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)

Tolerance to the analgesic effect of an opioid is a pharmacological phenomenon that occurs after its prolonged administration. Activation of the NMDA receptor (NMDAR) has been implicated in the cellular mechanisms of opioid tolerance. However, activation of NMDARs can lead to neurotoxicity under many circumstances. Here we demonstrate that spinal neuronal apoptosis was induced in rats made tolerant to morphine administered through intrathecal boluses or continuous infusion. The apoptotic cells were predominantly located in the superficial spinal cord dorsal horn, and most apoptotic cells also expressed glutamic acid decarboxylase, a key enzyme for the synthesis of the inhibitory neurotransmitter GABA. Consistently, increased nociceptive sensitivity to heat stimulation was observed in these same rats. Mechanistically, the spinal glutamatergic activity modulated morphine-induced neuronal apoptosis, because pharmacological perturbation of the spinal glutamate transporter activity or coadministration of morphine with the NMDAR antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate affected both morphine tolerance and neuronal apoptosis. At the intracellular level, prolonged morphine administration resulted in an upregulation of the proapoptotic caspase-3 and Bax proteins but a downregulation of the antiapoptotic Bcl-2 protein in the spinal cord dorsal horn. Furthermore, coadministration with morphine of N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (a pan-caspase inhibitor) or acetyl-aspartyl-glutamyl-valyl-aspart-1-aldehyde (a relatively selective caspase-3 inhibitor) blocked morphine-induced neuronal apoptosis. Blockade of the spinal caspase-like activity also partially prevented morphine tolerance and the associated increase in nociceptive sensitivity. These results indicate an opioid-induced neurotoxic consequence regulated by the NMDAR-caspase pathway, a mechanism that may have clinical implications in opioid therapy and substance abuse.
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PMID:Neuronal apoptosis associated with morphine tolerance: evidence for an opioid-induced neurotoxic mechanism. 1219 88

F 11782 (2",3"-bis-pentafluorophenoxyacetyl-4",6"ethylidene-beta-D-glucoside of 4'-phosphate-4'-dimethylepipodophyllotoxin-2N-methyl glucamine salt), is a novel dual catalytic inhibitor of topoisomerases I and II characterised by marked in vivo antitumour activity, which also proved cytotoxic and exhibited DNA damaging properties in vitro. Mechanisms associated with this cell killing by F 11782 have been examined in P388 leukaemia cells. Treatment with F 11782 resulted in a dose-dependent DNA fragmentation coupled with the characteristic morphological features of apoptosis. Apoptosis-inducing concentrations of F 11782 induced caspases-3/7 activation accompanied by proteolytic cleavage of poly(ADP-ribose)-polymerase, which could be inhibited by the caspase inhibitor acetyl-Asp-Glu-Val-Asp-aldehyde. In addition, F 11782-induced apoptosis in P388 cells was associated with an increased expression of the pro-apototic Bax protein, without significant changes in the level of the anti-apoptotic Bcl-2 protein, and with modification at the mitochondrial membrane function. These results indicate that F 11782 leads to apoptosis through a caspase-3/7 dependent mechanism and suggest that the so-called "mitochondrial pathway" is implicated in F 11782-induced apoptosis in P388 cells.
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PMID:Apoptotic cell death induction by F 11782 a novel dual catalytic inhibitor of topoisomerases I and II. 1262 89

Skeletal muscle atrophy is a common feature in alcoholism that affects up to two-thirds of alcohol misusers, and women appear to be particularly susceptible. There is also some evidence to suggest that malnutrition exacerbates the effects of alcohol on muscle. However, the mechanisms responsible for the myopathy remain elusive, and some studies suggest that acetaldehyde, rather than alcohol, is the principal pathogenic perturbant. Previous reports on rats dosed acutely with ethanol (<24 h) have suggested that increased proto-oncogene expression (i.e., c-myc) may be a causative process, possibly via activating preapoptotic or transcriptional pathways. We hypothesized that 1) increases in c-myc mRNA levels also occur in muscle exposed chronically to alcohol, 2) muscle of female rats is more sensitive than that from male rats, 3) raising acetaldehyde will also increase c-myc, 4) prior starvation will cause further increases in c-myc mRNA expression in response to ethanol, and 5) other genes involved in apoptosis (i.e., p53 and Bcl-2) would also be affected by alcohol. To test this, we measured c-myc mRNA levels in skeletal muscle of rats dosed either chronically (6-7 wk; ethanol as 35% of total dietary energy) or acutely (2.5 h; ethanol as 75 mmol/kg body wt ip) with ethanol. All experiments were carried out in male Wistar rats (approximately 0.1-0.15 kg body wt) except the study that examined gender susceptibility in male and female rats. At the end of the studies, rats were killed, and c-myc, p53, and Bcl-2 mRNA was analyzed in skeletal muscle by RT-PCR with an endogenous internal standard, GAPDH. The results showed that 1) in male rats fed ethanol chronically, there were no increases in c-myc mRNA; 2) increases, however, occurred in c-myc mRNA in muscle from female rats fed ethanol chronically; 3) raising endogenous acetaldehyde with cyanamide increased c-myc mRNA in acute studies; 4) starvation per se increased c-myc mRNA levels and at 1 day potentiated the acute effects of ethanol, indicative of a sensitization response; 5) the only effect seen with p53 mRNA levels was a decrease in muscle of rats starved for 1 day compared with fed rats, and there was no statistically significant effect on Bcl-2 mRNA in any of the experimental conditions. The increases in c-myc may well represent a preapoptotic effect, or even a nonspecific cellular stress response to alcohol and/or acetaldehyde. These data are important in our understanding of a common muscle pathology induced by alcohol.
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PMID:Acute and chronic effects of alcohol exposure on skeletal muscle c-myc, p53, and Bcl-2 mRNA expression. 1287 71

Cisplatin-selected cervix carcinoma HeLa cell lines induced less apoptosis, and weaker activation by cisplatin or Fas-activating antibody, of mitochondrial-associated caspase-9 and death receptor-mediated caspase-8 than did parental cells. Furthermore, less DISC (death-inducing signalling complex) was formed in cisplatin-selected cell lines than in parental cells. Ac-IETD-CHO (acetyl-Ile-Glu-Thr-Asp-aldehyde), which has a certain preference for inhibiting caspase-8, or Fas-antagonistic antibody, significantly inhibited cisplatin-induced apoptosis in both parental and cisplatin-selected HeLa cell lines. These results imply that cell-surface death signalling is inducible by cisplatin; that reduction of this pathway is associated with drug resistance, and that cisplatin-selected cells acquire cross-resistance to cell-surface death signalling. Sequential up-regulation of FLIP (FLICE-like inhibitory protein), but not Bcl-2, Bcl-x(L) or inhibitors of apoptosis protein (IAPs), was observed in resistant cells but not in parental cells. The inhibition of FLIP by FLIP antisense oligonucleotides promotes cisplatin and Fas-antibody-induced apoptosis. However, the modulation of apoptosis by FLIP antisense oligonucleotides in resistant cells is greater than that in parental cells. The presented data reveal that the up-regulation of FLIP may contribute to the suppression of apoptosis and thereby change cells that are resistant to cisplatin and Fas-mediated death signals. The results also show that cancer cells that have undergone long-term chemotherapy and become chemoresistant may change the FLIP level, becoming cross-resistant to death factors such as Fas.
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PMID:Up-regulation of FLIP in cisplatin-selected HeLa cells causes cross-resistance to CD95/Fas death signalling. 1291 32

Cytochrome c release is thought to play an important role in the initiation of apoptosis. The nature of the control exerted by Bcl-2 and Bcl-XL on such a pathway is not precisely known. We addressed this issue by square-wave pulse electroloading of exogenous cytochrome c into Jurkat cells. Three hours after cytochrome c loading into the cells, characteristic phenotypes of apoptosis were observed. However, a significant drop in the mitochondrial membrane potential (Deltapsim) was also observed, while cytochrome c was generally considered to act downstream from the mitochondria. Related to the Deltapsim drop, there was a release of proapoptotic proteins such as AIF and Smac from the mitochondria. This release, as well as NAD(P)H and cardiolipids oxidation, are linked to previous caspase activation. Cytochrome c-linked caspase activation also led to potassium efflux out of the cell. Overexpression of Bcl-2 and Bcl-XL or N-acetyl-DEVD-aldehyde treatment not only prevented the mitochondrial membrane potential decrease, but also protected cells from the apoptosis directly induced by cytochrome c electroloading. Bcl-2 and Bcl-XL protection is based on the inhibition of the caspase-dependent retroactive pathway affecting the mitochondrial compartment.
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PMID:Retroactive pathway involving mitochondria in electroloaded cytochrome c-induced apoptosis. Protective properties of Bcl-2 and Bcl-XL. 1449 21

Proliferation of small blood vessels in synovial tissues is one of the pathologic features of rheumatoid arthritis. In this study we tested the hypothesis that nitric oxide (NO) protects endothelial cells (ECs) against apoptogenic agents in vitro. Human umbilical-vein endothelial cells (HUVECs) were cultured with and without NO donor S -nitro- N -acetylpenicillamine (SNAP) and further incubated in the presence or absence of Z-leucine-leucine-leucine-aldehyde (LLL-CHO), etoposide, or C2-ceramide. After cultivation, apoptosis of HUVECs was quantified on the basis of disruption of mitochondrial transmembrane potential (DeltaPsim), activation of caspases, and the presence of hypodiploid DNA-positive cells. Treatment of HUVECs with LLL-CHO, etoposide, or C2-ceramide induced DeltaPsim, activation of caspase-3, caspase-8, and caspase-9 and the appearance of hypodiploid DNA-positive cells. NO production in HUVECs was clearly increased by SNAP. Apoptotic cell death in HUVECs induced by LLL-CHO, etoposide, and C2-ceramide was significantly suppressed by SNAP treatment. HUVECs in vitro expressed Bcl-2, Bcl-xL, and Bax; however, expression was not changed by SNAP treatment in the presence or absence of LLL-CHO, etoposide, or C2-ceramide. Although the molecule(s) responsible for the protective effects of NO remains to be identified, our data imply that NO protects HUVECs against mitochondrial perturbation caused by apoptogenic agents. These results suggest that NO promotes endothelial-cell proliferation and angiogenesis in the synovial tissues of patients with rheumatoid arthritis and that NO may be a therapeutic target for rheumatoid arthritis.
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PMID:Nitric oxide acts on the mitochondria and protects human endothelial cells from apoptosis. 1545 84

Polyamines are involved in the regulation of cellular growth and survival by interacting with processes like translation, transcription or ion transport. The aim of our study was to analyze whether polyamines induce apoptosis in hematopoetic cells and to investigate the molecular mechanisms involved. We found an induction of apoptosis by spermine in primary human cells and malignant tumor cell lines. Spermine-treatment resulted in an intracellular increase of reactive oxygen species. Apoptosis was mediated by a collapse of mitochondrial membrane potential, a decrease in Bcl-2 expression and a release of apoptosis mediating molecules from mitochondrial intermembrane space (cytochrome C, Smac/DIABLO). Spermine-mediated apoptosis was caspase-dependent. To test whether spermine mediates apoptosis through metabolites we analyzed the effects of several molecules that interfere with its catabolism. Aminoguanidine, an inhibitor of serum amine oxidase, aldehyde-dehydrogenase, which degrades aldehydes to less reactive molecules or N-acetyl-cysteine, a glutathion precursor, significantly inhibited spermine-mediated apoptosis. From these data we conclude that spermine-derived aldehydes and intracellular accumulation of reactive oxygen species result in mitochondria mediated apoptosis.
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PMID:Induction of apoptosis by spermine-metabolites in primary human blood cells and various tumor cell lines. 1615 48

Acetaldehyde, an inhibitor of mitochondrial function, has been widely used as a neurotoxin because it elicits a severe Parkinson's disease-like syndrome with elevation of the intracellular reactive oxygen species level and apoptosis. Rosiglitazone, a peroxisome proliferator-activated receptor-gamma agonist, has been known to show various non-hypoglycemic effects, including anti-inflammatory, anti-atherogenic, and anti-apoptotic. In this study, we investigated the protective effects of rosiglitazone on acetaldehyde-induced apoptosis in human neuroblastoma SH-SY5Y cells and attempted to examine its mechanism. Acetaldehyde-induced apoptosis was moderately reversed by rosiglitazone treatment. Our results suggest that the protective effects of rosiglitazone on acetaldehyde-induced apoptosis may be ascribed to ability to induce the expression of anti-oxidant enzymes and to regulate Bcl-2 and Bax expression. These data indicate that rosiglitazone may provide a useful therapeutic strategy for the prevention of progressive neurodegenerative disease such as Parkinson's disease.
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PMID:Rosiglitazone protects human neuroblastoma SH-SY5Y cells against acetaldehyde-induced cytotoxicity. 1636 Jan 19

Notch receptor-mediated intracellular events represent an ancient cell signaling system, and alterations in Notch expression are associated with various malignancies in which Notch may function as an oncogene or less commonly as a tumor suppressor. Notch signaling regulates cell fate decisions in the epidermis, including influencing stem cell dynamics and growth/differentiation control of cells in skin. Because of increasing evidence that the Notch signaling network is deregulated in human malignancies, Notch receptors have become attractive targets for selective killing of malignant cells. Compared with proliferating normal human melanocytes, melanoma cell lines are characterized by markedly enhanced levels of activated Notch-1 receptor. By using a small molecule gamma-secretase inhibitor (GSI) consisting of a tripeptide aldehyde, N-benzyloxycarbonyl-Leu-Leu-Nle-CHO, which can block processing and activation of all four different Notch receptors, we identified a specific apoptotic vulnerability in melanoma cells. GSI triggers apoptosis in melanoma cells, but only G2/M growth arrest in melanocytes without subsequent cell death. Moreover, GSI treatment induced a pro-apoptotic BH3-only protein, NOXA, in melanoma cells but not in normal melanocytes. The use of GSI to induce NOXA induction overcomes the apoptotic resistance of melanoma cells, which commonly express numerous cell survival proteins such as Mcl-1, Bcl-2, and survivin. Taken together, these results highlight the concept of synthetic lethality in which exposure to GSI, in combination with melanoma cells overexpressing activated Notch receptors, has lethal consequences, producing selective killing of melanoma cells, while sparing normal melanocytes. By identifying signaling pathways that contribute to the transformation of melanoma cells (e.g. Notch signaling), and anti-cancer agents that achieve tumor selectivity (e.g., GSI-induced NOXA), this experimental approach provides a useful framework for future therapeutic strategies in cutaneous oncology.
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PMID:Notch and NOXA-related pathways in melanoma cells. 1636 61

Aldehydes are widespread environmental and industrial compounds, which cause cytotoxicity, tissue damage, mutagenicity, and carcinogenicity leading to various disease conditions such as cardiovascular, bronchial, and visual complications. We have shown earlier that aldose reductase (AR) besides reducing glucose to sorbitol, efficiently reduces various toxic lipid-derived aldehydes, generated under oxidative stress, with K(m) in the physiological range. We have identified the role of AR in the prevention of various lipid aldehyde-induced cytotoxic signals leading to apoptosis in human lens epithelial cells (HLEC). HLEC were cultured without or with AR inhibitors followed by addition of various saturated and unsaturated lipid aldehydes with a carbon chain length varying from C3 to C10. The cell viability was assessed by cell counts and MTT assay, and apoptosis was measured by evaluating nucleosomal degradation and caspase-3 activation using specific ELISA kits. Although all the aldehydes caused apoptosis of HLEC, the unsaturated aldehydes were more toxic than saturated aldehydes. Inhibition of AR by sorbinil potentiated while the over-expression of AR prevented the apoptosis induced by various lipid aldehydes. AR over-expression also prevented the lipid aldehyde-induced activation of caspase-3, MAPK, JNK and the expression of Bcl-2 family of proteins in HLEC. The results indicate that the lipid aldehydes generated under oxidative stress are cytotoxic to HLEC leading to apoptosis and that the reduction of lipid aldehydes by AR would prevent it.
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PMID:Aldose reductase prevents aldehyde toxicity in cultured human lens epithelial cells. 1663 Nov 66


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