UNIPROT:P10415 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

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

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 (ROS) level and apoptosis. Adiponectin, secreted from adipose tissue, mediates systemic insulin sensitivity with liver and muscle as target organs. In this study, we investigated the protective effects of adiponectin on acetaldehyde-induced apoptosis in human neuroblastoma SH-SY5Y cells and attempted to examine its mechanism. Acetaldehyde-induced apoptosis was moderately reversed by adiponectin treatment. Our results suggest that the protective effects of adiponectin 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 adiponectin may provide a useful therapeutic strategy for the prevention of progressive neurodegenerative disease such as Parkinson's disease.
...
PMID:Adiponectin protects human neuroblastoma SH-SY5Y cells against acetaldehyde-induced cytotoxicity. 1681 56

Acrolein is a highly electrophilic alpha,beta-unsaturated aldehyde to which humans are exposed in many situations. It is an environmental pollutant that is responsible for multiple respiratory diseases and has been implicated in neurodegenerative diseases such as Alzheimer's disease. The hypothesis of the study is that the antioxidant N-acetylcysteine (NAC), a precursor of glutathione, could protect cells against acrolein-induced apoptosis. Exposure of Chinese hamster ovary cells to a noncytotoxic dose of acrolein (4 fmol/cell) depleted intracellular glutathione to 45% of initial levels. NAC, which increased intracellular glutathione levels by 30%, afforded protection against acrolein-induced cytotoxicity (loss of cell proliferation) and apoptosis. NAC protected against apoptosis by diminishing acrolein-induced activation of the mitochondrial death pathway. NAC inhibited acrolein-induced Bad translocation from the cytosol to the mitochondria, as well as Bcl-2 translocation from mitochondria to the cytosol, as evaluated by Western blot analysis. However, NAC had no effect on acrolein-induced Bax translocation to mitochondria and cytochrome c liberation into the cytosol. Meanwhile, NAC inhibited depolarization of mitochondrial membrane potential, as evaluated by rhodamine fluorescence using flow cytometry. NAC also inhibited procaspase-9 processing, activation of enzymatic activity of caspase-9, -7, and -8, and poly(ADP-ribose) polymerase cleavage induced by acrolein. Inhibition of acrolein-induced apoptosis using NAC was confirmed morphologically by diminished condensation of nuclear chromatin, as evaluated by fluorescence microscopy. These findings suggest that NAC could be potentially useful as a protective agent for people exposed to acrolein.
...
PMID:Inhibition of acrolein-induced apoptosis by the antioxidant N-acetylcysteine. 1720 47

Monoamine oxidases A and B (MAO A and MAO B) are the major enzymes that catalyze the oxidative deamination of monoamine neurotaransmitters such as dopamine (DA), noradrenaline, and serotonin in the central and peripheral nervous systems. MAO B is mainly localized in glial cells. MAO B also oxidizes the xenobiotic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to a parkinsonism-producing neurotoxin, 1-methyl-4-phenyl-pyridinium (MPP+). MAO B may be closely related to the pathogenesis of Parkinson's disease (PD), in which neuromelanin-containing DA neurons in the substantia nigra projecting to the striatum in the brain selectively degenerate. MAO B degrades the neurotransmitter DA that is deficient in the nigro-striatal region in PD, and forms H2O2 and toxic aldehyde metabolites of DA. H2O2 produces highly toxic reactive oxygen species (ROS) by Fenton reaction that is catalyzed by iron and neuromelanin. MAO B inhibitors such as L-(-)-deprenyl (selegiline) and rasagiline are effective for the treatment of PD. Concerning the mechanism of the clinical efficacy of MAO B inhibitors in PD, the inhibition of DA degradation (a symptomatic effect) and also the prevention of the formation of neurotoxic DA metabolites, i.e., ROS and dopamine derived aldehydes have been speculated. As another mechanism of clinical efficacy, MAO B inhibitors such as selegiline are speculated to have neuroprotective effects to prevent progress of PD. The possible mechanism of neuroprotection of MAO B inhibitors may be related not only to MAO B inhibition but also to induction and activation of multiple factors for anti-oxidative stress and anti-apoptosis: i.e., catalase, superoxide dismutase 1 and 2, thioredoxin, Bcl-2, the cellular poly(ADP-ribosyl)ation, and binding to glyceraldehydes-3-phosphate dehydrogenase (GAPDH). Furthermore, it should be noted that selegiline increases production of neurotrophins such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and glial cell line-derived neurotrphic factor (GDNF), possibly from glial cells, to protect neurons from inflammatory process.
...
PMID:Molecular mechanism of the relation of monoamine oxidase B and its inhibitors to Parkinson's disease: possible implications of glial cells. 1744 16

Anti-apoptotic proteins Bcl-2 and Bcl-xL are overexpressed in 80% of non Hodgkin's lymphoma cells and are thought to play an important role in the resistance of lymphoma cells to current chemotherapeutic agents. Gossypol, an orally-active polyphenolic aldehyde derived from the cotton plant, has been known to have potential anti-neoplastic activity. Recently, gossypol was found to bind to the BH3 binding groove of Bcl-xL and with lesser affinity to Bcl-2. The present study was conducted to determine whether gossypol increases the sensitivity of non-Hodgkin's lymphoma cells to the actions of chemotherapeutic agents by potentiating treatment-induced apoptosis. The interactions observed between gossypol and chemotherapeutic drugs were analyzed using the median effect principle (CalcuSyn analysis). Our data showed that treatment of Ramos cells with gossypol not only induced cell arrest on the G(0)/G(1) phase, but also augmented apoptosis and growth inhibition induced by etoposide (VP-16), doxorubicin hydrochloride (ADM), vincristine (VCR), and paclitaxel (taxol). However, when gossypol was combined with cisplatin (DDP) an antagonistic effect was observed. Gossypol-induced cell cycle arrest was accompanied by decreased expression of cyclin D1 in Ramos cells. In addition, the peroxisome proliferator-activated receptor (PARP) pathway is, at least in part, involved in the gossypol-induced apoptosis when combined with VP-16. These data indicate that single-agent gossypol is effective in inhibiting growth of non-Hodgkin's lymphoma cells in vitro and combination studies with certain secondary chemotherapeutic agents further demonstrate it's synergistic cytotoxicity. These findings support future preclinical and clinical studies of gossypol in the treatment of non-Hodgkin's lymphoma.
...
PMID:Synergistic cytotoxicity of Bcl-xL inhibitor, gossypol and chemotherapeutic agents in non-Hodgkin's lymphoma cells. 1834 25

Proteasome inhibitors display potent anti-neoplastic and anti-angiogenic properties both in vitro and in vivo. The mechanisms, however, by which proteasome inhibitors kill tumor cells are still fairly elusive as is the molecular basis of resistance to treatment. To address these questions, we employed a high-throughput Western blotting procedure to analyze changes in a subproteome of approximately 800 proteins in the promyelocytic leukemia cell line HL-60 upon treatment with the proteasome inhibitor PSI (Z-Ile-Glu(OtBu)-Ala-Leu-aldehyde) and correlated the changes of selected target proteins with the changes in two multidrug-resistant HL-60 variants. In total, 105 proteins were upregulated more than 1.5-fold after PSI treatment, while 79 proteins were downregulated. Activation of caspases-3 and -8, modulation of members of the Bcl-2 family as well as stimulation of stress signaling pathways was prominent during HL-60 apoptosis. We also identified changes in the abundance of proteins previously not known to be affected by proteasome inhibitors. In contrast, two multidrug-resistant HL-60 cell lines, overexpressing either MRP1 or P-glycoprotein were largely resistant to PSI-induced apoptosis and could not be resensitized by the pharmacological inhibitors of the drug efflux pumps MK571 or PSC833. Drug resistance was also independent of the upregulation of Bad. Overexpression of multidrug resistance proteins, P-glycoprotein and MRP-1 is thus not sufficient to explain resistance of HL-60 cells to treatment with proteasome inhibitor PSI, which remains more closely related to a low level of Bax expression and to the inability to activate JNK. Alternative routes to the acquisition of resistance to PSI have therefore to be considered.
...
PMID:Analysis of changes in the proteome of HL-60 promyeloid leukemia cells induced by the proteasome inhibitor PSI. 1846 79

Proteasome inhibitors and immunomodulatory drugs (IMiDs) have demonstrated clinical potential as novel therapies for non-Hodgkin lymphoma (NHL). Bortezomib, a peptide aldehyde derivative that inhibits the proteasome by binding directly to its active sites, is the most extensively studied agent in the clinical setting. Single-agent bortezomib is effective in several lymphoid malignancies, and is recommended for second-line treatment of mantle-cell lymphoma (MCL). Ongoing trials are investigating the combination of bortezomib with chemotherapy, and with agents that target Bcl-2 proteins. Although proteasome inhibitors are potentially potent anti-tumor drugs, the pleotropic nature of their biological effects means that further research is required to elucidate the optimal combinations, doses and schedules. In addition to proteasome inhibitors, the IMiDs, such as lenalidomide, have the potential to improve outcomes for patients with NHL. These drugs inhibit cell growth and proliferation by several mechanisms, including blocking the effect of growth factors and stimulating T cells and natural killer cells. Lenalidomide is particularly effective in lymphoproliferative disorders such as multiple myeloma, and is active in patients with various forms of NHL, with a favourable side-effect profile. Complimentary clinical and pharmacological features suggest that lenalidomide may be effective when combined with monoclonal antibodies. Ongoing and future studies will provide further information.
...
PMID:Novel approaches for the treatment of NHL: Proteasome inhibition and immune modulation. 1882 34

1. The liver, the main site of ethanol oxidation, is extremely vulnerable to the toxic effects of alcohol. Chronic alcohol intake has been shown to result in alcoholic liver disease, although the precise mechanism of action remains poorly understood. 2. The present study was designed to examine the impact of facilitated acetaldehyde metabolism via overexpression of aldehyde dehydrogenase-2 (ALDH2) on chronic alcohol ingestion-induced hepatic damage. Mice (wild-type Friend Virus B (FVB) and ALDH2 transgenic mice) were placed on a 4% alcohol or control diet for 12 weeks. Pro- and anti-apoptotic proteins, including p53, Omi/HtrA2, Bcl-2, Bax, X-linked inhibitor of apoptosis protein (XIAP), Akt, phosphorylated (p) Akt, the Akt downstream signalling molecule Pim and pPim, were examined using immunoblot analysis. Apoptosis and protein damage were assessed using the caspase 3 assay and protein carbonyl formation, respectively. 3. The data revealed that alcohol intake enhanced expression of p53, Omi/HtrA2, Bcl-2 and Bax without affecting XIAP expression or the Bcl-2/Bax ratio. Total Akt and pPim were downregulated in response to alcohol, whereas total Pim was upregulated in conjunction with unchanged pAkt. As a result, the pAkt : Akt and pPim : Pim ratios were elevated and reduced, respectively, in response to alcohol. All these effects that resulted from alcohol exposure were attenuated or ablated by ALDH2. 4. Collectively, the results suggest that ALDH2 may effectively ameliorate alcohol-induced hepatic apoptosis and changes in Akt as well as Pim signalling.
...
PMID:Overexpression of aldehyde dehydrogenase-2 attenuates chronic alcohol exposure-induced apoptosis, change in Akt and Pim signalling in liver. 1921 30

Chronic intake of alcohol results in multiple organ damage including brain. This study was designed to examine the impact of facilitated acetaldehyde breakdown via transgenic overexpression of mitochondrial aldehyde dehydrogenase-2 (ALDH2) on alcohol-induced cerebral cortical injury. ALDH2 transgenic mice were produced using the chicken beta-actin promoter. Wild-type FVB and ALDH2 mice were placed on a 4% alcohol or control diet for 12 weeks. Protein damage and apoptosis were evaluated with carbonyl formation, caspase and TUNEL assays. Western blot was performed to examine expression (or its activation) of ALDH2, the pro- and anti-apoptotic proteins caspase-8, Bax, Bcl-2, Omi/HtrA2, apoptosis repressor with caspase recruitment domain (ARC), FLICE-like inhibitory protein (FLIP), X-linked inhibitor of apoptosis protein (XIAP), Akt, glycogen synthase kinase-3beta (GSK-3beta), p38, c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK). Chronic alcohol intake led to elevated apoptosis in the absence of overt protein damage, the effect of which was ablated by the overexpression of ALDH2 transgene. Consistently, ALDH2 transgene significantly attenuated alcohol-induced upregulation of Bax, Omi/HtrA2 and XIAP as well as downregulation of Bcl-2 and ARC without affecting alcohol-induced increase of FLIP in cerebral cortex. Phosphorylation of Akt and GSK-3beta was dampened while total/phosphorylated JNK and p38 phosphorylation were elevated following chronic alcohol intake, the effects of which were abrogated by ALDH2 transgene. Expression of total Akt, GSK-3beta, p38 and ERK (total or phosphorylated) was not affected by either chronic alcohol intake or ALDH2 transgene. Our results suggested that transgenic overexpression of ALDH2 rescues chronic alcoholism-elicited cerebral injury possibly via a mechanism associated with Akt, GSK-3beta, p38 and JNK signaling.
...
PMID:Aldehyde dehydrogenase-2 transgene ameliorates chronic alcohol ingestion-induced apoptosis in cerebral cortex. 1942 58

Antisense oligonucleotide G3139 is designed for Bcl-2 downregulation and is known to induce toll-like receptor activation. Novel stabilized lipid-polycation-DNA (sLPD) nanoparticles were constructed and evaluated for the delivery of G3139 to human carcinoma KB cells and for bioactivity in vivo. Polyethylenimine (PEI) was incorporated as a DNA condensing agent. The lipid composition used was DOTAP/DDAB/Chol/TPGS/linoleic acid/hexadecenal at molar ratios of 30/30/34/1/5/0.2. The nanoparticles were stabilized by the formation of a reversible covalent bond between the aldehyde group on the cis-11-hexadecenal and amines on the PEI. When sLPDs were used to transfect KB cells, 90.4% Bcl-2 downregulation was observed, compared to no significant downregulation by free G3139 and 54.6% downregulation by nonstabilized LPD-G3139. The sLPDs were then evaluated for therapeutic efficacy in mice bearing KB subcutaneous tumors and were found to trigger a strong antitumor response, inhibiting tumor growth and prolonging survival with 72% increase in lifespan (ILS). Consistent with previous reports on other G3139 nanoparticles, the increased antitumor activities of sLPDs in vivo were found to be associated with increased cytokine induction rather than Bcl-2 downregulation, suggesting an immunological mechanism.
...
PMID:A covalently stabilized lipid-polycation-DNA (sLPD) vector for antisense oligonucleotide delivery. 2136 44

In the present study, we examined whether Acer okamotoanum (A. okamotoanum) sap decreased the serum alcohol and acetaldehyde levels after acute ethanol treatment in a rat model. Male rats were orally administered 25, 50 or 100% A. okamotoanum sap 30 min prior to oral challenge with 3 ml of ethanol (15 ml/kg of a 20% ethanol solution in water), and the blood concentrations of alcohol and acetaldehyde were analyzed up to 7 h after the treatment. Pre-treatment with the sap significantly decreased the blood ethanol and acetaldehyde concentrations after 5 h when compared with ethanol treatment alone (a negative control). The expression levels of liver alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) mRNA were increased significantly in animals pre-treated with A. okamotoanum sap when compared with negative and positive controls. The data suggest that sap pre-treatment enhanced the alcohol metabolism rate in the rat liver. To investigate the involvement of mitochondrial regulation in the ethanol-induced hepatocyte apoptosis, we carried out an immunohistochemical analysis of Bax and Bcl-2. Pre-treatment with sap significantly decreased Bax expression and increased Bcl-2 expression 7 h after ethanol administration when compared with the negative control. The data suggest that A. okamotoanum sap pre-treatment may reduce the alcohol-induced oxidative stress in the rat liver.
...
PMID:The sap of Acer okamotoanum decreases serum alcohol levels after acute ethanol ingestion in rats. 2168 30

<< Previous 1 2 3 4 5 6 7 Next >>