Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P30044 (antioxidant enzyme)
 8,037 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cord blood is source of colony-forming progenitors to vascular endothelial cells for potential use in cell therapies. These cells-called blood late outgrowth endothelial cells (OECs)-have undergone endothelial differentiation, but appear to still possess functional properties different from mature endothelial cells. A large-scale comparative proteomics screen of cord blood OECs versus human vein endothelial cells (HUVECs) using two-dimensional gel electrophoresis and mass spectrometry identified specific expression of manganese superoxide dismutase (MnSOD), a key antioxidant enzyme expressed in the mitochondria, in OECs but not in HUVECs. Immunoblotting verified significant MnSOD levels in all OEC isolates tested and maintained throughout passaging. Endothelial function and cell survival/proliferation assays in the presence of high cytotoxic doses of the superoxide generator compound LY83583 showed OECs profoundly better protected against oxidative stress than HUVECs. Such cytoprotective levels of MnSOD cells could give therapeutic cell transplants a survival advantage in necrotic or ischemic conditions.
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PMID:MnSOD marks cord blood late outgrowth endothelial cells and accompanies robust resistance to oxidative stress. 1701 Sep 41

Radiation-induced genomic instability (RIGI) manifests as a heritable increased rate of genetic alterations in the progeny of irradiated cells generations after the initial insult. The progeny can show an increased frequency of chromosomal translocations, deletions, mutations, micronuclei, and decreased plating efficiency. What perpetuates RIGI is unclear; however, persistently increased levels of reactive oxygen species (ROS) are frequently associated with genomically unstable clones. Furthermore, addition of free radical scavengers (e.g., DMSO, glycerol, and cationic thiol cysteamine) reduces the incidence of instability after irradiation, implicating a ROS-mediated role in RIGI induction. Because mitochondria are a major natural cellular source of ROS, we tested the hypothesis that mitochondrial dysfunction has a role in maintaining the elevated ROS levels in our irradiated, genetically unstable GM10115 Chinese hamster ovary cells. Amplex Red fluorometry measurements indicate that the relative contribution of uncoupler-sensitive mitochondrial hydrogen peroxide production to total cellular hydrogen peroxide generation is greater in unstable cells. Measurements of mitochondrial DNA levels and cell cytometric fluorescent measurements of Mitotracker Green FM indicate that differences in mitochondrial ROS production are not due to varying mitochondrial levels. However, mitochondrial respiration measured in digitonin-permeabilized cells is impaired in unstable clones. In addition, manganese superoxide dismutase, a major mitochondrial antioxidant enzyme, exhibits increased immunoreactivity but decreased enzyme activity in unstable clones, which along with decreased respiration rates may explain the increased levels of cellular ROS. These studies show that mitochondria from unstable cells are abnormal and likely contribute to the persistent oxidative stress in the unstable clones.
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PMID:A role for mitochondrial dysfunction in perpetuating radiation-induced genomic instability. 1707 57

Expression of manganese superoxide dismutase (MnSOD), a nuclear-encoded mitochondrial primary antioxidant enzyme, is protective against various paradigms of oxidative stress-induced brain injury. We have shown previously that the presence of an intronic nuclear factor site, kappaB (NF-kappaB), in the MnSOD gene is essential for the induction of MnSOD by tumor necrosis factor alpha (TNF-alpha). However, whether activation of NF-kappaB is protective against oxidative stress-induced neuronal injury is unclear. In the present study, we demonstrate that TNF-alpha activates NF-kappaB activity in neuronal, SH-SY5Y, cells and preferentially enhances the binding of p50 and p65 to the promoter/enhancer regions of the MnSOD gene. Binding of NF-kappaB members to the MnSOD gene leads to the induction of MnSOD mRNA and protein levels. Consequently, induction of MnSOD by TNF-alpha primes neuronal cells to develop resistance against subsequent exposure to beta-amyloid and FeSO(4). Taken together, these results suggest that NF-kappaB might exert its protective function by induction of MnSOD leading to subsequent protection against oxidative stress-induced neuronal injury.
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PMID:NF-kappaB-associated MnSOD induction protects against beta-amyloid-induced neuronal apoptosis. 1708 85

The present study demonstrates that manganese superoxide dismutase (MnSOD) (Escherichia coli), binds nitric oxide (*NO) and stimulates its decay under both anaerobic and aerobic conditions. The results indicate that previously observed MnSOD-catalyzed *NO disproportionation (dismutation) into nitrosonium (NO+) and nitroxyl (NO-) species under anaerobic conditions is also operative in the presence of molecular oxygen. Upon sustained aerobic exposure to *NO, MnSOD-derived NO- species initiate the formation of peroxynitrite (ONOO-) leading to enzyme tyrosine nitration, oxidation and (partial) inactivation. The results suggest that both ONOO- decomposition and ONOO(-)-dependent tyrosine residue nitration and oxidation are enhanced by metal centre-mediated catalysis. We show that the generation of ONOO- is accompanied by the formation of substantial amounts of H2O2. MnSOD is a critical mitochondrial antioxidant enzyme, which has been found to undergo tyrosine nitration and inactivation in various pathologies associated with the overproduction of *NO. The results of the present study can account for the molecular specificity of MnSOD nitration in vivo. The interaction of *NO with MnSOD may represent a novel mechanism by which MnSOD protects the cell from deleterious effects associated with overproduction of *NO.
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PMID:Consequences of MnSOD interactions with nitric oxide: nitric oxide dismutation and the generation of peroxynitrite and hydrogen peroxide. 1716 79

Oxidative stress is an important event in lesional skin of patients with chronic idiopathic urticaria (CIU). In the present study, we assessed blood oxidant/antioxidant status of patients suffering from CIU with positive response to autologous serum skin test (ASST) and with negative ASST, to improve our understanding of biological processes and the part of oxidative stress in this disease. Activities of manganese superoxide dismutase (MnSOD), copper-zinc superoxide dismutase (Cu/ZnSOD), glutathione peroxidase (GSH-PX), and catalase (CAT) as indices of enzymatic antioxidant capacity, as well as malondialdehyde (MDA) level as a maker of lipid peroxidation were measured in plasma and erythrocytes from 14 CIU female patients showing positive ASST, 31 CIU female patients with negative ASST and in 19 sex- and age-matched healthy subjects. The antioxidant enzyme activity in plasma and in erythrocytes did not differ significantly among the three groups. Also, the plasma and erythrocytes MDA levels were similar in the three groups. Based on our results, it seems that systemic activity of the enzymatic antioxidants (CuZn/SOD, MnSOD, GSH-Px, and CAT) as well as level of lipid peroxidation determined by MDA may not be increased in the course of immune-inflammatory processes associated with CIU. We also suggest that the systemic oxidant/antioxidant status of CIU patients, showing positive response to ASST, may not be different from that of CIU patients with negative ASST.
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PMID:Markers of antioxidant defence system and lipid peroxidation in peripheral blood of female patients with chronic idiopathic urticaria. 1717 48

This review focuses on evidence that oxidative stress during apoptosis is controlled, at least in part, by modulating cellular antioxidant defences. Evidence is presented from studies of apoptosis induced by glucocorticoids, HIV-1 infection and tumour necrosis factor-alpha. Glucocorticoid treatment of murine lymphocyte cell lines leads to the down-regulation of primary antioxidant defence enzymes, including catalase, superoxide dismutases, thioredoxin and DT-diaphorase. Following HIV-1 infection, disturbances in glutathione metabolism are seen, and decreased antioxidant enzyme activities have been reported for HIV-1-infected cell lines. The viral protein Tat may mediate these effects. Cellular resistance to apoptosis induced by tumour necrosis factor-alpha is modulated by the expression of manganese superoxide dismutase or Bcl-2. The loss of antioxidant defences is predicted to lead to oxidative stress, which could contribute to the mechanism of apoptosis through an effect on redox-sensitive transcription factors, calcium homeostasis or cysteine proteases.
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PMID:Modulation of the antioxidant defence as a factor in apoptosis. 1718 56

Adriamycin (ADR), a potent anti-tumor agent, produces reactive oxygen species (ROS) in cardiac tissue. Treatment with ADR is dose-limited by cardiotoxicity. However, the effect of ADR in the other tissues, including the brain, is unclear because ADR does not pass the blood-brain barrier. Some cancer patients receiving ADR treatment develop a transient memory loss, inability to handle complex tasks etc., often referred to by patients as chemobrain. We previously demonstrated that ADR causes CNS toxicity, in part, via systemic release of cytokines and subsequent generation of reactive oxygen and nitrogen species (RONS) in the brain. Here, we demonstrate that treatment with ADR led to an increased circulating level of tumor necrosis factor-alpha in wild-type mice and in mice deficient in the inducible form of nitric oxide (iNOSKO). However, the decline in mitochondrial respiration and mitochondrial protein nitration after ADR treatment was observed only in wild-type mice, not in the iNOSKO mice. Importantly, the activity of a major mitochondrial antioxidant enzyme, manganese superoxide dismutase (MnSOD), was reduced and the protein was nitrated. Together, these results suggest that NO is an important mediator, coupling the effect of ADR with cytokine production and subsequent activation of iNOS expression. We also identified the mitochondrion as an important target of ADR-induced NO-mediated CNS injury.
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PMID:Adriamycin-mediated nitration of manganese superoxide dismutase in the central nervous system: insight into the mechanism of chemobrain. 1722 39

Oxidative stress appears to be important in the pathogenesis of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). Single-nucleotide polymorphisms (SNPs) of antioxidant enzyme genes may play a part in determining individual susceptibility to these diseases. The Factors Influencing the Barrett's Adenocarcinoma Relationship (FINBAR) study is a population-based, case-control study of BE and EAC in Ireland. DNA from EAC (n = 207), BE (> or =3 cm BE at endoscopy with specialized intestinal metaplasia on biopsy, n = 189) and normal population controls (n = 223) were analyzed. Several SNPs spanning the genes for glutathione S-transferase P1 (GSTP1), manganese superoxide dismutase (MnSOD) and glutathione peroxidase 2 (GPX2) were genotyped using multiplex polymerase chain reaction and SNaPshottrade mark. The chi(2) test was used to compare genotype and allele frequencies between case and control subjects. Linkage disequilibrium between SNPs was quantified using Lewontin's D' value and haplotype frequency estimates obtained using Haploview. Eleven SNPs were genotyped (six for GSTP1, three for MnSOD and two for GPX2); all were in Hardy-Weinberg equilibrium. None was significantly associated with EAC or BE even before Bonferroni correction. Odds ratios for EAC for individual SNPs ranged from 0.68 [95% confidence interval (CI) 0.43-1.08] to 1.25 (95% CI 0.73-2.16), and for BE from 0.84 (95% CI 0.52-1.30) to 1.30 (95% CI 0.85-1.97). SNPs in all three genes were in strong linkage disequilibrium (D' > 0.887) but haplotype analysis did not show any significant association with EAC or BE. SNPs involving the GSTP1, MnSOD and GPX2 genes were not associated with BE or EAC. Further studies aimed at identifying susceptibility genes should focus on different antioxidant genes or different pathways.
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PMID:A population-based association study of SNPs of GSTP1, MnSOD, GPX2 and Barrett's esophagus and esophageal adenocarcinoma. 1727 36

Mice lacking Epas1, encoding the transcription factor Hypoxia-inducible Factor 2alpha (HIF-2alpha), exhibit an apparent mitochondrial disease state. Similarities between knock-outs of Epas1 and of Sod2, encoding the mitochondrial antioxidant enzyme manganese superoxide dismutase, led to the identification of Sod2 as a HIF-2alpha target gene. However, Sod2 levels in Epas1(-)(/)(-) liver are intermediate between that of Sod(+)(/)(-) and Sod2(-)(/)(-) mice, which have subtle or severe phenotypes, respectively. This suggests that additional HIF-2alpha target genes besides Sod2 contribute to the Epas1(-)(/)(-) mitochondrial disease state. To define the nature of the mitochondrial defect in Epas1(-)(/)(-) liver, we performed biophysical, biochemical, and molecular studies. In the setting of decreased Sod2 levels and increased oxidative stress, we found reduced respiration, sensitized mitochondrial permeability transition pore opening, intact electron transport chain activities, and impaired mitochondrial aconitase activity. Mitochondrial aconitase protein levels were preserved, whereas mRNA and protein levels for frataxin, the oxidative stress-regulated mitochondrial aconitase chaperone protein, were markedly reduced in Epas1(-)(/)(-) livers. The mouse Fxn promoter was preferentially activated by HIF-2alpha through a consensus HIF-responsive enhancer element. In summary, the studies reveal that Fxn, like Sod2, is a nuclear-encoded, mitochondrial-localized HIF-2alpha target gene required for optimal mitochondrial homeostasis. These findings expand upon the previously defined role of HIF-2alpha in the cellular response to oxidative stress and identify a novel link of HIF-2alpha with mitochondrial homeostasis.
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PMID:Hypoxia-inducible factor 2alpha regulates expression of the mitochondrial aconitase chaperone protein frataxin. 1732 95

The liver acinus displays a physiological periportal to perivenous oxygen gradient. This gradient was implicated to use reactive oxygen species (ROS) as mediators for the zonal gene expression. Mitochondria use oxygen and produce ROS, therefore they may contribute to the zonation of gene expression. To further elucidate this, we used the Cre-loxP system to generate a hepatocyte-specific null mutation of the mitochondrial antioxidant enzyme manganese superoxide dismutase (MnSOD) in mice. We found that ROS levels were enhanced in livers of MnSOD(-/-) mice which were reduced in size and displayed signs of liver failure such as intracellular protein droplets, increased apoptotic bodies and Bax levels as well as multinuclear hepatocytes. Further, the zonation of glutamine synthetase, glucokinase and phosphoenolpyruvate carboxykinase was no longer preserved. We conclude that deficiency of mitochondrial MnSOD initiates a dysregulation of zonated gene expression in liver.
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PMID:Deficiency of manganese superoxide dismutase in hepatocytes disrupts zonated gene expression in mouse liver. 1736 43


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