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The stomach exhibits an unusual ability to protect itself against the damage by various noxious factors due to several lines of mucosal defense such as continuous mucus-alkaline secretion, efficient mucosal blood flow, rapid mucosal regeneration and mucosal cell restitution with healing of lesions and ulcerations. All these abilities were originally attributed to the generation and action of various arachidonic acid metabolites, especially prostaglandins (PG) of E and I series. Although PG were generally accepted as highly gastroprotective agents in animals, their protective activity has not been definitively confirmed in humans and, most important, their ulcer healing properties were described only when applied in large gastric inhibitory doses. Other gastroprotective agents acting independently from PG include nitric oxide (NO), generated from L-arginine by NO synthase, certain neuropeptides such as calcitonin-gene related peptides (CGRP) released from the terminals of sensory nerves, certain gut hormones including gastrin, cholecystokinin, ghrelin and numerous growth factors such as epidermal growth factor (EGF), transforming growth factors (TGF) and platelet-derived growth factors (PDGF). Most recently, melatonin, produced from L-tryptophan in pineal gland, has been found to be expressed and generated in gastric mucosa in larger quantities than in pineal gland and to exert strong local gastroprotective and ulcer healing properties, especially against gastric lesions induced by non-steroidal anti-inflammatory drugs (NSAID), both in animals and humans. Future studies should reveal whether gastroprotective agents of endogenous origin have potential in the maintenance of gastric mucosal integrity and acceleration of healing of gastric lesions and ulcerations in humans. [ABSTRACT FROM AUTHOR]

The formation of acute gastric lesions depends upon the balance between the aggressive factors promoting mucosal damage and the natural defense mechanisms. Previous studies have shown that melatonin inhibits gastric acid secretion, enhances the release of gastrin, augments gastric blood flow (GBF), increases the cyclooxygenase-2 (COX-2)–prostaglandin (PG) system and scavenges free radicals, resulting in the prevention of stress-induced gastric lesions. Besides the pineal gland, melatonin is also generated in large amounts in the gastrointestinal tract and due to its antioxidant and anti-inflammatory properties; this indole might serve as local protective endogen preventing the development of acute gastric damage. The results of the present study indicate that stress-induced gastric lesions show circadian variations with an increase in the day time and a decline at night. These changes are inversely related to plasma melatonin levels. Following pinealectomy, stress-induced gastric mucosal lesions were more pronounced both during the day and at night, and were accompanied by markedly reduced plasma melatonin levels with a pronounced reduction in mucosal generation of prostaglandin E2 (PGE2), GBF and increased free radical formation and by small rise in plasma melatonin during the dark phase. We conclude that stress-induced gastric ulcerations exhibit a circadian variation with an increase in the day and attenuation at night and that these fluctuations of gastric stress ulcerogenesis occur also after pinealectomy, depending upon the interaction of COX–PG and free radicals, probably mediated by the changes in local gastric melatonin. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS) have high chemical reactivity, due to the presence of an uncoupled electron in their molecules. Therefore, they cause tissue damages, especially by lipid peroxidation. Lipid peroxides are metabolized to malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE). The increase of MDA and 4-HNE concentration indicates ROS-dependent tissue damage. Superoxide dismutase (SOD) is a main enzyme which neutralizes ROS into less noxious hydrogen peroxide. The decrease of SOD activity is related to impairment of protective mechanisms and leads to tissue injury. The hydrogen peroxide is further metabolized to water in the presence of reduced glutathione (GSH). The decrease of GSH level has detrimental consequences for cellular properties of antioxidative defence. Gastric mucosa, under stress conditions, exhibits intensification of lipid peroxidation (increase of MDA and 4-HNE), as well as the decrease of SOD activity and GSH concentration. This parameters appear to be useful for understanding of pathomechanisms of the origin of gastric mucosa damage in stress conditions. [ABSTRACT FROM AUTHOR]

Barrett's esophagus (BE) is a precancerous condition leading to the development of adenocarcinoma, associated with intestinal metaplasia. Nowadays, the rapid increase in the incidence of esophageal adenocarcinoma (EAC) has been observed worldwide. Despite the surgical treatment and the introduction of new chemotherapy forms, the 5-year period survival is still bad. In this paper, we provide an update on the pathogenesis of BE and EAC based on the interrelationship between prostaglandins (PG), growth factors (GF), GF receptors and peroxisome proliferator-activated receptors (PPARs) in chronic esophagitis, BE, and EAC. We also attempted to overview the involvement of cyclooxygenase (COX) products and pharmacological inhibitors of COX in the process of proliferation, angiogenesis and apoptosis resulting from their interactions with PPARs. Furthermore, the paper presents some experimental animal models of inducing an acute and chronic esophagitis and Barrett's esophagus, which are useful in understanding the pathogenesis of these diseases under clinical settings. Among the potential pathomechanisms, the cellular processes resulting from transactivation GF receptors by other factors such as PG and their biological activity in chronic inflammation and carcinogenesis are emphasized. Finally, we stressed the impact of the naturally occurring anti-oncogenic mechanisms and the recent advances in the innovative therapy against gastrointestinal cancers. [ABSTRACT FROM AUTHOR]

Abstract: Ghrelin, a 28-amino-acid peptide produced predominantly by oxyntic mucosa has been reported to affect the pancreatic exocrine function but the mechanism of its secretory action is not clear. The effects of intraduodenal (i.d.) infusion of ghrelin on pancreatic amylase outputs under basal conditions and following the stimulation of pancreatic secretion with diversion of pancreato-biliary juice (DPBJ) as well as the role of vagal nerve, sensory fibers and CCK in this process were determined. Ghrelin given into the duodenum of healthy rats at doses of 1.0 or 10.0 μg/kg increased pancreatic amylase outputs under basal conditions or following the stimulation of pancreatic secretion with DPBJ. Bilateral vagotomy as well as capsaicin deactivation of sensory fibers completely abolished all stimulatory effects of luminal ghrelin on pancreatic exocrine function. Pretreatment with lorglumide, a CCK1 receptor blocker, reversed the stimulation of amylase release produced by intraduodenal application of ghrelin. Intraduodenal ghrelin at doses of 1.0 or 10.0 μg/kg increased plasma concentrations of CCK and ghrelin. In conclusion, ghrelin given into the duodenum stimulates pancreatic enzyme secretion. Activation of vagal reflexes and CCK release as well as central mechanisms could be implicated in the stimulatory effect of luminal ghrelin on the pancreatic exocrine functions. [Copyright &y& Elsevier]

Background: The members of the family of heat shock factors coordinate the inducible transcription of heat shock genes in response to diverse stimuli. Any disturbances in signal transduction may lead to the attenuation of heat shock proteins synthesis and to cell death due to apoptosis. It has been shown by others that different nuclear factors, such as nuclear factor interleukine 6 or signal transducer and activator of transcription 3, co-operate with heat shock factors, mostly enhancing their activator effect on heat shock proteins genes expression. Therefore, we sought to determine whether apoptosis induced in the gastric epithelium exposed to live Helicobacter pylori might occur due to the elimination of HSP70 expression and deregulation of the heat shock response of the cell. Materials and Methods: Experiments were performed on KATO III gastric epithelial cells exposed to live cagA, vacA expressing Hp over different periods of time. Total cellular RNA, cytoplasmic and nuclear proteins were isolated for polimerase chain reaction, western-blot, electrophoretic mobility shift assay, decoy and co-immunoprecipitation studies. Results: We found that in human gastric epithelium exposed to Helicobacter pylori, heat shock factor 1 is bound and restrained in complexes by phosphorylated signal transducer and activator of transcription 3 protein. In consequence, heat shock factor 1 bound up with phosphorylated signal transducer and activator of transcription 3 protein is unable to activate HSP70 protein synthesis in KATO III cells under stress conditions. Helicobacter pylori also causes changes in bax/bcl-2 cellular equilibrium, leading to the induction of apoptosis. Conclusions: The observed phenomenon might be the mechanism whereby gastric epithelium adapts to the infection of Helicobacter pylori, eliminating cells which are damaged or altered by bacterial cytotoxic products from the tissue. [ABSTRACT FROM AUTHOR]

Abstract: It is assumed that an overproduction of gastric acid is the most important factor in the development of peptic ulcer. However, it has been also demonstrated that gastric defense mechanisms, which prevent mucosal injury, are enhanced by the same factors that increase acid secretion. The aim of this study was to examine the role of capsaicin-sensitive sensory nerves and histamine H1, H2, and H3 receptors in histamine-induced gastroprotection against stress ulcers. Studies were performed on rats with intact or ablated sensory nerves. Ablation of sensory nerves was induced by neurotoxic doses of capsaicin. Gastric ulcers were induced by water immersion and restrain stress. Before exposure to stress, rats were pretreated with saline (control), histamine (10 μmol/kg), histamine H1 receptor antagonist pyrilamine (100 μmol/kg), histamine H2 receptor antagonist ranitidine (100 μmol/kg), histamine H3 receptor antagonist thioperamide (100 μmol/kg), or a combination of histamine with these histamine receptor antagonists. Results: Histamine alone reduced ulcer area evoked by stress and this effect was accompanied by an increase in gastric mucosal blood flow and mucosal DNA synthesis, as well as a decrease in serum pro-inflammatory interleukin-1β concentration. Treatment with combination of pyrilamine plus histamine caused an increase in gastric ulcer area and serum interleukin-1β above the value observed in animals treated with saline, and this effect was accompanied by a decrease in gastric mucosal DNA synthesis. Ranitidine, in combination with histamine, reduced the ulcer area and serum interleukin-1β to a minimal value, whereas gastric mucosal blood flow and DNA synthesis reached a maximal value. Pretreatment with thioperamide before histamine administration abolished the histamine-evoked reduction in gastric ulcer area. Ablation of sensory nerves increased the ulcer area in animals treated with saline or histamine, or histamine in combination with pyrilamine or ranitidine. In animals with sensory nerves ablation combined with administration of thioperamide plus histamine, the ulcer area was similar to that in saline-treated animals with intact sensory nerves. We conclude that: (1) histamine exhibits protective effect against stress-induced gastric ulcer and that this gastroprotection is related to stimulation of histamine H1 and H3 receptors; (2) blockade of histamine H2 receptors exhibited beneficial effect on gastric mucosa against stress-induced gastric ulcers; and (3) ablation of sensory nerves aggravates stress-induced gastric ulcer and reduces histamine-evoked gastroprotection related to stimulation of histamine H3 receptors. [Copyright &y& Elsevier]