leptin and Stomach-Ulcer

Melatonin (MT) and its precursor L-tryptophan (TRP) are implicated in the protection of gastric mucosa against aspirin-induced lesions and in the acceleration of healing of idiopathic gastro-duodenal ulcers, but no information is available whether these agents are also effective in healing of gastroduodenal ulcers accompanied by Helicobacter pylori (H. pylori) infection. In this study three groups A, B and C, each including 7 H. pylori-positive patients with gastric ulcers and 7 H. pylori-positive patients with duodenal ulcers, aging 28-50 years, were randomly assigned for the treatment with omeprazole 20 mg twice daily combined with placebo (group A), MT administered in a dose of 5 mg twice daily (group B) or TRP applied in a dose of 250 mg twice daily (group C). All patients underwent routine endoscopy at day 0 during which the gastric mucosa was evaluated and gastric biopsies were taken for the presence of H. pylori and histopathological evaluation. The rate of ulcer healing was determined by gastroduodenoscopy at day 0, 7, 14 and 21 after the initiation of the therapy. Plasma MT, gastrin, ghrelin and leptin were measured by specific RIA. At day 21, all ulcers were healed in patients of groups B and C but only 3 out of 7 in group A of gastric ulcers and 3 out of 7 in duodenal ulcers. Initial plasma MT showed similar low levels in all three groups but it increased several folds above initial values in ulcer patients at day 7, 14 and 21. Plasma gastrin and leptin levels showed a significant rise over initial values in patients treated with omeprazole and placebo, MT or TRP while plasma ghrelin levels were not significantly affected by these treatments. We conclude that MT or TRP added to omeprazole treatment, significantly accelerates healing rate of H. pylori infected chronic gastroduodenal ulcers over that obtained with omeprazole alone and this likely depends upon the significant rise in plasma MT and possibly also in leptin levels, both hormones involved in the mechanism of gastroprotection and ulcer healing.

Topics: Adult; Anti-Infective Agents; Anti-Ulcer Agents; Drug Therapy, Combination; Duodenal Ulcer; Gastric Mucosa; Gastrins; Gastroscopy; Ghrelin; Helicobacter Infections; Helicobacter pylori; Humans; Intestinal Mucosa; Leptin; Melatonin; Middle Aged; Omeprazole; Stomach Ulcer; Treatment Outcome; Tryptophan; Wound Healing

Horses in training tend to become inappetant; however, the mechanism responsible for this training-induced inappetance is not known.. Training and/or ulcers alter the feed intake (FI) and hormonal and/or biochemical (active ghrelin, leptin, glucose, insulin and cortisol) responses to acute high intensity exercise.. Eight Standardbred mares underwent 3 interval exercise tests (IET) and 3 parallel control tests (CON) before (IET1) and after 8 weeks of training (IET2) and after treatment for gastric ulcers (IET3). Plasma samples were taken before (0 min), during (last 10 sec of velocities eliciting 40, 100 and 20% VO2max), and after (30 min, 60 min, 24 h) exercise (EX) or CON tests for RIA and colorimetric measurement of the concentrations of the above parameters. Samples were also collected before and after feeding. Horses were trained at a work intensity of 70% HRmax for 30 min/day, 5 days per week with FI measured daily.. There were no changes (P>0.05) in any variable during the parallel control trials. However, there was a mismatch between FI and digestible energy (DE) requirements (P<0.05) with EX horses not meeting their DE requirements during the post training IETs. During all IETs, ghrelin, glucose and cortisol increased (P<0.05) during EX. Leptin only increased (P<0.05) during EX in the post training IETs. Insulin remained low during EX, but increased (P<0.05) post EX.. High intensity exercise appeared to be associated with decreases in FI and alterations of leptin and ghrelin.. More research is needed to determine if there is a relationship between alterations of these hormones and changes in FI in horses that lose weight while in training.

Topics: Animals; Cross-Over Studies; Energy Intake; Exercise Test; Female; Ghrelin; Horse Diseases; Horses; Hydrocortisone; Leptin; Peptide Hormones; Physical Conditioning, Animal; Stomach Ulcer; Time Factors

Topics: Abdomen; Humans; Insulin Resistance; Leptin; Obesity; Obesity, Morbid; Pediatric Obesity; Stomach; Stomach Neoplasms; Stomach Ulcer; Upper Gastrointestinal Tract

To select the optimal combination of five active component of Banxia Xiexin Decoction on gastric ulcer rat, and observe its effect on Leptin and ET-1.. Eighty-seven SD rats were randomly divided into normal group, sham-operated group and acetic acid-induced gastric ulcer group, omeprazole group as a positive control, five active components (glycyrrhetic acid, beta-sitosterol, berberine, baicalin and ginsenoside) of Banxia Xiexin Decoction were divided into groups by L16 orthogonal design. The ulcer area, and the content of Leptin and ET-1, and the mRNA expression level of both were detected.. Among the sixteen orthogonal design groups, the ulcer area of these groups using both beta-sitosterol and berberine was the smallest (P < 0.05), the content of Leptin of these groups using both glycyrrhetic acid and ginsenoside was the highest in blood serum (P < 0.05), the group using glycyrrhetic acid had the minimum concentration of ET-1 in blood plasma. Compared with model group, berberine could raise the mRNA expression level of Leptin (P < 0.01), and beta-sitosterol could lower the mRNA expression level of ET-1 (P < 0.01).. The pathogenesis of gastric ulcer may be related with the down-regulation of concentration and mRNA expression level of Leptin, and upregulation of concentration and mRNA expression level of ET-1, the active components in Banxia Xiexin Decoction may upregulated Leptin and inhibit ET-1 to accelerate the healing of gastric ulcer.

Topics: Acetates; Animals; Berberine; Disease Models, Animal; Drugs, Chinese Herbal; Endothelin-1; Flavonoids; Gastric Mucosa; Leptin; Male; Plants, Medicinal; Random Allocation; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sitosterols; Stomach Ulcer

Leptin, a key hormone in regulation of food intake and energy expenditure, exerts pleiotropic cytokine-like biological effects. Its role in gastric ulcer healing is unclear. In this study, we investigated the role of leptin in gastric ulcer healing.. Experimental gastric ulcer was induced by focal serosal application of acetic acid in leptin-deficient ob/ob mice and wild-type mice. Healing of gastric ulcer and angiogenesis in the ulcer tissue was evaluated.. Gastric ulcer healing was delayed in ob/ob mice compared with that in wild-type mice. The impairment of ulcer healing observed in ob/ob mice was characterized by reduced expression of vascular endothelial growth factor (VEGF) and impairment of angiogenesis. Systemic administration of leptin to ob/ob mice reversed the impairment of gastric ulcer healing; this reversal was accompanied by an increase in VEGF expression and angiogenesis. Although mRNA for leptin was not expressed in normal gastric mucosa and not induced in ulcerous tissue, leptin receptor expression was markedly upregulated in gastric epithelial cells at ulcer margins, and was colocalized with VEGF.. These findings suggest that leptin promotes gastric ulcer healing by induction of angiogenesis in the granular tissue of ulcers via upregulation of VEGF expression.

Topics: Animals; Blotting, Western; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Neovascularization, Physiologic; Reverse Transcriptase Polymerase Chain Reaction; Statistics, Nonparametric; Stomach Ulcer; Up-Regulation; Vascular Endothelial Growth Factor A; Wound Healing

There are few data concerning protective effects of leptin on gastric epithelium treated with necrotic factors: ethanol, bile salts and hiperosmotic solutions. Further investigations are needed to establish the role of hormone leptin in gastroprotection and in the process of chronic gastric ulcers healing in animals. Exogenous leptin administration plays protective effects against 75% ethanol damage in gastric epithelium. Nitric oxide is involved in gastroprotective effects of leptin and CCK.

Topics: Acute Disease; Animals; Anti-Ulcer Agents; Gastric Mucosa; Leptin; Random Allocation; Rats; Rats, Wistar; Regional Blood Flow; Stomach Ulcer

To investigate the effects of leptin (1-20 microg/kg) on acidified ethanol (AE)- and indomethacin (Indo)-induced gastric lesions in rats and compare it with ranitidine, lanso-prazole, and omeprazole and to determine its mechanisms of actions.. Gastric ulcers, which were approximately 1 mm in width, formed in the glandular portion of the gastric mucosa produced by oral administration of either AE or Indo were taken as ulcer index. The inhibitory effect of subcutaneous administration of leptin, two proton pump inhibitors (PPIs) lansoprazole and omeprazole, or H(2)-receptor antagonist ranitidine 30 min before AE or Indo was evaluated. A radioimmunoassay was used to determine the PGE(2) concentration in the homogenate of the glandular portion of the stomach. We performed histological study of the glandular stomach for the evaluation of total, acidic, and sulfated mucus content.. Subcutaneous administration of leptin, two PPIs lansoprazole and omeprazole or H(2)-receptor antagonist ranitidine 30 min before AE or Indo produced a dose-dependent and reproducible inhibition of gastric ulcers (GUs). This inhibition was found to be more potent than other antagonists used. In N(G)-nitro L-arginine methyl ester (L-NAME)-pretreated animals, the ulcer prevention ability of leptin in AE-induced ulcer was significantly reduced, compared to rats without L-NAME pretreatment. However, the ulcer prevention ability of leptin was not altered by L-NAME treatment in Indo-induced ulcers. Leptin produced a dose-dependent increase in PGE(2) level in the gastric glandular tissues. Leptin also increased mucus secretion.. The results of the present study show that leptin inhibits GU formation by AE or Indo in a dose-dependent and reproducible manner in rats. The results also suggest that leptin prevents ulcer formation by increasing the activities of the cyclo-oxygenase and/or nitric oxide pathways and by increasing mucus secretion.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Animals; Anti-Ulcer Agents; Lansoprazole; Leptin; Nitric Oxide; Omeprazole; Prostaglandin-Endoperoxide Synthases; Ranitidine; Rats; Rats, Wistar; Stomach Ulcer

The previous studies demonstrated the pivotal role of capsaicin-sensitive peptidergic sensory neurons and vagal nerves in the maintenance of gastric mucosal integrity. The aim of the present study was: 1). to examine the effect of the functional ablation of sensory neurons with neurotoxic dose of capsaicin and surgical vagotomy on the course of healing of gastric ulcer in rat, and 2). to compare the ulcer healing action of leptin in rats with or without capsaicin-induced inactivation of sensory neurons. Three series of experiments (A, B and C) were performed in Wistar rats with gastric ulcers induced by acetic acid method. In series A, the course of ulcer healing was compared in rats with intact and capsaicin-inactivated sensory neurons. In the series B, the effect of vagotomy on the ulcer healing and accompanying changes in GBF were determined at day 8 and 16 after ulcer induction. The rats of series C, consisting of animals with intact nerves or those with capsaicin-denervation, received the 7-day treatment with exogenous leptin (10 microg/kg i.p. twice daily) to check whether blockade of sensory nerves could influence the acceleration of ulcer healing by this peptide. Capsaicin-induced ablation of sensory neurons significantly delayed ulcer healing and this was accompanied by the significant fall in the GBF and the significant rise in the gastric mucosal gene expression of IL-1beta and TNF-alpha. Vagotomy significantly delayed ulcer healing and led to decrease in GBF at ulcer margin. Treatment with exogenous leptin significantly accelerated ulcer healing, increased the GBF at ulcer margin and upregulated mRNA for iNOS and these effects were attenuated in rats with capsaicin-deactivation of sensory neurons. We conclude that: 1). vagal and sensory neurons contribute to the gastric ulcer healing process possibly due to the increase of GBF, the limitation of inflammatory response, and overexpression of TGFalpha and iNOS resulting in NO release, and 2). the acceleration of ulcer healing by leptin was attenuated in animals with capsaicin-denervation suggesting an involvement of neuropeptides released from sensory afferent nerves in the ulcer healing effect of this hormone.

Topics: Acetic Acid; Animals; Brain; Capsaicin; Cell Line, Tumor; Cyclooxygenase 1; Cyclooxygenase 2; Gastric Mucosa; Gastrointestinal Tract; Gene Expression Regulation, Enzymologic; Injections, Intraperitoneal; Injections, Subcutaneous; Interleukin-1; Isoenzymes; Leptin; Membrane Proteins; Neurons, Afferent; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Platelet Endothelial Cell Adhesion Molecule-1; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Wistar; RNA, Messenger; Stomach Ulcer; Tumor Necrosis Factor-alpha; Up-Regulation; Vagotomy; Vagus Nerve; Wound Healing

The peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-dependent nuclear receptor that has been implicated in the control of metabolism and numerous cellular processes, including cell cycle control, carcinogenesis, and inflammation. The present study was designed to investigate the effect of the specific PPARgamma ligand, pioglitazone, on the mucosal lesions induced by ischaemia and reperfusion (I/R) in rats.. I/R lesions were induced in Wistar rats by applying a small clamp to the coeliac artery for 30 min (ischaemic phase), followed by the removal of the clamp for 3 h (reperfusion phase). Vehicle (saline) or increasing doses of pioglitazone (2.5, 10, and 30 mg/kg i.g.) were given 30 min before exposure to I/R. The animals were killed immediately after the end of the reperfusion phase (time 0) and at 12 and 24h after I/R. The area of gastric lesions was measured by planimetry, and the gastric blood flow was determined by the H2 gas clearance method. The gastric mucosal gene expressions of PPARgamma, interleukin-1beta (IL-1beta), tumour necrosis factor alpha (TNF-alpha), leptin, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) were examined by RT-PCR. In addition, protein expression of COX-2 and leptin was assessed by Western blot.. The pretreatment with pioglitazone reduced in a dose-dependent manner the mean lesion area induced by I/R, and this effect was accompanied by a significant increase in the gastric blood flow. The decrease in gastric ulcerations by pioglitazone was also observed 12 and 24 h after the I/R. The PPARgamma mRNA was weakly expressed in the intact gastric mucosa but significantly up-regulated after exposure to I/R at each time interval studied. The expression of IL-1beta was not changed significantly after pioglitazone applied i.g. at doses 2.5 and 10 mg/kg, but it was down-regulated at the dose 30mg/kg. TNFalpha mRNA was strongly increased after the exposure to I/R, but it was down-regulated after pioglitazone pretreatment. In contrast, both leptin and COX-2 mRNA and protein expression were increased in the gastric mucosa after exposure to I/R. The pretreatment with pioglitazone caused a significant up-regulation of mRNA and protein expression of leptin, reaching its peak at the dose 30 mg/kg i.g. In contrast, COX-2 expression did not change significantly after the 2.5 and 10 mg/kg of pioglitazone, but it significantly decreased after pioglitazone at dose 30 mg/kg given to rats before exposure to I/R.. Pioglitazone reduces the acute erosions and deeper gastric lesions induced by I/R. The beneficial effect of this PPARgamma ligand on I/R-induced gastric damage may be due to its anti-inflammatory properties, especially to the reduction in TNF-alpha expression and to up-regulation of leptin mRNA in the gastric mucosa. The inhibition of COX-2 expression by pioglitazone may reflect the anti-inflammatory properties of this compound.

Topics: Amino Acid Sequence; Animals; Cyclooxygenase 1; Cyclooxygenase 2; Gastric Mucosa; Hypoglycemic Agents; Interleukin-1; Isoenzymes; Leptin; Male; Membrane Proteins; Models, Animal; Pioglitazone; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Reperfusion Injury; Splanchnic Circulation; Stomach Ulcer; Thiazoles; Thiazolidinediones; Transcription Factors; Tumor Necrosis Factor-alpha

Leptin was shown to exhibit similar to cholecystokinin (CCK) cytoprotective activity against acute gastric lesions, but its role in ulcer healing has not been examined. The aims of this study were: (1) to compare the effects of exogenous leptin to those of CCK on the course of healing of chronic gastric ulcers; (2) to study the gene and protein expression of leptin at the ulcer margin during ulcer healing; and (3) to assess the effects of leptin administration on the mucosal gene expression of main growth factor such as transforming growth factor alpha (TGFalpha). Gastric ulcers were produced in rats by the acetic acid method. Rats with ulcers were divided in following treatment groups: (1) vehicle; (2) leptin (10 microg/kg i.p.); (3) CCK (10 microg/kg s.c.); and (4) leptin or CCK with or without tyrphostin A46 (200 microg/kg i.p.), an inhibitor of epidermal growth factor (EGF)-receptor tyrosine kinase or NG-nitro-L-arginine (20 mg/kg i.g.), a blocker of nitric oxide synthase. Animals were euthanized 9 days after ulcer induction. The area of gastric ulcers and the gastric blood flow at the ulcer area were determined. In addition, mucosal biopsy samples were taken from the ulcer area for histological evaluation as well as for the determination of mRNA and protein expression for leptin and constitutive nitric oxide synthase (cNOS) and inducibile nitric oxide synthase (iNOS) by reverse-transcriptase polymerase chain reaction (RT-PCR) and Western blot, respectively. In addition, the gene expression for TGFalpha was analyzed by RT-PCR. Both leptin and CCK reduced significantly the ulcer area as compared to vehicle-treated group by approximately 50%. The treatment with tyrphostin or N(G)-nitro-L-arginine reversed in part the acceleration of ulcer healing by leptin and CCK. The expression of leptin mRNA and protein was significantly increased at the ulcer edge. The leptin-induced acceleration of ulcer healing was associated with increased expression of transcripts for TGFalpha as well as increased mRNA and protein expression for cNOS and iNOS at the ulcer margin. We conclude that leptin accelerates ulcer healing by mechanisms involving the up-regulation of TGFalpha and increased production of nitric oxide due to up-regulation of cNOS and iNOS in the ulcer area.

Topics: Animals; Enzyme Inhibitors; Gastric Mucosa; Gastrointestinal Agents; Leptin; Male; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type III; Nitroarginine; Rats; Rats, Wistar; RNA, Messenger; Sincalide; Stomach Ulcer; Transforming Growth Factor alpha; Tyrphostins

Lipopolysaccharides (LPS) are major components of the outer membrane of gram-negative bacteria playing a central role as potent endotoxins in the pathogenesis of endotoxic shock. Although large amounts of endotoxin may produce hemorrhagic lesions in the stomach, the possible gastroprotective effect of central or peripheral LPS against the acute gastric lesions has not been extensively studied. The aim of the present study was to compare the effect of intracerebroventricular (i.c.v.) and parenteral (i.p.) injection of LPS against gastric lesions induced by 100% ethanol. Male Wistar rats were treated either with a) vehicle (control); b) E-coli-LPS in various concentrations (1-10 microg/kg i.c.v or 0.1-40 mg/kg i.p.) followed 30 min later by 100% ethanol. The effects of pretreatment with nonselective inhibitor of nitric oxide synthase (L-NAME, 20 mg/kg i.g.) or selective inhibitor of inducible nitric oxide synthase, L-NIL (30 mg/kg i.g.) on the gastroprotection induced by LPS was investigated. One hour after ethanol application, the gastric blood flow (GBF) and the area of gastric lesions were determined. In addition, the mucosal expression of iNOS, cNOS and leptin was assessed using RT-PCR. LPS applied i.c.v. or i.p. dose dependently reduced gastric lesions induced by ethanol and this effect was similar to that observed after the administration of NO donor (SNAP). LPS-induced protection was significantly abolished by L-NAME and significantly attenuated by the selective inhibitor of iNOS (L-NIL). The expression of cNOS was detected in vehicle treated gastric mucosa and did not change after LPS administration. iNOS was not detectable in intact mucosa but its expression dose-dependently increased after the LPS administration. The i.c.v. administration of LPS did not upregulate further the iNOS expression, and dose-dependently inhibited the leptin mRNA expression in gastric mucosa. We conclude that LPS applied centrally or peripherally protects gastric mucosa against ethanol-induced damage through an increase in gastric microcirculation mediated by NO due to overexpression of iNOS. Transcriptional downregulation of leptin in gastric mucosa is probably due to the increased leptin release induced by the intracerebroventricular application lipopolysaccharide.

Topics: Animals; Brain; Cytoprotection; Ethanol; Gastric Mucosa; Injections, Intraventricular; Leptin; Lipopolysaccharides; NG-Nitroarginine Methyl Ester; Nitric Oxide; Penicillamine; Rats; Rats, Wistar; Regional Blood Flow; RNA, Messenger; Stomach Ulcer

Leptin, a product of ob-gene plays an important role in the regulation of food intake. Recently, leptin expression has been detected in gastric epithelium, but the physiologic role of gastric leptin remains unknown. The purpose of this study was: 1) to determine the effect of gastric injury by ethanol and aspirin on the expression of leptin in gastric mucosa and 2) to investigate whether exogenous leptin affects the integrity of gastric mucosa exposed to noxious agents such as ethanol or aspirin. In Wistar rats the acute gastric lesions were induced by intragastric application of 1.5 ml of 75% ethanol or acidified aspirin (100 mg/kg in 0.2 N HCl). Rats were divided into two groups and pretreated either with leptin (1-10 microg/kg i.p.) or vehicle (saline). Rats were anesthetized 1 h after i.g. induction of acute gastric lesions and the gastric blood flow (GBF) was measured by H2 gas clearance method. Then the rats were sacrificed, the stomach was excised and the mean lesions area was assessed by planimetry. In addition, mRNA and protein expression for leptin was analyzed in the gastric mucosa by reverse transcription polymerase chain reaction (RT-PCR) and Western blot, respectively. Both ethanol and acidified aspirin induced acute gastric lesions and led to significant reduction in GBF. In the intact gastric mucosa, the mRNA and protein expression for leptin was small but detectable. The exposure of gastric mucosa to noxious agents such as ethanol and aspirin was associated with markedly increased expression for gastric leptin at mRNA and protein level. Application of 75% ethanol or acidified aspirin caused wide-spread mucosal lesions. The pretreatment with exogenous leptin reduced dose-dependently these ethanol or aspirin-induced gastric lesions. The protective effects of exogenous leptin were accompanied by a significant attenuation of the fall of GBF. We conclude that: 1) Exogenous leptin exerts potent gastroprotective and hyperemic actions on gastric mucosa, and 2) Acute injury of gastric mucosa is associated with increased expression of leptin suggesting a possible role of this peptide in mediating of repair process in injured gastric mucosa.

Topics: Animals; Aspirin; Blotting, Western; Dose-Response Relationship, Drug; Ethanol; Gastric Mucosa; Leptin; Male; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stomach Ulcer