UNIPROT:P10415 - FACTA Search

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Query: UNIPROT:P10415 (Bcl-2)
33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Various physical and psychological stressors can cause thymocyte apoptosis and cell loss in rodents. Although glucocorticoids (GC) are commonly implicated, oxidative stress may also play a role. The purpose of this study was to examine the effect of an acute bout of strenuous treadmill running, and the antioxidant N-acetyl-L-cysteine (NAC) on thymocyte loss and apoptosis. Eighty-eight female C57BL/6 mice were given NAC (1 g/kg, i.p.) or saline (SAL) 30 min before 90 min of treadmill exercise at a 2 degrees slope (EX; 30 min at 22 m/min; 30 min at 25 m/min; and 30 min at 28 m/min) and sacrificed immediately (Imm) or 24 h following EX. Control mice (NonEX) were exposed to treadmill noise and vibration without running. Thymocytes were isolated and analyzed for phosphatidylserine (PS) externalization (Annexin V), loss of membrane integrity, mitochondria membrane depolarization, intracellular hydrogen peroxide (H(2)O(2)) production, and intracellular glutathione (GSH) as well as protein levels of caspase 3, Bcl-2, and cytosolic cytochrome c. Blood was analyzed for corticosterone (CORT) concentrations by radioimmunoassay. Exercise stress caused a significant increase in plasma CORT concentrations in EX + SAL + Imm and EX + NAC + Imm groups compared to NonEX mice. Relative to NonEX mice, thymocytes isolated from EX + SAL + Imm mice showed signs of an early apoptotic profile as indicated by decreased GSH stores and increased mitochondrial membrane depolarization. These effects were followed by a 50% reduction in thymocyte numbers 24 h post-exercise (EX + SAL + 24 h). Alterations in GSH levels, mitochondrial membrane depolarization, and thymocyte loss were not observed in mice receiving NAC. These results suggest that exercise-induced thymocyte apoptosis and cell loss may be mediated via an oxidative stress pathway.
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PMID:Mouse thymocyte apoptosis and cell loss in response to exercise and antioxidant administration. 1606 Nov 51

Rosmarinic acid (RA) is a naturally occurring polyphenolic and is found in several herbs in the Lamiaceae family, such as, Perilla frutescens. ADR is a potent anti-tumor drug, but is unfortunately potently cardiotoxic. This study was undertaken to investigate the inhibitory effect of RA on ADR-induced apoptosis in H9c2 cardiac muscle cells at a mechanistic level. In vitro, ADR significantly decreased the viabilities of H9c2 cells, and this was accompanied by apoptotic features, such as a change in nuclear morphology and caspase protease activation. RA was found to markedly inhibit these apoptotic characteristics by reducing intracellular ROS generation and by recovering the mitochondria membrane potential (delta psi). In addition, RA reversed the downregulations of GSH, SOD and Bcl-2 by ADR. In the present study, ADR was found to activate c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), transcriptional factor-activator-protein (AP)-1. We found that c-fos, Jun-B, Jun-D and p-c-Jun were super shifted by ADR, indicating that these proteins have an important role in the ADR-induced AP-1 activation. The inhibitions of JNK and ERK using appropriate inhibitors or dominant negative cell lines reduced ADR-induced apoptosis in H9c2 cardiac muscle cells. Taken together, these results suggest that RA can inhibit ADR-induced apoptosis in H9C2 cardiac muscle cells by inhibiting ROS generation and JNK and ERK activation. Thus, we propose that RA should be viewed as a potential chemotherapeutic that inhibits cardiotoxicity in ADR-exposed patients.
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PMID:Inhibitory effects of rosmarinic acid on adriamycin-induced apoptosis in H9c2 cardiac muscle cells by inhibiting reactive oxygen species and the activations of c-Jun N-terminal kinase and extracellular signal-regulated kinase. 1610 32

We examined the role of GSH in survival and cell death using GCS-2 cells that are deficient in glutamate cysteine ligase (gamma-glutamyl cysteine synthetase, gammaGCS), an enzyme essential for GSH synthesis. Cells maintained in 2.5 mM GSH have GSH levels that are approximately 2% of wild type and grow indefinitely; however, they express both pro- and anti-apoptotic Bcl-2 family members and have detectable levels of cytoplasmic cytochrome C. Withdrawal of GSH from the medium results in a fall in intracellular GSH to undetectable levels, decreased mitochondrial dehydrogenase activity, decreased anti-apoptotic factor RNAs, increased pro-apoptotic factor RNAs, additional cytochrome C release, and a fall in ATP levels; however, cells continue to grow for another 24h. At 48 h, these trends continue with the exception that mitochondrial membrane potential and ATP levels rise; DNA fragmentation begins at 48 h. Thus, severe reduction of GSH to 2% of wild type produces a metastable state compatible with survival, but complete absence of GSH triggers apoptosis.
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PMID:Survival and cell death in cells constitutively unable to synthesize glutathione. 1623 16

Experimental and clinical studies support the view that the semisynthetic tetracycline minocycline exhibits neuroprotective roles in several models of neurodegenerative diseases, including ischemia, Huntington, Parkinson diseases, and amyotrophic lateral sclerosis. However, recent evidence indicates that minocycline does not always present beneficial actions. For instance, in an in vivo model of Huntington's disease, it fails to afford protection after malonate intrastriatal injection. Moreover, it reverses the neuroprotective effect of creatine in nigrostriatal dopaminergic neurons. This apparent contradiction prompted us to analyze the effect of this antibiotic on malonate-induced cell death. We show that, in rat cerebellar granular cells, the succinate dehydrogenase inhibitor malonate induces cell death in a concentration-dependent manner. By using DFCA, monochlorobimane and 10-N-nonyl-Acridin Orange to measure, respectively, H2O2-derived oxidant species and reduced forms of GSH and cardiolipin, we observed that malonate induced reactive oxygen species (ROS) production to an extent that surpasses the antioxidant defense capacity of the cells, resulting in GSH depletion and cardiolipin oxidation. The pre-treatment for 4 h with minocycline (10-100 microM) did not present cytoprotective actions. Moreover, minocycline failed to block ROS production and to abrogate malonate-induced oxidation of GSH and cardiolipin. Additional experiments revealed that minocycline was also unsuccessful to prevent the mitochondrial swelling induced by malonate. Furthermore, malonate did not induce the expression of the iNOS, caspase-3, -8, and -9 genes which have been shown to be up-regulated in several models where minocycline resulted cytoprotective. In addition, malonate-induced down-regulation of the antiapoptotic gene Bcl-2 was not prevented by minocycline, controversially the mechanism previously proposed to explain minocycline protective action. These results suggest that the minocycline protection observed in several neurodegenerative disease models is selective, since it is absent from cultured cerebellar granular cells challenged with malonate.
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PMID:Minocycline fails to protect cerebellar granular cell cultures against malonate-induced cell death. 1624 43

Mitochondrial glutathione (mtGSH) depletion increases sensitivity of Bcl-2-overexpressing B16 melanoma (B16M)-F10 cells (high metastatic potential) to tumor necrosis factor-alpha (TNF-alpha)-induced oxidative stress and death in vitro. In vivo, mtGSH depletion in B16M-F10 cells was achieved by feeding mice (where the B16M-F10 grew as a solid tumor in the footpad) with an L-glutamine (L-Gln)-enriched diet, which promoted in the tumor cells an increase in glutaminase activity, accumulation of cytosolic L-glutamate, and competitive inhibition of GSH transport into mitochondria. L-Gln-adapted B16M-F10 cells, isolated using anti-Met-72 monoclonal antibodies and flow cytometry-coupled cell sorting, were injected into the portal vein to produce hepatic metastases. In l-Gln-adapted invasive (iB16M-Gln+) cells, isolated from the liver by the same methodology and treated with TNF-alpha and an antisense Bcl-2 oligodeoxynucleotide, viability decreased to approximately 12%. iB16M-Gln+ cell death associated with increased generation of O2*- and H2O2, opening of the mitochondrial permeability transition pore complex, and release of proapoptotic molecular signals. Activation of cell death mechanisms was prevented by GSH ester-induced mtGSH replenishment. The oxidative stress-resistant survivors showed an adaptive response that includes overexpression of manganese-containing superoxide dismutase (Mn-SOD) and catalase activities. By treating iB16M-Gln+ cells with a double anti- antisense therapy (Bcl-2 and SOD2 antisense oligodeoxynucleotides) and TNF-alpha, metastatic cell survival decreased to approximately 1%. Chemotherapy (taxol plus daunorubicin) easily removed this minimum percentage of survivors. This contribution identifies critical molecules that can be sequentially targeted to facilitate elimination of highly resistant metastatic cells.
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PMID:Bcl-2 and Mn-SOD antisense oligodeoxynucleotides and a glutamine-enriched diet facilitate elimination of highly resistant B16 melanoma cells by tumor necrosis factor-alpha and chemotherapy. 1626 11

Antisense technology was successfully employed to selectively reduce the expression of Bcl-2 in U937 cells, while leaving their redox status intact. These cells displayed enhanced sensitivity to mitochondrial permeability transition (MPT)-dependent apoptosis induced by arsenite and underwent a rapid, MPT-dependent necrotic response after exposure to otherwise nontoxic concentrations of peroxynitrite. Several lines of evidence consistently indicate that these low concentrations of peroxynitrite nevertheless commit cells to MPT, which is, however, prevented by a survival signaling in which arachidonic acid, protein kinase Calpha (PKCalpha), and Bcl-2 are sequentially involved. Bcl-2, however, was not the direct target of PKCalpha but most likely Bad, a protein involved in the regulation of Bcl-2 activity via heterodimerization. Further studies revealed that Bcl-2 does not afford protection in cells challenged with intrinsically toxic concentrations of peroxynitrite. This was due to depletion of GSH, an event leading to loss of the anti-MPT function of Bcl-2. Collectively, these results demonstrate a role of Bcl-2 in monocyte survival signaling preventing MPT-dependent necrosis induced by peroxynitrite, and provide an explanation for the reported observation that Bcl-2 fails to prevent necrosis mediated by intrinsically toxic levels of peroxynitrite.
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PMID:Role of Bcl-2 in the arachidonate-mediated survival signaling preventing mitochondrial permeability transition-dependent U937 cell necrosis induced by peroxynitrite. 1629 89

We have investigated whether maternal obstructive cholestasis during pregnancy (OCP) causes oxidative stress and apoptosis in rat placenta and whether treatment with ursodeoxycholic acid (UDCA, i.g., 60 microg/100 g b.wt./day, following complete biliary obstruction on day 14 of pregnancy) has protective effects on this organ. In rats with OCP, increased (15-fold) serum bile acid concentrations (BAs) together with signs of placental oxidative stress (lipid peroxidation and protein carbonylation) were found. The latter were partly prevented by UDCA, even though hypercholanemia was not corrected. Some elements of the antioxidant system (total glutathione content, GSH/GSSG ratio and catalase, glutathione peroxidase, and glutathione-S-transferase--but not glutathione reductase--activities) were impaired in placentas from the OCP group. UDCA treatment partly prevented changes in the antioxidant system. OCP induced an increase in Bax-alpha/Bcl-2 mRNA ratio, as determined by real-time quantitative PCR, suggesting enhanced susceptibility to apoptosis activation through the mitochondria-mediated pathway. Accordingly, the activity of caspase-3, but not caspase-8, was increased in OCP placentas, in which DNA-ladder analysis and TUNEL confirmed the existence of apoptosis. UDCA prevented changes in the Bax-alpha/Bcl-2 mRNA ratio and caspase-3 activity. In conclusion, OCP causes oxidative stress and apoptosis in rat placenta, which can be prevented by treatment with UDCA.
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PMID:Maternal cholestasis induces placental oxidative stress and apoptosis. Protective effect of ursodeoxycholic acid. 1631 35

Bcl-2 is best known for its anti-apoptotic function in a wide variety of cell types. The objective of this study was to investigate the effects of bcl-2 on the types of cell demise in the HeLa/bcl-2 cells induced by H2O2. The HeLa cell expressed stably bcl-2 was established and defined as the HeLa/bcl-2 cell strain, while the cell transfected with the empty expression vector was defined as the HeLa/vector cell strain. MTT assay revealed that the HeLa/bcl-2 cells showed a shorter life span. BrdU incorporation assay indicated that the bcl-2 exerted anti-demise effect on the HeLa/bcl-2 cells at the low concentration of H2O2. However, at the high concentration of H2O2, the death of the HeLa/bcl-2 cells was more than that of the HeLa/vector cells. The flow cytometry demonstrated that H2O2 mainly induced apoptosis in the HeLa/vector cells and elicited necrosis in the HeLa/bcl-2 cells. The addition of celecoxib to the cells treated by H2O2 could increase apoptosis in the HeLa/vector cells and convert necrosis into apoptosis in the HeLa/bcl-2 cells. The higher levels of cellular free radical and GSH were found in the HeLa/bcl-2 cells, but not in the HeLa/vector cells. With 200 microM H2O2 challenge for 48 h, the level of the cellular free radical was increased in the both strains, while the level of the GSH was decreased in the both strains. Celecoxib could reverse the difference between the both strains led by H2O2. Western blotting showed that the expression of COX-2 was always higher in the HeLa/bcl-2 cells than in the HeLa/vector cells under the both of treated and untreated with H2O2, while the level of COX-1 was relative stable in the both strains. These results suggested that the crosstalk between the bcl-2 and the COX-2 pathways could exist, the bcl-2 might up-regulate COX-2 to modify sensitivity to the types of demise in the HeLa/bcl-2 cell.
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PMID:Bcl-2 switches the type of demise from apoptosis to necrosis via cyclooxygenase-2 upregulation in HeLa cell induced by hydrogen peroxide. 1645 14

Pulse-treatment of U-937 human promonocytic cells with cadmium chloride followed by recovery caused caspase-9/caspase-3-dependent, caspase-8-independent apoptosis. However, pre-incubation with the glutathione (GSH)-suppressing agent DL-buthionine-(S,R)-sulfoximine (cadmium/BSO), or co-treatment with H2O2 (cadmium/H2O2), switched the mode of death to caspase-independent necrosis. The switch from apoptosis to necrosis did not involve gross alterations in Apaf-1 and pro-caspase-9 expression, nor inhibition of cytochrome c release from mitochondria. However, cadmium/H2O2-induced necrosis involved ATP depletion and was prevented by 3-aminobenzamide, while cadmium/BSO-induced necrosis was ATP independent. Pre-incubation with BSO increased the intracellular cadmium accumulation, while co-treatment with H2O2 did not. Both treatments caused intracellular peroxide over-accumulation and disruption of mitochondrial transmembrane potential (delta psi m). However, while post-treatment with N-acetyl-L-cysteine or butylated hydroxyanisole reduced the cadmium/BSO-mediated necrosis and delta psi m disruption, it did not reduce the effects of cadmium/H2O2. Bcl-2 over-expression, which reduced peroxide accumulation without affecting the intracellular GSH content, attenuated necrosis generation by cadmium/H2O2 but not by cadmium/BSO. By contrast, AIF suppression, which reduced peroxide accumulation and increased the GSH content, attenuated the toxicity of both treatments. These results unravel the existence of two different oxidation-mediated necrotic pathways in cadmium-treated cells, one of them resulting from ATP-dependent apoptosis blockade, and the other involving the concurrence of multiple regulatory factors.
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PMID:Regulation of apoptosis/necrosis execution in cadmium-treated human promonocytic cells under different forms of oxidative stress. 1653 69

The anti-cancer effects and possible mechanisms of the freshwater clam (Corbicula fluminea Muller) and its active compounds (FME) on cell viability in human leukemia HL-60 cells were investigated. This study demonstrated that FME was able to inhibit cell proliferation in a concentration- and time-dependent manner. Treatment with FME caused induction of caspase-2, caspase-3, caspase-6, caspase-8, and caspase-9 activity in a time-dependent manner, but not affect caspase-1 activity; it induced the proteolysis of DNA fragmentation factor (DFF-45) and poly(ADP-ribose) polymerase (PARP). Induction of cell death by FME was completely prevented by a pan-caspase inhibitor, Z-Val-Ala-Asp-fluoromethyl ketone (Z-VAD-FMK) and a caspase-2 inhibitor, Z-Val-Asp-Val-Ala-Asp-FMK (Z-VDVAD-FMK). Furthermore, treatment with FME caused a rapid loss of mitochondrial transmembrane potential, stimulation of generation of reactive oxygen species (ROS), release of mitochondrial cytochrome c into cytosol, and GSH depletion. Anti-oxidants such as N-acetylcysteine, catalase, superoxide dismutase, allopurinol, and pyrrolidine dithiocarbamate, but not diphenylene iodonium, significantly inhibited FME-induced cell death. In addition, the results showed that FME-induced apoptosis was accompanied by up-regulation of Bax and Bad, and down-regulation of Bcl-2 and Bcl-XL. Taken together, induction of apoptosis on HL-60 cells by FME was mainly associated with ROS production, GSH depletion, mitochondrial dysfunction, and caspase activation.
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PMID:Apoptosis-inducing active components from Corbicula fluminea through activation of caspase-2 and production of reactive oxygen species in human leukemia HL-60 cells. 1654 98

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