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)

Neurotoxic properties of L-dopa and dopamine (DA)-related compounds were assessed in human neuroblastoma SH-SY5Y cells with reference to their structural relationship. L-Dopa and its metabolites containing two free hydroxyl residues on their benzene ring showed toxicity in the cell, which was prevented by superoxide dismutase (SOD) and reduced glutathione (GSH), but not by catalase. Furthermore, a synthetic derivative of DA, 3-hydroxy-4-methoxyphenethylamine (HMPE) containing methoxy residue at position 4 in the benzene ring, exerted partial cytotoxicity, which was not prevented by SOD, GSH or catalase. However, the metabolites containing methoxy residue at position 3 failed to show a toxic effect in the SH-SY5Y cells. Moreover, DA induced apoptotic cell death, which was observed by nuclear and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining and measurement of caspase-3 activity; this compound up-regulated apoptotic factor p53 while down-regulating anti-apoptotic factor Bcl-2. In the cell-free in vitro electron spin resonance (ESR) spectrometry, DA possessing two hydroxyl groups showed generation of DA-semiquinone radicals, which were markedly prevented by addition of SOD or GSH but not by catalase. On the other hand, methylation of one of the hydroxyl residues on the benzene ring of DA converted DA to an unoxidizable compound (3-MT or HMPE), and caused it to lose the property to produce semiquinone radicals. It has been previously reported that SOD acting as a superoxide:semiquinone oxidoreductase prevents quinone formation, and that reduced GSH through forming a complex with DA-quinone prevents quinone binding to the thiol group of the intact protein. Therefore, the present results suggest that DA and its metabolites containing two hydroxyl residues exert cytotoxicity mainly due to generation of highly reactive quinones.
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PMID:Apoptosis-inducing neurotoxicity of dopamine and its metabolites via reactive quinone generation in neuroblastoma cells. 1249 14

Reduced cell proliferation and increased levels of cellular glutathione (GSH) are characteristic for cells that overexpress the anti-apoptotic Bcl-2 protein. We investigated the influence of various Bcl-2 domains on both these characteristics. Rat CC531 colorectal cancer cells were stably transfected with the human bcl-2 gene (CCbcl2 cells) or with bcl-2 gene constructs missing a coding sequence for a func-tional domain, BH1 (CCDeltaBH1 cells), BH3 (CCDeltaBH3 cells), BH4 (CCDeltaBH4 cells) or the transmembrane region (CCDeltaTM cells). We measured GSH levels in exponentially and confluent growing bcl-2-transfected cell populations. The fraction of S-phase cells during exponential growth was significantly reduced in CCbcl2, CCDeltaBH1, CCDeltaBH3, and CCDeltaTM cells compared with parental CC531, neo-transfected CC531 and CCDeltaBH4 cells. GSH levels in these bcl-2 transfectants were significantly higher than in the parental line measured at 50% confluence; at 100% confluence they reached a similar level as found in parental cells. Independently from the presence of BH1, BH3 or TM domains, overexpression of Bcl-2 reduces cellular proliferation under conditions of increased GSH levels. This apparent link is lost in CCDeltaBH4 cells; these cells are not reduced in cellular proliferation and harbour significantly higher GSH levels than found in the other transfectants. Studies on the subcellular localization revealed an extremely low expression of the Bcl-2 protein lacking the N-terminal BH4 domain in nuclear fractions. Nuclear translocation of Bcl-2 requires the presence of the BH4 domain and seems prominent in reducing cellular proliferation.
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PMID:The role of various Bcl-2 domains in the anti-proliferative effect and modulation of cellular glutathione levels: a prominent role for the BH4 domain. 1255 59

Proteasomal dysfunction has been implicated in the pathogenesis of Parkinson's disease (PD). We examined the effect of a selective proteasomal inhibitor, epoxomicin, on primary cultured mesencephalic neurons. Exposing rat cultured mesencephalic neurons to epoxomicin for 24 h resulted in neurotoxicity in a dose-dependent manner. Epoxomicin caused mitochondrial dysfunction, reduction in reduced glutathione (GSH), and increased generation of free radicals. Neuronal damage was significantly blocked by antioxidative/GSH-augmenting agents. Epoxomicin also increased the expression of Bax and decreased that of Bcl-2, which may cause mitochondrial dysfunction and release of free radicals. Dopaminergic neurons were preferentially resistant to the toxicity of epoxomicin. Inhibiting the synthesis of tetrahydrobiopterin (BH(4)), which has been reported to have antioxidative function, increased the susceptibility of dopaminergic neurons, whereas increasing BH(4) levels protected non-dopaminergic neurons. These findings suggest that BH(4) is at least in part a contributing factor to grand the resistance to dopaminergic neurons against epoxomicin neurotoxicity. Our results suggest that proteasome inhibition causes the neurotoxicity in mesencephalic neurons, but that is not sufficient to reproduce the selective damage to dopaminergic neurons, such as that seen in PD.
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PMID:Effect of proteasome inhibitor on cultured mesencephalic dopaminergic neurons. 1257 83

Growing evidence indicates that viral replication is regulated by the redox state of the host cell. We demonstrate that cells of different origins display differential permissivity for influenza A virus replication, depending on their intracellular redox power as reflected by Bcl-2 expression and glutathione (GSH) content. Bcl-2 expressing cells were found to have higher intracellular levels of GSH and to produce lower amounts of virus than Bcl-2 negative cells. Two different steps in the virus life-cycle were involved in Bcl-2/GSH mediated viral inhibition: 1) expression of late viral proteins (in particular hemagglutinin and matrix); and 2) nuclear-cytoplasmic translocation of viral ribonucleoproteins (vRNPs). Buthionine-sulfoximine-induced inhibition of GSH synthesis in Bcl-2 expressing cells caused an increase in the expression of late viral proteins but did not restore vRNP export to the cytoplasm. Collectively, our findings show that both Bcl-2 expression and GSH content contribute to the host cell's ability to down-regulate influenza virus replication, although their effects are exerted at different stages of the viral life-cycle. In certain cell populations, this form of down-regulation might conceivably favor the establishment of persistent viral infection.
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PMID:Influenza A virus replication is dependent on an antioxidant pathway that involves GSH and Bcl-2. 1259 79

Mitochondria play central roles in cellular metabolism and apoptosis and are a major source of reactive oxygen species (ROS). We investigated the role of ROS and mitochondria in radiation-induced apoptosis in multiple myeloma cells. Two distinct levels of ROS were generated following irradiation: a small increase observed early, and a pronounced late increase, associated with depletion of reduced glutathione (GSH) and collapse of mitochondrial membrane potential (deltapsi(m)). Exogenous ROS and caspase-3 induced deltapsi(m) drop and cytochrome c release from mitochondria, which could be prevented by molecular (dominant-negative caspase-9) and pharmacologic (zVAD-fmk) caspase inhibitors and overexpression of Bcl-2. Exogenous ROS also induced mitochondrial permeability transition (PT) pore opening and cytochrome c release in isolated mitochondria, which could be blocked by inhibition of PT with cyclosporin A. These results indicate that the late ROS production is associated with increased PT pore opening and decreased deltapsi(m), and GSH, events associated with caspase activation and cytochrome c release.
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PMID:The late increase in intracellular free radical oxygen species during apoptosis is associated with cytochrome c release, caspase activation, and mitochondrial dysfunction. 1270 Jun 32

Ethinyl estradiol (EE) is a strong promoter and weak hepatocarcinogen in rats. Previously, we demonstrated that EE enhanced the transcript levels of nuclear genome- and mitochondrial genome-encoded genes and respiratory chain activity in female rat liver, and also inhibited transforming growth factor beta (TGFbeta)-induced apoptosis in cultured liver slices and hepatocytes from female rats. In this study, using cultured female rat hepatocytes, we observed that EE, within 24 h, increased the transcript levels of the mitochondrial genome-encoded genes cytochrome oxidase subunits I, II, and III. This effect was accompanied by increased mitochondrial respiratory chain activity, as reflected by increased mitochondrial superoxide generation, and detected by lucigenin-derived chemiluminescence and cellular ATP levels. EE also enhanced the levels of Bcl-2 protein. Biochemical analyses indicated that EE significantly increased both the levels of glutathione (reduced [GSH] and oxidized [GSSG] forms) per mg protein in mitochondria and nuclei, while the percentage of total glutathione in the oxidized form was not affected. This finding was supported by confocal microscopy. These effects caused by EE may contribute, at least in part, to the EE-mediated inhibition of hepatic apoptosis.
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PMID:Enhanced mitochondrial gene transcript, ATP, bcl-2 protein levels, and altered glutathione distribution in ethinyl estradiol-treated cultured female rat hepatocytes. 1285 39

B16 melanoma (B16M) cells with high GSH content show high metastatic activity. However, the molecular mechanisms linking GSH to metastatic cell survival are unclear. The possible relationship between GSH and the ability of Bcl-2 to prevent cell death was studied in B16M cells with high (F10) and low (F1) metastatic potential. Analysis of a Bcl-2 family of genes revealed that B16M-F10 cells, as compared with B16M-F1 cells, overexpressed preferentially Bcl-2 (approximately 5.7-fold). Hepatic sinusoidal endothelium-induced B16M-F10 cytotoxicity in vitro increased from approximately 19% (controls) to approximately 97% in GSH-depleted B16M-F10 cells treated with an antisense Bcl-2 oligodeoxynucleotide (Bcl-2-AS). l-Buthionine (S,R)-sulfoximine-induced GSH depletion or Bcl-2-AS decreased the metastatic growth of B16M-F10 cells in the liver. However, the combination of l-buthionine (S,R)-sulfoximine and Bcl-2-AS abolished metastatic invasion. Bcl-2-overexpressing B16M-F1/Tet-Bcl-2 and B16M-F10/Tet-Bcl-2 cells, as compared with controls, showed an increase in GSH content, no change in the rate of GSH synthesis, and a decrease in GSH efflux. Thus, Bcl-2 overexpression may increase metastatic cell resistance against oxidative/nitrosative stress by inhibiting release of GSH. In addition, Bcl-2 availability regulates the mitochondrial GSH (mtGSH)-dependent opening of the permeability transition pore complex. Death in B16M-F10 cells was sharply activated at mtGSH levels below 30% of controls values. However, this critical threshold increased to approximately 60% of control values in Bcl-2-AS-treated B16M-F10 cells. GSH ester-induced replenishment of mtGSH levels (even under conditions of cytosolic GSH depletion) prevented cell death. Our results indicate that survival of B16M cells with high metastatic potential can be challenged by inhibiting their GSH and Bcl-2 synthesis.
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PMID:Down-regulation of glutathione and Bcl-2 synthesis in mouse B16 melanoma cells avoids their survival during interaction with the vascular endothelium. 1288 29

Oxidative stress is a main mediator in nitric oxide (NO) -induced neurotoxicity and has been implicated in the pathogenesis of many neurodegenerative disorders. Green tea polyphenols are usually expected as potent chemo-preventive agents due to their ability of scavenging free radicals and chelating metal ions. However, not all the actions of green tea polyphenols are necessarily beneficial. In the present study, we demonstrated that higher-concentration green tea ployphenols significantly enhanced the neurotoxicity by treatment of sodium nitroprusside (SNP), a nitric oxide donor. SNP induced apoptosis in human neuroblastoma SH-SY5Y cells in a concentration and time-dependent manner, as estimated by cell viability assessment, FACScan analysis and DNA fragmentation assay, whereas treatment with green tea polyphenols alone had no effect on cell viability. Pre-treatment with lower-dose green tea polyphenols (50 and 100 microm) had only a slightly deleterious effect in the presence of SNP, while higher-dose green tea polyphenols (200 and 500 microm) synergistically damaged the cells severely. Further research showed that co-incubation of green tea polyphenols and SNP caused loss of mitochondrial membrane potential, depletion of intracellular GSH and accumulation of reactive oxygen species, and exacerbated NO-induced neuronal apoptosis via a Bcl-2 sensitive pathway.
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PMID:Green tea polyphenols enhance sodium nitroprusside-induced neurotoxicity in human neuroblastoma SH-SY5Y cells. 1291 27

Arsenic trioxide (As(2)O(3)) has been used successfully in the treatment of acute promyelocytic leukemia. However, effects of As(2)O(3) in normal peripheral blood T cells have not been studied in detail. The purpose of this study was to investigate whether As(2)O(3) would induce apoptosis in normal T cells and therefore may have immunosuppressive side effects. Apoptosis was measured by terminal deoxynucleotidyl transferase-mediated nick end labeling assay, caspase activation by flow cytometry and colorimetric assay, mitochondrial transmembrane potential (deltapsi(m)), intracellular reactive oxygen species (ROS), and intracellular reduced glutathione (GSH) by flow cytometry. The release of cytochrome c and apoptosis-inducing factor (AIF) from the mitochondria was measured by confocal microscopy, and the expression of molecules regulating apoptosis was measured by Western blotting. As(2)O(3), at clinically achievable therapeutic concentrations, induces apoptosis in peripheral blood T cells. As(2)O(3)-induced apoptosis was associated with reduced deltapsi(m), enhanced generation of intracellular ROS, decreased levels of intracellular GSH, release of cytochrome c and AIF from the mitochondria, activation of caspases, down-regulation of Bcl-2 and Bcl-x(L), and up-regulation of Bax expression. In addition, exogenous GSH protected lymphocytes from As(2)O(3)-induced apoptosis. Furthermore, overexpression of Bcl-2 inhibited As(2)O(3)-induced apoptosis and blocked depolarization of deltapsi(m), generation of ROS, and release of both cytochrome c and AIF. These data indicate that As(2)O(3) induces apoptosis in T cells by enhancing oxidative stress and that Bcl-2 appears to play a major role in As(2)O(3)-induced apoptosis.
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PMID:Arsenic trioxide induces apoptosis in peripheral blood T lymphocyte subsets by inducing oxidative stress: a role of Bcl-2. 1293 60

A substantial body of data from clinical and laboratory studies indicates that reactive oxygen intermediates are implicated in the pathogenesis of diverse human diseases, including cancer, diabetes, and neurodegenerative disorders. Oxidative stress induced by reactive oxygen intermediates often causes cell death via apoptosis that is regulated by a plenty of functional genes and their protein products. Bcl-2, which is an integral intermitochondrial membrane protein, blocks apoptosis induced by a wide array of death signals. In spite of extensive research, the molecular milieu that characterizes the antiapoptotic function of Bcl-2 is complex and not fully identified. Recently, there are several lines of evidence that Bcl-2 functions via antioxidant pathways to prevent apoptosis. Thus, bcl-2-overexpressing cells exhibit elevated expression of antioxidant enzymes and higher levels of cellular GSH compared with the control cells transfected with the vector alone. There has been increasing evidence supporting that the redox-sensitive transcription factor nuclear factor kappaB regulates the activity and/or expression of antioxidative and antiapoptotic target genes and promotes cell survival against oxidative cell death. This commentary focuses on the antioxidative functions of Bcl-2 and underlying molecular mechanisms in relation to its antiapoptotic property. The role of Bcl-2 in regulation of nuclear factor kappaB signaling pathways and possible cross-talk with mitogen-activated protein kinases are also discussed.
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PMID:Potentiation of cellular antioxidant capacity by Bcl-2: implications for its antiapoptotic function. 1455 11


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