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)

Glial activation and oxidative stress are both consequences of brain aging. To investigate whether glial activation causes oxidative stress or not, the immune activator, lipopolysaccharide (LPS), was intraventricularly injected into the rat brain. The expression of candidate genes were examined by in situ hybridization histochemistry (ISHH) combined with immunohistochemistry for glial markers over a period of time up to 24 h after the LPS injection. The mRNA for glial fibrillary acidic protein (GFAP) was elevated around the injection site by 2 h, and the volume of elevated expression spread to the entire brain after 6 h, with higher levels present in the injected hemisphere. The level of inducible isoform of nitric oxide synthase (i-NOS) mRNA increased in a punctate-like pattern in the region of the injection by 6 h and this response spread to the entire brain after 12 h. These results indicate that the glia are activated for at least 24 h after a single LPS injection. The mRNAs for a heat-shock protein (HSP70) and for the manganese-dependent superoxide dismutase (Mn-SOD) were elevated in the ipsilateral hemisphere as early as 2 h post-injection, but these responses subsided nearly to basal levels by 4 h. These levels of mRNAs for these genes increased again after 6 h of the LPS injection; thus, the earlier increases of the messages appeared to be associated with the survival surgery procedure. With microautoradiographic analysis, scattered OX-42 positive cells expressed i-NOS mRNA after 6 h post-injection, but elevation of Mn-SOD mRNA was not detected in either microglia or astrocytes at any time point examined. The level for Cu/Zn-SOD mRNA did not alter at any time point. The beta-amyloid precursor protein (betaAPP) mRNAs were elevated beginning at 6 h. These results indicate that chronic glial activation leads to a condition of oxidative stress in the brain. The data also suggest that LPS injection could be used to study the effects of chronic glial activation on the survival of neuronal populations that could be at risk from oxidative stress.
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PMID:Indicators of glial activation and brain oxidative stress after intraventricular infusion of endotoxin. 968 67

To define the mechanism of nitric oxide (NO) action in the glomerulus, we attempted to identify genes that are regulated by NO in rat glomerular mesangial cells. We identified a Cu/Zn superoxide dismutase (SOD) that was strongly induced in these cells by treatment with S-nitroso-glutathione as a NO-donating agent. Bacterial lipopolysaccharide (LPS) acutely decreased Cu/Zn SOD mRNA levels. The LPS-mediated decrease in Cu/Zn SOD is reversed by endogenously produced NO, as LPS also induced a delayed strong iNOS expression in these cells in vitro, which is accompanied by increased Cu/Zn SOD expression. NO dependency of Cu/Zn SOD mRNA recovery could be demonstrated by inhibition of this process by L-NG-monomethylarginine, an inhibitor of NOS enzymatic activity. To demonstrate the in vivo relevance of our observations, we have chosen LPS-treated rats as a model for induction of a systemic inflammatory response. In these animals, we demonstrate a direct coupling of Cu/Zn SOD expression levels to the presence of NO, as Cu/Zn SOD mRNA levels declined during acute inflammation in the presence of a selective inhibitor of iNOS. We propose that the up-regulation of Cu/Zn SOD by endogenous NO may serve as an adaptive, protective mechanism to prevent the formation of toxic quantities of peroxynitrite in conditions associated with iNOS induction during endotoxic shock.
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PMID:Identification of copper/zinc superoxide dismutase as a novel nitric oxide-regulated gene in rat glomerular mesangial cells and kidneys of endotoxemic rats. 1022 30

The effect of the induction of i-NOS in primary glial cultures was studied with respect to the protein levels of reactive oxygen species (ROS) scavenging enzymes and the cytotoxicity of nitric oxide (.NO) formation at different levels of artificially generated superoxide. Stimulation of the cultures by bacterial lipopolysaccharides and gamma-interferon resulted in an induction of i-NOS exclusively in microglial cells. Among the ROS scavenging enzymes superoxide dismutase (Cu/Zn- and Mn-isoform), glutathione peroxidase and catalase only mitochondrial Mn-SOD was found to be upregulated in the course of i-NOS induction (Western blots). Although .NO formation did not affect cell viability at physiological levels of superoxide over a time period of 4 days, it caused an oxidative load particularly in microglial cells as observed by monitoring the oxidation of dichloro-dihydrofluorescein, an indicator for the formation of peroxynitrite and ROS. Elevated levels of superoxide, generated either intracellularly by paraquat or extracellularly via xanthine oxidase and hypoxanthine, resulted dose-dependently in a larger decline of cell viability in the .NO forming cultures compared to controls (release of lactate dehydrogenase, citrate synthase, stainability by propidium iodide, and tetramethylrhodamine). NOS-inhibitors reduced the degree of cell damage to that seen for control cultures, indicating an ONOO--/.NO mediated mechanism of cell damage. Our data support the concept that i-NOS catalyzed .NO-formation leads to an ONOO--mediated increased oxidative load. At physiological levels of superoxide and within a wide range of higher superoxide levels this nitrosative stress is well balanced in cultured glial cells by protective mechanisms.
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PMID:Peroxynitrite mediated damage and lowered superoxide tolerance in primary cortical glial cultures after induction of the inducible isoform of NOS. 1049 18

The basal expression patterns of NO synthase (NOS; endothelial [eNOS], neuronal [nNOS], and cytokine-inducible [iNOS]) and superoxide dismutase (SOD; extracellular membrane bound [ECSOD], MnSOD, and CuZnSOD) isoforms in ferret heart (tissue sections and isolated myocytes) were determined by immunofluorescent localization. We demonstrate the following for the first time in the mammalian heart: (1) heterogeneous expression patterns of the 3 NOS and 3 SOD isoforms among different tissue and myocyte types; (2) colocalization of eNOS and ECSOD at both the tissue and myocyte levels; (3) a significant gradient of eNOS and ECSOD expression across the left ventricular (LV) wall, with both enzymes being highly expressed and colocalized in LV epicardial myocytes but markedly reduced in LV endocardial myocytes; and (4) specific subcellular localization patterns of eNOS and the 3 SOD isoforms. In particular, eNOS and ECSOD are demonstrated (electron and confocal microscopy) to be specifically localized to the sarcolemma of ventricular myocytes. Similar heterogeneous eNOS and ECSOD expression patterns were also obtained in human LV tissue sections, underscoring the general importance of these novel findings. Our data suggest a strong functional correlation between the activities of sarcolemmally localized myocyte eNOS and ECSOD in governing NO*/O(2-) interactions and suggest that NO-related modulatory effects on cardiac myocyte protein and/or ion channel function may be significantly more complex than is presently believed.
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PMID:Heterogeneous basal expression of nitric oxide synthase and superoxide dismutase isoforms in mammalian heart : implications for mechanisms governing indirect and direct nitric oxide-related effects. 1050 82

Primary glial cultures are able to express the inducible isoform of nitric oxide synthase (i-NOS) upon stimulation by bacterial lipopolysaccharides (LPS) and gamma-interferon (gamma-IfN). Immunocytochemical studies revealed, that under our experimental conditions i-NOS is expressed exclusively by the microglial cells and not in the astrocytes. Nitric oxide (NO) formation represents an oxidative load for the microglial cells, as observed by the oxidation rate of the ROS- and peroxynitrite indicator dichloro-dihydrofluorescein (DCF-H) in these cells. However, cell viability was not affected by the nitric oxide formation, indicating some form of protection against the higher oxidative load. Upregulation of Mn-SOD in the mitochondria in the course of the induction of i-NOS and, compared to the astrocytes, higher GSH levels in the microglial cells probably explain the resistance of the cultures against nitrosative stress. Increased SOD-activities in the mitochondria could lower the superoxide concentration in this organelle and may prevent an oxidative and/or nitrosative damage via a decreased peroxynitrite formation. The higher GSH-levels in the microglial cells of unstimulated cultures represents a buffer which, under the conditions of i-NOS catalyzed NO-formation, prevents a decline of the microglial GSH-levels below that of the astrocytes.
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PMID:Nitrosative stress in primary glial cultures after induction of the inducible isoform of nitric oxide synthase (i-NOS). 1096 32

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

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

This study was performed to investigate the role of reactive oxygen species and inducible nitric oxide (NO) synthase (iNOS) and cyclooxygenase-2 (COX-2) metabolites in the lipopolysaccharide effect on bradykinin-induced relaxation in middle cerebral arteries from normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs). LPS exposure (10 microg/ml for 1-5 h) reduced bradykinin relaxation; this effect appeared earlier and was greater in arteries from SHR than WKY rats. LPS also reduced the relaxation to the NO donor diethylamine (DEA)-NO; however, LPS modified neither the bradykinin relaxation after inhibiting NO synthesis with N(G)-monomethyl-L-arginine (0.1 mM) nor endothelial NOS expression. In arteries from WKY rats, the respective iNOS and COX-2 inhibitors aminoguanidine (0.1 mM) and NS-398 (10 microM) and the superoxide anion scavenger SOD (100 U/ml) reduced the LPS effect on bradykinin relaxation; however, the thromboxane A(2) (TxA(2))PGH(2) receptor antagonist SQ-29548 (1 microM) and the H(2)O(2) scavenger catalase (1,000 U/ml) did not modify the LPS effect. In arteries from SHR, all of these drugs reduced the LPS effect. LPS exposure (5 h) increased superoxide anion levels in arteries from both strains and TxA(2) levels only in SHR. COX-2 expression rose to a similar level in arteries from both strains after 1 and 5 h of LPS incubation, whereas expression of Cu/Zn- and Mn-SOD only increased after 5 h. In conclusion, in segments from WKY rats, LPS reduced bradykinin-induced relaxation through increased production of NO (from iNOS) and superoxide anion. The greater LPS effect observed in arteries from SHR seems to be related to higher participation of reactive oxygen species and contractile prostanoids (probably TxA(2)).
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PMID:Hypertension alters role of iNOS, COX-2, and oxidative stress in bradykinin relaxation impairment after LPS in rat cerebral arteries. 1500 39

Reactive oxygen species (ROS) and nitric oxide (NO) have a role in the development of pulmonary fibrosis after bleomycin administration. The ROS production induces an antioxidant response, involving superoxide dismutases (SODs), catalase, and glutathione peroxidases. We compared in situ oxidative burden and antioxidant enzyme activity in bleomycin-injured rat lungs and normal controls. ROS expression and catalase, glucose-6-phosphate-dehydrogenase (G6PHD), and NOS/NADPH-diaphorase activity were investigated by using histochemical reactions. Nitric oxide synthase (e-NOS and i-NOS) and SOD (MnSOD, Cu/ZnSOD, ECSOD) expression was investigated immunohistochemically. After treatment ROS production was enhanced in both phagocytes and in type II alveolar epithelial cells. Mn, Cu/Zn, and ECSOD were overexpressed in parenchymal cells, whereas interstitium expressed ECSOD. Catalase and G6PHD activity was moderately increased in parenchymal and inflammatory cells. NOS/NADPH-d activity and i-NOS expression increased in alveolar and bronchiolar epithelia and in inflammatory cells. It can be suggested that the concomitant activation of antioxidant enzymes is not adequate to scavenge the oxidant burden induced by bleomycin lung damage. Inflammatory cells and also epithelial cells are responsible of ROS and NO production. This oxidative and nitrosative stress may be a substantial trigger in TGF-beta1 overexpression by activated type II pneumocytes, leading to fibrotic lesions.
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PMID:In situ assessment of oxidant and nitrogenic stress in bleomycin pulmonary fibrosis. 1630 78


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