Plasma insulin, leptin, adiponectin, resistin, ghrelin, and melatonin in nonalcoholic steatohepatitis patients treated with melatonin.

Insulin resistance, oxidative stress, and an abnormal production of adipokines and cytokines are implicated in the pathogenesis of nonalcoholic steatohepatitis (NASH). Recently, we reported a significant improvement in plasma liver enzymes among patients with NASH treated with melatonin. In this study, we investigated the effect of melatonin, administered at a dose of 10 mg/day for 28 days to 16 patients with histologically proven NASH on insulin resistance (HOMA-IR), on the plasma levels of adiponectin, leptin, ghrelin, and resistin. Additionally, plasma levels of aminotransferases and gamma glutamyltranspeptidase as well as plasma concentrations of melatonin were evaluated. Median baseline values of HOMA-IR, leptin (ng/mL), and resistin (pg/mL) in patients with NASH were significantly higher in comparison with controls: 4.90 versus 1.60, 10.70 versus 4.30, and 152 versus 91, respectively. Median adiponectin level (µg/mL) was decreased in patients compared to controls: 6.40 versus 16.25; no significant difference in ghrelin levels between patients and controls was found. After melatonin treatment, the median value of HOMA-IR was significantly reduced by 60% as compared to baseline values, whereas adiponectin, leptin, and ghrelin plasma levels rose significantly by 119%, 33%, and 20%, respectively; the difference between pre-/posttreatment in plasma resistin levels was not significant. These findings make melatonin a suitable candidate for testing in patients with NASH in the large controlled clinical trials.

Melatonin or L-tryptophan accelerates healing of gastroduodenal ulcers in patients treated with omeprazole.

Melatonin and L-tryptophan (Trp) are highly gastroprotective in humans, but no study has assessed their impact on healing of chronic gastroduodenal ulcers in humans. Three groups (A, B and C) of 14 idiopathic patients in each treatment group with gastroduodenal chronic ulcers were treated with omeprazole (20 mg twice daily) combined either with placebo (group A), melatonin (group B) or with Trp (group C). The rate of ulcer healing was determined by gastroduodenoscopy at day 0, 7, 14 and 21 after initiation of therapy. Plasma melatonin, gastrin, ghrelin and leptin were measured by RIA. On day 7, omeprazole by itself (group A) had not healed any ulcers, but four ulcers were healed with omeprazole plus melatonin and two with omeprazole plus tryptophan. At day 21, all ulcers were healed in patients treated with melatonin or Trp, but only 10-12 ulcers were healed in placebo-treated patients. After treatment with omeprazole plus melatonin (group B) or Trp (group C), plasma melatonin levels rose several-fold above initial values. Plasma gastrin level also rose significantly during treatment with omeprazole plus melatonin or Trp, but it was also significantly increased in patients treated with omeprazole plus placebo. Plasma ghrelin levels did not change significantly after treatment with melatonin or Trp, while plasma leptin increased significantly in patients treated with melatonin or Trp but not with placebo. We conclude that melatonin or Trp, when added to omeprazole treatment, accelerates ulcer healing and this likely depends mainly upon the significant increments in plasma melatonin.

Day/night differences in stress-induced gastric lesions in rats with an intact pineal gland or after pinealectomy.

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 E(2) (PGE(2)), 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.

Implications of reactive oxygen species and cytokines in gastroprotection against stress-induced gastric damage by nitric oxide releasing aspirin.

BACKGROUND AND AIMS: Nitric oxide-releasing aspirin (NO-ASA) has been shown to inhibit cyclo-oxygenase and prostaglandin generation without causing mucosal damage, but the role of reactive oxygen species (ROS) and cytokines in the action of ASA and NO-ASA against acute gastric damage has been little studied. METHODS AND MATERIALS: We compared the effect of NO-ASA and ASA on gastric lesions provoked by water-immersion and restraint stress (WRS), ischemia-reperfusion, and 100% ethanol. We determined the number and area of gastric lesions, gastric blood flow (GBF), plasma concentration of proinflammatory cytokines IL-1beta and TNFalpha, expression of superoxide dismutase (SOD) and glutathione peroxidase (GPx), ROS generation, and the malondialdehyde (MDA) concentration as an index of lipid peroxidation. RESULTS: Pretreatment with NO-ASA attenuated dose-dependently gastric erosions provoked by WRS, ischemia-reperfusion, and ethanol. In contrast, ASA aggravated significantly WRS-induced lesions, and this was accompanied by a fall in the GBF, suppression of prostaglandin E(2) generation, and significant rise in ROS chemiluminescence and in plasma TNFalpha and IL-1beta levels. ASA also enhanced significantly the mucosal MDA content and downregulated SOD and GPx mRNA, and these effects were markedly reduced by NO-ASA. CONCLUSION: Coupling of NO to ASA attenuates stress, ischemia-reperfusion, and ethanol-induced damage due to mucosal hyperemia mediated by NO, which compensates for prostaglandin deficiency induced by ASA. ASA aggravates WRS damage via enhancement of ROS and cytokine generation and suppression of SOD and GPx, and these effects are counteracted by NO released from NO-ASA.

Case presentation of gastrinoma combined with gastric carcinoid with the longest survival record -- Zollinger-Ellison syndrome: pathophysiology, diagnosis and therapy.

BACKGROUND: Zollinger-Ellison syndrome is a very rare disease caused by tumor with gastrin producing cells accompanied by hypergastrinemia leading to gastric hypersecretion and peptic ulcers and their complications. CASE STUDY: Female case of gastrinoma (Zollinger-Ellison syndrome; Z-E) with a record of 38 yrs of survival. Acute gastro-duodenal ulcers started at 28 yr of age and Z-E was diagnosed by using gastrin assays. Basal and maximal acid outputs and ratio of basal/maximal outputs were away over normal limits. Because of ulcer recurrence and complications, patient was subjected to several gastric surgeries but refused total gastrectomy. She was also treated with many H2-receptor (R) antagonists and proton-pump inhibitors (PPI), each new drug being initially highly effective but then showing declining efficacy except when PPI, lansoprazole was used. The gastrin level rose in the course of disease from initial high value of 2000 pg/mL to the extreme 4500 ng/mL at present. During the last 2 yrs, metastasis mainly to liver developed and they were successfully treated by synthetic octapeptide derivative of somatostatin and, as a result, metastatis partly reduced and plasma gastrin drasticly decreased. Biopsy taken from liver metastasis showed the presence of typical gastrinoma cells with gastrin and chromogranin, while that from oxyntic mucosa revealed the ECL-cell hyperplasia with carcinoid tumors and unexpected gastric atrophy. CONCLUSIONS: This phenomenal case described in this article might be the new proven evidence needed by gastroenterologists to overturn the traditional treatment using total gastrectomy as a treatment of choice to the partial gastrectomy combined with proton pump inhibitors.