Alternative Therapy in the Prevention of Experimental and Clinical Inflammatory Bowel Disease. Impact of Regular Physical Activity, Intestinal Alkaline Phosphatase and Herbal Products.

Inflammatory bowel diseases (IBD), such as ulcerative colitis and Crohn's disease, are multifactorial, chronic, disabling, and progressive diseases characterised by cyclical nature, alternating between active and quiescent states. While the aetiology of IBD is not fully understood, this complex of diseases involve a combination of factors including the genetic predisposition and changes in microbiome as well as environmental risk factors such as high-fat and low-fibre diets, reduced physical activity, air pollution and exposure to various toxins and drugs such as antibiotics. The prevalence of both IBD and obesity is increasing in parallel, undoubtedly proving the existing interactions between these risk factors common to both disorders to unravel poorly recognized cell signaling and molecular alterations leading to human IBD. Therefore, there is still a significant and unmet need for supportive and adjunctive therapy for IBD patients directed against the negative consequences of visceral obesity and bacterial dysbiosis. Among the alternative therapies, a moderate-intensity exercise can benefit the health and well-being of IBD patients and improve both the healing of human IBD and experimental animal colitis. Intestinal alkaline phosphatase (IAP) plays an essential role in the maintenance of intestinal homeostasis intestinal and the mechanism of mucosal defence. The administration of exogenous IAP could be recommended as a therapeutic strategy for the cure of diseases resulting from the intestinal barrier dysfunction such as IBD. Curcumin, a natural anti-inflammatory agent, which is capable of stimulating the synthesis of endogenous IAP, represents another alternative approach in the treatment of IBD. This review was designed to discuss potential "nonpharmacological" alternative and supplementary therapeutic approaches taking into account epidemiological and pathophysiological links between obesity and IBD, including changes in the functional parameters of the intestinal mucosa and alterations in the intestinal microbiome.

Curcumin: A Potent Protectant against Esophageal and Gastric Disorders.

Turmeric obtained from the rhizomes of Curcuma longa has been used in the prevention and treatment of many diseases since the ancient times. Curcumin is the principal polyphenol isolated from turmeric, which exhibits anti-inflammatory, antioxidant, antiapoptotic, antitumor, and antimetastatic activities. The existing evidence indicates that curcumin can exert a wide range of beneficial pleiotropic properties in the gastrointestinal tract, such as protection against reflux esophagitis, Barrett's esophagus, and gastric mucosal damage induced by nonsteroidal anti-inflammatory drugs (NSAIDs) and necrotizing agents. The role of curcumin as an adjuvant in the treatment of a Helicobacter pylori infection in experimental animals and humans has recently been proposed. The evidence that this turmeric derivative inhibits the invasion and proliferation of gastric cancer cells is encouraging and warrants further experimental and clinical studies with newer formulations to support the inclusion of curcumin in cancer therapy regimens. This review was designed to analyze the existing data from in vitro and in vivo animal and human studies in order to highlight the mechanisms of therapeutic efficacy of curcumin in the protection and ulcer healing of the upper gastrointestinal tract, with a major focus on addressing the protection of the esophagus and stomach by this emerging compound.

Melatonin in Prevention of the Sequence from Reflux Esophagitis to Barrett's Esophagus and Esophageal Adenocarcinoma: Experimental and Clinical Perspectives.

Melatonin is a tryptophan-derived molecule with pleiotropic activities which is produced in all living organisms. This "sleep" hormone is a free radical scavenger, which activates several anti-oxidative enzymes and mechanisms. Melatonin, a highly lipophilic hormone, can reach body target cells rapidly, acting as the circadian signal to alter numerous physiological functions in the body. This indoleamine can protect the organs against a variety of damaging agents via multiple signaling. This review focused on the role played by melatonin in the mechanism of esophagoprotection, starting with its short-term protection against acute reflux esophagitis and then investigating the long-term prevention of chronic inflammation that leads to gastroesophageal reflux disease (GERD) and Barrett's esophagus. Since both of these condition are also identified as major risk factors for esophageal carcinoma, we provide some experimental and clinical evidence that supplementation therapy with melatonin could be useful in esophageal injury by protecting various animal models and patients with GERD from erosions, Barrett's esophagus and neoplasia. The physiological aspects of the synthesis and release of this indoleamine in the gut, including its release into portal circulation and liver uptake is examined. The beneficial influence of melatonin in preventing esophageal injury from acid-pepsin and acid-pepsin-bile exposure in animals as well as the usefulness of melatonin and its precursor, L-tryptophan in prophylactic and supplementary therapy against esophageal disorders in humans, are also discussed.

Exploiting Significance of Physical Exercise in Prevention of Gastrointestinal Disorders.

BACKGROUND: Physical activity can be involved in the prevention of gastrointestinal (GI)-tract diseases, however, the results regarding the volume and the intensity of exercise considered as beneficial for protection of gastrointestinal organs are conflicting. AIMS AND METHODS: The main objective of this review is to provide a comprehensive and updated overview on the beneficial and harmful effects of physical activity on the gastrointestinal tract. We attempted to discuss recent evidence regarding the association between different modes and intensity levels of exercise and physiological functions of the gut and gut pathology. RESULTS: The regular, moderate exercise can exert a beneficial effect on GI-tract disorders such as reflux esophagitis, peptic ulcers, cholelithiasis, constipation and Inflammatory Bowel Disease (IBD) leading to the attenuation of the symptoms. This voluntary exercise has been shown to reduce the risk of colorectal cancer. On the other hand, there is considerable evidence that the high-intensity training or prolonged endurance training can exert a negative influence on GI-tract resulting in the exacerbation of symptoms. CONCLUSION: Physical activity can exhibit a beneficial effect on a variety of gastrointestinal diseases, however, this effect depends upon the exercise mode, duration and intensity. The accumulated evidence indicate that management of gastrointestinal problems and their relief by the exercise seems to be complicated and require adjustments of physical activity training, dietary measures and medical monitoring of symptoms. More experimental and clinical studies on the effects of physical activity on GI-tract disorders are warranted. Especially, the association between the exercise intensity and data addressing the underlying mechanism(s) of the exercise as the complementary therapy in the treatment of gastrointestinal disorders, require further determination in animal models and humans.

Mechanisms of curcumin-induced gastroprotection against ethanol-induced gastric mucosal lesions.

BACKGROUND: Curcumin, a pleiotropic substance used for centuries in traditional medicine, exhibits antioxidant, anti-inflammatory and antiproliferative efficacy against various tumours, but the role of curcumin in gastroprotection is little studied. We determined the effect of curcumin against gastric haemorrhagic lesions induced by 75% ethanol and alterations in gastric blood flow (GBF) in rats with cyclooxygenase-1 (COX-1) and COX-2 activity inhibited by indomethacin, SC-560 or rofecoxib, inhibited NO-synthase activity, capsaicin denervation and blockade of TRPV1 receptors by capsazepine. METHODS: One hour after ethanol administration, the gastric mucosal lesions were assessed by planimetry, the GBF was examined by H2 gas clearance, plasma gastrin was determined by radioimmunoassay, and the gastric mucosal mRNA expression of Cdx-2, HIF-1α, HO-1 and SOD 2 was analysed by RT-PCR. RESULTS: Curcumin, in a dose-dependent manner, reduced ethanol-induced gastric lesions and significantly increased GBF and plasma gastrin levels. Curcumin-induced protection was completely reversed by indomethacin and SC-560, and significantly attenuated by rofecoxib, L-NNA, capsaicin denervation and capsazepine. Curcumin downregulated Cdx-2 and Hif-1α mRNA expression and upregulated HO-1 and SOD 2, and these effects were reversed by L-NNA and further restored by co-treatment of L-NNA with L-arginine. CONCLUSIONS: Curcumin-induced protection against ethanol damage involves endogenous PG, NO, gastrin and CGRP released from sensory nerves due to activation of the vanilloid TRPV1 receptor. This protective effect can be attributed to the inhibition of HIF-1α and Cdx-2 expression and the activation of HO-1 and SOD 2 expression.

Carbon Monoxide (CO) Released from Tricarbonyldichlororuthenium (II) Dimer (CORM-2) in Gastroprotection against Experimental Ethanol-Induced Gastric Damage.

The physiological gaseous molecule, carbon monoxide (CO) becomes a subject of extensive investigation due to its vasoactive activity throughout the body but its role in gastroprotection has been little investigated. We determined the mechanism of CO released from its donor tricarbonyldichlororuthenium (II) dimer (CORM-2) in protection of gastric mucosa against 75% ethanol-induced injury. Rats were pretreated with CORM-2 30 min prior to 75% ethanol with or without 1) non-selective (indomethacin) or selective cyclooxygenase (COX)-1 (SC-560) and COX-2 (celecoxib) inhibitors, 2) nitric oxide (NO) synthase inhibitor L-NNA, 3) ODQ, a soluble guanylyl cyclase (sGC) inhibitor, hemin, a heme oxygenase (HO)-1 inductor or zinc protoporphyrin IX (ZnPPIX), an inhibitor of HO-1 activity. The CO content in gastric mucosa and carboxyhemoglobin (COHb) level in blood was analyzed by gas chromatography. The gastric mucosal mRNA expression for HO-1, COX-1, COX-2, iNOS, IL-4, IL-1ß was analyzed by real-time PCR while HO-1, HO-2 and Nrf2 protein expression was determined by Western Blot. Pretreatment with CORM-2 (0.5-10 mg/kg) dose-dependently attenuated ethanol-induced lesions and raised gastric blood flow (GBF) but large dose of 100 mg/kg was ineffective. CORM-2 (5 mg/kg and 50 mg/kg i.g.) significantly increased gastric mucosal CO content and whole blood COHb level. CORM-2-induced protection was reversed by indomethacin, SC-560 and significantly attenuated by celecoxib, ODQ and L-NNA. Hemin significantly reduced ethanol damage and raised GBF while ZnPPIX which exacerbated ethanol-induced injury inhibited CORM-2- and hemin-induced gastroprotection and the accompanying rise in GBF. CORM-2 significantly increased gastric mucosal HO-1 mRNA expression and decreased mRNA expression for iNOS, IL-1ß, COX-1 and COX-2 but failed to affect HO-1 and Nrf2 protein expression decreased by ethanol. We conclude that CORM-2 released CO exerts gastroprotection against ethanol-induced gastric lesions involving an increase in gastric microcirculation mediated by sGC/cGMP, prostaglandins derived from COX-1, NO-NOS system and its anti-inflammatory properties.

Mechanisms of esophageal protection, gastroprotection and ulcer healing by melatonin. implications for the therapeutic use of melatonin in gastroesophageal reflux disease (GERD) and peptic ulcer disease.

Melatonin is a potent reactive oxygen metabolite scavenger and antioxidant that has been shown to influence many physiological functions of the gastrointestinal (GI) tract including secretion, motility, digestion and absorption of nutrients. The role of melatonin in gastroduodenal defense and ulcer healing has been the subject of recent investigations. Melatonin produced in the GI mucosa plays an important role in protection against noxious agents thus contributing to the maintenance of GI integrity and to esophageal protection, gastroprotection and ulcer healing. This review was designed to summarize the involvement of melatonin, conventionally considered as a major hormone of the pineal gland, in the maintenance of gastric mucosal integrity, gastroprotection, ulcer healing and intestinal disorders. Melatonin was originally shown to attenuate gastric mucosal lesions but controversy exists in the literature as to whether melatonin derived from the pineal gland, considered as the major source of this indole, or rather gastrointestinal melatonin plays predominant role in gastroprotection. Intragastric and central administration of exogenous melatonin and L-tryptophan, this indoleamine precursor, affords protection against gastric hemorrhagic damage caused by the exposure of gastric mucosa to variety of non-topical and topical ulcerogens such as stress, ethanol and ischemia-reperfusion. The speed of ulcer healing in experimental animals and humans is accelerated by melatonin. This indoleamine could be also effective against the esophageal lesions provoked by reflux esophagitis in animal models and prevents the incidence of GERD in humans. The melatonin-induced gastroprotection is accompanied by an increase in gastric blood flow, plasma melatonin concentration, enhancement in mucosal generation of PGE2, luminal NO content and plasma gastrin levels. Melatonin scavenges reactive oxygen metabolites, exerts anti-oxidizing and anti-inflammatory actions and inhibits the formation of metalloproteinases- 3 and -9; both implicated in the pathogenesis of gastrointestinal injury and formation of gastric ulcers. Blockade of MT2 receptors by luzindole, significantly attenuated melatonin- and L-tryptophan-induced protection and increased the speed of ulcer healing and these effects were accompanied by an increase in the GBF and luminal content of NO suggesting that melatonin exhibits gastroprotection and hyperemia via activation of MT2 receptors and release of NO. The accumulated evidence indicates that the melatonin-induced gastroprotection and the enhancement in healing rate of gastric ulcers may involve the gastroprotective factors derived from the activation of PG/COX and NO/NOS systems as well as gastrin which also was shown to exhibit protective and trophic effects in the upper GItract. Interestingly, pinealectomy, which suppressed plasma melatonin levels, markedly exacerbated gastric lesions induced by topical and non-topical ulcerogens and these effects are counteracted by a concurrent supplementation with melatonin. Evidence is provided that exogenous melatonin and that converted from its precursor, L-tryptophan, attenuates acute gastric lesions and accelerates ulcer healing via interaction with MT2 receptors due to an enhancement of gastric microcirculation, probably mediated by NO and PG derived from NOS and COX-1 and COX-2 overexpression and activity. The pineal gland plays an important role in the limitation of gastric mucosal injury and the acceleration of ulcer healing via releasing endogenous melatonin, which attenuates oxidative stress and exerts anti-inflammatory action.

Importance of the pineal gland, endogenous prostaglandins and sensory nerves in the gastroprotective actions of central and peripheral melatonin against stress-induced damage.

Melatonin attenuates acute gastric lesions induced by topical strong irritants because of scavenging of free radicals, but its role in the pathogenesis of stress-induced gastric lesions has been sparingly investigated. In this study we compared the effects of intragastric (i.g.) or intracerebroventricular (i.c.v.) administration of melatonin and its precursor, L-tryptophan, with or without concurrent treatment with luzindole, a selective antagonist of melatonin MT2 receptors, on gastric lesions induced by water immersion and restraint stress (WRS). The involvement of pineal gland, endogenous prostaglandins (PG) and sensory nerves in gastroprotective action of melatonin and L-tryptophan against WRS was studied in intact or pinealectomized rats or those treated with indomethacin or rofecoxib to suppress cyclooxygenase (COX)-1 and COX-2, respectively, and with capsaicin to induce functional ablation of the sensory nerves. In addition, the influence of i.c.v. and i.g. melatonin on gastric secretion was tested in a separate group of rats equipped with gastric fistulas. At 3.5 hr after the end of WRS, the number of gastric lesions was counted, the gastric blood flow (GBF) was determined by H2-gas clearance technique and plasma melatonin and gastrin levels were measured by specific radioimmunoassay (RIA). Biopsy mucosal samples were taken for determination of expression of mRNA for COX-1 and COX-2 by reverse transcriptase-polymerase chain reaction (RT-PCR) and of the mucosal generation of prostaglandin E2 (PGE2) by RIA. Melatonin applied i.g. (1.25-10 mg/kg) or i.c.v. (1.25-10 microg/kg) dose-dependently inhibited gastric acid secretion and significantly attenuated the WRS-induced gastric damage. This protective effect of melatonin was accompanied by a significant rise in the GBF and plasma melatonin and gastrin levels and in mucosal generation of PGE2. Pinealectomy, which suppressed plasma melatonin levels, aggravated the gastric lesions induced by WRS and these effects were counteracted by i.g. or i.c.v. application of melatonin. Luzindole abolished completely the gastroprotective effects of melatonin and L-tryptophan and attenuated significantly the rise in GBF evoked by the indoleamine and its precursor. Indomethacin and rofecoxib, which diminished PGE2 biosynthesis by c. 90 and 75% or capsaicin denervation, attenuated significantly melatonin- and L-tryptophan-induced protection and the rise in the GBF. Both the protection and the hyperemia were restored by addition of exogenous CGRP to capsaicin-denervated animals. COX-1 mRNA was detected by RT-PCR in the intact and melatonin-treated gastric mucosa, while COX-2 mRNA, which was undetectable in the intact gastric mucosa, appeared in WRS-exposed mucosa, especially in the melatonin-treated animals and this was accompanied by increased generation of PGE2 in gastric mucosa. Pinealectomy downregulated COX-2 mRNA and this effect was reversed by supplementation of pinealectomized animals with melatonin. We conclude that, (a) exogenous melatonin and its precursor, L-tryptophan, attenuates WRS-induced gastric lesions via interaction with MT2 receptors, (b) this protective action of melatonin is because of an enhancement of gastric microcirculation, probably mediated by PGE2 derived from COX-2 overexpression and activity, the activation of brain-gut axis involving CGRP released from sensory nerves, and the release of gastrin and (c) the pineal plays an important role in the limitation of WRS-induced gastric lesions via releasing melatonin, which exerts gastroprotective and hyperemic activities against stress ulcerogenesis.

Grapefruit-seed extract attenuates ethanol-and stress-induced gastric lesions via activation of prostaglandin, nitric oxide and sensory nerve pathways.

AIM: Grapefruit-seed extract (GSE) containing flavonoids, possesses antibacterial and antioxidative properties but whether it influences the gastric defense mechanism and gastroprotection against ethanol- and stress-induced gastric lesions remains unknown. METHODS: We compared the effects of GSE on gastric mucosal lesions induced in rats by topical application of 100% ethanol or 3.5 h of water immersion and restraint stress (WRS) with or without (A) inhibition of cyclooxygenase (COX)-1 activity by indomethacin and rofecoxib, the selective COX-2 inhibitor, (B) suppression of NO-synthase with L-NNA (20 mg/kg ip), and (C) inactivation by capsaicin (125 mg/kg sc) of sensory nerves with or without intragastric (ig) pretreatment with GSE applied 30 min prior to ethanol or WRS. One hour after ethanol and 3.5 h after the end of WRS, the number and area of gastric lesions were measured by planimetry, the gastric blood flow (GBF) was assessed by H2-gas clearance technique and plasma gastrin levels and the gastric mucosal generation of PGE2, superoxide dismutase (SOD) activity and malonyldialdehyde (MDA) concentration, as an index of lipid peroxidation were determined. RESULTS: Ethanol and WRS caused gastric lesions accompanied by the significant fall in the GBF and SOD activity and the rise in the mucosal MDA content. Pretreatment with GSE (8-64 mg/kg i g) dose-dependently attenuated gastric lesions induced by 100% ethanol and WRS; the dose reducing these lesions by 50% (ID50) was 25 and 36 mg/kg, respectively, and this protective effect was similar to that obtained with methyl PGE2 analog (5 microg/kg i g). GSE significantly raised the GBF, mucosal generation of PGE2, SOD activity and plasma gastrin levels while attenuating MDA content. Inhibition of PGE2 generation with indomethacin or rofecoxib and suppression of NO synthase by L-NNA or capsaicin denervation reversed the GSE-induced protection and the accompanying hyperemia. Co-treatment of exogenous calcitonine gene-related peptide (CGRP) with GSE restored the protection and accompanying hyperemic effects of GSE in rats with capsaicin denervation. CONCLUSION: GSE exerts a potent gastroprotective activity against ethanol and WRS-induced gastric lesions via an increase in endogenous PG generation, suppression of lipid peroxidation and hyperemia possibly mediated by NO and CGRP released from sensory nerves.

Protective effect of melatonin and its precursor L-tryptophan on acute pancreatitis induced by caerulein overstimulation or ischemia/reperfusion.

Melatonin, a pineal secretory product, synthesized from l-tryptophan, has received increased attention because of its antioxidative and immunomodulatory properties. It has been detected in the gut and shown to protect the gastric mucosa, and liver from acute damage, but the role of melatonin in the protection of the pancreas against acute inflammation is not clear. The aim of this study was to investigate the effects of melatonin and its precursor, l-tryptophan, on caerulein-induced pancreatitis (CIP) and on ischemia/reperfusion (I/R)-provoked pancreatitis in rats. CIP was induced by subcutaneous infusion of caerulein to the rats (25 microg/kg). I/R was induced by clamping of the inferior splenic artery for 30 min followed by 2 hr of reperfusion. Melatonin (10, 25 or 50 mg/hr) or l-tryptophan (50, 100 or 250 mg/kg) was given as a bolus intraperitoneal (i.p.) injection 30 min prior to the onset of pancreatitis. CIP and I/R were confirmed by histologic examination and manifested by typical pancreatic edema, by an increase of plasma levels of amylase (by 500% in CIP and by 40% in I/R) and the pro-inflammatory tumor necrosis factor alpha (TNFalpha) (by 500%). Lipid peroxidation products such as malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), were increased several fold in the pancreas CIP and I/R, whereas pancreatic blood flow (PBF) was significantly reduced in these animals. Pretreatment of rats subjected to CIP or to I/R with melatonin (25 or 50 mg/kg i.p.) or l-tryptophan (100 or 250 mg/kg i.p.) significantly reduced pancreatic edema, plasma levels of amylase and TNFalpha and diminished pancreatic MDA + 4-HNE contents, while enhancing PBF, pancreatic integrity and plasma levels of the anti-inflammatory interleukin 10 (IL-10). This was accompanied by a marked and dose-dependent rise of plasma melatonin immunoreactivity. Gene expression of N-acetyl transferase, an enzyme involved in melatonin biosynthesis, was detected in the pancreas of normal rats and was significantly enhanced in the rats with CIP. We conclude that exogenous melatonin, and that produced from l-tryptophan, attenuates pancreatic damage induced by CIP or by I/R and this effect may be attributable to the reduction in lipid peroxidation and TNFalpha release combined with an increase of plasma anti-inflammatory IL-10 in rats with acute pancreatitis.