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 H(2)-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% (ID(50)) was 25 and 36 mg/kg, respectively, and this protective effect was similar to that obtained with methyl PGE2 analog (5 μg/kg i g). GSE significantly raised the GBF, mucosal generation of PGE(2), SOD activity and plasma gastrin levels while attenuating MDA content. Inhibition of PGE(2) 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

Pioglitazone, a specific ligand of peroxisome proliferator-activated receptor-gamma, protects pancreas against acute cerulein-induced pancreatitis

AIM: To determine the effect of pioglitazone, a specific peroxisome proliferator-activated receptor-γ (PPARγ) ligand, on the development of acute pancreatitis (AP) and on the expression of heat shock protein 70 (HSP70) in the pancreas. METHODS: AP was induced in rats by subcutaneous infusion of cerulein for 5 h. Pancreatic blood flow was measured by laser Doppler flowmetry. Plasma lipase activity, interleukin-1β (IL-1β) and IL-10 were determined. Pancreatic weight and histology were evaluated and pancreatic DNA synthesis and blood flow as well as pancreatic mRNA for IL-1β and HSP70 were assessed in rats treated with pioglitazone alone or in combination with cerulein. RESULTS: Pioglitazone administered (10-100 mg/kg i.g.) 30 min before cerulein, attenuated dose-dependently the pancreatic tissue damage in cerulein-induced pancreatitis (CIP) as demonstrated by the improvement of pancreatic histology, reduction in plasma lipase activity, plasma concentration of pro-inflammatory IL-1β and its gene expression in the pancreas and attenuation of the pancreatitis-evoked fall in pancreatic blood flow. CIP increased pancreatic HSP70 mRNA and protein expression in the pancreas and this effect was enhanced by pioglitazone treatment. CONCLUSION: Pioglitazone attenuates CIP and the beneficial effect of this pioglitazone is multifactorial probably due to its anti-inflammatory activities, to the suppression of IL-1β and to the overexpression of HSP70. PPARγ ligands could represent a new therapeutic option in the treatment of AP

Ischemic preconditioning inhibits development of edematous cerulein-induced pancreatitis : involvement of cyclooxygenases and heat shock protein 70

AIM: To determine whether ischemic preconditioning (IP) affects the development of edematous cerulein-induced pancreatitis and to assess the role of cyclooxygenase-1 (COX-1), COX-2, and heat shock protein 70 (HSP 70) in this process. METHODS: In male Wistar rats, IP was performed by clamping of celiac artery (twice for 5 min at 5-min intervals). Thirty minutes after IP or sham operation, acute pancreatitis was induced by cerulein. Activity of COX-1 or COX-2 was inhibited by resveratrol or rofecoxib, respectively (10 mg/kg). RESULTS: IP significantly reduced pancreatic damage in cerulein-induced pancreatitis as demonstrated by the improvement of pancreas histology, reduction in serum lipase and poly-C ribonuclease activity, and serum concentration of pro-inflammatory interleukin (IL)-1β. Also, IP attenuated the pancreatitis-evoked fall in pancreatic blood flow and pancreatic DNA synthesis. Serum level of anti-inflammatory IL-10 was not affected by IP. Cerulein-induced pancreatitis and IP increased the content of HSP 70 in the pancreas. Maximal increase in HSP 70 was observed when IP was combined with cerulein-induced pancreatitis. Inhibition of COXs, especially COX-2, reduced the protective effect of IP in edematous pancreatitis. CONCLUSION: Our results indicate that IP reduces pancreatic damage in cerulein-induced pancreatitis and this effect, at least in part, depends on the activity of COXs and pancreatic production of HSP 70

PORTAL: Pilot study on the safety and tolerance of preoperative melatonin application in patients undergoing major liver resection: a double-blind randomized placebo-controlled trial

<p>Abstract</p> <p>Background</p> <p>Major surgical procedures facilitate systemic endotoxinemia and formation of free radicals with subsequent inflammatory changes that can influence the postoperative course. Experimental data suggest that preoperative supraphysiological doses of melatonin, a potent immuno-modulator and antioxidant, would decrease postoperative infectious and non-infectious complications induced by major abdominal surgery.</p> <p>Methods/Design</p> <p>A randomized controlled double blind single center clinical trial with two study arms comprising a total of 40 patients has been designed to assess the effects of a single preoperative dose of melatonin before major liver resection. Primary endpoints include the determination of safety and tolerance of the regimen as well as clinical parameters reflecting pathophysiological functions of the liver. Furthermore, data on clinical outcome (infectious and non-infectious complications) will be collected as secondary endpoints to allow a power calculation for a randomized clinical trial aiming at clinical efficacy.</p> <p>Discussion</p> <p>Based on experimental data, this ongoing clinical trial represents an advanced element of the research chain from bench to bedside in order to reach the highest level of evidence-based clinical facts to determine if melatonin can improve the general outcome after liver resection.</p> <p>Trial Registration</p> <p>EudraCT200600530815</p