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

Cell death following ischemia-reperfusion injury is a major concern in clinical issues such as organ transplantation and trauma. The need to identify agents with a potential for preventing such damage has assumed great importance. We have evaluated the efficacy of picroliv, a potent antioxidant derived from the plant Picrorhiza kurrooa, in protecting against hepatic ischemia-reperfusion injury in vivo. Picroliv was fed to male Sprague Dawley rats in a dose of 12 mg/kg once daily by oral gavage for 7 days prior to hepatic ischemia. Ischemia was induced by occluding the hepatic pedicel with a microaneurysm clip for 30 min and reperfusion was allowed thereafter for varying period (15-120 min) by releasing the microaneurysm clip. Picroliv pretreatment resulted in better hepatocyte glycogen preservation and reduced apoptosis. Reduction in apoptosis was associated with decreased mRNA expression of caspase-3 and Fas. Oxidant induced cellular damage as measured by tissue malondialdehyde (MDA) levels was significantly less following picroliv pretreatment. Both a reduction in neutrophil infiltration and an increased level of intracellular antioxidant enzyme superoxide dismutase possibly contributed to the reduction in tissue lipid peroxidation. Tissue inflammatory cytokines level of interleukin-1alpha (IL-1alpha) and interleukin-1beta (IL-1beta) was also lower in picroliv group. Furthermore, picroliv pretreatment resulted in enhanced proliferating cell nuclear antigen (PCNA) immunoreactivity. These studies strongly suggest picroliv to be a promising agent for ameliorating injury following ischemia-reperfusion.
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PMID:Picroliv preconditioning protects the rat liver against ischemia-reperfusion injury. 1081 54

Glutathione peroxidase is an antioxidant enzyme that is involved in the control of cellular oxidative state. Recently, unregulated oxidative state has been implicated as detrimental to neural cell viability and involved in both acute and chronic neurodegeneration. In this study we have addressed the importance of a functional glutathione peroxidase in a mouse ischemia/reperfusion model. Two hours of focal cerebral ischemia followed by 24 h of reperfusion was induced via the intraluminal suture method. Infarct volume was increased three-fold in the glutathione peroxidase-1 (Gpx-1) -/- mouse compared with the wild-type mouse; this was mirrored by an increase in the level of apoptosis found at 24 h in the Gpx-1 -/- mouse compared with the wild-type mouse. Neuronal deficit scores correlated to the histologic data. We also found that activated caspase-3 expression is present at an earlier time point in the Gpx-1 -/- mice when compared with the wild-type mice, which suggests an enhanced susceptibility to apoptosis in the Gpx-1 -/- mouse. This is the first known report of such a dramatic increase, both temporally and in level of apoptosis in a mouse stroke model. Our results suggest that Gpx-1 plays an important regulatory role in the protection of neural cells in response to the extreme oxidative stress that is released during ischemia/reperfusion injury.
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PMID:Increased infarct size and exacerbated apoptosis in the glutathione peroxidase-1 (Gpx-1) knockout mouse brain in response to ischemia/reperfusion injury. 1157 47

1-Methyl-4-phenylpyridinium (MPP(+)) is a neurotoxin used in cellular models of Parkinson's Disease. Although intracellular iron plays a crucial role in MPP(+)-induced apoptosis, the molecular signalling mechanisms linking iron, reactive oxygen species (ROS) and apoptosis are still unknown. We investigated these aspects using cerebellar granule neurons (CGNs) and human SH-SY5Y neuroblastoma cells. MPP(+) enhanced caspase 3 activity after 24 h with significant increases as early as 12 h after treatment of cells. Pre-treatment of CGNs and neuroblastoma cells with the metalloporphyrin antioxidant enzyme mimic, Fe(III)tetrakis(4-benzoic acid)porphyrin (FeTBAP), completely prevented the MPP(+)-induced caspase 3 activity as did overexpression of glutathione peroxidase (GPx1) and pre-treatment with a lipophilic, cell-permeable iron chelator [N, N '-bis-(2-hydroxybenzyl)ethylenediamine-N, N '-diacetic acid, HBED]. MPP(+) treatment increased the number of TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labelling)-positive cells which was completely blocked by pre-treatment with FeTBAP. MPP(+) treatment significantly decreased the aconitase and mitochondrial complex I activities; pre-treatment with FeTBAP, HBED and GPx1 overexpression reversed this effect. MPP(+) treatment increased the intracellular oxidative stress by 2-3-fold, as determined by oxidation of dichlorodihydrofluorescein and dihydroethidium (hydroethidine). These effects were reversed by pre-treatment of cells with FeTBAP and HBED and by GPx1 overexpression. MPP(+)-treatment enhanced the cell-surface transferrin receptor (TfR) expression, suggesting a role for TfR-induced iron uptake in MPP(+) toxicity. Treatment of cells with anti-TfR antibody (IgA class) inhibited MPP(+)-induced caspase activation. Inhibition of nitric oxide synthase activity did not affect caspase 3 activity, apoptotic cell death or ROS generation by MPP(+). Overall, these results suggest that MPP(+)-induced cell death in CGNs and neuroblastoma cells proceeds via apoptosis and involves mitochondrial release of ROS and TfR-dependent iron.
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PMID:1-Methyl-4-phenylpyridinium (MPP+)-induced apoptosis and mitochondrial oxidant generation: role of transferrin-receptor-dependent iron and hydrogen peroxide. 1252 38

We investigate the death route induced by potassium depletion in cerebellar granule cells in 0-15 h time range and study whether and how mutual relationship occurs between the cell antioxidant and proteolytic system. To achieve this, we incubated cells in the absence or presence of inhibitors of the antioxidant system, including superoxide dismutase and catalase, and of the proteolytic system, consisting of proteasomes and caspases, and investigated whether and how (i) cell survival, (ii) reactive oxygen species (ROS) production and (iii) antioxidant enzyme and caspase-3 activity change as a function of time after the apoptotic stimulus. The involvement of both antioxidant and proteolytic system on cytochrome c release was also investigated. Cell survival was found to increase in the presence of either proteasome or caspase inhibitors. On the contrary, as a result of the antioxidant system impairment, shift from apoptosis to necrosis occurs. We show that the antioxidant system, which exhibits a huge activity increase up to 3 h after apoptosis induction, is subjected to the proteasome-dependent proteolysis and that the increase in the antioxidant system found in the absence of proteasome activity is accompanied by ROS production decrease. Consistently, the early ROS-dependent release of cytochrome c was found to be prevented when the activity of the antioxidant system increased. Finally, caspase-3 activation was prevented by the inhibitors of both antioxidant system and proteasome.
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PMID:The apoptosis/necrosis transition in cerebellar granule cells depends on the mutual relationship of the antioxidant and the proteolytic systems which regulate ROS production and cytochrome c release en route to death. 1260 21

The pharmacological properties of garlic and its derivatives are long known, and their underling mechanisms are being extensively investigated. In this study we have addressed the effects of diallyl disulfide (DADS), an oil-soluble garlic molecule, on cell growth of neuroblastoma cell SH-SY5Y, focusing on the redox events associated with this compound. Treatment of SH-SY5Y cells with DADS resulted in arrest of cell cycle in G(2)/M phase and commitment to apoptosis through the activation of the mitochondrial pathway (Bcl-2 down-regulation, cytochrome c release into the cytosol, and activation of caspase-9 and caspase-3). The earliest oxidative event observed after DADS treatment was the increase of production of reactive oxygen species, which reached the maximum yield on 30 min of DADS treatment. The oxidative burst resulted in protein and lipid damage as demonstrated by protein carbonyl accumulation and lipid peroxidation. We demonstrated that apoptosis induction was highly dependent on the activation of the redox-sensitive c-Jun NH(2)-terminal kinase (JNK)/c-Jun pathway. In particular, we established that DADS treatment induces JNK dissociation from glutathione S-transferase and its activation by phosphorylation. Moreover, treatment with JNK inhibitor I significantly reduced DADS-induced apoptosis and treatment with the spin trap 5,5'-dimethyl-1-pyrroline N-oxide or overexpression of the antioxidant enzyme copper, zinc superoxide dismutase, resulted in the inhibition of DADS-mediated toxicity through attenuation of JNK/c-Jun pathway activation. Overall, the results suggest a pivotal role for oxidative stress in DADS-induced apoptosis and, taking into account that tumor cells are deficient in antioxidants, suggest a plausible utilization of this compound as an antiproliferative agent in cancer therapy.
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PMID:Reactive oxygen species-dependent c-Jun NH2-terminal kinase/c-Jun signaling cascade mediates neuroblastoma cell death induced by diallyl disulfide. 1452 20

The objective of this work was to test the hypothesis that endurance training may be protective against in vivo doxorubicin (DOX)-induced cardiomyopathy through mitochondria-mediated mechanisms. Forty adult (6-8 wk old) male Wistar rats were randomly divided into four groups (n = 10/group): nontrained, nontrained + DOX treatment (20 mg/kg), trained (14 wk of endurance treadmill running, 60-90 min/day), and trained + DOX treatment. Mitochondrial respiration, calcium tolerance, oxidative damage, heat shock proteins (HSPs), antioxidant enzyme activity, and apoptosis markers were evaluated. DOX induces mitochondrial respiratory dysfunction, oxidative damage, and histopathological lesions and triggers apoptosis (P < 0.05, n = 10). However, training limited the decrease in state 3 respiration, respiratory control ratio (RCR), uncoupled respiration, aconitase activity, and protein sulfhydryl content caused by DOX treatment and prevented the increased sensitivity to calcium in nontrained + DOX-treated rats (P < 0.05, n = 10). Moreover, training inhibited the DOX-induced increase in mitochondrial protein carbonyl groups, malondialdehyde, Bax, Bax-to-Bcl-2 ratio, and tissue caspase-3 activity (P < 0.05, n = 10). Training also increased by approximately 2-fold the expression of mitochondrial HSP-60 and tissue HSP-70 (P < 0.05, n = 10) and by approximately 1.5-fold the activity of mitochondrial and cytosolic forms of SOD (P < 0.05, n = 10). We conclude that endurance training protects heart mitochondrial respiratory function from the toxic effects of DOX, probably by improving mitochondrial and cell defense systems and reducing cell oxidative stress. In addition, endurance training limited the DOX-triggered apoptosis.
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PMID:Moderate endurance training prevents doxorubicin-induced in vivo mitochondriopathy and reduces the development of cardiac apoptosis. 1579 86

Doxorubicin (Dox) is a highly effective antineoplastic antibiotic associated with a dose-limiting cardiotoxicity that may result in irreversible cardiomyopathy and heart failure. The purpose of this study was to examine the effects of low-intensity exercise training (LIET) during the course of Dox treatment on cardiac function, myosin heavy chain expression, oxidative stress, and apoptosis activation following treatment. Male Sprague-Dawley rats either remained sedentary or were exercise trained on a motorized treadmill at 15 m/min, 20 min/day, 5 days/wk (Monday through Friday) for 2 wk. During the same 2-wk period, Dox (2.5 mg/kg) or saline was administered intraperitoneally to sedentary and exercised rats 3 days/wk (Monday, Wednesday, Friday) 1-2 h following the exercise training sessions (cumulative Dox dose: 15 mg/kg). Five days following the final injections, hearts were isolated for determination of left ventricular (LV) function, lipid peroxidation, antioxidant enzyme protein expression, 72-kDa heat shock protein expression, caspase-3 activity, and myosin heavy chain isoform expression. Dox treatment significantly impaired LV function and increased caspase-3 activity in sedentary animals (P < 0.05). LIET attenuated the LV dysfunction and apoptotic signal activation induced by Dox treatment and increased glutathione peroxidase expression, but it had no significant effect on lipid peroxidation, protein expression of myosin heavy chain isoforms, 72-kDa heat shock protein, or superoxide dismutase isoforms. In conclusion, our data suggest that LIET applied during chronic Dox treatment protects against cardiac dysfunction following treatment, possibly by enhancing antioxidant defenses and inhibiting apoptosis.
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PMID:Low-intensity exercise training during doxorubicin treatment protects against cardiotoxicity. 1621 Apr 42

Reactive oxygen species have been implicated as a cause of cancer and aging in mammals. Mice deficient for the antioxidant enzyme CuZn-superoxide dismutase (Sod1) have a decreased life span and an elevated incidence of liver cancer. To test the hypothesis that the cancer-prone phenotype in such mice is due to accelerated spontaneous mutation accumulation, we crossed these mutants with mice harboring a neutral lacZ mutation reporter gene. At 2 months of age, the lacZ mutation frequency in the liver of the hybrid animals was already twice as high as in littermate controls of the same age. This difference in mutation frequency increased to >3-fold at 6 months of age, after which it did not increase any further. Characterization of the mutation spectra in liver of the Sod1-null mice indicated mainly GC-to-TA transversions and GC-to-AT transitions, signature mutations of oxidative stress. The accelerated mutation accumulation in liver was accompanied by an increased frequency of apoptotic cells, as indicated by an increase in both terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling- and caspase 3-stained cells at 6 and 12 months of age. In kidney, an elevated mutation frequency above controls of approximately 2.5-fold was found not earlier than at 6 months. No increased mutation accumulation was observed in brain or spleen. These results support the hypothesis, that oxidative stress is an important causal factor of cancer in mammals.
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PMID:Organ-specific increase in mutation accumulation and apoptosis rate in CuZn-superoxide dismutase-deficient mice. 1635 31

Cholinergic and gabaergic systems play an important role generating electroencephalographic activity and regulating vigilance states. Pilocarpine is a cholinergic agonist commonly used to induce seizures and an epilepticus-like state in rodents. A relationship between status epilepticus and reactive oxygen species has been also suggested which could result in seizure-induced neurodegeneration. The aim of this study was to evaluate the existence of oxidative damage as well as the antioxidant enzyme response in cortex and hippocampus after the administration of an intraperitoneal (350 mg/kg) and an intracerebroventricular (360 microg, 1 microl) pilocarpine injection in rats. The GABA agonist muscimol (1 mg/kg, i.p.), with described neuroprotective properties, was used as a negative control. Only systemic pilocarpine induced oxidative damage. Malondialdehyde levels, as a marker of lipid peroxidation (LP), increased in both regions (55-56%). Catalase (52-80%) and superoxide dismutase (53-60%) activities also rose in both regions but glutathione peroxidase activity only increased in cortex (45%). Glutathione reductase and caspase-3 activity did not change. In conclusion, systemic pilocarpine produced oxidative brain damage, whereas local pilocarpine brain injection had no effects. Moreover, the enzymatic determinations performed in this study are a good tool to study brain injury in pharmacological manipulations such as the ones used in short recording EEG studies.
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PMID:Antioxidant response analysis in the brain after pilocarpine treatments. 1664 87

(+)-Catechin possesses a broad range of pharmacological properties, including antioxidative effect. However, little is reported on the mechanism by which (+)-catechin protects microglia cells from DNA damage by oxidative stress. In this study, TUNEL assay and DNA electrophorysis indicated that (+)-catechin markedly blocked DNA fragmentation and apoptosis of microglia cells by tBHP exposure. A potent antioxidative effect of (+)-catechin was confirmed by comparison with a putative antioxidant agent, N-acetylcysteine at the lower doses. Furthermore, the increased intracellular ROS by tBHP exposure were scavenged by elevated activities of catalase (CAT) and superoxide dismutase (SOD) after (+)-catechin treatment. (+)-Catechin partially inhibited the activation of caspase-3, thereby both cleavage of poly (ADP-ribose) polymerase (PARP) and degradation of inhibitor of caspase-activated DNase (ICAD) were effectively abolished. In addition, the expression of PARP for repair of impaired DNA was significantly increased by (+)-catechin treatment. Taken together, these data suggest that protective effects of (+)-catechin against oxidative DNA damage of microglia cells is exerted by the increased expression of DNA repair enzyme PARP and antioxidant enzyme activities.
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PMID:Elevated levels of DNA repair enzymes and antioxidative enzymes by (+)-catechin in murine microglia cells after oxidative stress. 1675 84


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