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.

FLP Recombinase-Mediated Induction of Cu/Zn-Superoxide Dismutase Transgene Expression Can Extend the Life Span of Adult Drosophila melanogaster Flies

Abstract: Yeast FLP recombinase was used in a binary transgenic system (“FLP-OUT”) to allow induced overexpression of catalase and/or Cu/Zn-superoxide dismutase (Cu/ZnSOD) in adult Drosophila melanogaster. Expression of FLP recombinase was driven by the heat-inducible hsp70 promoter. Once expressed, FLP catalyzed the rearrangement and activation of a target construct in which expression of catalase or Cu/ZnSOD cDNAs was driven by the constitutive actin5C promoter. In this way a brief heat pulse (120 or 180 min, total) of young adult flies activated transgene expression for the rest of the life span. FLP-OUT allows the effects of induced transgene expression to be analyzed in control (no heat pulse) and experimental (heat pulse) populations with identical genetic backgrounds. Under the conditions used, the heat pulse itself always had neutral or slightly negative effects on the life span. Catalase overexpression significantly increased resistance to hydrogen peroxide but had neutral or slightly negative effects on the mean life span. Cu/ZnSOD overexpression extended the mean life span up to 48%. Simultaneous overexpression of catalase with Cu/ZnSOD had no added benefit, presumably due to a preexisting excess of catalase. The data suggest that oxidative damage is one rate-limiting factor for the life span of adult Drosophila. Finally, experimental manipulation of the genetic background demonstrated that the life span is affected by epistatic interactions between the transgene and allele(s) at other loci. An increasing number of data suggest that oxidative damage contributes to the aging process in Drosophila melanogaster and other organisms. The oxygen radical superoxide is produced primarily as a by-product of normal oxidative respiration in mitochondria. Superoxide can be converted by multiple pathways in vivo to the highly reactive hydroxyl radical. Hydroxyl radical and other oxygen radicals cause significant damage to cellular macromolecules including protein, DNA, and lipids (1, 48, 61). The enzymes catalase and Cu/Zn-superoxide dismutase (Cu/ZnSOD) are primary cellular defenses against oxygen radicals, and their functions are conserved from Escherichia coli to humans. Cu/ZnSOD converts superoxide to H2O2, and catalase converts H2O2 to H2O and O2. These cellular defenses against oxidative damage are not completely efficient, since oxidatively damaged macromolecules have been found to accumulate in virtually all aging organisms examined. In humans, mutations in Cu/ZnSOD which increase oxidative stress cause the neurodegenerative disease familial amyotrophic lateral sclerosis (10, 14, 42). Oxidative damage has also been implicated in several other neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease (52). Increased wild-type Cu/ZnSOD activity can also have negative effects. Constitutive overexpression of Cu/ZnSOD in transgenic mice by using the homologous promoter causes cell-typespecific developmental and functional abnormalities generally attributed to disruption of normal oxidative stress defenses (3, 5).

NADPH oxidase-derived free radicals are key oxidants in alcohol-induced liver disease.

Abstract: In North America, liver disease due to alcohol consumption is an important cause of death in adults, although its pathogenesis remains obscure. Despite the fact that resident hepatic macrophages are known to contribute to early alcohol-induced liver injury via oxidative stress, the exact source of free radicals has remained a mystery. To test the hypothesis that NADPH oxidase is the major source of oxidants due to ethanol, we used p47phox knockout mice, which lack a critical subunit of this major source of reactive oxygen species in activated phagocytes. Mice were treated with ethanol chronically, using a Tsukamoto-French protocol, for 4 weeks. In wild-type mice, ethanol caused severe liver injury via a mechanism involving gut-derived endotoxin, CD14 receptor, production of electron spin resonance–detectable free radicals, activation of the transcription factor NF-κB, and release of cytotoxic TNF-α from activated Kupffer cells. In NADPH oxidase–deficient mice, neither an increase in free radical production, activation of NF-κB, an increase in TNF-α mRNA, nor liver pathology was observed. These data strongly support the hypothesis that free radicals from NADPH oxidase in hepatic Kupffer cells play a predominant role in the pathogenesis of early alcohol-induced hepatitis by activating NF-κB, which activates production of cytotoxic TNF-α.

Oxidant mechanisms in toxic acute renal failure

Abstract: Over the last decade, there is accumulating evidence for a role of reactive oxygen metabolites in the pathogenesis of a variety of renal diseases, including gentamicin, glycerol, cisplatin, and cyclosporine A models of toxic acute renal failure. Gentamicin has been shown both in in vitro and in vivo studies to enhance the generation of reactive oxygen metabolites. Iron is important in models of tissue injury, presumably because it is capable of catalyzing free-radical formation. Gentamicin has been shown to cause release of iron from renal cortical mitochondria. Scavengers of reactive oxygen metabolites as well as iron chelators provide protection in gentamicin-induced nephrotoxicity. In glycerol-induced acute renal failure, an animal model of rhabdomyolysis, there is enhanced generation of hydrogen peroxide, and scavengers of reactive oxygen metabolites and iron chelators provide protection. Although the dogma is that the myoglobin is the source of iron, recent studies suggest that cytochrome P450 may be an important source of iron in this model. In addition, there are marked alterations in antioxidant defenses, such as glutathione, as well as changes in heme oxygenase. Several recent in vitro and in vivo studies indicate an important role of reactive oxygen metabolites in cisplatin-induced nephrotoxicity. Thus, catalytic iron is increased both in vitro and in vivo by cisplatin, and iron chelators as well as hydroxyl radical scavengers have been shown to be protective. Recent studies indicate that cytochrome P450 may also be an important source of the catalytic iron in cisplatin nephrotoxicity. Cyclosporine A has been shown to enhance generation of hydrogen peroxide in vitro and enhance lipid peroxidation in vitro and in vivo. Antioxidants have been shown to be protective in cyclosporine A nephrotoxicity. This collective body of evidence suggests an important role for reactive oxygen metabolites in toxic acute renal failure and may provide therapeutic opportunities of preventing or treating acute renal failure in humans.

Smoking and low antioxidant levels increase oxidative damage to sperm DNA.

Abstract: Our previous studies have shown that men with low ascorbate intake have markedly increased oxo8dG in the DNA of their sperm. Because cigarette smoke is high in oxidants and depletes plasma and tissue antioxidants, oxidative DNA damage in sperm and tocopherol and ascorbate levels in seminal plasma were determined in smokers and non-smokers. The level in sperm DNA of oxo8dG, an oxidative lesion of guanine, was 50% higher in smokers compared to nonsmokers (p = 0.005). The concentration of alpha-tocopherol in seminal plasma was decreased in smokers by 32% (p = 0.03). Smoking and low antioxidant levels increase oxidative damage to sperm DNA. We discuss the possibility that paternal smoking causes mutations in sperm that lead to cancer, birth defects, and genetic diseases in offspring.