagonists for PARs with improved potency, selectivity and stability. The amidation of the C-terminal of PARs-activating peptides increases the potency and metabolic resistance, particularly in vivo . Substitution of the Nterminal serine residue of PAR-2-activating peptides with a furoyl group dramatically enhances both potency and metabolic resistance, providing the most potent PAR-2 agonist. Some peptide mimetics and / or non-peptide compounds have also been developed as antagonists for PAR-1 and PAR-4. PARs are widely distributed in the mammalian body, especially throughout the alimentary systems, and play various roles in physiological / pathophysiological conditions; i.e. modulation of salivary, gastric or pancreatic glandular exocrine secretion and gastrointestinal smooth muscle motility, gastric mucosal cytoprotection, suppression / facilitation of visceral pain and inflammation, etc. Thus, PARs are now considered novel therapeutic targets, and development of selective agonists and / or antagonists for PARs might provide novel strategy for clinical treatment of various diseases that are resistant to current therapeutics. Keywords: protease (proteinase)-activated receptor (par), protease, structure-activity relationship, gastrointestinal tract

Physiological functions of protease-activated receptor-2

Protease-activated receptors (PARs) are a family of G-protein-coupled-seven-trans-membrane-domain-receptors activated by specific proteases, consisting of four family members. PAR-2, a receptor activated by trypsin, tryptase or coagulation factors VIIa and Xa, is unevenly distributed throughout the mammalian body, modulating multiple physiological functions. In the gastrointestinal tract, PAR-2 is involved in gastric mucosal cytoprotection, smooth muscle motility modulation, salivary and pancreatic exocrine secretion, intestinal ionic transport, etc. In the circulatory system, endothelial PAR-2, upon activation, induces vascular relaxation by mechanisms dependent on nitric oxide or endothelium-derived hyperpolarizing factor (EDHF), resulting in hypotension in vivo. In the respiratory system, PAR-2 appears to play a dual role, being pro- and anti-inflammatory. In the nervous system, PAR-2 present in capsaicin-sensitive sensory neurons participates in processing of pain information. PAR-2 is thus involved in a variety of physiological and pathophysiological functions. PAR-2 is now considered one of the most important molecules as a target for drug development.

Suppression by protease-activated receptor-2 activation of gastric acid secretion in rats

Activation of protease-activated receptor-2 (PAR-2), a receptor activated by trypsin/tryptase, induces neurally mediated gastric mucus secretion accompanied by mucosal cytoprotection. In the present study, we investigated whether PAR-2 could modulate gastric acid secretion in rats. Messenger RNAs for PAR-2 and PAR-1 were detected in the gastric mucosa and smooth muscle. The PAR-2-activating peptide SLIGRL-NH 2, but not the inactive control peptide, when administered i.v., strongly suppressed gastric acid secretion in response to carbachol, pentagastrin or 2-deoxy- d-glucose in the rats with a pylorus ligation. The PAR-2-mediated suppression of acid secretion was resistant to cyclooxygenase inhibition or ablation of sensory neurons by capsaicin. Our results provide novel evidence that in addition to stimulating neurally mediated mucus secretion, activation of PAR-2 suppresses gastric acid secretion independently of prostanoid production or sensory neurons. These dual actions of PAR-2 would result in gastric mucosal cytoprotection.

Capsazepine partially inhibits neurally mediated gastric mucus secretion following activation of protease-activated receptor 2.

1. Protease-activated receptor 2 (PAR2), present in capsaicin-sensitive sensory neurons, induces gastric mucus secretion and mucosal cytoprotection. 2. We studied the possible cross-talk between PAR2 and vanilloid receptor 1 (VR1). The VR1 antagonist capsazepine partially inhibited the PAR2-mediated increase in gastric mucus secretion. 3. Thus, activation of VR1 is responsible, at least in part, for the neurally mediated mucosal cytoprotection following activation of PAR2.

The protease-activated receptor-2 agonist induces gastric mucus secretion and mucosal cytoprotection.

Protease-activated receptor-2 (PAR-2), a receptor activated by trypsin/tryptase, modulates smooth muscle tone and exocrine secretion in the salivary glands and pancreas. Given that PAR-2 is expressed throughout the gastrointestinal tract, we investigated effects of PAR-2 agonists on mucus secretion and gastric mucosal injury in the rat. PAR-2-activating peptides triggered secretion of mucus in the stomach, but not in the duodenum. This mucus secretion was abolished by pretreatment with capsaicin, which stimulates and ablates specific sensory neurons, but it was resistant to cyclo-oxygenase inhibition. In contrast, capsaicin treatment failed to block PAR-2-mediated secretion from the salivary glands. Intravenous calcitonin gene-related peptide (CGRP) and neurokinin A markedly elicited gastric mucus secretion, as did substance P to a lesser extent. Specific antagonists of the CGRP1 and NK2, but not the NK1, receptors inhibited PAR-2-mediated mucus secretion. Pretreatment with the PAR-2 agonist strongly prevented gastric injury caused by HCl-ethanol or indomethacin. Thus, PAR-2 activation triggers the cytoprotective secretion of gastric mucus by stimulating the release of CGRP and tachykinins from sensory neurons. In contrast, the PAR-2-mediated salivary exocrine secretion appears to be independent of capsaicin-sensitive sensory neurons.

Cyclooxygenase-1 and an alternatively spliced mRNA in the rat stomach: effects of aging and ulcers.

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.

Adaptive gastric mucosal cytoprotection in rats: different modes of action by three mild irritants.

The mechanisms of adaptive mucosal cytoprotection by mild irritants were investigated in rats. In an ex vivo chamber preparation, application of 20% ethanol, 5% NaCl or 0.3 M HCl to the posterior side of the mucosa significantly protected that side of the stomach against mucosal damage caused by subsequent exposure to 100% ethanol, with contralateral transmission of protection to the anterior side by 20% ethanol and 0.3 M HCl. Atropine or lidocaine significantly reversed the cytoprotection of 20% ethanol. Bilateral vagotomy partially prevented the antilesion action of 20% ethanol, and completely prevented the action of 0.3 M HCl. However, the three mild irritants did not affect gastric mucosal blood flow, but restored the ion transport mechanism which was depressed by ethanol. It is therefore concluded that the three mild irritants have their own distinctive cytoprotective mechanisms against ethanol ulceration, which is predominantly not mediated by effects on the vascular system of the gastric mucosa.

Gastric Mucosal Cytoprotection in the Rat by Scavenging Oxygen-Derived Free Radicals

Oxygen-derived free radicals are cytotoxic and promote tissue damage. Dimethyl sulfoxide (DMSO) and allopurinol scavenge hydroxyl radicals, and the latter agent also inhibits the enzyme xanthine oxidase, which is responsible for the formation of superoxide anions. These agents were given daily by gavage (1 ml/d). After 2 days of administration as 1, 2, or 5% solutions, the H+ output of the rat with or without pyloric ligation was not significantly affected. After six hours reserpine (5 mg/kg i.p.) or serotonin (50 mg/kg i.p.) produced ischemic mucosal injury in all stomachs (39 +/- 5.2 mm2 and 25.9 +/- 2.8 mm2, mean +/- standard error of the mean [SEM], n = 10). Pretreatment for 2 days with 1 ml/d of 1% allopurinol or DMSO significantly (p less than 0.001) protected the rat against the reserpine (23 +/- 2.1 mm2 and 24 +/- 1.9 mm2, respectively, vs 39 +/- 5.2 mm2, n = 10) and serotonin injury (10 +/- 1.5 mm2 and 11 +/- 1.8 mm2, respectively, vs 25.9 +/- 2.8 mm2, n = 10). However, 2 days pretreatment with 1 ml/d of 2% allopurinol or DMSO was more effective (p less than 0.001) in this respect, and injury only developed in 40% of the rats given reserpine (8 +/- 1.2 mm2 and 9 +/- 1.6 mm2) and in 20% of those given serotonin (2.4 +/- 0.4 mm2 and 1.9 +/- 0.5 mm2). Similar pretreatment with 5% solutions completely protected the rat stomach against the reserpine and serotonin injuries without significantly influencing the H+ output.(ABSTRACT TRUNCATED AT 250 WORDS)

Do sensory neurons mediate adaptive cytoprotection of gastric mucosa against bile acid injury?

Do sensory neurons mediate adaptive cytoprotection of gastric mucosa against bile acid injury?

Vagotomy Effect on Gastric Prostaglandins

Prostaglandins have been implicated in gastric mucosal cytoprotection. Vagotomy results in both cytoprotection and increased mucosal prostaglandin concentrations. However, the mechanism by which vagotomy affects prostaglandin generation remains unknown. In this study we compared vagotomy with long-term acid suppression using anticholinergic (atropine sulfate) or histamine2-receptor antagonism (cimetidine) and assessed mucosal injury and prostaglandin generation during graded stress. Vagotomy correlated with decreases in injury only in severe stress, while both atropine and cimetidine decreased injury also during moderate stress. Prostaglandin generation decreased in all groups during severe stress. Compared with sham operation, vagotomy, atropine, and cimetidine were all associated with increased mucosal prostaglandin generation in all stress periods. During severe stress, both atropine and cimetidine also evidenced higher prostaglandin generation than did vagotomy. These results suggest that vagotomy primarily decreases acid secretion, which then secondarily results in increased mucosal generation.