Bielański W

Exogenous and endogenous ghrelin in gastroprotection against stress-induced gastric damage

Ghrelin, identified in the gastric mucosa has been involved in control of food intake and growth hormone (GH) release but little is known about its influence on gastric secretion and mucosal integrity. The effects of ghrelin on gastric secretion, plasma gastrin and gastric lesions induced in rats by 75% ethanol or 3.5 h of water immersion and restraint stress (WRS) were determined. Exogenous ghrelin (5, 10, 20, 40 and 80 microg/kg i.p.) increased gastric acid secretion and attenuated gastric lesions induced by ethanol and WRS and this was accompanied by the significant rise in plasma ghrelin level, gastric mucosal blood flow (GBF) and luminal NO concentrations. Ghrelin-induced protection was abolished by vagotomy and attenuated by suppression of COX, deactivation of afferent nerves with neurotoxic dose of capsaicin or CGRP(8-37) and by inhibition of NOS with L-NNA but not influenced by medullectomy and administration of 6-hydroxydopamine. We conclude that ghrelin exerts a potent protective action on the stomach of rats exposed to ethanol and WRS, and these effects depend upon vagal activity, sensory nerves and hyperemia mediated by NOS-NO and COX-PG systems.

Leptin Protects the Pancreas from Damage Induced by Caerulein Overstimulation by Modulating Cytokine Production

Background: Recent identification of specific leptin receptors in the pancreas suggests that this peptide may also play some role in this gland. Aim: To examine the effect of intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) administration of leptin in rats on caerulein-induced pancreatitis (CIP), pancreatic gene expression of leptin and inflammatory cytokine production. Methods: caerulein (25 µg/kg) was infused subcutaneously into conscious rats over 5 h to produce CIP. Leptin (1, 5, or 10 µg/kg) was injected i.p. or i.c.v. 30 min prior to the CIP induction. The plasma level of TNFα and IL-4 was determined by ELISA, while plasma leptin was measured by RIA and leptin gene expression in pancreas by RT-PCR. Results: CIP was characterized by the usual pancreatic edema, reduction in pancreatic blood flow (PBF) and an increase in serum levels of amylase, TNFα and IL-4. Pretreatment with i.p. or i.c.v. leptin of the CIP rats partially reversed the harmful effects of CIP on the pancreas, and reduced pancreatic inflammation and the fall in PBF. This was accompanied by a dose-dependent reduction in serum levels of amylase and TNFα, while serum IL-4 in the CIP rats pretreated with leptin rose dose-dependently as compared to control rats with CIP alone. Pretreatment with leptin resulted in the dose-dependent rise in plasma leptin level over that observed in vehicle-treated controls. Leptin mRNA expression in the pancreas was dose-dependently increased after infusion of caerulein. Leptin content in isolated pancreatic acini was also increased dose-dependently by caerulein added to the incubation medium bathing these acini. Conclusions: (1) Exogenous leptin protects the pancreas against damage by CIP; (2) endogenous leptin seems to limit the extend of pancreatic damage, and (3) these protective effects of leptin could be attributed to the reduction in TNFα and to the increase in IL-4 production.

Helicobacter pylori–gastrin link in MALT lymphoma

There is accumulating evidence for the role of Helicobacter pylori in the development of gastric cancer as well as of lymphomas that arise in mucosa‐associated lymphoid tissue (MALT). We reported recently that gastric cancer patients show high prevalence of cagA‐positive H. pylori and express gastrin and gastrin receptors enabling them to stimulate tumour growth in autocrine fashion.

Gastroprotective action of orexin-A against stress-induced gastric damage is mediated by endogenous prostaglandins, sensory afferent neuropeptides and nitric oxide.

Orexin-A, identified in the neurons and endocrine cells in the gut, has been implicated in control of food intake and sleep behavior but little is known about its influence on gastric secretion and mucosal integrity. The effects of orexin-A on gastric secretion and gastric lesions induced in rats by 3.5 h of water immersion and restraint stress (WRS) or 75% ethanol were determined. Orexin-A (5-80 microg/kg i.p.) increased gastric acid secretion and attenuated gastric lesions induced by WRS and this was accompanied by the significant rise in plasma orexin-A, CGRP and gastrin levels, the gastric mucosal blood flow (GBF), luminal NO concentration and an increase in mRNA for CGRP and overexpression of COX-2 protein and the generation of PGE(2) in the gastric mucosa. Orexin-A-induced protection was abolished by selective OX-1 receptor antagonist, vagotomy and attenuated by suppression of COX-1 and COX-2, deactivation of afferent nerves with neurotoxic dose of capsaicin, pretreatment with CCK(2)/gastrin antagonist, CGRP(8-37) or capsazepine and by inhibition of NOS with L-NNA. This study shows for the first time that orexin-A exerts a potent protective action on the stomach of rats exposed to non-topical ulcerogens such as WRS or topical noxious agents such as ethanol and these effects depend upon hyperemia mediated by COX-PG and NOS-NO systems, activation of vagal nerves and sensory neuropeptides such as CGRP released from sensory nerves probably triggered by an increase in gastric acid secretion induced by this peptide.

Influence of COX-2 Inhibition by Rofecoxib on Serum and Tumor Progastrin and Gastrin Levels and Expression of PPARγ and Apoptosis-Related Proteins in Gastric Cancer Patients

Cyclooxygenase-2 (COX-2) expression and certain growth hormones, such as gastrin, have been related to gastric carcinogenesis, but little is known about the factors that enhance this COX-2 expression and whether specific blockade of this enzyme has any influence on tumor growth and progression. Our objective was to determine the influence of a specific COX-2 inhibitor, rofecoxib (Vioxx), on serum and tumor levels of gastrin and its precursor, progastrin, as well as on tumor gene expression of COX-2, peroxisome proliferator-activated receptor gamma (PPARγ), and apoptosis-related proteins (Bax and Bcl-2, caspase-3, and survivin). Twenty-four gastric cancer (GC) patients entered this study and were examined twice, once before and then following a 14-day treatment with Vioxx at a dose of 25 mg twice daily. For comparison, 48 age- and sex-matched healthy controls and 24 similarly matched Helicobacter pylori (Hp)-positive subjects were enrolled and treated with Vioxx as GC patients. Serum levels of anti-Hp and anti-CagA antibodies as well as IL-8 and TNF-α were measured by enzyme-linked immunosorbent assay (ELISA), while serum and tumor contents of progastrin and amidated gastrin were determined by specific RIA. Tumor gene and protein expressions of COX-2, PPARγ, Bax and Bcl-2, caspase-3, and survivin were determined by RT-PCR and western blot. The overall Hp and CagA seropositivity in 24 GC patients was significantly higher (82% and 47%) than in 48 controls (61% and 22%) but not in 24 Hp-infected subjects (100% and 38%). Serum IL-8 and TNF-α values were significantly higher in GC patients than in controls without GC or Hp-infected controls. Median serum progastrin and gastrin levels were found to be significantly higher in GC than in controls without GC and in Hp-positive subjects. Treatment of GC patients with Vioxx resulted in a significant decrease in plasma and tumor contents of both progastrin and gastrin, and this was accompanied by the increment in tumor expression of COX-2, PPARγ, Bax, and caspase-3 with a concomitant reduction in Bcl-2 and survivin expression. We conclude that: (1) GC patients show significantly higher Hp and CagA seropositivity than age- and sex-matched controls, but not Hp-positive subjects, indicating that infection with cytotoxic Hp is linked to GC. (2) Serum progastrin and gastrin levels are signficantly higher in GC patients than in matched controls, confirming that both gastrins may be implicated in gastric carcinogenesis. (3) GC patients exhibit significantly higher levels of IL-8 and TNF-α than non-GC controls and Hp-positive subjects, probably reflecting more widespread gastritis in GC. (4) COX-2, PPARγ, Bcl-2, and survivin were overexpressed in gastric tumor, but the inhibition of COX-2 activity by Vioxx resulted in a significant reduction in serum and tumor levels of progastrin and gastrin and serum IL-8 and TNF-α levels, suggesting that gastrin and proinflammatory cytokines could mediate the up-regulation of COX-2 in gastric cancerogenesis. (5) Vioxx also enhanced expression of COX-2, PPARγ, Bax, and caspase-3, while inhibiting the expression of Bcl-2 and survivin, suggesting that COX-2 blockade might be useful in chemoprevention against cancer possibly due to enhancement of the PPAR-γ and proapoptotic proteins-dependent apoptosis and the reduction in progastrin/gastrin-induced promotion of tumor growth.

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

Abstract:u2002 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 10u2003mg/day for 28u2003days 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.

Effects of cyclooxygenase-2 inhibition on serum and tumor gastrins and expression of apoptosis-related proteins in colorectal cancer

The objective of the present study was to determine the influence of cyclooxygenase-2 (COX-2) inhibition by Celecoxib (CLX) in humans with distal colorectal adenocarcinoma (CRC) on serum and tumor levels of progastrin and gastrin and serum levels of proinflammatory cytokines (IL-8, TNF-α). In addition, the effects of this CLX treatment on tumor and adjacent mucosa expression of gastrin, its receptors (CCK2), and COX-1 and COX-2, as well as protein expression of the active form of nuclear factor κ B (NFκ B) and the apoptotic-related proteins Bcl-2 and survivin, have been examined. Ten distal CRC patients were examined twice, once before and then after 14-day treatment with CLX (200 mg bid). Large biopsy samples were taken from the tumor and intact mucosa 10 cm above the tumor. For comparison, 20 age- and sex-matched healthy controls were enrolled and treated with CLX as CRC patients. Serum levels of IL-8 and TNF-α were measured by enzyme-linked immunosorbent assay, and serum levels of amidated gastrins and progastrin, by specific radioimmunoassay. The gene or protein expressions of progastrin, gastrin, CCK2, COX-1, COX-2, Bcl-2, and survivin as well as NFκ B were determined by RT-PCR or Western blot in biopsy samples of tumor and intact mucosa of CRC patients. Serum IL-8 and TNF-α values were severalfold higher in CRC patients than in controls. The increase in serum proinflammatory cytokines was accompanied by increased expression of the active form of NFκ B. Serum progastrin levels were also found to be significantly higher in CRC than in controls. Treatment of CRC with CLX resulted in a significant decrease in serum levels of progastrin and this was accompanied by an increment in tumor expression of COX-2 with a concomitant reduction in gastrin, Bcl-2, survivin, and NFκ B expression. We conclude that (1) distal CRC patients show significantly higher serum progastrin levels than matched healthy controls, confirming that this hormone may be implicated in rectal carcinogenesis; (2) CRC patients exhibit significantly higher serum levels of IL-8 and TNF-α than healthy controls, probably reflecting more widespread inflammatory reaction in the colonic mucosa in CRC; (3) gastrin, COX-2, Bcl-2, survivin, and NFκ B were overexpressed in CRC tumor compared to intact mucosa, but treatment with CLX significantly reduced serum levels of progastrin and IL-8 and TNF-α, which could mediate the up-regulation of COX-2 in CRC; and (4) CLX also enhanced expression of COX-2, while inhibiting the expression of gastrin, Bcl-2, survivin, and NFκ B, suggesting that COX-2 inhibition might be useful in chemoprevention against CRC, possibly due to suppression of the antiapoptotic proteins and reduction in progastrin-induced and NFκ B-promoted tumor growth.

Usefulness of 13C-methacetin breath test in liver function testing in Amanita phalloides poisoning; breast feeding woman case

Introduction. Mortality from ingestion of the mushroom Amanita phalloides still remains as high as 8–10%. In critical patients, liver dialysis can bridge the patient to liver transplantation, which may be a lifesaving procedure. We report the use of 13C-methacetin breath test (13C-MBT) in monitoring hepatic function in a case of A. phalloides poisoning. Case report. A 33-year-old woman ate mushrooms that she had picked. After 8 h, she developed nausea and vomiting, abdominal cramps, and diarrhea, which lasted for another 24 h. On the third day, features of liver injury were seen. Pharmacologic therapy failed and she underwent liver dialysis on days 4 and 5. A 13C-MBT was used to evaluate hepatic functional reserve before the first and after the second dialysis. A liver transplantation on day 6 was successful. Discussion. The breath test results showed that at 40 min after substrate ingestion the mean 13C-MBT cumulative oxidation percentage was 10.5 ± 3.8% in healthy controls, whereas in our patient this parameter decreased from 0.09% on the fourth day to 0.02% on the fifth day. Conclusions. 13C-MBT is a simple, non-invasive diagnostic tool which may be useful as a predictor of outcome and as a marker of the severity of liver damage.

Relationship between ghrelin and Helicobacter pylori infection in Polish adult shepherds and their children: HELICOBACTER PYLORI INFECTION AND GHRELIN

Ghrelin stimulates food intake and body weight gain. The stomach is the major source of circulating ghrelin, but controversy exists over the relationship between ghrelin release and Helicobacter pylori infection.