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)

Insulin stimulates the production of superoxide and hydrogen peroxide in various tissues. Hydrogen peroxide has been proposed to be an intracellular second messenger for insulin and a moderator of cellular proliferation and differentiation. We previously found that cell proliferation is increased in small intestinal mucosa of streptozotocin-diabetic rats. The current study was undertaken to determine if superoxide dismutase (SOD), the enzyme that converts superoxide to hydrogen peroxide, is altered in the mucosa of the alimentary tract and renal cortex of the diabetic rat, and if so, whether SOD responds to insulin treatment. Total SOD and cyanide-insensitive [manganese-containing SOD (Mn SOD)] SOD were measured by the nitroblue tetrazolium inhibition assay. We studied ad libitum fed animals, where diabetics are hyperphagic and pair-fed animals, where hyperphagia is not present. Since cyclic nucleotides appear to control cell proliferation in some tissues, we also measured cAMP and cGMP in mucosa of the small intestine. In ad libitum fed animals, total SOD was depressed in the mucosa of duodenum, jejunum, and ileum, but not in the cecum or colon of the streptozotocin-diabetic rats. The level of Mn-SOD was not affected by diabetes or insulin treatment, but the cyanide-sensitive [copper- and zinc containing SOD (Cu-Zn SOD] SOD was depressed in the small intestine and colon of diabetic rats. Insulin treatment restored total and Cu-Zn SOD activity in the small intestine to normal and increased Cu-Zn SOD activity in the colon to normal. Pair-fed animals showed the same changes in the SOD activity of jejunal mucosa that were found in ad libitum fed animals. In renal cortex, diabetes did not alter total SOD, but increased Mn SOD and decreased Cu-Zn SOD. Both responses were reversed by insulin treatment. Cyclic nucleotide concentrations were not affected by diabetes. We conclude that SOD enzymes re altered in diabetes, at least in proliferating tissues. Responses are tissue specific. The mucosa of the small intestine and colon show decreased Cu-Zn SOD, the SOD of the cecum is unaffected, and the kidney shows increased Mn SOD and decreased Cu-Zn SOD. The SOD responses of diabetics are reversed by insulin treatment.
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PMID:Superoxide dismutase activity in the intestine of the streptozotocin-diabetic rat. 704 72

Endothelium-dependent relaxations mediated by NO are impaired in a mouse model of human atherosclerosis. Our objective was to characterize the mechanisms underlying endothelial dysfunction in aortas of apolipoprotein E (apoE)-deficient mice, treated for 26 to 29 weeks with a lipid-rich Western-type diet. Aortic rings from apoE-deficient mice showed impaired endothelium-dependent relaxations to acetylcholine (10(-)(9) to 10(-)(5) mol/L) and Ca(2+) ionophore (10(-)(9) to 10(-)(6) mol/L) and endothelium-independent relaxations to diethylammonium (Z)-1-(N,N-diethylamino)diazen-1-ium-1,2-diolate (DEA-NONOate, 10(-)(10) to 10(-)(5) mol/L) compared with aortic rings from C57BL/6J mice (P<0.05). By use of confocal microscopy of an oxidative fluorescent probe (dihydroethidium), increased superoxide anion (O(2)(-)) production was demonstrated throughout the aortic wall but mainly in smooth muscle cells of apoE-deficient mice. CuZn-superoxide dismutase (SOD) and Mn-SOD protein expressions were unaltered in the aorta exposed to hypercholesterolemia. A cell-permeable SOD mimetic, Mn(III) tetra(4-benzoic acid) porphyrin chloride (10(-)(5) mol/L), reduced O(2)(-) production and partially normalized relaxations to acetylcholine and DEA-NONOate in apoE-deficient mice (P<0.05). [(14)C]L-Citrulline assay showed a decrease of Ca(2+)-dependent NOS activity in aortas from apoE-deficient mice compared with C57BL/6J mice (P<0.05), whereas NO synthase protein expression was unchanged. In addition, cGMP levels were significantly reduced in the aortas of apoE-deficient mice (P<0.05). Our results demonstrate that in apoE-deficient mice on a Western-type fat diet, impairment of endothelial function is caused by increased production of O(2)(-) and reduced endothelial NO synthase enzyme activity. Thus, chemical inactivation of NO with O(2)(-) and reduced biosynthesis of NO are key mechanisms responsible for endothelial dysfunction in aortas of atherosclerotic apoE-deficient mice.
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PMID:Mechanism of endothelial dysfunction in apolipoprotein E-deficient mice. 1139 13

Preconditioning adaptation induced by transient ischemia can increase brain tolerance to oxidative stress, but the underlying neuroprotective mechanisms are not fully understood. Recently, we developed a human brain-derived cell model to investigate preconditioning mechanism in SH-SY5Y neuroblastoma cells.(1) Our results demonstrate that a non-lethal serum deprivation-stress for 2 h (preconditioning stress) enhanced the tolerance to a subsequent lethal oxidative stress (24 h serum deprivation) and also to 1-methyl-4-phenyl-pyridinium (MPP(+)).(2) Two-hour non-lethal preconditioning stress increased the expression of neuronal nitric oxide (NOS1/nNOS) mRNA, Fos, Ref-1, NOS protein, and then nitric oxide (*NO) production. As well as MnSOD expression, the *NO-cGMP-PKG pathway mediated the preconditioning-induced upregulation of antiapoptotic protein Bcl-2 and the downregulation of adaptor protein p66(shc). We also propose that cGMP-mediated preconditioning-induced adaptation against oxidative stress may be due to the synthesis of a new protein, such as thioredoxin (Trx) since the protective effect can be blocked by Trx reductase inhibitor.(3) The antioxidative potency of Trx was approximately 100 and 1,000 times greater than GSNO and GSH, respectively. These results suggest that *NO-cGMP-PKG signaling pathway plays an important role in the preconditioning-induced neuroprotection, and perhaps cardioprotection, against oxidative stress.
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PMID:Preconditioning-mediated neuroprotection: role of nitric oxide, cGMP, and new protein expression. 1207 58

To investigate whether nitric oxide (*NO) is neurotoxic or neuroprotective in the brain, we compared the in vivo role of S-nitroso-N-acetylpenicillamine (SNAP) with that of sodium nitroprusside (SNP) on ferrous citrate-induced oxidative stress and neuronal loss in the rat nigrostriatal dopaminergic system. It is known that light irradiation releases *NO from its donor compounds; these irradiated *NO donors were used as sham controls in this study. Intranigral infusion of ferrous citrate (4.2 nmol) into the rat midbrain substantia nigra compacta area caused acute lipid peroxidation in the substantia nigra and chronic dopamine depletion in the caudate nucleus. Coinfusion of freshly prepared SNAP (0-8.4 nmol) or *NO (about 2 nmol), but not SNP, rescued iron-induced dopamine depletion in the rat brain in vivo. In fact, SNP produced prooxidative effects similar to ferrous citrate both in vivo and in vitro, since SNP is a redox iron complex. Consistently, *NO and SNAP inhibited, whereas SNP potentiated, *OH generation and lipid peroxidation evoked by ferrous citrate in vitro. We previously reported that freshly prepared, but not irradiated, S-nitroso-L-glutathione (GSNO) protected brain dopamine neurons against oxidative stress in vivo. As well as these antioxidative properties, our recent reports (see (Ref. 1)) indicate that *NO/GSNO activated guanylyl cyclase, increased cGMP and that could lead to PKG-mediated expression of MnSOD, Bcl-2, and thioredoxin for preconditioning neuroprotection against 1-methyl-4-phenylpyridinium (MPP(+)).(1) In conclusion, *NO and S-nitrosothiols (e.g., GSNO and SNAP) can scavenge reactive oxygen species and activate the heme moiety of guanylyl cyclase, resulting in protection of brain dopamine neurons through both antioxidative and antiapoptotic mechanisms.
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PMID:Contradictory effects of sodium nitroprusside and S-nitroso-N-acetylpenicillamine on oxidative stress in brain dopamine neurons in vivo. 1207 63

Clinical studies suggest that estrogen may improve cognition in Alzheimer's patients. Basic experiments demonstrate that 17beta-estradiol protects against neurodegeneration in both cell and animal models. In the present study, a human SH-SY5Y cell model was used to investigate molecular mechanisms underlying the receptor-mediated neuroprotection of physiological concentrations of 17beta-estradiol. 17beta-estradiol (<10 nM) concomitantly increased neuronal nitric oxide synthase (NOS1) expression and cell viability. 17beta-estradiol-induced neuroprotection was blocked by the receptor antagonist ICI 182,780, also prevented by inhibitors of NOS1 (7-nitroindazole), guanylyl cyclase (LY 83,583), and cGMP-dependent protein kinase (PKG) (Rp-8-pCPT-cGMPs). In addition to the expression of NOS1 and MnSOD, 17beta-estradiol increased the expression of the redox protein thioredoxin (Trx), which was blocked by the inhibition of either cGMP formation or PKG activity. The expression of heme oxygenase 2 and brain-derived neurotrophic factor was not altered. Estrogen receptor-enhanced cell viability against oxidative stress may be linked to Trx expression because the Trx reductase inhibitor, 5,5'-dithio-bis(2-nitrobenzoic acid) significantly reduced the cytoprotective effect of 17beta-estradiol. Furthermore, Trx (1 microM) inhibited lipid peroxidation, proapoptotic caspase-3, and cell death during oxidative stress caused by serum deprivation. We conclude that cGMP-dependent expression of Trx--the redox protein with potent antioxidative and antiapoptotic properties--may play a pivotal role in estrogen-induced neuroprotection.
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PMID:17beta-estradiol activates ICI 182,780-sensitive estrogen receptors and cyclic GMP-dependent thioredoxin expression for neuroprotection. 1262 28

The markers of the bioavailability of NO (endothelium-dependent relaxation to acetylcholine and cyclic GMP content) in the thoracic aorta of apolipoprotein-E-deficient (ApoE KO) mice, 20 weeks old with enriched cholesterol diet or 35 weeks old on regular chow, are not decreased, in contrast with other models of atherosclerosis. However, severe hypercholesterolemia, the presence of atherosclerotic lesions and increased NADPH oxidase activity have been reported as early as at 20 weeks of age. The present experiments were designed to test if an increased capacity of NO production in these mice explains this paradox. The expressions of the 3 isoforms of NO synthase (NOS) were compared in ApoE KO and C57Bl/6J mice using Western blot and localized by immunohistochemistry. No adaptive increase in the expression of NOS was detected in ApoE KO mice. NO bioavailability could also be preserved by upregulation of enzymes involved in redox status such as CuZn or Mn superoxide dismutase and catalase. However, these enzymes were less expressed in ApoE KO mice than in control mice. These results highlight that ApoE KO mice represent an atypical model of atherosclerosis.
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PMID:Persistence of the nitric oxide pathway in the aorta of hypercholesterolemic apolipoprotein-E-deficient mice. 1280 44

Delayed cardio- and neuroprotection are observed following a preconditioning procedure evoked by a brief and nontoxic oxidative stress due to deprivation of oxygen, glucose, serum, trophic factors, and/or antioxidative enzymes. Preconditioning protection can be observed in vivo and is under clinical trials for preservation of cell viability following organ transplants of liver. Previous studies indicated that ischemic preconditioning increases the expression of heat-shock proteins (HSPs) and nitric oxide synthase (NOS). Our pilot studies indicate that the treatment of neuronal NOS inhibitor (7-nitroindazole) and 6Br-cGMP blocks and mimics, respectively, preconditioning protection in human neuroblastoma SH-SY5Y cells. This minireview focuses on nitric oxide-mediated cellular adaptation and the related cGMP/PKG signaling pathway in a compensatory mechanism underlying preconditioning-induced hormesis. Both preconditioning and 6Br-cGMP increase the induction of human thioredoxin (Trx) mRNA and protein for cytoprotection, which is largely prevented by transfection of cells with Trx antisense but not sense oligonucleotides. Cytosolic Trx1 and mitochondrial Trx2 suppress free radical formation, lipid peroxidation, oxidative stress, and mitochondria-dependent apoptosis; knock out/down of either Trx1 or Trx2 is detrimental to cell survival. Other recent findings indicate that a transgenic increase of Trx in mice increases tolerance against oxidative nigral injury caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Trx1 can be translocated into nucleus and phosphoactivated CREB for a delayed induction of mitochondrial anti-apoptotic Bcl-2 and antioxidative MnSOD that is known to increase vitality and survival of cells in the brain and the heart. In conclusion, preconditioning adaptation or a brief oxidative stress induces a delayed nitric oxide-mediated compensatory mechanism for cell survival and vitality in the central nervous system and the cardiovascular system. Preconditioning-induced adaptive tolerance may be signaling through a cGMP-dependent induction of cytosolic redox protein Trx1 and subsequently mitochondrial proteins such as Bcl-2, MnSOD, and perhaps Trx2 or HSP70.
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PMID:Induction of thioredoxin and mitochondrial survival proteins mediates preconditioning-induced cardioprotection and neuroprotection. 1596 87

Hormesis, a stress tolerance, can be induced by ischemic preconditioning stress. In addition to preconditioning, it may be induced by other means, such as gas anesthetics. Preconditioning mechanisms, which may be mediated by reprogramming survival genes and proteins, are obscure. A known neurotoxicant, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), causes less neurotoxicity in the mice that are preconditioned. Pharmacological evidences suggest that the signaling pathway of NO-cGMP-PKG (protein kinase G) may mediate preconditioning phenomenon. We developed a human SH-SY5Y cell model for investigating ()NO-mediated signaling pathway, gene regulation, and protein expression following a sublethal preconditioning stress caused by a brief 2-h serum deprivation. Preconditioned human SH-SY5Y cells are more resistant against severe oxidative stress and apoptosis caused by lethal serum deprivation and 1-methyl-4-phenylpyridinium (MPP(+)). Both sublethal and lethal oxidative stress caused by serum withdrawal increased neuronal nitric oxide synthase (nNOS/NOS1) expression and ()NO levels to a similar extent. In addition to free radical scavengers, inhibition of nNOS, guanylyl cyclase, and PKG blocks hormesis induced by preconditioning. S-nitrosothiols and 6-Br-cGMP produce a cytoprotection mimicking the action of preconditioning tolerance. There are two distinct cGMP-mediated survival pathways: (i) the up-regulation of a redox protein thioredoxin (Trx) for elevating mitochondrial levels of antioxidant protein Mn superoxide dismutase (MnSOD) and antiapoptotic protein Bcl-2, and (ii) the activation of mitochondrial ATP-sensitive potassium channels [K(ATP)]. Preconditioning induction of Trx increased tolerance against MPP(+), which was blocked by Trx mRNA antisense oligonucleotide and Trx reductase inhibitor. It is concluded that Trx plays a pivotal role in ()NO-dependent preconditioning hormesis against MPTP/MPP(+).
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PMID:Roles of thioredoxin in nitric oxide-dependent preconditioning-induced tolerance against MPTP neurotoxin. 1600 85

The long-term effects of 50 microM CdCl(2) on the enzymatic and non-enzymatic antioxidative defences of pea (Pisum sativum L.) plants was studied in terms of activity, protein content and transcripts levels. Cadmium caused a reduction of the total glutathione content (GSH+GSSG), with the reduced form of glutathione (GSH) being most affected. The content of ascorbic acid (ASC) was also decreased by the treatment. The transcript levels of catalase (CAT) and monodehydroascorbate reductase (MDHAR) showed a Cd-dependent increase, although CAT activity and its protein content were depressed, which suggests a posttranslational modification of this protein induced by cadmium. Glutathione reductase (GR), and ascorbate peroxidase (APX) did not change significantly, either in activity or accumulation of transcript. However, cadmium treatment provoked a strong reduction in mRNA, protein level and activity of CuZn-superoxide dismutase (SOD), being the most negatively affected antioxidative enzyme, and in less extent of Mn-SOD. Transcriptome analysis of the antioxidative enzymes in leaves of pea plants grown with cadmium and treated with some modulators of the signal transduction cascade suggested that at least Ca(2+) channels, phosphorylation/dephosphorylation processes, nitric oxide, cGMP, salicylic acid (SA) and H(2)O(2) were involved in some steps between the cadmium signal and transcript expression of CuZn-SOD, CAT and MDHAR. This indicated the existence of cross-talk between these elements and reactive oxygen species (ROS) metabolism during cadmium stress.
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PMID:Differential expression and regulation of antioxidative enzymes by cadmium in pea plants. 1707 18

We investigated the effects of betamethasone on oxidative stress and impaired vasodilation in a lamb model of persistent pulmonary hypertension (PPHN). We treated pregnant ewes following fetal ductal ligation with betamethasone or saline for 48 h before delivery. Response of fetal pulmonary arteries to nitric oxide synthase (NOS) agonist adenosine triphosphate (ATP) and nitric oxide (NO) donor, s-nitroso-n-acetyl-penicillamine (SNAP) was determined in tissue bath. Pulmonary artery endothelial cells (PAEC) from fetal lambs with ductal ligation or sham ligation were treated with betamethasone or its vehicle for 48 h. Expression of endothelial NOS (eNOS), endothelin, endothelin-B (ET-B) receptor, and CuZn- and Mn-superoxide dismutase (SOD) in PAEC was studied. Intracellular cGMP and superoxide levels and interaction of eNOS with heat shock protein 90 (Hsp90) were determined in PAEC. Antenatal betamethasone improved the relaxation response of pulmonary arteries to ATP and SNAP in PPHN. PPHN was associated with decreases in eNOS and ET-B receptor and increase in prepro-endothelin mRNA levels. Betamethasone decreased prepro-endothelin mRNA and ET-1 pro-peptide levels and increased eNOS and MnSOD protein levels in PPHN. Betamethasone reversed the increased superoxide/decreased cGMP levels and restored Hsp90-eNOS interactions in PPHN. Betamethasone reduces oxidative stress and improves response of pulmonary arteries to vasodilators in lambs with PPHN.
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PMID:Betamethasone attenuates oxidant stress in endothelial cells from fetal lambs with persistent pulmonary hypertension. 1804 18


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