ROS-induced Lipid Peroxidation Research Articles

Melatonin as an organoprotector in the stomach and the pancreas

Melatonin was thought to originate primarily from the pineal gland and to be secreted during the night, but recent studies revealed that gastrointestinal (GI) tract presents another, many times larger, source of melatonin that contributes significantly to the circulating concentration of this indole. Melatonin may exert a direct effect on GI tissues but its major influence on GI organs seems to occur indirectly, via the brain-gut axis including peripheral receptors, sensory afferent (vagal or sympathetic) pathways and central nervous system (CNS) acting on these organs via autonomic efferents and neuromediators. This article reviews and updates our experience with the fascinating molecule, as related to GI organs, with special focus on secretory activity of the stomach and pancreas and the maintenance of their tissue integrity. In addition to being released into the circulation, melatonin is also discharged into the gut lumen and this appears to be implicated in the postprandial stimulation of pancreatic enzyme secretion, mediated by melatonin-induced release of cholecystokinin, acting through entero-gastro-pancreatic reflexes. Although exerting certain differences in the mechanism of action on gastric and pancreatic secretory activities, melatonin derived from its precursor L-tryptophan, exhibits similar highly protective actions against the damage of both the stomach and the pancreas and accelerates the healing of chronic gastric ulcerations by stimulating the microcirculation and cooperating with arachidonate metabolites such as prostaglandins, with nitric oxide released from vascular endothelium, and/or sensory nerves and with their neuropeptides such as calcitonin gene related peptide. The beneficial effects of melatonin results in gastro- and pancreato-protection, prevents various forms of gastritis and pancreatitis through the activation of specific MT2-receptors and scavenges reactive oxygen species (ROS). Melatonin counteracts the increase in the ROS-induced lipid peroxidation and preserves, at least in part, the activity of key anti-oxidizing enzymes such as superoxide dismutase. It is proposed that melatonin should be considered as the agent exerting an important role in prevention of gastric and pancreatic damage and in accelerating healing of gastric ulcers.

Role of reactive oxygen species and glutathione in inorganic mercury-induced injury in human glioma cells.

The present study was undertaken to examine the role of reactive oxygen species (ROS) and glutathione (GSH) in glia cells using human glioma cell line A172 cells. HgCl2 caused the loss of cell viability in a dose-dependent manner. HgCl2-induced loss of cell viability was not affected by H2O2 scavengers catalase and pyruvate, a superoxide scavenger superoxide dismutase, a peroxynitrite scavenger uric acid, and an inhibitor of nitric oxide N(G)-nitro-arginine Methyl ester. HgCl2 did not cause changes in DCF fluorescence, an H2O2-sensitive fluorescent dye. The loss of cell viability was significantly prevented by the hydroxyl radical scavengers dimethylthiourea and thiourea, but it was not affected by antioxidants DPPD and Trlox. HgCl2-induced loss of cell viability was accompanied by a significant reduction in GSH content. The GSH depletion was almost completely prevented by thiols dithiothreitol and GSH, whereas the loss of viability was partially prevented by these agents. Incubation of cells with 0.2 mM buthionine sulfoximine for 24 hr, a selective inhibitor of gamma-glutamylcysteine synthetase, resulted in 56% reduction in GSH content without any change in cell viability. HgCl2 resulted in 34% reduction in GSH content, which was accompanied by 59% loss of cell viability. These results suggest that HgCl2-induced cell death is not associated with generation of H2O2 and ROS-induced lipid peroxidation. In addition, these data suggest that the depletion of endogenous GSH itself may not play a critical role in the HgCl2-induced cytotoxicity in human glioma cells.

Free radical scavenging by lazaroids improves renal blood flow during sepsis

Acute kidney failure in surgical patients is often related to severe infection. Renal vasoconstriction is a major factor in the genesis of kidney failure. Reactive oxygen species (ROS) are known to mediate kidney injury after ischemia-reperfusion and are increased during sepsis. The role of ROS as mediators of intrarenal vasoconstriction and renal dysfunction during sepsis is unclear. Lazaroids such as U74389G are radical quenching antioxidants that inhibit ROS-induced lipid peroxidation. We sought to determine whether radical scavenging affected the renal microvascular response to a septic challenge. In vivo videomicroscopy was used to study the rat hydronephrotic kidney. Interlobular artery (ILA) diameter and flow, afferent and efferent arteriolar diameters, and cardiac output were measured. U74389G or vehicle was infused before a bolus injection of live Escherichia coli or normal saline solution. U74389G alone had no effect on the renal vessels or hemodynamics. E. coli caused preglomerular vasoconstriction (ILA, -32%; afferent, -30% of baseline) and hypoperfusion (-66%) despite increased cardiac output (+54%). U74389G significantly attenuated both the constriction (ILA, -16%; afferent, -9%) and hypoperfusion (-38%) but not increased cardiac output (+41%). E. coli bacteremia led to preglomerular vasoconstriction and hypoperfusion. Inhibition of lipid peroxidation with the radical scavenger U74389G reduced this effect without altering central hemodynamic responses. Free radicals have a deleterious effect on the renal microcirculation during bacteremia, and these data suggest that antioxidants may be of value in preventing sepsis-associated kidney failure.

Protective effects of hsp70 in inflammation.

Inflammation results from the recruitment to a given tissue or organ and the activation of leucocytes, among which the monocytes-macrophages play a major role. These phagocytic cells produce high levels of reactive oxygen species (ROS) as well as cytokines. Whereas both ROS and cytokines have the potential to regulate the expression of heat shock (HS)/stress proteins (HSP), it appears that these proteins in turn have the ability to protect cells and tissues from the deleterious effects of inflammation. The mechanisms by which such protection occurs include prevention of ROS-induced DNA strand breaks and lipid peroxidation as well as protection from mitochondrial structure and function. In vivo, HS protects organs against a number of lesions associated with the increased production of ROS and/or cytokines. In an animal model for adult respiratory distress syndrome, an acute pulmonary inflammatory condition, HS completely prevented mortality. HSP (hsp70 in particular) may also exert protective effects in the immune system by contributing to the processing and presentation of bacterial and tumoral antigens. The analysis of the expression of hsp70 may prove of diagnostic and prognostic value in inflammatory conditions and therapeutical applications are being considered.