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)

After an ischemic episode induced by the electrocoagulation of the left middle cerebral artery (MCA) in mouse, neurons within the damaged territory die either by an apoptotic or by a necrotic process. Most of the cortical neurons within the ischemic area display both morphological and biochemical signs of programmed cell death: nuclear condensation, DNA degradation, formation of apoptotic bodies, and glutathione depletion. In fact, apoptosis essentially contributes to the expansion of the ischemic lesion and the maximum of damaged territory is reached 24 h postocclusion. Several potentially neuroprotective pathways have been evidenced in different experimental models of ischemia including the activation of antioxidant enzyme activities and/or the recruitment of neurotrophic as well as antiapoptotic factors. In our model of permanent focal ischemia induced by MCA occlusion, we measured the temporal synthesis of nerve growth factor (NGF) and examined the status of antioxidant enzymes as well as Bcl-2 antiapoptotic product. We detected in both cortices a transient increase of NGF which peaks at 6 h. Moreover, we reported that glutathione peroxidase is recruited with a time course which parallels NGF synthesis. Finally, we observed the induction of Bcl-2 in safe neurons; this may represent a self-protective response against ischemia-induced apoptosis. We provide evidence that in a model of permanent focal ischemia, several neuroprotective pathways could be coactivated.
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PMID:Recruitment of several neuroprotective pathways after permanent focal ischemia in mice. 987 75

We have recently reported that members of the bcl-2 gene family are expressed and estradiol regulated in rabbit luteal cells during corpus luteum (CL) regression, and that estradiol and hCG are effective inhibitors of apoptosis in the rabbit CL in vivo and in vitro. As Bcl-2 and related proteins are known to regulate levels of reactive oxygen species or their intermediates in cells as one possible mechanism to control apoptosis, the present studies were designed to examine if oxidative stress plays a role in luteal cell apoptosis during CL regression in the rabbit. In the first set of experiments, healthy CL obtained from day 11 pseudopregnant rabbits were incubated in serum-free medium for 2 h in the absence or presence of superoxide dismutase (SOD; 1.5-150 U/ml), ascorbic acid (1-100 mM), N-acetyl-L-cysteine (25 and 50 mM), or catalase (10-1000 U/ml). Cells within CL incubated in medium alone exhibited extensive apoptosis (examined by analysis of extracted DNA using 3'-end labeling), and this onset of apoptosis was blocked in a dose-dependent fashion by treatment with SOD, ascorbic acid, N-acetyl-L-cysteine, or catalase. In the second set of experiments, expression of bax and bcl-x in CL after in vitro treatment without and with 100 U/ml SOD was examined. Although SOD treatment did not alter the levels of bcl-x messenger RNA (mRNA) over the 2-h incubation period, this antioxidant enzyme significantly reduced the levels of bax mRNA in incubated CL. In the final set of experiments, we observed that expression of mitochondrial- or manganese-containing SOD was significantly increased by treatment of isolated CL with 1 microg/ml hCG in vitro, whereas bax mRNA levels were significantly reduced under the same culture conditions. Collectively, these data indicate that the gonadotropin-mediated inhibition of apoptosis in rabbit luteal cells involves enhanced expression of the oxidative stress response gene, manganese-containing SOD, whose protein product may then function to protect luteal cells directly from the damaging effect of reactive oxygen species and/or indirectly by acutely down-regulating expression of Bax, a prooxidant member of the Bcl-2 protein family.
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PMID:Antioxidants mimic the ability of chorionic gonadotropin to suppress apoptosis in the rabbit corpus luteum in vitro: a novel role for superoxide dismutase in regulating bax expression. 1034 42

Huntington's disease (HD) is a hereditary neurodegenerative disorder presenting with chorea, dementia, and extensive striatal neuronal death. The mechanism through which the widely expressed mutant HD gene mediates a slowly progressing striatal neurotoxicity is unknown. Glutamate receptor-mediated excitotoxicity has been hypothesized to contribute to the pathogenesis of HD. Here we show that transgenic HD mice expressing exon 1 of a human HD gene with an expanded number of CAG repeats (line R6/1) are strongly protected from acute striatal excitotoxic lesions. Intrastriatal infusions of the N-methyl-D-aspartate (NMDA) receptor agonist quinolinic acid caused massive striatal neuronal death in wild-type mice, but no damage in transgenic HD littermates. The remarkable neuroprotection in transgenic HD mice occurred at a stage when they had not developed any neurological symptoms caused by the mutant HD gene. At this stage there was no change in the number of striatal neurons and astrocytes in untreated R6/1 mice, although the striatal volume was decreased by 17%. Moreover, transgenic HD mice had normal striatal levels of NMDA receptors, calbindin D28k (calcium buffer), superoxide dismutase activity (antioxidant enzyme), Bcl-2 (anti-apoptotic protein), heat shock protein 70 (stress-induced anti-apoptotic protein), and citrate synthase activity (mitochondrial enzyme). We propose that the presence of exon 1 of the mutant HD gene induces profound changes in striatal neurons that render these cells resistant to excessive NMDA receptor activation.
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PMID:Transgenic mice expressing a Huntington's disease mutation are resistant to quinolinic acid-induced striatal excitotoxicity. 1041 43

Recent work has focused attention on the role of oxidative stress in various acute and chronic neurodegenerative diseases. Low concentrations of the powerful antioxidant glutathione (GSH) and impaired brain energy metabolism, particularly in the substantia nigra, are key features of Parkinson's disease (PD). The main goal of this study was to better characterize the deleterious effects of brain GSH depletion on mitochondrial function. We depleted GSH in the brains of newborn wild-type (WT) and transgenic (Tg) mice overproducing either human Cu/Zn-superoxide dismutase (h-CuZnSOD) or human Bcl2 (h-Bcl-2), by subcutaneous injection of l-buthionine sulfoximine (BSO), a specific inhibitor of gamma-glutamylcysteine synthetase. GSH was 97% depleted in brain homogenates and 90% depleted in brain mitochondria for both WT and Tg mice. This depletion of brain GSH led to a decrease in the activity of the GSH-dependent antioxidant enzyme glutathione peroxidase, both in WT and in Tg animals. BSO treatment decreased the activities of respiratory complexes I, II, and IV in the brain homogenates of WT mice. BSO-treated h-CuZnSOD or h-Bcl-2 Tg mice had no respiratory chain deficiencies. Thus, brain GSH depletion leads to the impairment of mitochondrial respiratory chain activity. The protection of mitochondrial respiratory function by overproduction of Bcl-2 may result from a decrease in the generation of reactive oxygen species (ROS) or lipid peroxidation. The protection of mitochondria by overproduction of CuZnSOD is consistent with the involvement of superoxide or superoxide-derived ROS in the mitochondrial dysfunction caused by brain GSH depletion. This study demonstrates that the antioxidant balance is critical for maintenance of brain mitochondrial function, and its disruption may contribute to the pathogenesis of PD.
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PMID:Overproduction of Cu/Zn-superoxide dismutase or Bcl-2 prevents the brain mitochondrial respiratory dysfunction induced by glutathione depletion. 1041 49

Calorie restriction (CR) is known to delay the aging process in rodents and is postulated to act by decreasing free radical generation and increasing antioxidant enzyme activity. The present study was designed to investigate the effect of CR and age on oxidative stress-induced apoptosis and associated changes in the levels of TNF-alpha, and Bcl-2 in splenic T lymphocytes. Ad libitum (AL)- or CR-fed C57BL/6J mice were sacrificed either at 6 (young) or 18 (old) months and splenic lymphocytes were incubated with or without 25 micro M H2O2 to induce apoptosis. Apoptosis increased with age in cells of AL-fed mice incubated with H2O2. CR prevented this rise in apoptosis in total splenic lymphocytes and in CD4(+) and CD8(+) T lymphocyte subsets either with or without H2O2. Free radicals increased and mitochondrial membrane potential decreased in aged mice. CR prevented these changes and also prevented the age-associated increase in TNF-alpha and loss of Bcl-2 in total splenic lymphocytes and in CD4(+) and CD8(+) lymphocyte subsets. In summary, lymphocytes in aged AL-fed mice were much more susceptible to oxidative stress-induced apoptosis whereas CR normalized apoptosis by preventing the increase in TNF-alpha and the decrease in Bcl-2 associated with aging.
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PMID:Inhibition of H2O2-induced apoptosis of lymphocytes by calorie restriction during aging. 1242 90

Oxidative stress plays a causative role in the development of hepatic fibrosis and apoptosis. Estradiol (E2) is an antioxidant, and idoxifene is a tissue-specific selective estrogen-receptor modulator. We have previously demonstrated that E2 inhibits hepatic fibrosis in rat models of hepatic fibrosis and that the actions of E2 are mediated through estrogen receptors (ERs). This study reports on the antiapoptotic role of idoxifene and E2, and the functions of ER subtypes ER-alpha and ER-beta in hepatocytes undergoing oxidative stress. Lipid peroxidation was induced in cultured rat hepatocytes with ferric nitrilotriacetate solution with idoxifene or E2. Oxidative stress-induced early apoptosis was linked to its ability to inhibit not only the expression of Bcl-2 and Bcl-XL but the production of antioxidant enzymes as well and to stimulate Bad expression. Hepatocytes possessed functional ER-beta, but not ER-alpha, to respond directly to idoxifene and E2. Idoxifene and E2 suppressed oxidative stress-induced reactive oxygen species generation and lipid peroxidation, and their antiapoptotic effects on the activation of activator protein-1 and nuclear factor-kappaB, the loss of antioxidant enzyme activity, and Bcl-2 family protein expression in early apoptotic hepatocytes were blocked by the pure ER antagonist ICI 182,780. Our results indicate that idoxifene and E2 could enhance antiapoptotic activity through ER-beta during oxidative damage in hepatocytes.
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PMID:Idoxifene and estradiol enhance antiapoptotic activity through estrogen receptor-beta in cultured rat hepatocytes. 1275 72

Thioredoxin reductase (TrxR) in conjunction with thioredoxin (Trx) is a ubiquitous intracellular oxidoreductase system with antioxidant and redox regulatory roles. The properties of TrxR in combination with the functions of Trx position this system at the core of cellular thiol redox control and antioxidant defense. In some human tumors, the thioredoxin system is found over-expressed. Because of its role in stimulating cancer cell growth and as an inhibitor of apoptosis, the Trx system offers a target for the development of drugs to treat and prevent cancer. In a previous research, we successfully synthesized a novel organoselenium compound BBSKE(1,2-[bis(1,2-Benzisoselenazolone-3(2H)-ketone)]ethane, BBSKE, PCT: CN02/00412) targeting the TrxR, and it has demonstrated the inhibitory effect on the growth of a variety of human cancer cells from various organs. In this study, we investigated the inhibitory effect of BBSKE on TrxR activity in PC-3 and DU145 human prostate cancer cell lines, and its antitumoral effect on these two cell lines. Treatment of BBSKE inhibited the TrxR activity in both of the cell lines in a dose-dependent manner and it also inhibited the proliferation of these two cell lines in a dose-dependent manner. Cell cycle analysis showed S phase arrest in both of the cell lines following 48 h exposure to BBSKE. During the S arrest, analysis of cell cycle regulatory proteins demonstrated that BBSKE increased the protein levels of cyclinA, cyclinE, and P21, but decreased the levels of cyclinB1, cyclinD1, and Cdk4. Furthermore, BBSKE decreased the protein level of Bcl-2 but increased the level of Bax, and induced apoptosis in PC-3 and DU145 human prostate cancer cell lines. These results suggest that this novel TrxR inhibitor inhibits the proliferation of prostate cancer cells via S phase arrest and apoptosis in association with the regulation of multiple molecules in the cell cycle.
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PMID:A novel organoselenium compound induces cell cycle arrest and apoptosis in prostate cancer cell lines. 1296 29

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

We have investigated the mechanisms of induction of apoptosis by the antineoplastic ether lipid ET-18-OCH3 (ALP) in sensitive S49wt mouse lymphoma cells and ALP-resistant S49ar variants, both with wild-type p53, and in related L1210 cells with mutated p53. Ether lipid-resistant S49ar cells were cross-resistant to extracellular stress factors (cold shock, heat shock, H2O2, dimethylsulfoxide) and to radiation-induced apoptosis but not to physiological apoptotic signals (dexamethasone, growth factor deprivation, thapsigargin, C2-ceramide) and expressed similar levels of the apoptosis-regulating proteins Bcl-2, Bcl-X, Bax, Bad and Bak as did the parent S49wt cells. The uptake of [3H]-ALP was strongly reduced in the stress-resistant cells but this was not associated with significant differences in membrane cholesterol:phospholipid content nor in membrane microviscosity. In S49ar cells the activity of the antioxidant enzyme glutathione peroxidase (GSH-Px) was increased 4-fold and depletion of glutathione with the drug L-buthionine-S-R-sulfoximine (L-BSO) lowered the resistance of S49ar cells to ALP, stress factors and ionising radiation. The results indicate that ether lipids induce apoptosis by imposing a special form of physico-chemical stress, mediated by reactive oxygen species but independent of p53 status. The capacity of glutathione-dependent anti-oxidant defence appeared an important and shared determinant of the sensitivity to ether lipids, several types of extracellular stress and ionising radiation.
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PMID:Signalling steps in apoptosis by ether lipids. 1463 26

Oxidative stress plays a causative role in the development of hepatic fibrosis and apoptosis. Estradiol (E2) is an antioxidant, and idoxifene is a tissue-specific selective estrogen receptor modulator. We have previously demonstrated that E2 inhibits hepatic fibrosis in a rat model of hepatic fibrosis induced with dimethylnitrosamine (DMN), and suppresses activation of the nuclear factor (NF)-kappaB proinflammatory transcription factor in cultured rat hepatocytes undergoing oxidative stress. This study reports on the antioxidant and antiapoptotic role of idoxifene and E2 in the DMN model of hepatic fibrosis. The DMN model rats were administered with idoxifene or E2, and were examined activity of superoxide dismutase (SOD) and glutathione peroxidase (GPx) and expression of Bcl-2 family proteins in the liver. During the course of hepatofibrogenesis after DMN treatment, serum levels of lactate dehydrogenase (LDH), a biomarker for necrosis, and hepatic levels of malondialdehyde (MDA), an end product of lipid peroxidation, increased rapidly for 3 days. On day 14, serum LDH levels normalized, and hepatic fibrosis developed with increased levels of MDA and collagen and decreased production of SOD and GPx in the liver. Fibrotic liver also showed downregulation of Bcl-2 and Bcl-X(L) expression and upregulation of Bad expression. Idoxifene and E2 suppressed DMN-mediated necrosis, lipid peroxidation, the loss of antioxidant enzyme activity, and proapoptotic status in Bcl-2 family protein expression as well as hepatic fibrosis. These findings indicate that, in addition to their antiinflammatory and antifibrotic action, idoxifene and E2 could enhance antioxidant and antiapoptotic activity in hepatic fibrosis in rats.
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PMID:Antioxidant and antiapoptotic activities of idoxifene and estradiol in hepatic fibrosis in rats. 1465 78


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