Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04179 (MnSOD)
 2,777 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CYP2E1 induction by ethanol is one mechanism by which ethanol creates oxidative stress in the liver. The superoxide dismutases (SODs) are an important antioxidant enzyme defense system against reactive oxygen species (ROS). To investigate the protective role of SOD against CYP2E1-dependent toxicity, a transfected HepG2 cell line overexpressing CYP2E1 (E47 cells) was infected with adenoviral vectors containing Cu/Zn-SOD complementary DNA (cDNA) (Ad.SOD1) and Mn-SOD cDNA (Ad.SOD2). Forty-eight hours after infection, intracellular levels and activity of Cu/Zn-SOD and Mn-SOD were increased about 2- and 3-fold, respectively. Localization of the overexpressed Cu/Zn-SOD in the cytosol and Mn-SOD in the mitochondria was confirmed by assaying the levels and activity of SOD in the corresponding isolated fractions. Arachidonic acid (AA) plus iron-induced cell death was partially prevented in both Ad.SOD1- and Ad.SOD2-infected E47 cells. Overexpression of Cu/Zn-SOD and Mn-SOD also partially protected E47 cells from the increase in reactive oxygen production and lipid peroxidation and the loss of mitochondrial membrane potential induced by AA and iron. Infection with Cu/Zn-SOD and Mn-SOD also protected the E47 cells against AA toxicity or buthionine sulfoximine (BSO)-dependent toxicity. CYP2E1 levels and catalytic activity were not altered by overexpression of Cu/Zn-SOD or Mn-SOD. Cu/Zn-SOD in the cytosol and Mn-SOD in mitochondria each are capable of protecting HepG2 cells expressing CYP2E1 against cytotoxicity induced by pro-oxidants. In conclusion, these enzymes may be useful in the prevention or improvement of liver injury produced by agents known to be metabolized by CYP2E1 to reactive intermediates and to cause oxidative stress.
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PMID:Adenovirus-mediated expression of Cu/Zn- or Mn-superoxide dismutase protects against CYP2E1-dependent toxicity. 1457 53

Superoxide dismutases (SOD) convert superoxide radicals into less damaging hydrogen peroxide. The opportunistic human pathogen Candida albicans is known to express CuZnSOD (SOD1) and MnSOD (SOD3) in the cytosol and MnSOD (SOD2) in the mitochondria. We identified three additional CuZn-containing superoxide dismutases, SOD4, SOD5, and SOD6, within the sequence of the C. albicans genome. The transcription of SOD5 was up-regulated during the yeast to hyphal transition of C. albicans, and SOD5 was induced when C. albicans cells were challenged with osmotic or with oxidative stresses. SOD5 transcription was also increased when cells were grown on nonfermentable substrates as the only carbon source. The Rim101p transcription factor was required for all inductions observed, whereas the Efg1p transcription factor was specifically needed for serum-modulated expression. Deletion of SOD5 produced a viable mutant strain that showed sensitivity to hydrogen peroxide when cells were grown in nutrient-limited conditions. Sod5p was found to be necessary for the virulence of C. albicans in a mouse model of infection. However, the sod5 mutant strain showed the same resistance to macrophage attack as its parental strain, suggesting that the loss of virulence in not due to an increased sensitivity to macrophage attack.
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PMID:Superoxide dismutases in Candida albicans: transcriptional regulation and functional characterization of the hyphal-induced SOD5 gene. 1461 19

Aminoglycosides are commonly used antibiotics that often induce ototoxicity leading to permanent hair cell loss and hearing impairment. The ototoxic effects of aminoglycosides have been linked to oxidative stress. To determine the feasibility of antioxidant gene therapy for protecting the inner ear against aminoglycoside-induced oxidative stress, we used adenoviral vectors for overexpression of catalase, Cu/Zn superoxide dismutase (SOD1), and Mn superoxide dismutase (SOD2). We inoculated adenoviruses designated Ad.cat, Ad.SOD1, and Ad.SOD2 into the left guinea pig cochlea. Five days later, an ototoxic combination of kanamycin and ethacrynic acid was systemically administered. Artificial perilymph and adenovirus without a gene cassette (Ad.null) were used as controls. Biochemical analysis showed significant increase in catalase and a moderate elevation in SOD2 levels in tissues of the cochlea inoculated with the respective vectors. Auditory brain-stem responses were measured to monitor hearing thresholds. Animals were sacrificed 7 days after the ototoxic insult and their hair cells counted. Hair cells and hearing thresholds were significantly protected by Ad.cat and Ad.SOD2, while results with Ad.SOD1 were inconsistent. Control ears showed no significant protective effects. The results demonstrate that the expression of functional enzymes in the inner ear is feasible using adenoviral-mediated gene delivery. Furthermore, they confirm that reactive oxygen species contribute to aminoglycoside ototoxicity and suggest antioxidant gene therapy as a potential therapeutic strategy to reduce inner ear oxidative stress.
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PMID:Antioxidant gene therapy can protect hearing and hair cells from ototoxicity. 1475 1

Saccharomyces cerevisiae expresses two forms of superoxide dismutase (SOD): MnSOD, encoded by SOD2, which is located within the mitochondrial matrix, and CuZnSOD, encoded by SOD1, which is located in both the cytosol and the mitochondrial intermembrane space. Because two different SOD enzymes are located in the mitochondrion, we examined the relative roles of each in protecting mitochondria against oxidative stress. Using protein carbonylation as a measure of oxidative stress, we have found no correlation between overall levels of respiration and the level of oxidative mitochondrial protein damage in either wild type or sod mutant strains. Moreover, mitochondrial protein carbonylation levels in sod1, sod2, and sod1sod2 mutants are not elevated in cells harvested from mid-logarithmic and early stationary phases, suggesting that neither MnSOD nor CuZnSOD is required for protecting the majority of mitochondrial proteins from oxidative damage during these early phases of growth. During late stationary phase, mitochondrial protein carbonylation increases in all strains, particularly in sod1 and sod1sod2 mutants. By using matrix-assisted laser desorption ionization time-of-flight mass spectrometry, we have found that specific proteins become carbonylated in sod1 and sod2 mutants. We identified six mitochondrial protein spots representing five unique proteins that become carbonylated in a sod1 mutant and 19 mitochondrial protein spots representing 11 unique proteins that become carbonylated in a sod2 mutant. Although some of the same proteins are carbonylated in both mutants, other proteins are not. These findings indicate that MnSOD and CuZnSOD have both unique and overlapping functions in the mitochondrion.
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PMID:Mitochondrial protein oxidation in yeast mutants lacking manganese-(MnSOD) or copper- and zinc-containing superoxide dismutase (CuZnSOD): evidence that MnSOD and CuZnSOD have both unique and overlapping functions in protecting mitochondrial proteins from oxidative damage. 1538 44

The brain's anti-oxidant response to highly elevated oxygen (O2) partial pressures is poorly understood. In this study we hypothesized that hyperbaric O2 (HBO2) would stimulate superoxide dismutase (SOD) transcription in the oxidative stress-sensitive rat hippocampus and measured the time course and extent of the changes in hippocampal mRNA for all three SOD isoforms and total SOD enzyme activity. Comparisons were made between exposures to 2 hours of 1 atmosphere pressure normobaric oxygen (NBO); 2 hours of 3 atmospheres HBO2; and room air. Hyperoxia (HBO2 > NBO) was associated with statistically significant increases in transcript levels of the antioxidant enzymes SOD2 (MnSOD) and SOD3 (EC-SOD) at 6 and 18 hours but not SOD1 (Cu, Zn SOD) respectively. Hyperoxia, however, did not affect total hippocampal SOD activity measured at 6 and 24 hours, indicating that the mRNA responses were necessary to maintain the anti-oxidant enzyme activity after oxidative stress.
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PMID:Superoxide dismutase responds to hyperoxia in rat hippocampus. 1548 85

Hydroxyl radical, ascorbate free radical, superoxide dismutase (SOD) activities, Cu,Zn-SOD protein, Mn-SOD protein, 8-hydroxy-2' -deoxyguanosine (8-OHdG) and metals were compared in red blood cells (RBC), plasma and/or cerebrospinal fluid (CSF) between patients with sporadic amyotrophic lateral sclerosis (SALS), familial ALS (FALS) showing the Leu126Ser mutation in the Cu, Zn-SOD gene and controls. In patients with FALS or SALS, concentrations of hydroxyl radical in blood and ascorbate free radical and 8-OHdG in CSF were higher than control group values, while SOD activities in RBC and CSF were lower. In contrast, Cu, Zn-SOD protein concentrations in RBC were low only in FALS patients. Concentrations of Cu in CSF of SALS patients were higher than in controls. Thus, the pathogenesis of increased oxidative stress differs between SALS patients and FALS patients with a mutant Leu126Ser SOD1 gene.
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PMID:Oxidative stress and metal content in blood and cerebrospinal fluid of amyotrophic lateral sclerosis patients with and without a Cu, Zn-superoxide dismutase mutation. 1582 69

Selegiline, a therapeutic agent of Parkinson's disease, is known to have neuroprotective properties that may involve its regulatory effects on antioxidant enzymes. We evaluated effects of selegiline on activities of catalase (CAT), Cu,Zn-superoxide dismutase (SOD1) and Mn-SOD (SOD2) in the striatum, cortex and hippocampus of 8- and 25-week-old rats, and on SOD activities and glutathione levels in mesencephalic slice cultures. Selegiline (2 mg/kg) significantly increased CAT and SOD2 activities in the striatum, but not in the cortex and hippocampus, of 25-week-old rats. In contrast, selegiline failed to increase CAT and SOD activities in three brain regions of 8-week-old rats, whereas L: -dopa significantly increased SOD1 activity in the striatum. In slice cultures, selegiline increased SOD1 and SOD2 activities with a maximal effective concentration of 10(-8) and 10(-10) M, respectively. Moreover, selegiline significantly increased glutathione level. These results suggest that selegiline can decrease oxidative stress in nigrostriatum by augmenting various antioxidant systems, each of which responds optimally to different concentrations of selegiline.
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PMID:Effects of selegiline on antioxidant systems in the nigrostriatum in rat. 1595 53

Previous studies have shown that testosterone production by the Leydig cells of aged Brown Norway rats is reduced from the relatively high levels produced by Leydig cells of young rats and that this reduction is not secondary to decreased serum luteinizing hormone concentration. The free radical theory of aging proposes that imbalance between pro-oxidants and the antioxidant defense system ultimately results in oxidative damage to cellular processes. With this in mind, we hypothesized herein that age-related reductions in steroidogenesis by Brown Norway rat Leydig cells may be associated with the impairment of the antioxidant defense system of these cells. To begin to test this hypothesis, we compared the activities and steady-state mRNA and protein levels of the antioxidant enzymes copper zinc (CuZn) superoxide dismutase (CuZnSOD, SOD1), manganese (Mn) superoxide dismutase (MnSOD, SOD2), and glutathione peroxidase (GPx) and the levels of reduced and oxidized glutathione in Leydig cells isolated from the testes of young (4-month-old) and aged (20-month-old) Brown Norway rats. For some studies, Leydig cells were isolated separately from aged testes that either had regressed because of age-related losses of germ cells or that were nonregressed. SOD (total) and GPx activities were found to decrease significantly with age whether or not the testes were regressed. CuZnSOD and MnSOD mRNA levels decreased with aging, though the magnitude of the decreases were considerably lower than the respective decreases in enzyme activities. GPx mRNA levels also decreased, which is consistent with the decreases seen in enzyme activity. MnSOD protein expression declined with age, and to a lesser extent, CuZnSOD did as well. Reduced and oxidized glutathione also exhibited age-related reductions in cells from both normal and regressed aged testes. The age-related decreases in Leydig cell antioxidant enzyme activities, gene expression, and protein levels and in glutathione were consistent with the hypothesis that the loss of steroidogenic function that accompanies Leydig cell aging may result in part from a decrease in the fidelity of the cellular antioxidant defense system.
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PMID:Aging and the brown Norway rat leydig cell antioxidant defense system. 1630 8

Gel electrophoresis and Western blotting of frontal cortex homogenates have been carried out in sporadic Creutzfeldt-Jakob disease (CJD) cases and age-matched controls to gain understanding of the expression of glycation-end products (AGEs). N-Carboxymethyl-lysine (CML) and N-carboxyethyl-lysine (CEL) were used as markers of glycoxidation; 4-hydroxynonenal (4-HNE) and malondialdehyde-lysine (MDAL) as markers of lipoxidation; and nitrotyrosine (N-tyr) and neuronal, endothelial and inducible nitric oxide synthase (nNOS, eNos and iNos) as markers of protein nitration and as sources of NO production, respectively. Age receptor (RAGE) and Cu/Zn superoxide dismutase (SOD1) and Mn superoxide dismutase (SOD2) expression levels were also examined. The results showed a significant increase in the expression levels of AGE (p<0.05), CEL (p<0.001), RAGE (p<0.05), HNE-modified proteins (p<0.01), nNOS, iNOS and eNOS (p<0.01 and p<0.05, respectively), N-tyr (p<0.05), and SOD1 (p<0.05) and SOD2 (p<0.05). No relationship was observed between PrP genotype, PrP type, PrP burden, and expression levels of oxidative stress markers. The present findings demonstrate oxidative, glycoxidative, lipoxidative and nitrative protein damage, accompanied by increased oxidative responses, in the cerebral cortex in sporadic CJD. These results provide support for the concept that oxidative stress may have important implications in the pathogenesis of prion diseases.
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PMID:Oxidation, glycoxidation, lipoxidation, nitration, and responses to oxidative stress in the cerebral cortex in Creutzfeldt-Jakob disease. 1631 Aug 93

Superoxide dismutases (SOD) are important anti-oxidant enzymes that guard against superoxide toxicity. Various SOD enzymes have been characterized that employ either a copper, manganese, iron or nickel co-factor to carry out the disproportionation of superoxide. This review focuses on the copper and manganese forms, with particular emphasis on how the metal is inserted in vivo into the active site of SOD. Copper and manganese SODs diverge greatly in sequence and also in the metal insertion process. The intracellular copper SODs of eukaryotes (SOD1) can obtain copper post-translationally, by way of interactions with the CCS copper chaperone. CCS also oxidizes an intrasubunit disulfide in SOD1. Adventitious oxidation of the disulfide can lead to gross misfolding of immature forms of SOD1, particularly with SOD1 mutants linked to amyotrophic lateral sclerosis. In the case of mitochondrial MnSOD of eukaryotes (SOD2), metal insertion cannot occur post-translationally, but requires new synthesis and mitochondrial import of the SOD2 polypeptide. SOD2 can also bind iron in vivo, but is inactive with iron. Such metal ion mis-incorporation with SOD2 can become prevalent upon disruption of mitochondrial metal homeostasis. Accurate and regulated metallation of copper and manganese SOD molecules is vital to cell survival in an oxygenated environment.
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PMID:Activation of superoxide dismutases: putting the metal to the pedal. 1682 95


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