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)

Alterations in renal superoxide dismutase (SOD) isozymes were examined in cancerous tissues of human renal cell carcinoma and the corresponding non-cancerous renal tissues. Cu,Zn-SOD activities in cancerous tissues were lower than those in normal tissues. Mn-SOD activities were varied in the cases examined, whereas no significant difference between cancerous and normal tissues was observed for Mn- or total-SOD activities. Immunoblot analysis showed that the loss in enzyme activity in cancerous tissue was greater than the decrease in protein content for either isozyme. The selective decrease in Cu,Zn-SOD activities in cancerous tissue observed in this study suggests that the cytoplasmic defense against free radical damage appears to be reduced in renal cell carcinoma.
Res Commun Mol Pathol Pharmacol
PMID:Enzyme activity and protein content of superoxide dismutase isozymes in human renal cell carcinoma. 1175 74

Many individuals with cardiovascular diseases undergo periodic exercise conditioning with or with out medication. Therefore, this study investigated the interaction of exercise training and chronic nitric oxide synthase (NOS) inhibitor (Nitro-L-Arginine Methyl Ester, L-NAME) treatment on blood pressure and its correlation with aortic nitric oxide (NO), antioxidant defense system and oxidative stress parameters in rats. Fisher 344 rats were divided into four groups: (1) sedentary control, (2) exercise training (ET) for 8 weeks, (3) L-NAME (10 mg/kg, subcutaneous for 8 weeks) and (4) ET + L-NAME. Blood pressure (BP) was monitored weekly for 8 weeks with tail-cuff method. The animals were sacrificed 24 h after last treatments and thoracic aortic rings were isolated and analyzed. Exercise conditioning resulted in a significant increase in respiratory exchange ratio (RER), aortic NO production, NO synthase activity and inducible iNOS protein expression. Training significantly enhanced aortic GSH levels, GSH/GSSG ratio and up-regulation of aortic CuZn-SOD, Mn-SOD, catalase (CAT), glutathione peroxidase (GSH-Px) activity and protein expression and significantly decreased aortic lipid peroxidation. Chronic L-NAME administration resulted in a significant depletion of aortic NO, NOS activity, endothelial (eNOS) and iNOS protein expression, GSH level, GSH/GSSG ratio, down-regulation of aortic antioxidant enzyme activities and protein expressions. Aortic xanthine oxidase (XO) activity significantly increased with increased lipid peroxidation and protein oxidation after L-NAME administration. The biochemical changes were accompanied by increased in BP. Interaction of training and chronic NOS inhibitor treatment resulted in normalization of BP and aortic antioxidant enzyme activity and protein expression, up-regulation of aortic GSH/GSSG ratio, NO levels, Mn-SOD protein expression, depletion of GSSG, protein oxidation and lipid peroxidation. The data suggest that training attenuated the oxidative injury caused by chronic NOS inhibitor treatment by up-regulating the NO and antioxidant systems and lowering the BP in rats.
Mol Cell Biochem 2002 Feb
PMID:Exercise conditioning attenuates the hypertensive effects of nitric oxide synthase inhibitor in rat. 1195 54

Mutations in mitochondrial genes encoded by both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA have been implicated in a wide range of degenerative diseases. MtDNA base substitution and rearrangement mutations can cause myopathy, cardiomyopathy, ophthalmological defects, growth retardation, movement disorders, dementias, and diabetes. nDNA mutations can affect mtDNA replication and transcription, increase mtDNA mutations through defects in the adenine nucleotide translocator isoform 1 (ANT1), or cause Leigh's syndrome, as a result of defects in oxidative phosphorylation (OXPHOS) structural genes. Mouse models of mtDNA base substitution mutations have been created by introducing the mtDNA 16S rRNA chloramphenicol (CAP)-resistance mutation into the mouse female germline. This resulted in ophthalmological defects in chimeras and perinatal lethality resulting from myopathy and cardiomyopathy in mutant animals. Mouse models of mtDNA rearrangements have resulted in animals with myopathy, cardiomyopathy, and nephropathy. Conditional inactivation of the mouse nDNA mitochondrial transcription factor (Tfam) gene in the heart caused neonatal lethal cardiomyopathy, whereas its inactivation in the pancreatic beta-cells caused diabetes. Mutational inactivation of the mouse Ant1 gene resulted in myopathy, cardiomyopathy, and multiple mtDNA deletions in association with elevated reactive oxygen species (ROS) production. This suggests that multiple mtDNA deletion syndrome can be caused by increased ROS damage. The inactivation of the uncoupler protein genes (Ucp) 1-3 resulted in alterations in delta mu H+ and increased ROS production. Inactivation of the Ucp2 gene, which is expressed in the pancreatic beta-cells, resulted in increased islet ATP, increased serum insulin levels, and suppression of the diabetes of the ob/ob mouse genotype. Transgenic mice with altered beta-cell ATP-sensitive K+ channels (KATP) also developed diabetes. Mutational inactivation of the mitochondrial antioxidant genes for glutathione peroxidase (GPx1) and Mn superoxide dismutase (Sod2) caused reduced energy production and neonatal lethal dilated cardiomyopathy, respectively, the later being ameliorated by treatment with MnSOD mimics. Partial Sod2 deficiency (+/-) resulted in mice with increased mitochondrial damage during aging, and treatment of C. elegans with catalytic antioxidant drugs can extend their life-span. Mice deficient in cytochrome-c died early in embryogenesis, but cells derived from these embryos had a complete deficiency in mitochondrial apoptosis. Mice lacking the proapoptotic Bax and Bak genes were not able to release cytochrome-c from the mitochondrion and were blocked in apoptosis. Mice lacking Apaf1, Cas9, and Cas3 did release mitochondrial cytochrome-c and were blocked in the downstream steps of apoptosis. These animal studies confirm that alterations in mitochondrial energy generation, ROS production, and apoptosis can all contribute to the pathophysiology of mitochondrial disease.
Methods Mol Biol 2002
PMID:Animal models for mitochondrial disease. 1201 5

Overexpression of c-Myc or E2F1 sensitizes host cells to various types of apoptosis. Here, we found that overexpressed c-Myc or E2F1 induces accumulation of reactive oxygen species (ROS) and thereby enhances serum-deprived apoptosis in NIH3T3 and Saos-2. During serum deprivation, MnSOD mRNA was induced by NF-kappaB in mock-transfected NIH3T3, while this induction was inhibited in NIH3T3 overexpressing c-Myc or E2F1. In these clones, E2F1 inhibited NF-kappaB activity by binding to its subunit p65 in competition with a heterodimeric partner p50. In addition to overexpressed E2F1, endogenous E2F1 released from Rb was also found to inhibit NF-kappaB activity in a cell cycle-dependent manner by using E2F1(+/+) and E2F1(-/-) murine embryonic fibroblasts. These results indicate that E2F1 promotes apoptosis by inhibiting NF-kappaB activity.
Mol Cell 2002 May
PMID:E2F1 and c-Myc potentiate apoptosis through inhibition of NF-kappaB activity that facilitates MnSOD-mediated ROS elimination. 1204 38

There are numerous studies describing the neuroprotective effects of Ginkgo biloba extract EGb 761 on patients with disturbances of vigilance, memory and cognitive functions associated with aging and senility. Describing the pattern of gene expression in EGb 761-treated human hNT neurons may elucidate the molecular pathways leading to the neuroprotection. We used cDNA macroarrays including genes implicated in the antioxidant and stress responses to define the transcriptional effects of EGb 761 (250 microg/ml, 24 hr) on human hNT neurons. Seven genes were identified whose expression was strongly modified by the EGb 761 treatment. Three groups are distinguished: genes encoding transcription factors (increase of NF-kappaB p65 subunit and zinc finger protein 91 mRNAs, and decrease of c-myc transcripts), genes involved in antioxidant defenses (increase of the CuZn SOD mRNAs, and decrease of glutathione reductase and glutathione S-transferase pi mRNAs) and genes involved in stress responses (up-regulation of HSP70 transcripts). Consistent with the modulation of mRNAs by EGb 761, the enzymatic activities of glutathione reductase and glutathione S-transferase were decreased. Surprisingly, CuZn SOD activity was decreased despite increased abundance of the mRNAs; furthermore MnSOD activity was unmodified, and thus the effect of EGb 761 was specific to CuZn SOD. These results support the idea that modulation of target genes and transcription factors may be involved in the neuroprotective action of EGb 761.
Cell Mol Biol (Noisy-le-grand) 2002 Sep
PMID:The Ginkgo biloba extract EGb 761 increases viability of hnt human neurons in culture and affectsthe expression of genes implicated in the stress response. 1239 74

The Pseudomonas aeruginosa secretory product pyocyanin damages lung epithelium, likely due to redox cycling of pyocyanin and resultant superoxide and H(2)O(2) generation. Subcellular site(s) of pyocyanin redox cycling and toxicity have not been well studied. Therefore, pyocyanin's effects on subcellular parameters in the A549 human type II alveolar epithelial cell line were examined. Confocal and electron microscopy studies suggested mitochondrial redox cycling of pyocyanin and extracellular H(2)O(2) release, respectively. Pyocyanin decreased mitochondrial and cytoplasmic aconitase activity, ATP levels, cellular reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide, and mitochondrial membrane potential. These effects were transient at low pyocyanin concentrations and were linked to apparent cell-mediated metabolism of pyocyanin. Overexpression of MnSOD, but not CuZnSOD or catalase, protected cellular aconitase, but not ATP, from pyocyanin-mediated depletion. This suggests that loss of aconitase activity is not responsible for ATP depletion. How pyocyanin leads to ATP depletion, the mechanism of cellular metabolism of pyocyanin, and the impact of mitochondrial pyocyanin redox cycling on other cellular events are important areas for future study.
Am J Physiol Lung Cell Mol Physiol 2003 Feb
PMID:Subcellular localization of Pseudomonas pyocyanin cytotoxicity in human lung epithelial cells. 1241 38

The Fe- and Mn-containing superoxide dismutases catalize the same reaction and have almost superimposable active sites. Therefore, the details of their mechanisms have been assumed to be similar. However, we now show that the pH dependence of Escherichia coli MnSOD activity reflects a different active site proton equilibrium in (oxidized) Mn(3+)SOD than the event that affects the active site pK of oxidized FeSOD. We find that the universally conserved Tyr34 that has a pK above 11.5 in Fe(3+)SOD is responsible for the pK near 9.5 of Mn(3+)SOD and, thus, that the oxidized state pK of Mn(3+)SOD corresponds to an outer-sphere event whereas that of Fe(3+)SOD corresponds to an inner sphere event [Bull, C.; Fee, J. A. J. Am. Chem. Soc. 1985, 107, 3295-3304]. We also present the first description of a reduced-state pK for MnSOD. Mn(2+)SOD's pK involves deprotonation of Tyr34, as does Fe(2+)SOD's pK [Sorkin, D. L.; Miller A.-F. Biochemistry 1997, 36, 4916-4924]. However, the values of the pKs, 10.5 and 8.5 respectively, are quite different and Mn(2+)SOD's pK affects the coordination geometry of Mn(2+), most likely via polarization of the conserved Gln146 that hydrogen bonds to axially coordinated H(2)O. Our findings are consistent with the different electronic configurations of Mn(2+/3+) vs Fe(2+/3+), such as the stronger hydrogen bonding between Gln146 and coordinated solvent in MnSOD than that between the analogous Gln69 and coordinated solvent in FeSOD, and the existence of weakly localized H(2)O near the sixth coordination site of Mn(2+) in Mn(2+)SOD [Borgstahl et al. J. Mol. Biol. 2000, 296, 951-959].
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PMID:Comparison and contrasts between the active site PKs of Mn-superoxide dismutase and those of Fe-superoxide dismutase. 1247 51

Antioxidant enzymes are critical in oxidative stress responses. Radioresistant variants isolated from MCF-7 human carcinoma cells following fractionated ionizing radiation (MCF+FIR cells) or overexpression of manganese superoxide dismutase (MCF+SOD cells) demonstrated dose-modifying factors at 10% isosurvival of 1.8 and 2.3, respectively. MCF+FIR and MCF-7 cells (exposed to single-dose radiation) demonstrated 5- to 10-fold increases in MnSOD activity, mRNA, and immunoreactive protein. Radioresistance in MCF+FIR and MCF+SOD cells was reduced following expression of antisense MnSOD. DNA microarray analysis and immunoblotting identified p21, Myc, 14-3-3 zeta, cyclin A, cyclin B1, and GADD153 as genes constitutively overexpressed (2- to 10-fold) in both MCF+FIR and MCF+SOD cells. Radiation-induced expression of these six genes was suppressed in fibroblasts from Sod2 knockout mice (-/-) as well as in MCF+FIR and MCF+SOD cells expressing antisense MnSOD. Inhibiting NF-kappa B transcriptional activity in MCF+FIR cells, by using mutant I kappa B alpha, inhibited radioresistance as well as reducing steady-state levels of MnSOD, 14-3-3 zeta, GADD153, cyclin A, and cyclin B1 mRNA. In contrast, mutant I kappa B alpha was unable to inhibit radioresistance or reduce 14-3-3 zeta, GADD153, cyclin A, and cyclin B1 mRNAs in MCF+SOD cells, where MnSOD overexpression was independent of NF-kappa B. These results support the hypothesis that NF-kappa B is capable of regulating the expression of MnSOD, which in turn is capable of increasing the expression of genes that participate in radiation-induced adaptive responses.
Mol Cell Biol 2003 Apr
PMID:Manganese superoxide dismutase-mediated gene expression in radiation-induced adaptive responses. 1264 Jan 21

Both NADH dehydrogenase (complex I) and aconitase are inactivated partially in vitro by superoxide (O2-.) and other oxidants that cause loss of iron from enzyme cubane (4Fe-4S) centers. We tested whether hypoxia-reoxygenation (H-R) by itself would decrease lung epithelial cell NADH dehydrogenase, aconitase, and succinate dehydrogenase (SDH) activities and whether transfection with adenoviral vectors expressing MnSOD (Ad.MnSOD) would inhibit oxidative enzyme inactivation and thus confirm a mechanism involving O2-. Human lung carcinoma cells with alveolar epithelial cell characteristics (A549 cells) were exposed to <1% O2-5% CO2 (hypoxia) for 24 h followed by air-5% CO2 for 24 h (reoxygenation). NADH dehydrogenase activity was assayed in submitochondrial particles; aconitase and SDH activities were measured in cell lysates. H-R significantly decreased NADH dehydrogenase, aconitase, and SDH activities. Ad.MnSOD increased mitochondrial MnSOD substantially and prevented the inhibitory effects of H-R on enzyme activities. Addition of alpha-ketoglutarate plus aspartate, but not succinate, to medium prevented cytotoxicity due to 2,3-dimethoxy-1,4-naphthoquinone. After hypoxia, cells displayed significantly increased dihydrorhodamine fluorescence, indicating increased mitochondrial oxidant production. Inhibition of NADH dehydrogenase, aconitase, and SDH activities during reoxygenation are due to excess O2-. produced in mitochondria, because enzyme inactivation can be prevented by overexpression of MnSOD.
Am J Physiol Lung Cell Mol Physiol 2003 Jul
PMID:Mitochondrial complex I, aconitase, and succinate dehydrogenase during hypoxia-reoxygenation: modulation of enzyme activities by MnSOD. 1266 64

Reactive oxygen species have been established as key mediators of cardiac injury following ischemia/reperfusion (I/R). We hypothesized that superoxide formation at different subcellular locations following cardiac I/R injury may differentially regulate cellular responses that determine pathophysiologic outcomes. Recombinant adenoviruses expressing Cu/ZnSOD or MnSOD were utilized to modulate superoxide levels in the cytoplasmic or mitochondrial compartments, respectively, prior to coronary artery I/R injury in the rat heart. Ectopic expression of both MnSOD and Cu/ZnSOD afforded protection from I/R injury, as evidenced by a significant reduction in serum creatine kinase levels, infarct size, malondialdehyde levels, and apoptotic cell death in comparison to controls. MnSOD and Cu/ZnSOD expression also significantly altered the kinetics of NF kappa B and AP-1 activation following I/R injury, characterized by a delayed induction of NF kappa B and abrogated AP-1 response. Western blot analysis of Bcl-2, Bcl-xL, Bad, Caspase 3, PDK1, and phospho-Akt also revealed SOD-mediated changes in gene expression consistent with protection and decreased apoptosis. These findings support the notion that both mitochondrial and cytoplasmic-derived SOD induce changes in AP-1 and NF kappa B activity, creating an antiapoptotic microenvironment within cardiomyocytes that affords protection following I/R injury.
Mol Ther 2003 Mar
PMID:Genetic redox preconditioning differentially modulates AP-1 and NF kappa B responses following cardiac ischemia/reperfusion injury and protects against necrosis and apoptosis. 1266 30


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