Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent reports have implicated a possible role of reactive oxygen species (ROS) in the induction and mediation of apoptosis and DNA damage. Oxidative DNA base modification induced by cupric nitrilotriacetate (Cu-NTA) and the following apoptosis were observed in human promyelocytic leukemia HL-60 cells. We measured the level of ROS in the cells by using a fluorescence probe, 2',7'-dichlorofluorescein diacetate (DCFH-DA), and the amount of a modified DNA base, 8-hydroxydeoxyguanosine (8-OHdG) by HPLC-ECD. It was found that Cu-NTA exposure significantly enhanced ROS and 8-OHdG formation in the cells. Meanwhile, we observed both DNA fragmentation and morphological changes characteristic of apoptosis, which was also determined quantitatively by flow cytometry and showed dose- and time-dependent manners. Furthermore, several antioxidants such as dimethyl sulfoxide (DMSO), superoxide dismutase (SOD), and catalase were used to detect whether the apoptosis could be blocked. Only DMSO protected against this form of cell death. To elucidate molecular events in the apoptosis, expressions of Bcl-2 protein family members, such as Bcl-2, Bcl-X and Bax, and heat shock protein 70 (HSP-70) were measured by western blotting using specific antibodies. The levels of Bax and Bcl-Xs remained largely unchanged, but the Bcl-2 and Bcl-XL expression showed down-regulation. After 24 h incubation in the presence of copper, the levels of Bcl-2 and Bcl-XL reduced about 33.8% and 51.1% compared with untreated cells, respectively. Furthermore, after 16 h incubation, the level of HSP-70 expression was about 3.4-fold greater than that in untreated cells, suggesting that HSP-70 is important in increasing resistance to oxidative stress induced by Cu-NTA. But overexpression of HSP-70 failed to protect HL-60 cells from apoptosis induced by Cu-NTA. We inferred that Cu-NTA may induce oxidative DNA damage through free radical injuries, which may turn on the apoptosis in HL-60 cells.
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PMID:Cupric nitrilotriacetate induces oxidative DNA damage and apoptosis in human leukemia HL-60 cells. 974 94

Apoptosis plays a crucial role in maintaining genomic integrity by selectively removing the most heavily damaged cells from the population. Under that premise, the dysregulation of apoptosis may result in an inappropriate survival of mutated cells. This study demonstrates that ectopic expression of Bcl-2 effectively suppresses benzene-active metabolites, 1,4-hydroquinone- and 1, 4-benzoquinone-induced apoptosis in human leukemic HL-60 cells, as evidenced by morphological changes and DNA fragmentation. Although reactive oxygen species production largely contributes to the benzene metabolites-induced apoptotic cell death, Bcl-2 fails to attenuate the benzene metabolites-elicited increase of reactive oxygen species in HL-60 cells, as confirmed by flow cytometry analysis. These data suggest that Bcl-2 prevents benzene metabolites-induced apoptosis at the downstream of oxidative damage events. This study also determines the level of 8-hydroxydeoxyguanosine (8-OH-dGua), an indicator for oxidative DNA damage, in neo- and Bcl-2-overexpressing HL-60 cells after treating with 1,4-hydroquinone or 1,4-benzoquinone. Interestingly, our results indicate that a majority of the 8-OH-dGua is efficiently removed in neo control cells within 3 to 6 h, whereas only 25 to 35% of 8-OH-dGua is repaired in Bcl-2 transfectants even for 24 h. Similarly, another oxidative DNA base, thymine glycol, failed to repair and was retained in genomic DNA of Bcl-2 transfectants. The above findings suggest that Bcl-2 may retain benzene metabolites-induced oxidative DNA damage in surviving cells. Indeed, the failure of repairing 8-OH-dGua and thymine glycol in benzene metabolites-treated Bcl-2 survivors increases the number of mutation frequencies at the hprt locus. Results in this study thus provide a novel benzene-induced carcinogenesis mechanism by which up-regulation of Bcl-2 protein may promote the susceptibility to benzene metabolites-induced mutagenesis by overriding apoptosis and attenuating DNA repair capacity.
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PMID:Suppression of apoptosis by Bcl-2 to enhance benzene metabolites-induced oxidative DNA damage and mutagenesis: A possible mechanism of carcinogenesis. 1022 May 68

Apoptosis plays a critical role in maintaining genomic integrity by selectively removing the most heavily damaged cells from the population. Reactive oxygen species (ROS) and certain inflammatory cytokines are always elevated during the human carcinogenic process. However, the biological significance of the interplay between ROS and inflammatory cytokine remains elusive. This study demonstrates that interleukin-6 (IL-6) effectively protects gastric cancer cells from the apoptosis induced by hydrogen peroxide (H(2)O(2)). The cell death signaling JNK pathway elicited by H(2)O(2) is also inhibited by IL-6. We further found that Mcl-1, but not other Bcl-2 family members, was up-regulated by IL-6, by a substantial level over 24 h. We further transfected a mcl-1 expression vector, pCMV-mcl-1, into the AGS cells, and successfully obtained several mcl-1-overexpressing clones. Flow cytometric analysis shows that these mcl-1-overexpressing AGS cells are more resistant to the apoptosis induced by H(2)O(2) when compared with the neo control AGS cells. Consistently, the activation of the JNK pathway induced by H(2)O(2) is also blocked in mcl-1-overexpressed cells. These results indicate that the anti-apoptotic effect of IL-6 is, at least in part, due to the up-regulation of mcl-1. To our surprise, either IL-6 exposure or mcl-1 overexpression fails to reduce the level of intracellular peroxides in the AGS cells triggered by H(2)O(2). This study also determined the level of 8-hydroxydeoxyguanosine (8-OH-dGua), an indicator for oxidative DNA lesions in IL-6-treated or mcl-1-overexpressed AGS cells after treatment with H(2)O(2). Notably, our results indicate that a majority of the 8-OH-dGua is efficiently removed in the AGS cells without IL-6 treatment, whereas only approximately 50% of the 8-OH-dGua was repaired in the IL-6-treated AGS cells after 24 h. Similarly, approximately 60-70% of the 8-OH-dGua also failed to repair and was retained in the genomic DNA of the mcl-1 transfectants. Results in this study provide a novel mechanism by which up-regulation of the Mcl-1 protein by IL-6 may enhance the susceptibility to H(2)O(2)-induced oxidative DNA lesions by overriding apoptosis.
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PMID:IL-6 inhibits apoptosis and retains oxidative DNA lesions in human gastric cancer AGS cells through up-regulation of anti-apoptotic gene mcl-1. 1175 24

Cell loss and neuritic/cytoskeletal lesions represent two of the major categories of dementia-associated structural abnormalities in Alzheimer's disease (AD). Cell loss is ultimately mediated by apoptosis and mitochondrial DNA damage due to enhanced sensitivity to oxidative stress, but the mechanism responsible for the neuritic/cytoskeletal lesions including the abnormal proliferation of cortical neurites is not known. This study examines the potential role of oxygen free radical injury as a factor contributing to both cell death and neuritic sprouting cascades in AD. PNET2 human neuronal cells were treated with H2O2 (8 micro M to 88 micro M) for 24 hours and then analyzed for viability, DNA damage, and pro-apoptosis, survival, and sprouting gene expression and signaling. H2O2-treatment resulted in dose-dependent increases in cell death due to genomic and mitochondrial DNA damage associated with increased levels of 8-OHdG and the p53 and CD95 pro-apoptosis genes, reduced levels of the Bcl-2 survival gene, activation of JNK and p38 stress kinases, and inhibition of PI3 kinase survival signaling. However, the H2O2-treated cells also manifested increased expression of growth and sprouting molecules, including GAP-43, nitric oxide synthase 3, neuronal thread protein (NTP; approximately 17 kD and approximately 21 kD forms), proliferating cell nuclear antigen, and phospho-Erk MAPK, and normal levels of the AD-associated approximately 41 kD NTP species, cyclin dependent kinase 5 (cdk-5), and phospho-tau. In addition, the H2O2-treated cells had increased levels of p25, the catalytically active and stable cleavage product of p35, which regulates cdk-5 activity. Previous studies demonstrated p25 accumulation in AD brains and p25-induced hyperphosphorylation of tau and neuronal apoptosis. The findings herein suggest that oxygen free radical injury in human CNS neuronal cells is sufficient to cause some but not all of the pro-death and pro-sprouting molecular abnormalities that occur in AD.
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PMID:Oxygen free radical injury is sufficient to cause some Alzheimer-type molecular abnormalities in human CNS neuronal cells. 1221 88

Parkinson's disease is characterized by a progressive loss of dopaminergic neurons in the substantia nigra zona compacta, and in other subcortical nuclei associated with a widespread occurrence of Lewy bodies. The causes of cell death in Parkinson's disease are still poorly understood, but a defect in mitochondrial oxidative phosphorylation and enhanced oxidative stress have been proposed. We have examined 3-morpholinosydnonimine (SIN-1)-induced apoptosis in control and metallothionein-overexpressing dopaminergic neurons, with a primary objective to determine the neuroprotective potential of metallothionein against peroxynitrite-induced neurodegeneration in Parkinson's disease. SIN-1 induced lipid peroxidation and triggered plasma membrane blebbing. In addition, it caused DNA fragmentation, alpha-synuclein induction, and intramitochondrial accumulation of metal ions (copper, iron, zinc, and calcium), and enhanced the synthesis of 8-hydroxy-2-deoxyguanosine. Furthermore, it down-regulated the expression of Bcl-2 and poly(ADP-ribose) polymerase, but up-regulated the expression of caspase-3 and Bax in dopaminergic (SK-N-SH) neurons. SIN-1 induced apoptosis in aging mitochondrial genome knockout cells, alpha-synuclein-transfected cells, metallothionein double-knockout cells, and caspase-3-overexpressed dopaminergic neurons. SIN-1-induced changes were attenuated with selegiline or in metallothionein-transgenic striatal fetal stem cells. SIN-1-induced oxidation of dopamine to dihydroxyphenylacetaldehyde was attenuated in metallothionein-transgenic fetal stem cells and in cells transfected with a mitochondrial genome, and enhanced in aging mitochondrial genome knockout cells, in metallothionein double-knockout cells and caspase-3 gene-overexpressing dopaminergic neurons. Selegiline, melatonin, ubiquinone, and metallothionein suppressed SIN-1-induced down-regulation of a mitochondrial genome and up-regulation of caspase-3 as determined by reverse transcription-polymerase chain reaction. The synthesis of mitochondrial 8-hydroxy-2-deoxyguanosine and apoptosis-inducing factors were increased following exposure to 1-methyl-4-phenylpyridinium ion or rotenone. Pretreatment with selegiline or metallothionein suppressed 1-methyl-4-phenylpyridinium ion-, 6-hydroxydopamine-, and rotenone-induced increases in mitochondrial 8-hydroxy-2-deoxyguanosine accumulation. Transfection of aging mitochondrial genome knockout neurons with mitochondrial genome encoding complex-1 or melanin attenuated the SIN-1-induced increase in lipid peroxidation. SIN-1 induced the expression of alpha-synuclein, caspase-3, and 8-hydroxy-2-deoxyguanosine, and augmented protein nitration. These effects were attenuated by metallothionein gene overexpression. These studies provide evidence that nitric oxide synthase activation and peroxynitrite ion overproduction may be involved in the etiopathogenesis of Parkinson's disease, and that metallothionein gene induction may provide neuroprotection.
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PMID:Metallothionein attenuates 3-morpholinosydnonimine (SIN-1)-induced oxidative stress in dopaminergic neurons. 1288 Apr 80

To determine the temporal changes in oxidative stress, mitogen-activated protein (MAP) kinases and mitochondrial apoptotic proteins, and their relationship to myocyte apoptosis in the remote noninfarcted myocardium after myocardial infarction (MI), rabbits were randomly assigned to either coronary artery ligation to produce MI or sham operation. The animals were sacrificed at 1, 4, 8, or 12 weeks after coronary artery occlusion. Sham rabbits were sacrificed at 12 weeks after surgery. MI rabbits exhibited progressive increases of left ventricular (LV) end-diastolic pressure and end-diastolic dimension, and progressive decreases of LV fractional shortening and dP/dt over 12 weeks. The LV remodeling with LV chamber dilation and LV systolic dysfunction was temporally associated with progressive increases of cardiac oxidative stress as evidenced by decreased myocardial reduced-to-oxidized-glutathione ratio and increased myocardial 8-hydroxydeoxyguanosine and myocyte apoptosis. The ERK and JNK activities were decreased while p38 MAP kinase activity was increased with age of MI. The extent of p38 MAP kinase activation correlated with Bcl-2 phosphorylation. Bcl-2 protein was decreased in both mitochondrial and cytosolic fractions with age of MI. Bax protein was increased in both mitochondrial and cytosolic fractions. Cytochrome c was reduced in mitochondrial fraction and increased in cytosolic fraction in a time-dependent manner after MI. Cleaved caspase 9 and caspase 3 proteins were time-dependently increased after MI. These data suggest that p38 MAP kinase activation is not only time-dependent after MI, but also correlates with oxidative stress, Bcl-2 phosphorylation, and myocyte apoptosis. These changes in the remote noninfarcted myocardium may contribute to LV remodeling and dysfunction after MI.
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PMID:Progressive left ventricular remodeling, myocyte apoptosis, and protein signaling cascades after myocardial infarction in rabbits. 1594 20

Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons in the substantia nigra zona compacta and in other subcortical nuclei associated with a widespread occurrence of Lewy bodies. The causes of cell death in Parkinson's disease are still poorly understood, but a defect in mitochondrial oxidative phosphorylation and enhanced oxidative stress has been proposed. We have examined 3-morpholinosydnonimine (SIN-1)-induced apoptosis in control and metallothionein-overexpressing dopaminergic neurons, with a primary objective to determine the neuroprotective potential of metallothionein (MT) against peroxynitrite-induced neurodegeneration in PD. SIN-1 induced lipid peroxidation and triggered plasma membrane blebbing. In addition, it caused DNA fragmentation, alpha-synuclein induction, and intramitochondrial accumulation of metal ions (copper, iron, zinc, and calcium), and it enhanced the synthesis of 8-hydroxy-2-deoxyguanosine. Furthermore, it downregulated the expression of Bcl-2 and poly(adenosine diphosphate-ribose) polymerase, but upregulated the expression of caspase-3 and Bax in dopaminergic (SK-N-SH) neurons. SIN-1 induced apoptosis in aging mitochondrial genome knockout cells, alpha-synuclein-transfected cells, metallothionein double-knockout cells, and caspase-3-overexpressed dopaminergic neurons. SIN-1-induced changes were attenuated with selegiline or in metallothionein-transgenic striatal fetal stem cells. SIN-1-induced oxidation of dopamine (DA) to dihydroxyphenylacetaldehyde (DopaL) was attenuated in metallothionein-transgenic fetal stem cells and in cells transfected with a mitochondrial genome, and was enhanced in aging mitochondrial genome knockout cells, in metallothionein double-knockout cells, and caspase-3 gene-overexpressing dopaminergic neurons. Selegiline, melatonin, ubiquinone, and metallothionein suppressed SIN-1-induced downregulation of a mitochondrial genome and upregulation of caspase-3 as determined by reverse transcription polymerase chain reaction. These studies provide evidence that nitric oxide synthase activation and peroxynitrite ion overproduction may be involved in the etiopathogenesis of PD, and that metallothionein gene induction may provide neuroprotection.
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PMID:Peroxynitrite in the pathogenesis of Parkinson's disease and the neuroprotective role of metallothioneins. 1629 Dec 39

Solar UV radiation, in particular its UVB component, is the primary cause of many adverse biological effects, the most damaging of which is skin cancer. Here, we assessed the photochemopreventive effect of delphinidin, a major anthocyanidin present in many pigmented fruits and vegetables, on UVB-mediated responses in human immortalized HaCaT keratinocytes and SKH-1 hairless mouse skin. We found that pretreatment of cells with delphinidin (1-20 microM for 24 hours) protected against UVB (15-30 mJ/cm2, 24 hours)-mediated (i) decrease in cell viability and (ii) induction of apoptosis. Furthermore, we found that pretreatment of HaCaT cells with delphinidin inhibited UVB-mediated (i) increase in lipid peroxidation; (ii) formation of 8-hydroxy-2'-deoxyguanosine (8-OHdG); (iii) decrease in proliferating cell nuclear antigen expression; (iv) increase in poly(ADP-ribose) polymerase cleavage; (v) activation of caspases; (vi) increase in Bax; (vii) decrease in Bcl-2; (viii) upregulation of Bid and Bak; and (ix) downregulation of Bcl-xL. Topical application of delphinidin (1 mg/0.1 ml DMSO/mouse) to SKH-1 hairless mouse skin inhibited UVB-mediated apoptosis and markers of DNA damage such as cyclobutane pyrimidine dimers and 8-OHdG. Taken together our results suggest that treatment of HaCaT cells and mouse skin with delphinidin inhibited UVB-mediated oxidative stress and reduced DNA damage, thereby protecting the cells from UVB-induced apoptosis.
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PMID:Delphinidin, an anthocyanidin in pigmented fruits and vegetables, protects human HaCaT keratinocytes and mouse skin against UVB-mediated oxidative stress and apoptosis. 1690 16

Increases in NADPH oxidase activity, oxidative stress, and myocyte apoptosis coexist in failing hearts. In cardiac myocytes in vitro inhibition of NADPH oxidase reduces apoptosis. In this study, we tested the hypothesis that NADPH oxidase inhibition reduces myocyte apoptosis and improves cardiac function in heart failure after myocardial infarction (MI). Rabbits with heart failure induced by MI and sham-operated animals were randomized to orally receive apocynin, an inhibitor of NADPH oxidase (15 mg per day) or placebo for 4 weeks. Left ventricular (LV) dimension and function were assessed by echocardiography and hemodynamics. Myocardial NADPH oxidase activity was measured by superoxide dismutase-inhibitable cytochrome c reduction assay, NADPH oxidase subunit p47phox expression by Western blot and immunofluorescence analysis, myocardial oxidative stress evaluated by 8-hydroxydeoxyguanosine (8-OHdG) and 4-hydroxy-2-nonenal (4-HNE) using immunohistochemistry, and myocyte apoptosis by TUNEL assay. MI rabbits exhibited LV dilatation and systolic dysfunction measured by LV fractional shortening and the maximal rate of LV pressure rise (dP/dt). These changes were associated with increases in NADPH oxidase activity, p47phox protein expression, 8-OHdG expression, 4-HNE expression, myocyte apoptosis, and Bax protein and a decrease in Bcl-2 protein. Apocynin reduced NADPH oxidase activity, p47phox protein, oxidative stress, myocyte apoptosis, and Bax protein, increased Bcl-2 protein, and ameliorated LV dilatation and dysfunction after MI. The results suggest that inhibition of NADPH oxidase may represent an attractive therapeutic approach to treat heart failure.
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PMID:Inhibition of NADPH oxidase reduces myocardial oxidative stress and apoptosis and improves cardiac function in heart failure after myocardial infarction. 1760 36

The present study was undertaken to examine whether lycopene is able to counteract 7-ketocholesterol (7-KC)-induced oxidative stress and apoptosis in human macrophages. Human THP-1 macrophages were exposed to 7-KC (10-25 microM) alone and in combination with lycopene (0.5-2 microM), and we monitored changes in cell oxidative status [reactive oxygen species (ROS) production, NOX-4, hsp70 and hsp90 expressions, 8-OHdG formation] and in cell proliferation and apoptosis. After 24 h of treatment, lycopene significantly reduced the increase in ROS production and in 8-OHdG formation induced by the oxysterol in a dose-dependent manner. Moreover, the carotenoid strongly prevented the increase of NOX-4, hsp70 and hsp90 expressions as well as the phosphorylation of the redox-sensitive p38, JNK and ERK1/2 induced by the oxysterol. The attenuation of 7-KC-induced oxidative stress by lycopene coincided with a normalization of cell growth in human macrophages. Lycopene prevented the arrest in G0/G1 phase of cell cycle induced by the oxysterol and counteracted the increased expression of p53 and p21. Concomitantly, it inhibited 7-KC-induced apoptosis, by limiting caspase-3 activation and the modulatory effects of 7-KC on AKT, Bcl-2, Bcl-xL and Bax. Comparing the effects of lycopene, beta-carotene and (5Z)-lycopene on ROS production, cell growth and apoptosis show that lycopene and its isomer were more effective than beta-carotene in counteracting the dangerous effects of 7-KC in human macrophages. Our study suggests that lycopene may act as a potential antiatherogenic agent by preventing 7-KC-induced oxidative stress and apoptosis in human macrophages.
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PMID:Lycopene prevents 7-ketocholesterol-induced oxidative stress, cell cycle arrest and apoptosis in human macrophages. 1915 29


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