Oxidative stress

About: Oxidative stress is a research topic. Over the lifetime, 86513 publications have been published within this topic receiving 3845790 citations. The topic is also known as: oxydative stress.

Mechanisms of Acetaminophen-Induced Liver Necrosis

Abstract: Although considered safe at therapeutic doses, at higher doses, acetaminophen produces a centrilobular hepatic necrosis that can be fatal. Acetaminophen poisoning accounts for approximately one-half of all cases of acute liver failure in the United States and Great Britain today. The mechanism occurs by a complex sequence of events. These events include: (1) CYP metabolism to a reactive metabolite which depletes glutathione and covalently binds to proteins; (2) loss of glutathione with an increased formation of reactive oxygen and nitrogen species in hepatocytes undergoing necrotic changes; (3) increased oxidative stress, associated with alterations in calcium homeostasis and initiation of signal transduction responses, causing mitochondrial permeability transition; (4) mitochondrial permeability transition occurring with additional oxidative stress, loss of mitochondrial membrane potential, and loss of the ability of the mitochondria to synthesize ATP; and (5) loss of ATP which leads to necrosis. Associated with these essential events there appear to be a number of inflammatory mediators such as certain cytokines and chemokines that can modify the toxicity. Some have been shown to alter oxidative stress, but the relationship of these modulators to other critical mechanistic events has not been well delineated. In addition, existing data support the involvement of cytokines, chemokines, and growth factors in the initiation of regenerative processes leading to the reestablishment of hepatic structure and function.

Does superoxide underlie the pathogenesis of hypertension

Abstract: Although active oxygen species play important roles in the pathogenesis of various diseases, the molecular mechanism for oxygen toxicity in vascular diseases remains to be elucidated. Since endothelium-derived relaxing factor (EDRF) is inactivated by superoxide radicals in vitro, oxidative stress in and around vascular endothelial cells may affect the circulatory status of animals. To study the role of superoxide radicals and related enzymes, such as superoxide dismutase (SOD), in vascular diseases, we have developed a fusion protein (HB-SOD) consisting of human Cu/Zn-type SOD and a C-terminal basic peptide with high affinity for heparan sulfate on endothelial cells. When injected intravenously, HB-SOD bound to vascular endothelial cells, underwent transcellular transport, and localized within vascular walls by a heparin-inhibitable mechanism. The blood pressure of spontaneously hypertensive rats (SHR) but not normal animals was decreased significantly by HB-SOD. Heparin inhibited the depressor effect of HB-SOD. In contrast, native SOD had no effect on blood pressure of either SHR or normal rats. Neither H2O2-inactivated HB-SOD nor the C-terminal heparin-binding peptide showed such a depressor effect, suggesting that the catalytic function of HB-SOD is responsible for its depressor action. To know the source of superoxide radicals, we determined xanthine oxidase activity in the aorta and uric acid levels in the plasma. Although no appreciable difference in xanthine oxidase activity was found between the two animal groups, uric acid levels were significantly higher in SHR than in normal rats. Oxypurinol, a potent inhibitor of xanthine oxidase, also decreased the blood pressure of SHR but not of normal rats. These findings indicate that superoxide radicals in and around vascular endothelial cells play critical roles in the pathogenesis of hypertension of SHR.

Isoprostanes: markers and mediators of oxidative stress

Abstract: Some years ago it was discovered that prostaglandin F2-like compounds are formed in vivo by nonenzymatic free radical-catalyzed peroxidation of arachidonic acid. Because these compounds are a series of isomers that contain the prostane ring of prostaglandins, they were termed F2-isoprostanes. Intermediates in the isoprostane pathway are prostaglandin H2-like compounds that become reduced to form F2-isoprostanes but also undergo rearrangement in vivo to form E2-, D2-, A2-, J2-isoprostanes, isothromboxanes, and highly reactive gamma-ketoaldehydes, termed isoketals. Analogous compounds have also been shown to be formed from free radical mediated oxidation of docosoahexaenoic acid. Because docosahexaenoic acid is highly enriched in neurons, these compounds have been termed neuroprostanes and neuroketals. An important aspect of the discovery of isoprostanes is that measurement of F2-isoprostanes has emerged as one of the most reliable approaches to assess oxidative stress status in vivo, providing an important tool to explore the role of oxidative stress in the pathogenesis of human disease. Measurement of F4-neuroprostanes has also proved of value in exploring the role of oxidative stress in neurodegenerative diseases. Products of the isoprostane pathway have been found to exert potent biological actions and therefore may participate as physiological mediators of disease.