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)

Cytosolic and mitochondrial alterations induced by exposure of rat astroglial primary cultures to reactive oxygen species (ROS) generated by a xanthine/xanthine oxidase (X/XO) mixture or by lipopolysaccharide (LPS) have been investigated biochemically and immunochemically. In the presence of ROS generated by X/XO, a significant decrease in Cu,Zn superoxide dismutase (Cu,Zn-SOD) and in glutamine synthetase (GS) activity was observed whereas mitochondrial Mn-SOD activity and enzyme protein levels were significantly enhanced. Similar effects on GS, Cu,Zn- and Mn-SOD activities were observed by glucose/glucose oxidase treatment of the cells. Addition of LPS to the cell growth medium also specifically induces Mn-SOD synthesis but was without effect on Cu,Zn-SOD. It is suggested that in all these tested situations, hydrogen peroxide could represent a specific inducer of the observed phenomenon and it may therefore be considered as an intracellular messenger involved in the regulation of some aspects of astroglial oxidative metabolism, particularly the defence against ROS.
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PMID:Modulation of oxygen-radical-scavenging enzymes by oxidative stress in primary cultures of rat astroglial cells. 894 Jun 11

The present study was designed to identify the mechanism of increased oxidant stress in the rat model of anti-glomerular basement membrane nephritis. Sixty-three Sprague-Dawley rats were injected with nephrotoxic serum and evaluated 1 to 24 hours later. In these rats, CeCl3 deposition, an index of hydrogen peroxide production, was observed on the surfaces of glomerular endothelial cells and polymorphonuclear leukocytes, whereas no such depositions were observed in controls. Renal cortical level of lipid peroxidation products (phosphatidylcholine hydroperoxide) was significantly (p < 0.05) elevated at one hour after the injection and remained elevated at least for 24 hours. Protein levels of glomerular Mn-superoxide dismutase (SOD) decreased from 1.55 +/- 0.38 microgram/mg protein to 0.67 +/- 0.18 microgram/mg protein at one hour and normalized by 12 hours after the injection. The activity of the enzyme showed a similar trend. In contrast, Mn-SOD mRNA increased 3.4-fold at 3 hours after the injection. In situ hybridization showed increased Mn-SOD mRNA expression in glomeruli. Cu/Zn-SOD mRNA expression was transiently suppressed. These results indicated that both increase in local production of reactive oxygen species (ROS) and reduction in antioxidant enzyme activities are responsible for the enhanced oxidant stress in the heterologous phase of anti-glomerular basement membrane nephritis. The paradoxical increase in Mn-SOD mRNA expression indicates that the posttranscriptional down regulation of Mn-SOD (i.e., reduction in protein and activity) and the increased ROS may activate transcription of the gene.
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PMID:Mechanism of elevated local oxidant stress in early anti-glomerular basement membrane nephritis: an evaluation of oxidant production and superoxide dismutase expression. 894 Aug 25

The production of superoxide (O2-) under hyperoxic conditions is markedly accentuated leading to the generation of potent oxidants such as hydrogen peroxide (H2O2), hydroxyl radical (HO.), and peroxynitrite (ONOO-). Superoxide dismutase (SOD), by rapidly removing O2-, reduces the tissue concentration of O2- and prevents the production of HO. and ONOO-. Three forms of SOD exist in the lung: CuZnSOD, MnSOD, and extracellular SOD. Considerable supportive, though not all conclusive, evidence suggests that all three forms of SOD are essential for the pulmonary defense against oxygen toxicity, and that enhancement of pulmonary SOD has the potential of protecting against oxygen toxicity.
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PMID:Superoxide dismutase and pulmonary oxygen toxicity. 903 27

The oxidative stress related consequences of physical training at high altitude are not known. The hypothesis was tested that physical training and exposure to high altitude have adverse effects on free radical generation and activities of antioxidant enzymes. The present results showed that 4 weeks of exercise at an altitude of 4000 m increased the activity of Mn-SOD in both white and red types of skeletal muscle. The activities of Cu,Zn-SOD, catalase, and glutathione peroxidase, as well as the level of lipid peroxidation measured by TBARS and lipid hydroperoxides, did not change significantly. In contrast, the level of reactive carbonyl derivatives measured by anti-2,4-dinitrophenylhydrazone antibodies and spectrophotometry showed an increase in both types of muscle of altitude trained rats compared with sea level trained and control groups. It was suggested that the oxidative modification of certain amino acids is due to the increasing gap between activity of SOD and peroxide scavenging enzymes, which results in increases in the number of hydrogen peroxide molecules. Thus, since the mechanism of generation and/or the mode of action of radicals resulting in lipid peroxidation and protein oxidation appears to be different in vivo, both processes should be studied during oxidative stress.
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PMID:High altitude training increases reactive carbonyl derivatives but not lipid peroxidation in skeletal muscle of rats. 903 49

The enzyme superoxide dismutase (SOD), which catalyzes the dismutation of the superoxide radical, is present in the cytosol and mitochondria of all oxygen-respiring eukaryotes. The cytosolic form contains copper and zinc (CuZnSOD), whereas the mitochondrial form contains manganese (MnSOD). The latter protein is synthesized in the cytosol as a MnSOD precursor, containing an N-terminal mitochondrial-targeting sequence. CuZnSOD is sensitive toward cyanide (CN) and hydrogen peroxide (H2O2), but MnSOD is not. Assays for SOD activity in cytosol from the hepatopancreas of the blue crab, Callinectes sapidus, showed the presence of a CN/H2O2-insensitive form of SOD. No CN/H2O2-sensitive CuZnSOD was found. This unexpected phenomenon was shown to occur in all decapod crustacea (crabs, lobsters, shrimp) examined. The cytosolic and mitochondrial SODs of C. sapidus were purified by means of ion-exchange, size-exclusion, and reverse-phase HPLC. The cytosolic SOD is a homodimeric protein, which exists in a monomer-dimer equilibrium (24 kDa left and right arrow 48 kDa). The protein contains approximately 1 Mn per subunit. No copper or zinc is present. Amino acid sequence analysis identified the novel cytosolic SOD as a MnSOD precursor with an abnormal mitochondrial-targeting sequence. The mitochondrial SOD of C. sapidus is similar to the MnSOD found in other eukaryotes. N-Terminal amino sequences of mitochondrial and cytosolic blue crab MnSOD differ in several positions. The MnSODs are thus encoded for by two different genes. The paradigm that all eukaryotes contain intracellular CuZnSOD and that MnSOD occurs exclusively in the mitochondria appears not to apply to a large group of marine arthropods.
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PMID:The paradigm that all oxygen-respiring eukaryotes have cytosolic CuZn-superoxide dismutase and that Mn-superoxide dismutase is localized to the mitochondria does not apply to a large group of marine arthropods. 934 Dec 31

The effect of hydrogen peroxide (H2O2) on the expression of different antioxidant enzymes was investigated in primary rat hepatocytes and the rat hepatoma H4IIE cell line. Catalase mRNA expression and enzyme activity decreased during rat hepatocyte culture. Exposure of hepatocytes to H2O2 prevented this decrease in catalase mRNA expression, catalase expression was induced 2-fold. MnSOD message levels showed a peak after 12 h of culture and MnSOD enzyme activity increased similarly. MnSOD mRNA expression was also induced after exposure to H2O2. Cu/ZnSOD mRNA expression remained constant during culturing and was not affected by H2O2 treatment. In confluent hepatoma H4IIE cells catalase mRNA expression was lower than in early hepatocyte cultures and could be induced 2-fold upon treatment with H2O2. Actinomycin D alone caused the same amount of induction of catalase mRNA in rat hepatocytes as in combination with H2O2. Exposure of hepatocytes to cycloheximide did not influence the induction of catalase mRNA by H2O2. In rat hepatoma H4IIE cells the induction of catalase mRNA by H2O2 was prevented by the addition of actinomycin D or cycloheximide. Although induction of catalase mRNA by H2O2 was found in rat hepatocytes and H4IIE cells, gene expression of catalase does not appear to be regulated in both cell types in the same manner.
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PMID:Alterations of antioxidant enzyme expression in response to hydrogen peroxide. 943 11

Structural and biochemical characterization of the nonliganding residue glutamine 143 near the manganese of human Mn superoxide dismutase (hMnSOD), a homotetramer of 22 kDa, reveals a functional role for this residue. In the wild-type protein, the side-chain amide group of Gln 143 is about 5 A from the metal and is hydrogen-bonded to Tyr 34, which is a second prominent side chain adjacent to the metal. We have prepared the site-specific mutant of hMnSOD with the conservative replacement of Gln 143 --> Asn (Q143N). The crystal structure of Q143N shows that the side-chain amide nitrogen of residue 143 is 1.7 A more distant from the manganese than in the wild-type enzyme. The Tyr 34 side-chain hydroxyl in Q143N is also moved to become 0.6 A more distant from the metal due to an additional water molecule. Differential scanning calorimetry showed that Q143N is slightly more stable than the wild-type enzyme with Tm for the main unfolding transition increased by 2 degrees C to 90.7 degrees C. Pulse radiolysis and stopped-flow spectrophotometry reveal that unlike wild-type hMnSOD, which is strongly inhibited by peroxide, Q143N MnSOD exhibits no product inhibition even at concentrations of O2. - in the millimolar range, and its catalysis follows Michaelis kinetics with no evidence of cooperativity. However, the overall catalytic activity of this mutant was decreased 2-3 orders of magnitude compared with the wild-type MnSOD, which can account for its lack of product inhibition. Q143N MnSOD lacked the visible absorption spectrum typical of wild-type Mn(III)SOD. Also, unlike the wild-type Mn(III)SOD, which is electron paramagnetic resonance (EPR) silent, Q143N MnSOD has a complex EPR spectrum with many resonances in the region below 2250 G. We conclude that the Gln 143 --> Asn mutation has increased the reduction potential of manganese to stabilize Mn(II), indicating that Gln 143 has a substantial role in maintaining a reduction potential favorable for the oxidation and reduction cycles in the catalytic disproportionation of superoxide. A solvent hydrogen isotope effect near 2 for kcat in catalysis by Q143N hMnSOD indicates rate-contributing proton transfers to form product hydroperoxide anion or hydrogen peroxide. The data demonstrate a prominent role for Gln 143 in maintaining the microenvironment of the manganese and in efficient catalysis of superoxide dismutation to oxygen and hydrogen peroxide.
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PMID:Probing the active site of human manganese superoxide dismutase: the role of glutamine 143. 953 88

The function of the prion protein (PrPc) remains uncertain. It has been suggested that prion protein expression may aid cellular resistance to oxidative stress by influencing the activity of Cu/Zn superoxide dismutase (Cu,Zn SOD). The activity of Cu,Zn SOD was investigated in mice with different levels of PrPc expression. Increasing levels of PrPc expression were linked to increased levels of Cu,Zn SOD activity. Western-blot and Northern-blot analysis indicated that mice either lacking or overexpressing PrPc had levels of Cu,Zn SOD mRNA equivalent to those expressed in wild-type mice. Mice overexpressing the prion protein had lower levels of resistance to oxidative stress but higher expression levels of glutathione peroxidase, probably due to increased levels of hydrogen peroxide produced by increased Cu,Zn SOD activity. When cells were metabolically labelled with radioactive copper, increased radioactivity was immunoprecipitated with Cu,Zn SOD from mice with higher levels of PrPc. In addition, diethyldithiocarbamate, a copper chelator that inactivates Cu,Zn SOD by capturing copper from the molecule, is more able to inactivate Cu,Zn SOD expressed in animals with higher levels of PrPc. As recent studies have suggested that PrPc may regulate some aspect of copper metabolism, it is suggested that PrPc expression may regulate Cu,Zn SOD activity by influencing copper incorporation into the molecule.
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PMID:Prion protein expression and superoxide dismutase activity. 971 1

Nitric oxide (NO) released from (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1- ium-1,2-diolate (DETA/NO or NOC-18) induces apoptosis in human leukemia HL-60 cells. In this study, we isolated a HL-60 variant cell line, HL-NR6, that is resistant to DETA/NO toxicity as assessed by DNA fragmentation, morphology, and colony forming ability. The variant cells also showed resistance to reactive oxygen species (ROS) such as superoxide and hydrogen peroxide as well as NO donors, but not to anti-tumor drugs. We found that HL-NR6 cells when compared with HL-60 cells possessed twice the activities of Cu,Zn-superoxide dismutase (Cu,Zn-SOD) and catalase, but no change in Mn-SOD nor in glutathione peroxidase. Immunoblotting confirmed the high levels of both enzymes in the variant cell. We also observed that ROS generation following DETA/NO exposure was substantially higher in HL-60 cells than in HL-NR6 cells, using the 2',7'-dichlorofluorescein fluorometric method. Moreover, the SOD mimetic Mn(III) tetrakis(1-methyl-4-pyridyl) porphyrin and exogenous catalase effectively attenuated DETA/NO-elicited DNA fragmentation in HL-60 cells. Taken together, these data suggested that the NO resistance in HL-NR6 cells is associated with the increased Cu,Zn-SOD/catalase and that NO-mediated apoptosis in HL-60 cells is correlated with the generation of ROS and derived molecules like peroxynitrite.
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PMID:Resistance to nitric oxide-mediated apoptosis in HL-60 variant cells is associated with increased activities of Cu,Zn-superoxide dismutase and catalase. 989 23

Epiandrosterone (EA), dehydroepiandrosterone (DHEA), and their sulfate (-S) and acetate (-A) conjugates were investigated for effects on isolated pancreatic islets and RINm5F insulinoma cells. Interleukin-1 beta (IL-1 beta) inhibited glucose-stimulated insulin release in cultured islets, but the presence of EA, EA-A, and to a lesser extent EA-S, preserved the secretory response. IL-1 beta also increased islet nitrite production, which was antagonized by EA and EA-A, but not by EA-S. EA, EA-A, DHEA, and DHEA-A, but not EA-S and DHEA-S inhibited glucose-stimulated insulin release from islets. This response may be related to the inhibition of glucose transport by EA, EA-A, DHEA, DHEA-A, and DHEA-S, as observed in RINm5F cells. EA, EA-A, DHEA, and DHEA-A also inhibited glucose metabolism in RINm5F cells, whereas EA-S and DHEA-S had no effect. EA, EA-A, DHEA, and DHEA-A, but not the sulfate conjugates, also inhibited RINm5F cell IL-1 beta-induced nitric oxide synthase (iNOS) activity. IL-1 beta also increased cytosolic Cu/Zn-superoxide dismutase (SOD) and mitochondrial Mn-SOD in RINm5F cells. EA inhibited RINm5F cell Cu/Zn-SOD in the presence and absence of IL-1 beta, whereas EA-S increased basal enzyme activity and did not affect the IL-1 beta response. EA did not affect basal Mn-SOD activity and inhibited IL-1 beta-stimulated activity, whereas EA-S was without effect. IL-1 beta had no effect on catalase activity in RINm5F cells, whereas EA, EA-A, and DHEA-A inhibited catalase activity. Thus, EA and DHEA and their acetate congeners protected the beta-cell from the inhibitory effects of IL-1 beta, and inhibited glucose transport and oxidation, and inducible nitricoxide synthase expression. EA and DHEA also had profound effects on Cu/Zn-SOD, which may alter the toxic effects of hydrogen peroxide generation in beta-cells.
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PMID:Rat pancreatic islet and RINm5F cell responses to epiandrosterone, dehydroepiandrosterone and interleukin-1 beta. 1007 38


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