Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P30044 (antioxidant enzyme)
 8,037 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have shown that testosterone production by the Leydig cells of aged Brown Norway rats is reduced from the relatively high levels produced by Leydig cells of young rats and that this reduction is not secondary to decreased serum luteinizing hormone concentration. The free radical theory of aging proposes that imbalance between pro-oxidants and the antioxidant defense system ultimately results in oxidative damage to cellular processes. With this in mind, we hypothesized herein that age-related reductions in steroidogenesis by Brown Norway rat Leydig cells may be associated with the impairment of the antioxidant defense system of these cells. To begin to test this hypothesis, we compared the activities and steady-state mRNA and protein levels of the antioxidant enzymes copper zinc (CuZn) superoxide dismutase (CuZnSOD, SOD1), manganese (Mn) superoxide dismutase (MnSOD, SOD2), and glutathione peroxidase (GPx) and the levels of reduced and oxidized glutathione in Leydig cells isolated from the testes of young (4-month-old) and aged (20-month-old) Brown Norway rats. For some studies, Leydig cells were isolated separately from aged testes that either had regressed because of age-related losses of germ cells or that were nonregressed. SOD (total) and GPx activities were found to decrease significantly with age whether or not the testes were regressed. CuZnSOD and MnSOD mRNA levels decreased with aging, though the magnitude of the decreases were considerably lower than the respective decreases in enzyme activities. GPx mRNA levels also decreased, which is consistent with the decreases seen in enzyme activity. MnSOD protein expression declined with age, and to a lesser extent, CuZnSOD did as well. Reduced and oxidized glutathione also exhibited age-related reductions in cells from both normal and regressed aged testes. The age-related decreases in Leydig cell antioxidant enzyme activities, gene expression, and protein levels and in glutathione were consistent with the hypothesis that the loss of steroidogenic function that accompanies Leydig cell aging may result in part from a decrease in the fidelity of the cellular antioxidant defense system.
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PMID:Aging and the brown Norway rat leydig cell antioxidant defense system. 1630 8

Manganese superoxide dismutase (MnSOD, SOD2) is an essential primary antioxidant enzyme which converts superoxide radical to hydrogen peroxide within the mitochondrial matrix. MnSOD plays a prominent role in protection against many apoptotic stimuli. Its absence may therefore impair the cellular redox balance and enhance apoptosis. Our data show that in Jurkat T cells, following oligomerization of the Fas receptor, MnSOD is selectively degraded during apoptosis. In the presence of cycloheximide, an inhibitor of protein synthesis, the rates of cell death and MnSOD degradation were accelerated. Fas-induced MnSOD cleavage was partially inhibited in the presence of the pan-caspase inhibitor, z-VAD-fmk. MnSOD in the mitochondrial fractions was cleaved in vitro by treatment with the cytosolic fraction of Fas-activated cells. Moreover, two possible cleavage sites of recombinant hMnSOD by direct interaction with recombinant caspase-3 were noted. Cellular and mitochondrial factors were found to be necessary for the interaction. These factors include intracellular mobilization of calcium. Our data indicate that inactivation of MnSOD in receptor-mediated apoptosis by caspase-specific degradation would render the mitochondria sensitive to the steady-state production of superoxide, decrease the steady-state flux of H(2)O(2), expedite the loss of mitochondrial function, and potentiate apoptosis.
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PMID:Manganese superoxide dismutase inactivation during Fas (CD95)-mediated apoptosis in Jurkat T cells. 1715 82

HIV-associated dementia, like several other neurodegenerative diseases, is characterized by selective degeneration of neurons amidst survival of glial cells like astroglia. The molecular basis of such selective susceptibility within the same milieu remains largely unknown. Neurons are rarely infected by the virus. However, they are vulnerable to viral products, like HIV-1 coat protein gp120. Interestingly, gp120 induced oxidative stress in neurons, but not in astroglia. This led us to postulate that astroglia were armed with a more efficient antioxidant system than neurons. Here, we report that the constitutive level of MnSOD (SOD2), the major cellular antioxidant enzyme, is significantly higher in astroglia than in neurons. Furthermore, gp120 treatment enhanced MnSOD levels in astroglia but decreased the same in neurons. This increase in astroglial MnSOD was dependent on NF-kappaB, the crucial transcription factor required for sod2 gene transcription. Blocking NF-kappaB with p65-antisense, p65-si-RNA, or a specific inhibitor, NBD peptide, led to reduced MnSOD levels and enhanced vulnerability of astroglia to gp120. Additionally, neurons were found to have a lower constitutive level of NF-kappaB p65 than astrocytes. Overexpression of p65 increased the level of MnSOD in neurons. This, in turn, elicited greater neuronal resistance to gp120. Taken together, our study suggests that astroglia manifest a higher threshold for gp120-induced lethality than neurons due to greater MnSOD availability, which is demonstrated due to greater level of NF-kappaB p65.
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PMID:Differential regulation of Mn-superoxide dismutase in neurons and astroglia by HIV-1 gp120: Implications for HIV-associated dementia. 1751 66

A variety of gene mutations can cause familial forms of Parkinson's disease (PD) or amyotrophic lateral sclerosis (ALS). Mutations in the synaptic protein alpha-synuclein (alpha-Syn) cause PD. Mutations in the antioxidant enzyme superoxide dismutase-1 (SOD1) cause ALS. The mechanisms of human mutant a-Syn and SOD1 toxicity to neurons are not known. Transgenic (tg) mice expressing human mutant alpha-Syn or SOD1 develop profound fatal neurologic disease characterized by progressive motor deficits, paralysis, and neurodegeneration. Ala-53-->Thr (A53T)-mutant alpha-Syn and Gly-93-->Ala (G93A)-mutant SOD1 tg mice develop prominent mitochondrial abnormalities. Interestingly, although nigral neurons in A53T mice are relatively preserved, spinal motor neurons (MNs) undergo profound degeneration. In A53T mice, mitochondria degenerate in neurons, and complex IV activity is reduced. Furthermore, mitochondria in neurons develop DNA breaks and have p53 targeted to the outer membrane. Nitrated a-Syn accumulates in degenerating MNs in A53T mice. mSOD1 mouse MNs accumulate mitochondria from the axon terminals and generate higher levels of reactive oxygen/nitrogen species than MNs in control mice. mSOD1 mouse MNs accumulate DNA single-strand breaks prior to double-strand breaks occurring in nuclear and mitochondrial DNA. Nitrated and aggregated cytochrome c oxidase subunit-I and nitrated SOD2 accumulate in mSOD1 mouse spinal cord. Mitochondria in mSOD1 mouse MNs accumulate NADPH diaphorase and inducible NOS (iNOS)-like immunoreactivity, and iNOS gene deletion significantly extends the lifespan of G93A-mSOD1 mice. Mitochondrial changes develop long before symptoms emerge. These experiments reveal that mitochondrial nitrative stress and perturbations in mitochondrial trafficking may be antecedents of neuronal cell death in animal models of PD and ALS.
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PMID:Transgenic mice with human mutant genes causing Parkinson's disease and amyotrophic lateral sclerosis provide common insight into mechanisms of motor neuron selective vulnerability to degeneration. 1759 75

Increasing data suggest that oxidative stress, due to an increased production of reactive oxygen species and/or a decrease in antioxidants, is involved in the pathophysiology of pulmonary hypertension. Several antioxidant systems regulate the presence of oxidant species in vivo, and of primary interest are the superoxide dismutases (SOD) and catalase. However, little is known about the expression of antioxidant enzymes during the development of pulmonary hypertension. This study uses our lamb model of increased postnatal pulmonary blood flow, secondary to in utero aortopulmonary graft placement (shunt lambs), to investigate the expression patterns as well as activities of antioxidant enzymes during the early development of pulmonary hypertension. Protein levels of catalase, SOD1, SOD2, and SOD3 were evaluated by Western blot, and the activities of catalase and SOD were also quantified. In control lambs, protein expression and activities of catalase and SOD2 increased postnatally (P < 0.05). However, SOD1 and SOD3 protein levels did not change. In shunt lambs, catalase, SOD1, and SOD2 protein levels all increased over the first 8 wk of life (P < 0.05). However, SOD3 did not change. This was associated with an increase in the activities of catalase and SOD2 (P < 0.05). Compared with control lambs, catalase and SOD2 protein levels were decreased in 2-wk-old shunt lambs and this was associated with increased levels of hydrogen peroxide (H(2)O(2)) and superoxide (P < 0.05). Developmentally superoxide but not H(2)O(2) levels significantly increased in both shunt and control lambs with levels being significantly higher in shunt compared with control lambs at 2 and 4 but not 8 wk. These data suggest that the antioxidant enzyme systems are dynamically regulated postnatally, and this regulation is altered during the development of pulmonary hypertension secondary to increased pulmonary blood flow. An increased understanding of these alterations may have important therapeutic implications for the treatment of pulmonary hypertension secondary to increased pulmonary blood flow.
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PMID:Lung antioxidant enzymes are regulated by development and increased pulmonary blood flow. 1763 9

Mice lacking the 66 kDa isoform of the adapter molecule shcA (p66(shcA)) display increased resistance to oxidative stress and delayed aging. In cultured cell lines, p66 promotes formation of Reactive Oxygen Species (ROS) in mitochondria, and apoptotic cell death in response to a variety of pro-oxidant noxious stimuli. As mitochondrial ROS and oxidative cell damage are clearly involved in alcohol-induced pathology, we hypothesized that p66 may also have a role in ethanol. In vivo, changes observed in p66+/+ mice after 6-week exposure to ethanol in the drinking water, including elevated serum alanine aminotransferase (ALT), liver swelling and evident liver steatosis, were significantly attenuated in p66-/- mutant mice. Biochemical analysis of liver tissues revealed induction of the p66 protein by ethanol, whereas p66-deficient livers responded to alcohol with a significant upregulation of the mitochondrial antioxidant enzyme MnSOD, nearly absent in control mice. Evidence of an inverse correlation between expression level of p66 and protection from alcohol-induced oxidative stress was also confirmed in vitro in primary hepatocytes and in HepG2-E47 cells, an ethanol-responsive hepatoma cell line. In fact, MnSOD upregulation by exposure to ethanol in vitro was much more pronounced in p66KO versus wild-type isolated liver cells, and blunted in HepG2 cells overexpressing p66shc. p66 overexpression also prevented the activation of a luciferase reporter gene controlled by the SOD2 promoter, indicating that p66 repression of MnSOD operates at a transcriptional level. Finally, p66 generated ROS in HepG2 cells and potentiated oxidative stress and mitochondrial depolarization by ethanol. Taken together, the above observations clearly indicate a role for p66 in alcohol-induced cell damage, likely via a cell-autonomous mechanism involving reduced expression of antioxidant defenses and mitochondrial dysfunction.
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PMID:Role of the life span determinant P66(shcA) in ethanol-induced liver damage. 1849 Aug 96

Reactive oxygen species (ROS) and their control by antioxidant enzymes are involved in the physiology of the female reproductive system. Thus, it is important to understand the regulation of key antioxidant enzymatic pathways. The roles of estrogen and progesterone in regulating the physiological functions of the endometrium have become central dogma. We examined the effects of ovarian steroids on superoxide dismutases (SOD1 and SOD2), catalase (CAT), glutathione peroxidase (GPX), and glutathione reductase (GSR) activities in the aglandular caruncular and glandular inter-caruncular endometrial tissues of ovariectomized (OVX) ewes and in OVX ewes treated with estradiol (E2), progesterone (P4), or both hormones according to schedules designed to produce physiological changes of these hormones during the estrous cycle. The activities SOD2, CAT, GPX and GSR in both endometrial tissues were unaffected by P4 treatment. The activity of SOD1 in the aglandular tissue was unaffected by P4 treatment, however this treatment decreased SOD1 activity in the glandular tissue (P < 0.01). Treatment with E2, either alone or in combination with P4, decreased SOD1 (P < 0.01), CAT (P < 0.01) and GPX (P < 0.05) activities in both endometrial tissues. The activity of GSR decreased only in the glandular tissue (P < 0.05) after E2 treatment, either alone or in combination with P4. No change in SOD2 activity was detected in both endometrial tissues after administration of E2, P4 or both hormones. This study provides the first firm evidence for the role of ovarian steroid hormones in the regulation of the activities of key antioxidant enzyme in the endometrium of female mammals.
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PMID:Regulation of key antioxidant enzymatic systems in the sheep endometrium by ovarian steroids. 1851 5

In normal state of a cell, endogenous antioxidant enzyme system maintains the level of reactive oxygen species generated by mitochondrial respiratory chain. Mitochondrial superoxide dismutase [SOD; manganese SOD (MnSOD) or SOD2] neutralizes highly reactive superoxide radical (O(*-)(2)), the first member in the plethora of mitochondrial reactive oxygen species. A polymorphism in the target sequence of MnSOD enzyme, Val(16)Ala, is known to disrupt proper targeting of the enzyme from cytosol to mitochondrial matrix where it acts on O(*-)(2) to dismutate it to hydrogen peroxide (H(2)O(2)). A change in the level of O(*-)(2) and of H(2)O(2) in mitochondria modulates the molecular mechanisms of apoptosis, cellular adhesion, and cell proliferation and thus play key role in cancer development. Previous studies investigating the association between MnSOD Val(16)Ala polymorphism and cancer risk have revealed inconsistent results. We conducted a meta-analysis on these studies. Our meta-analysis on total of 7,366 cancer cases and 9,102 controls from 13 published case-control studies showed no overall association of this polymorphism either with breast cancer risk or for cancer risk as such (for Ala homozygous odds ratio, 0.98; 95% confidence interval, 0.90-1.07 and odds ratio, 1.02; 95% confidence interval, 0.91-1.14, respectively). Also, there was no major effect in either recessive or dominant model for the MnSOD Val(16)Ala. However, a proper evaluation of this polymorphism with cancer link demands experiments involving large sample size, cross-tabulation of gene-gene, gene-environment interactions, and linkage studies, as cell biological experiments clearly correlate critical levels of mitochondrial O(*-)(2) and H(2)O(2) to carcinogenesis.
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PMID:Target sequence polymorphism of human manganese superoxide dismutase gene and its association with cancer risk: a review. 1906 42

A primary antioxidant enzyme in mitochondria, manganese superoxide dismutase (MnSOD), plays a critical role in the survival of aerobic life. It is well documented that, compared with normal cell counterparts, MnSOD level is decreased in neoplastic transformed cells but is increased in aggressive cancers. However, the underlying mechanism for the observed dysregulation of MnSOD in cancer is unknown. We have identified previously a unique set of mutations located in the promoter region of the SOD2 gene in several types of cancer cells. We found that a C-to-T transition at -102 and an insertion of A at -93 down-regulate MnSOD transcription by interrupting the formation of a single-stranded loop that is essential for a high level of promoter activity. Here, we show that the additional downstream mutation, C-to-G transversion at -38, creates a binding site for the transcription factors specificity protein 1 (Sp1) and activating protein 2 (AP-2). The promoter function is regulated by the relative levels of Sp1 and AP-2. In cytokine-induced expression of the SOD2 gene, Sp1 cooperates with a transcriptional complex containing nuclear factor-kappaB and nucleophosmin. The presence of AP-2 attenuates this induction. Our results suggest that the high level of MnSOD observed in aggressive cancer cells may be due, in part, to the absence of AP-2 transcriptional repression.
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PMID:Mutations in the SOD2 promoter reveal a molecular basis for an activating protein 2-dependent dysregulation of manganese superoxide dismutase expression in cancer cells. 1907 33

Cerebral ischemia and reperfusion increase superoxide anions (O(2)(*-)) in brain mitochondria. Manganese superoxide dismutase (Mn-SOD; SOD2), a primary mitochondrial antioxidant enzyme, scavenges superoxide radicals and its overexpression provides neuroprotection. However, the regulatory mechanism of Mn-SOD expression during cerebral ischemia and reperfusion is still unclear. In this study, we identified the signal transducer and activator of transcription 3 (STAT3) as a transcription factor of the mouse Mn-SOD gene, and elucidated the mechanism of O(2)(*-) overproduction after transient focal cerebral ischemia (tFCI). We found that Mn-SOD expression is significantly reduced by reperfusion in the cerebral ischemic brain. We also found that activated STAT3 is usually recruited into the mouse Mn-SOD promoter and upregulates transcription of the mouse Mn-SOD gene in the normal brain. However, at early postreperfusion periods after tFCI, STAT3 was rapidly downregulated, and its recruitment into the Mn-SOD promoter was completely blocked. In addition, transcriptional activity of the mouse Mn-SOD gene was significantly reduced by STAT3 inhibition in primary cortical neurons. Moreover, we found that STAT3 deactivated by reperfusion induces accumulation of O(2)(*-) in mitochondria. The loss of STAT3 activity induced neuronal cell death by reducing Mn-SOD expression. Using SOD2-/+ heterozygous knock-out mice, we found that Mn-SOD is a direct target of STAT3 in reperfusion-induced neuronal cell death. Our study demonstrates that STAT3 is a novel transcription factor of the mouse Mn-SOD gene and plays a crucial role as a neuroprotectant in regulating levels of reactive oxygen species in the mouse brain.
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PMID:Regulation of Mn-superoxide dismutase activity and neuroprotection by STAT3 in mice after cerebral ischemia. 1947 27


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