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)

In this report we show that ubiquinone cytochrome c reductase (complex III) from isolated rat heart mitochondria when inhibited with antimycin A, produces a large amount of superoxide as measured by the chemiluminescent probe coelenterazine. When mitochondria are inhibited with myxothiazol or stigmatellin, there is no detectable formation of superoxide. The antimycin A-sensitive free radical production can be dramatically reduced using either myxothiazol or stigmatellin. This suggests that the antimycin A-sensitive generation of superoxides originates primarily from the Q(o) semiubiquinone. When manganese superoxide dismutase depleted submitochondrial particles (SMP) were inhibited with myxothiazol or stigmatellin, a large superoxide signal was observed. These two inhibitors likely increase the concentration of the Q(i) semiquinone at the N center. The antimycin A-sensitive signal can, in the case of both the mitochondria and the SMP, be dissipated by the addition of copper zinc superoxide dismutase, suggesting that the measured coelenterazine signal was a result of superoxide production. Taken together, this data suggests that free radicals generated from the Q(i) species are more effectively eliminated by MnSOD in intact mitochondria.
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PMID:Superoxides from mitochondrial complex III: the role of manganese superoxide dismutase. 1098 Apr 5

Cyclooxygenase-2 (COX-2) is an essential enzyme for prostaglandin synthesis from arachidonic acid, during which considerable amounts of superoxide are produced. During pathological conditions, superoxide and nitric oxide (NO) rapidly form peroxynitrite, a potent cytotoxin, causing symptoms referred to as oxidative stress response. Superoxide is controlled by enzymes such as manganese- or copper-zinc-dependent superoxide dismutase (Mn-SOD, CuZn-SOD), glutathione peroxidase (GPx) and antioxidants derived from heme oxygenase (HO) activity such as biliverdin and bilirubin. NO derives from 3 NO-synthases (NOS I-III) from which the calcium-dependent NOS-I and III are activated rapidly due to hyperexcitation. We studied the induction of COX-2 by immunohistochemistry at days 1, 2 and 5 following cortical photothrombosis in normal and MK-801 treated rats. The results showed a weak constitutive, neuronal expression of COX-2 in cortex and amygdala. Layers II+III contained considerably more COX-2 than infragranular layers. One and 2 days following injury COX-2 was highly upregulated in the supragranular layers of the whole injured hemisphere compared with sham-operated animals and compared to the contralateral unlesioned hemisphere, whereas at day 5 COX-2 levels had returned to baseline. MK-801 treatment caused a reduction in COX-2 upregulation at day one and by day 2 no significant differences between injured and contralateral hemisphere were measurable. COX-2 positive neurons were found in close association with NOS-I containing neurons and their fibers but were not colocalized. In addition, codistribution of COX-2 was found with HO-1, CuZn-SOD and GPx containing cells, whereas COX-2 was colocalized with HO-2 and/or MnSOD in cortical neurons.
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PMID:Unilateral upregulation of cyclooxygenase-2 following cerebral, cortical photothrombosis in the rat: suppression by MK-801 and co-distribution with enzymes involved in the oxidative stress cascade. 1111 8

Dietary copper- and iron restriction was achieved by application of the whole milk diet to growing rats in the course of 50 days. Three distinct responses of cytosolic and mitochondrial aconitases as well as of antioxidant defense system (CuZnSOD, MnSOD, catalase and GSH) to the dietary copper- and iron deficiency were established in liver, kidney and heart from experimental rats. The results were discussed with a view to the participation of ROS-generating processes in copper- and iron-deficient state. Differences in oxidative stability of cytosolic and mitochondrial aconitase activity of both control and experimental rats were also found. The in vitro increased aconitase activity of cytosol and the unchanged one of mitochondria from liver upon exposure of preparations to air were proved in vivo upon dietary copper- and iron restriction. This finding was interpreted to suggest the existence of putative aconitase activity.
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PMID:Effect of dietary copper and iron restriction on aconitase activity and antioxidant capacity of liver, kidney and heart from growing rats. 1114 Jan 69

We examined the effects of a variety of ligands/activators of the peroxisome proliferator-activated receptor (PPAR) on the expression of the superoxide scavenger enzyme, Cu2+,Zn2+-superoxide dismutase (CuZn-SOD), and the superoxide generating enzyme nicotinamide adenine dinucleotide phosphate (reduced form) (NADPH) oxidase in primary cultures of human umbilical vein endothelial cells (HUVEC) and human aorta endothelial cells (HAEC). Our data show that 3 types of PPARs, PPARalpha, PPARbeta/delta/Nuc1, and PPARgamma are expressed in endothelial cells. Bezafibrate, which is a ligand/activator for PPARalpha, increased the CuZn-SOD gene expression and protein levels in endothelial cells. Troglitazone and pioglitazone, which are ligands/activators for PPARgamma, also induced PPARalpha gene and protein expression and increased CuZn-SOD gene expression and protein levels in addition to increasing PPARgamma gene and protein expression in endothelial cells. Moreover, with treatment of monounsaturated and polyunsaturated fatty acids (PUFA), the CuZn-SOD mRNA levels were positively correlated with PPARalpha mRNA levels (r = .872, P < .0001) in primary endothelial cells. In addition, the phorbol myristate acetate (PMA)-stimulated or PMA-nonstimulated 22-kd a-subunit (p22phox) mRNA levels and 47-kd a-subunit (p47phox) protein levels in NADPH oxidase were decreased by treatment with PPARalpha and PPARgamma ligands/activators. These results suggest that PPARalpha and PPARgamma gene and protein expression in endothelial cells may play a physiologic role as radical scavengers, although the details of these mechanisms remain to be established.
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PMID:The ligands/activators for peroxisome proliferator-activated receptor alpha (PPARalpha) and PPARgamma increase Cu2+,Zn2+-superoxide dismutase and decrease p22phox message expressions in primary endothelial cells. 1117 67

Patients with Down's syndrome (DS) show elevated levels of copper, zinc-containing superoxide dismutase (SOD1) and appear to have increased lipid peroxidation and oxidative damage to DNA as well as elevated glutathione peroxidase activity. Increasing SOD1 levels by gene transfection in NT-2 and SK-N-MC cell lines also led to a rise in glutathione peroxidase activity, but this was nevertheless accompanied by decreased proliferation rates, increased lipid peroxidation and protein carbonyls, and a trend to a rise in 8-hydroxyguanine and protein-bound 3-nitrotyrosine. Transfection of these cell lines with DNA encoding two mutant SOD1 enzymes (G37R and G85R) associated with familial amyotrophic lateral sclerosis (FALS), produced similar, but more severe changes, i.e. even lower growth rates, higher lipid peroxidation, 3-nitrotyrosine and protein carbonyl levels, decreased GSH levels, raised GSSG levels and higher glutathione peroxidase activities. Since G85R has little SOD activity, these changes cannot be related to increased O(2)(-) scavenging. In no case was SOD2 (mitochondrial Mn-SOD) level altered. Our cellular systems reproduce many of the biochemical changes observed in patients with DS or ALS, and in transgenic mice overexpressing mutant SOD1. They also show the potentially deleterious effects of SOD1 overexpression on cellular proliferation, which may be relevant to abnormal development in DS.
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PMID:Effect of overexpression of wild-type and mutant Cu/Zn-superoxide dismutases on oxidative damage and antioxidant defences: relevance to Down's syndrome and familial amyotrophic lateral sclerosis. 1118 15

Superoxide dismutases (SODs) are involved in the protection of cells from oxygen toxicity. However, several papers have reported that the overexpression of CuZn-SOD causes oxidative damage to cells. We investigated a mechanism by which an excess of SODs accelerates oxidative stress. The presence of CuZn-SOD, Mn-SOD or Mn(II) enhanced the frequency of DNA damage induced by hydrogen peroxide (H2O2) and Cu(II), and altered the site specificity of the latter: H2O2 induced Cu(II)-dependent DNA damage with high frequency at the 5'-guanine of poly G sequences; when SODs were added, the frequency of cleavages at thymine and cytosine residues increased. SODs also enhanced the formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine by H2O2 and Cu(II). We conclude that SODs may increase carcinogenic risks, e.g. of tumors in Down syndrome.
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PMID:Superoxide dismutases enhance H2O2-induced DNA damage and alter its site specificity. 1133 89

The expression of the HIV-1 Tat protein in HeLa cells resulted in a 2.5-fold decrease in the activity of the antioxidant enzyme glutathione peroxidase (GPX). This decrease seemed not to be due to a disturbance in selenium (Se) uptake. Indeed, the intracellular level of Se was similar in parental and tat-transfected cells. A Se enrichment of the medium did not lead to an identical GPX activity in both cell lines, suggesting a disturbance in Se utilization. Total intracellular 75Se selenoproteins were analyzed. Several quantitative differences were observed between parental and tat-transfected cells. Mainly, cytoplasmic glutathione peroxidase and a 15-kDa selenoprotein were decreased in HeLa-tat cells, while phospholipid hydroperoxide glutathione peroxidase and low-molecular-mass selenocompounds were increased. Thioredoxin reductase activity and total levels of 75Se-labeled proteins were not different between the two cell types. The effect of Tat on GPX mRNA levels was also analyzed. Northern blots revealed a threefold decrease in the GPX/glyceraldehyde phosphate dehydrogenase mRNA ratio in HeLa-tat versus wild type cells. By deregulating the intracellular oxidant/antioxidant balance, the Tat protein amplified UV sensitivity. The LD50 for ultraviolet radiation A was 90 J/cm2 for HeLa cells and only 65 J/cm2 for HeLa-tat cells. The oxidative stress occurring in the Tat-expressing cells and demonstrated by the diminished ratio of reduced glutathione/oxidized glutathione was not correlated with the intracellular metal content. Cellular iron and copper levels were significantly decreased in HeLa-tat cells. All these disturbances, as well as the previously described decrease in Mn superoxide dismutase activity, are part of the viral strategy to modify the redox potential of cells and may have important consequences for patients.
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PMID:Human immunodeficiency virus type 1 Tat protein impairs selenoglutathione peroxidase expression and activity by a mechanism independent of cellular selenium uptake: consequences on cellular resistance to UV-A radiation. 1136 44

Spodoptera frugiperda Sf-9 (Sf-9) and Trichoplusia ni BTI-Tn-5B1-4 (Tn-5B1-4) insect cell lines were found to contain unique assemblages of antioxidant enzymes. Specifically, the Sf-9 insect cell line contained Manganese and Copper-Zinc superoxide dismutase (MnSOD and CuZnSOD) for reducing the superoxide radical (O(2)(*-)) to hydrogen peroxide (H(2)O(2)) and ascorbate peroxidase (APOX) for reducing the resulting H(2)O(2) to H(2)O. Approximately one third of the total SOD activity was found to be MnSOD. The Tn-5B1-4 cells were also found to contain MnSOD (approximately two thirds of the total SOD activity), CuZnSOD and APOX activities. However, the Tn-5B1-4 cell line, in contrast to the Sf-9 cell line, contained catalase (CAT) activity for reducing H(2)O(2) to H(2)O. Both the Sf-9 and Tn-5B1-4 cell lines contained glutathione reductase and dehydroascorbic acid reductase activities for regenerating the reduced forms of glutathione and ascorbic acid, respectively. In addition, both cell lines contained glutathione S-transferase peroxidase activity towards hydroperoxides other than H(2)O(2). Finally, neither cell line contains the glutathione peroxidase activity that is ubiquitous in mammalian cells.
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PMID:Antioxidant defense systems of two lipidopteran insect cell lines. 1136 23

The mechanism of DNA damage by a metabolite of the carcinogen o-anisidine in the presence of metals was investigated by the DNA sequencing technique using 32P-labeled human DNA fragments. The o-anisidine metabolite, o-aminophenol, caused DNA damage in the presence of Cu(II). The DNA damage was inhibited by catalase and bathocuproine, suggesting the involvement of H2O2 and Cu(I). The formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine by o-aminophenol increased in the presence of Cu(II). We conclude that Cu(II)-mediated oxidative DNA damage by this o-anisidine metabolite seems to be relevant for the expression of the carcinogenicity of o-anisidine. o-Aminophenol plus Cu(II) caused preferential DNA damage at the 5'-site guanine of GG and GGG sequences. When CuZn-SOD or Mn-SOD was added, the DNA damage was enhanced and its predominant cleavage sites were changed into thymine and cytosine residues. We consider that SOD may increase the frequency of mutations due to DNA damage induced by o-aminophenol and thus increase its carcinogenic potential.
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PMID:Oxidative DNA damage induced by a metabolite of carcinogenic o-anisidine: enhancement of DNA damage and alteration in its sequence specificity by superoxide dismutase. 1137 Jun 71

Nitroxyl (NO(-)) may be produced by nitric-oxide synthase and by the reduction of NO by reduced Cu,Zn-SOD. The ability of NO(-) to cause oxidations and of SOD to inhibit such oxidations was therefore explored. The decomposition of Angeli's salt (AS) produces NO(-) and that in turn caused the aerobic oxidation of NADPH, directly or indirectly. O(2) was produced concomitant with the aerobic oxidation of NADPH by AS, as evidenced by the SOD-inhibitable reduction of cytochrome c. Both Cu,Zn-SOD and Mn-SOD inhibited the aerobic oxidation of NADPH by AS, but the amounts required were approximately 100-fold greater than those needed to inhibit the reduction of cytochrome c. This inhibition was not due to a nonspecific protein effect or to an effect of those large amounts of the SODs on the rate of decomposition of AS. NO(-) caused the reduction of the Cu(II) of Cu,Zn-SOD, and in the presence of O(2), SOD could catalyze the oxidation of NO(-) to NO. The reverse reaction, i.e. the reduction of NO to NO(-) by Cu(I),Zn-SOD, followed by the reaction of NO(-) with O(2) would yield ONOO(-) and that could explain the oxidation of dichlorofluorescin (DCF) by Cu(I),Zn-SOD plus NO. Cu,Zn-SOD plus H(2)O(2) caused the HCO(3)(-)-dependent oxidation of DCF, casting doubt on the validity of using DCF oxidation as a reliable measure of intracellular H(2)O(2) production.
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PMID:Copper,zinc superoxide dismutase as a univalent NO(-) oxidoreductase and as a dichlorofluorescin peroxidase. 1146 12


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