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At least 19 recordsLinked to original sources

PubMed1997

Oxidative stress: oxidants and antioxidants.

An imbalance between oxidants and antioxidants in favour of the oxidants, potentially leading to damage, is termed 'oxidative stress'. Oxidants are formed as a normal product of aerobic metabolism but can be produced at elevated rates under pathophysiological conditions. Antioxidant defense involves several strategies, both enzymatic and non-enzymatic. In the lipid phase, tocopherols and carotenes as well as oxy-carotenoids are of interest, as are vitamin A and ubiquinols. In the aqueous phase, there are ascorbate, glutathione and other compounds. In addition to the cytosol, the nuclear and mitochondrial matrices and extracellular fluids are protected. Overall, these low molecular mass antioxidant molecules add significantly to the defense provided by the enzymes superoxide dismutase, catalase and glutathione peroxidases.

Animals↗

PubMed1995

Free radicals, oxidative stress, oxidized low density lipoprotein (LDL), and the heart: antioxidants and other strategies to limit cardiovascular damage.

The heart is the most susceptible of all the organs to premature aging and free radical oxidative stress. Clinical research has clearly documented the role of free radical damage and the progression of numerous degenerative diseases, particularly cardiovascular disease. This may be the result of acute ischemia-reperfusion injury, endothelial damage of hyperhomocysteinemia, as well as chronic oxidative damage secondary to lipid peroxidation. Fortunately, although highly responsive, and therefore vulnerable to the effects of oxidative stress, the heart is also receptive to the benefits of targeted phytonutrients, antioxidants, and nutritionals. The effects of antioxidant nutrients have been extensively evaluated in epidemiological, population, and clinical studies. Phytonutrients such as the natural flavonoids and carotenoids found in fresh fruits and vegetables or vitamins C, E, and beta-carotene have powerful antioxidant effects. In addition, minerals like selenium and nutrients such as coenzyme Q10 will minimize free radical risk and optimize a favorable outcome from the ubiquitous presence of oxidative stress on the cardiovascular system. The B complex, particularly folic acid, B12, and B6 are also essential in the prevention of hyperhomocysteinemia, another major risk factor for the circulatory system. Measures to minimize accumulation of heavy metals in the body, especially iron and copper, which are capable of initiating adverse free radical reactions, will also help to assuage oxidative stress. Thus, the combination of a healthy diet supplemented with antioxidants and phytonutrients may be useful in the prevention and promotion of optimum cardiovascular health.

Antioxidants↗

PubMed2005

Role of mitochondria in toxic oxidative stress.

Oxidative stress and mitochondrial oxidative damage have been implicated in the etiology of numerous common diseases. The critical mitochondrial events responsible for oxidative stress-mediated cell death (toxic oxidative stress), however, have yet to be defined. Several oxidative events implicated in toxic oxidative stress include alterations in mitochondrial lipids (e.g., cardiolipin), mitochondrial DNA, and mitochondrial proteins (eg. aconitase and uncoupling protein 2). Furthermore, recent findings indicate the enrichment of mitochondrial membranes with vitamin E protects cells against the toxic effects of oxidative stress. This review briefly summarizes the role of these mitochondrial events in toxic oxidative stress, including: 1) the protective role of mitochondrial vitamin E in toxic oxidative stress, 2) the role of mitochondrial DNA in toxic oxidative stress, 3) the interaction between cardiolipin and cytochrome c in mitochondrial regulation of apoptosis, 4) the role of mitochondrial aconitase in oxidative neurodegeneration, and 5) the role of mitochondrial uncoupling protein 2 in the pathogenesis of type 2 diabetes.

Aconitate Hydratase↗

PubMed2002

Nitric oxide protects astrocytes from oxidative stress.

Oxidative stress in astrocytes has been observed in a number of pathological conditions, however the effect of nitric oxide on oxidatively stressed astrocytes remains unclear. The goal of this research was to determine how nitric oxide influences the mechanism of peroxide-induced oxidative stress in astrocytes. We used enriched mouse-astrocyte cultures and tertiary-butyl hydroperoxide to study astrocyte oxidative stress. Cellular integrity was measured at the ultrastructural level by electron microscopy and plasma membrane integrity measured by lactate dehydrogenase release. Mitochondrial swelling and disruption of cristae were observed by electron microscopy in the absence of damage to other organelles. Astrocytes exposed to peroxide eventually succumbed to necrotic loss of plasma membrane integrity. However, when astrocytes were subjected to oxidative stress in the presence of nitric oxide, mitochondrial integrity was preserved and cell death delayed. This protection of nitric oxide resembled that of iron chelation and nitric oxide reduced susceptibility usually associated with iron-loaded astrocytes exposed to oxidative stress. Taken together, these data suggest that nitric oxide can act as a powerful antioxidant for astrocytes preserving mitochondrial and cellular integrity during oxidative stress.

Animals↗

PubMed2004

Lipid peroxidation cannot be used as a universal criterion of oxidative stress.

Oxidative stress is a term used to denote the imbalance between the concentrations of reactive oxygen and nitrogen species and the defense mechanisms of the body. Although it is generally accepted that such an imbalance plays a pivotal role in many pathologies, the term "oxidative stress" remains ill defined. In an attempt to evaluate the relationship between various assays of oxidative stress, we have analyzed the correlations between the results reported in those publications in which "oxidative stress" has been assayed by at least two methods. We found good correlations between the concentrations of several peroxidation products, including malondialdehyde, F2-Isoprostanes, lipid hydroperoxides, conjugated dienes, glutathione and protein carbonyls, but not with other criteria of "individual oxidative status" such as the concentration of antioxidants and products of DNA fragmentation (the "comet" assay). In light of these findings, we divide the assays used for evaluation of "oxidative stress" into the following three categories: (i) assays based on measuring the concentrations of oxidation products of lipids, proteins and DNA, as well as the concentrations of antioxidants, (ii) assays used to evaluate the oxidative and reductive capacity of biological fluids and (iii) assays used to evaluate the ex vivo susceptibility of lipids to oxidation upon their exposure to a source of free radicals. Our analyses demonstrate that oxidative stress cannot be defined in universal terms. Two results are of special interest:1.the commonly used criteria based on lipid peroxidation can not be regarded as a general estimate of the individual "oxidative status".2.the levels of antioxidants exhibit a non-monotonic relation with other criteria for oxidative stress. Further research is required to evaluate the significance of the latter finding.

Antioxidants↗

PubMed2004

Diabetes induces p66shc gene expression in human peripheral blood mononuclear cells: relationship to oxidative stress.

Oxidative stress plays a role in cardiovascular dysfunction. This is of interest in diabetes, a clinical condition characterized by oxidative stress and increased prevalence of cardiovascular disease. The role of p66(shc) in oxidative stress-related response has been demonstrated by resistance to and reduction of oxidative stress and prolonged lifespan in p66(shc-/-) mice. In this study we assess p66(shc) gene expression in peripheral blood mononuclear cells (PBM) from type 2 diabetic patients and healthy subjects. The p66(shc) mRNA level was assessed using RT-PCR with two sets of primers mapping for different p66(shc) regions. p66(shc) is expressed in both monocytes and lymphocytes. The level of p66(shc) mRNA was significantly higher in type 2 diabetic patients compared with controls (0.38 +/- 0.07 densitometric units vs. 0.13 +/- 0.08; P < 0.0001). In addition, total plasma 8-isoprostane levels, a marker of oxidative stress, were higher in type 2 diabetics (0.72 +/- 0.04 ng/ml) than in normal subjects (0.43 +/- 0.04, P < 0.001) and were significantly correlated to the p66(shc) mRNA level in PBM from type 2 diabetics (r(2) = 0.47; P = 0.0284). In conclusion, diabetes induces p66(shc) gene expression in circulating PBM; this up-regulation in expression is significantly associated with markers of oxidative stress. p66(shc) gene expression in PBM may represent a useful tool to investigate the oxidative stress involved in the pathogenesis of long-term diabetic complications.

Adaptor Proteins, Signal Transducing↗

PubMedDate not supplied

Redefining oxidative stress.

Oxidative stress is often defined as an imbalance of pro-oxidants and antioxidants, which can be quantified in humans as the redox state of plasma GSH/GSSG. Plasma GSH redox in humans becomes oxidized with age, in response to oxidative stress (chemotherapy, smoking), and in common diseases (type 2 diabetes, cardiovascular disease). However, data also show that redox of plasma GSH/GSSG is not equilibrated with the larger plasma cysteine/cystine (Cys/CySS) pool, indicating that the "balance" of pro-oxidants and antioxidants cannot be defined by a single entity. The major cellular thiol/disulfide systems, including GSH/GSSG, thioredoxin- 1 (-SH(2)/-SS-), and Cys/CySS, are not in redox equilibrium and respond differently to chemical toxicants and physiologic stimuli. Individual signaling and control events occur through discrete redox pathways rather than through mechanisms that are directly responsive to a global thiol/disulfide balance such as that conceptualized in the common definition of oxidative stress. Thus, from a mechanistic standpoint, oxidative stress may be better defined as a disruption of redox signaling and control. Adoption of such a definition could redirect research to identify key perturbations of redox signaling and control and lead to new treatments for oxidative stress-related disease processes.

Animals↗

PubMed1999

Differential regulation of p21 by p53 and Rb in cellular response to oxidative stress.

Oxidative stress to mammalian cells causes cellular damage and triggers inducible cellular responses leading to cell death by apoptosis. In this paper, we report that p53 was required for programmed cell death induced by oxidative stress in both mouse and human cells and that p53 transactivation was involved in induction of oxidative cell death. Furthermore, we show that p21 was highly responsive to oxidative stress in a p53-dependent manner and that ectopic expression of p21 could increase cellular susceptibility to oxidative stress in the absence of p53. However, p21 was not required for p53-directed oxidative cell death because mouse embryo fibroblasts MEFs lacking p21(p21-/- MEFs) were still susceptible to oxidative cell death. Interestingly, bax, a cell-death mediator regulated by p53, was overexpressed in p21-/- MEFs that underwent cell death by oxidative stress, suggesting a compensation for loss of p21 that may be responsible for the existence of cell-death responses in p21-knockout mouse fibroblasts. Finally, we provide evidence that the retinoblastoma gene product (Rb) is a negative regulator of p21 and a repressor of the cellular apoptotic process. Because p21 is regulated by p53 positively and by Rb negatively, p21 may be a link between p53 and Rb in determining cell fate after oxidative damage.

Animals↗

PubMed2000

Influence of different hemodialysis membranes on red blood cell susceptibility to oxidative stress.

Oxidative stress is crucial in red blood cell (RBC) damage induced by activated neutrophils in in vitro experiments. The aim of the study was to evaluate whether the bioincompatibility phenomena occurring during hemodialysis (HD) (where neutrophil activation with increased free radical production is well documented) may have detrimental effects on RBC. We evaluated RBC susceptibility to oxidative stress before and after HD in 15 patients using Cuprophan, cellulose triacetate, and polysulfone membrane. RBC were incubated with t-butyl hydroperoxide as an oxidizing agent both in the presence and in the absence of the catalase inhibitor sodium azide. The level of malonaldehyde (MDA), a product of lipid peroxidation, was measured at 0, 5, 10, 15, and 30 min of incubation. When Cuprophan membrane was used, the MDA production was significantly higher after HD, indicating an increased susceptibility to oxidative stress in comparison to pre-HD. The addition of sodium azide enhanced this phenomenon. Both cellulose triacetate and polysulfone membranes did not significantly influence RBC susceptibility to oxidative stress. Neither the level of RBC reduced glutathione nor the RBC glutathione redox ratio changed significantly during HD with any of the membranes used. The RBC susceptibility to oxidative stress was influenced in different ways according to the dialysis membrane used, being increased only when using the more bioincompatible membrane Cuprophan, where neutrophil activation with increased free radical production is well documented. The alterations found in this study might contribute to the reduced RBC longevity of HD patients where a bioincompatible membrane is used.

Biocompatible Materials↗

PubMed1998

Age-related changes in activation of mitogen-activated protein kinase cascades by oxidative stress.

Oxidative stress is thought to play a critical role in aging and the pathogenesis of human disease. Molecular studies of both the physiologic function of oxidants and the deleterious consequences of exposure to oxidative stress have suggested that signal transduction cascades may be targeted by oxidants. Here, we review recent studies from this laboratory examining the molecular basis for the activation of mitogen-activated protein kinases by oxidative stress and the influence of these pathways on cellular fate. We examine the association between constitutive activation of extracellular signal-regulated kinase (ERK) and cancer, and discuss how such mechanisms may contribute to oxidant-induced skin carcinogenesis. We also address the relationship between a decline in activation of this same pathway and the aged phenotype. In this regard, we review evidence that a decrease in activation of ERK by growth factor correlates with a reduced proliferative capacity in the isolated rat hepatocyte model, and we provide new data indicating that the activation of the ERK pathway in response to oxidant stimuli is also decreased with age. Further evidence demonstrates that this alteration is associated with both a reduced mitogenic response and a decline in hepatocyte cell survival in response to oxidative stress. Finally, we provide perspective on how modulations in ERK signaling may interplay with other changes in signal transduction cascades in the aging process.

Aging↗

PubMed2002

Nitrotyrosine: new findings as a marker of postprandial oxidative stress.

Oxidative stress plays an important role in diabetic vascular complications. It has been shown that an imbalance in the ratio of nitric oxide to superoxide anion due to a prevalence of the superoxide anion leads to an alteration in vascular reactivity. Under these conditions an increase in peroxynitrite (ONOO-) production, resulting from the reaction between nitric oxide (NO) and superoxide (O2-), may be hypothesised. ONOO- is responsible for nitration of tyrosine residues in proteins; therefore the presence of nitrotyrosine (NT) in plasma proteins is considered indirect evidence of ONOO- production. NT has been found in the plasma of patients with diabetes, but it is not detectable in the plasma of healthy controls. NT plasma values are correlated with plasma glucose concentrations, and further studies exploring the effects of acute hyperglycaemia on NT formation confirmed that NT is produced both in normal subjects during hyperglycaemic clamp and in working hearts from rats during hyperglycaemic perfusion. Postprandial hypertriglyceridemia and hyperglycaemia are considered risk factors for cardiovascular disease. Evidence suggests that postprandial hypertriglyceridaemia and hyperglycaemia induce an endothelial dysfunction through an oxidative stress; however, the specific roles of these two factors are matters for debate. In a clinical study, high-fat load and glucose alone each produced a decrease in endothelial function and an increase in NT in normal subjects and patients with diabetes. These effects were more pronounced when high-fat load and glucose were combined. Short-term simvastatin treatment had no effect on lipid parameters, but reduced the effects of high-fat load, glucose alone, and both high-fat load and glucose on endothelial function and NT Long-term simvastatin treatment was accompanied by a smaller increase in postprandial triglycerides, which was followed by smaller variations in endothelial function and NT. This study showed an independent and cumulative effect of postprandial hypertriglyceridemia and hyperglycaemia on endothelial function, suggesting oxidative stress as a common mediator of these effects. Simvastatin shows a beneficial effect on oxidative stress and endothelial dysfunction, which may be ascribed to a direct effect as well as the lipid-lowering action of the drug. These studies indicate that ONOO- is generated in diabetes, suggesting the possible involvement of ONOO- in the development of diabetic complications.

Animals↗

PubMed2003

Protein carbonyl groups as biomarkers of oxidative stress.

Oxidative stress, an imbalance toward the pro-oxidant side of the pro-oxidant/antioxidant homeostasis, occurs in several human diseases. Among these diseases are those in which high levels of protein carbonyl (CO) groups have been observed, including Alzheimer's disease (AD), rheumatoid arthritis, diabetes, sepsis, chronic renal failure, and respiratory distress syndrome. What relationships might be among high level of protein CO groups, oxidative stress, and diseases remain uncertain.The usage of protein CO groups as biomarkers of oxidative stress has some advantages in comparison with the measurement of other oxidation products because of the relative early formation and the relative stability of carbonylated proteins. Most of the assays for detection of protein CO groups involve derivatisation of the carbonyl group with 2,4-dinitrophenylhydrazine (DNPH), which leads to formation of a stable dinitrophenyl (DNP) hydrazone product. This then can be detected by various means, such as spectrophotometric assay, enzyme-linked immunosorbent assay (ELISA), and one-dimensional or two-dimensional electrophoresis followed by Western blot immunoassay. At present, the measurement of protein CO groups after their derivatisation with DNPH is the most widely utilized measure of protein oxidation.

Animals↗

PubMed2005

Phosphoinositide 3-kinase signaling in the cellular response to oxidative stress.

Oxidative stress is linked to the pathogenesis and pathobiochemistry of various diseases, including cancer, diabetes and cardiovascular disorders. The non-specific damaging effect of reactive oxygen species (ROS) generated during oxidative stress is involved in the development of diseases, as well as the activation of specific signaling cascades in cells exposed to the higher oxidant load. A cellular signaling cascade that is activated by several types of reactive oxygen species is the phosphoinositide 3'-kinase (PI 3-kinase)/protein kinase B (PKB) pathway, which regulates cellular survival and fuel metabolism, thus establishing a link between oxidative stress and signaling in neoplastic, metabolic or degenerative diseases. Several links of PI 3-kinase/PKB signaling to ROS are discussed in this review, with particular focus on the molecular mechanisms involved in the regulation of PI 3-kinase signaling by oxidative stress and important players such as (i) the glutathione and glutaredoxin system, (ii) the thioredoxin system and (iii) Ser/Thr- and Tyr phosphatases.

Animals↗

PubMed2002

Changes in the antioxidant content of mononuclear leukocytes from mice with endotoxin-induced oxidative stress.

Oxidative stress, associated with a high production of reactive oxygen species (ROS) by immune cells, is involved in the endotoxic shock caused by endotoxin. This oxidative stress is linked to the inability of the immune cells to maintain adequate levels of antioxidants with free radical-scavenging action. Glutathione (GSH) and ascorbic acid (AA) are intracellular and extracellular antioxidants (ROS scavengers) that improve the leukocyte functions. Therefore, in the present work we have determined the reduced GSH and AA content in axillary nodes, spleen, thymus and peritoneal mononuclear leukocytes from BALB/c mice subjected to lethal endotoxic shock produced by intraperitoneal injection of E. coli lipopolysaccharide (LPS, 100 mg/kg), at several times (0, 2, 4, 12 and 24 h) after LPS injection. Endotoxic shock decreased the levels of AA in the leukocytes from the three organs as well as the levels of GSH in axillary nodes and spleen cells while it increased the GSH levels in thymus and peritoneum. These results are in agreement with the oxidative stress and the altered function previously observed in those leukocytes, and they suggest that antioxidant administration may be useful for the treatment of endotoxic shock and other oxidative stress situations with altered immunological responses.

Animals↗

PubMed2005

Amphetamine neurotoxicity: cause and consequence of oxidative stress.

Oxidative stress has been demonstrated to occur in response to high doses of substituted amphetamines such as methamphetamine (METH) and 3,4-methlyene-dioxymethamphetamine (MDMA). This term represents a set of complex and multi-faceted precursor events that occur in both a parallel and serial manner, eventually converging to produce oxidative damage. This critical review goes beyond the compilation of previously well-documented evidence demonstrating that oxidative stress mediates METH and MDMA toxicity to dopamine and/or serotonin nerve terminals. The diverse causes, effects, and impact of pro-oxidative processes produced by these drugs are highlighted, integrated, and assembled into a proposed temporal sequence in an effort to explain the long-term neurochemical changes produced by amphetamines. Multiple factors are considered, including dopamine, glutamate, impaired mitochondrial bioenergetics, and inflammatory processes, all of which converge and are necessary but alone may be insufficient to cause damage to dopamine and/or 5-HT terminals. In addition, the processes linking inflammation and oxidative stress are considered and described as a feedforward process. The self-perpetuating cycle of inflammation and oxidative stress that is initiated by dopamine, glutamate, and mitochondrial dysfunction may extend well beyond the acute pharmacodynamic effects of the drugs and could represent an underlying and potentially progressive degenerative process.

Amphetamines↗

PubMed2003

Deleterious activation of poly(ADP-ribose)polymerase-1 in brain after in vivo oxidative stress.

Oxidative stress has been shown to be implicated in the pathogenesis of central nervous system injuries such as cerebral ischemia and trauma, and chronic neurodegenerative diseases. In vitro studies show that oxidative stress, particularly peroxynitrite, could trigger DNA strand breaks, which lead to the activation of repairing enzymes including Poly(ADP-ribose) Polymerase-1 (PARP-1). As excessive activation of this enzyme induces cell death, we examined whether such a cascade also occurs in vivo in a model of oxidative stress in rat brain. For this purpose, the mitochondrial toxin malonate, which promotes free radical production, was infused into the left striatum of rats. Immunohistochemistry showed that 3-nitrotyrosine, an indicator of nitrosative stress, and poly(ADP-ribose), a marker of poly(ADP-ribose)polymerase-1 activation, were present as early as 1 h after malonate, and that they persisted for 24 h. The PARP inhibitor, 3-aminobenzamide, significantly reduced the lesion and inhibited PARP-1 activation induced by malonate. These results demonstrate that oxidative stress induced in vivo in the central nervous system leads to the activation of poly(ADP-ribose)polymerase-1, which contributes to neuronal cell death.

Animals↗

PubMed2005

Inhibition of glycogen synthase kinase-3 protects cells from intrinsic but not extrinsic oxidative stress.

Oxidative stress is linked to neuronal dysfunction and death in many diseases. Glycogen synthase kinase-3 often promotes apoptosis, so this investigation tested whether glycogen synthase kinase-3 is linked to oxidative stress-induced apoptosis. Both intrinsic oxidative stress induced by the mitochondrial inhibitor rotenone and extrinsic oxidative stress induced by exogenously added H2O2 activated Bax, caspase-2, and caspase-3 in human neuroblastoma SH-SY5Y cells. Inhibitors of glycogen synthase kinase-3 blocked rotenone-induced, but not H2O2-induced, activation of both caspases, but not Bax activation. Thus, glycogen synthase kinase-3 is an important component of intrinsic oxidative stress-induced apoptosis that acts downstream of mitochondrial Bax activation, and there are substantial differences in the role of glycogen synthase kinase-3, and lithium's effects, in apoptotic signaling induced by intrinsic and extrinsic oxidative stress.

Caspases↗

PubMed2004

Overexpression of antioxidant enzyme peroxiredoxin 5 protects human tendon cells against apoptosis and loss of cellular function during oxidative stress.

Oxidative stress and apoptosis are implicated in tendon degeneration. Peroxiredoxin 5 (PRDX5) is a novel thioredoxin peroxidase recently identified in mammals, participating directly in eliminating hydrogen peroxide (H(2)O(2)) and neutralizing other reactive oxygen species (ROS). We have previously reported that PRDX5 is upregulated in degenerative human tendon. However, the effects of this upregulation on human tendon cell function remain unknown, in particular, with regards to oxidative stress conditions. Here we report that exposure of human tendon cells to 50 microM H(2)O(2) for 24 h (in vitro oxidative stress) caused a significant increase in the percentage of apoptotic cells (P<0.05) as assessed by flow cytometric analysis of Annexin V binding, accompanied by increased PRXD5 mRNA and protein expression. Overexpression of PRDX5 in human tendon cells via transfection inhibited H(2)O(2)-induced tendon cell apoptosis by 46% (P<0.05), and prevented the decrease in tendon cell collagen synthesis which occurs under H(2)O(2) challenge, although the decrease in collagen synthesis was small. Results from our study indicate that the antioxidant enzyme PRDX5 plays a protective role in human tendon cells against oxidative stress by reducing apoptosis and maintaining collagen synthesis.

Annexin A5↗