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)

Caffeic acid phenyl ester (CAPE), a biologically active ingredient of propolis, has several interesting biological properties including antioxidant, anti-inflammatory, antiviral, immunostimulatory, anti-angiogenic, anti-invasive, anti-metastatic and carcinostatic activities. Recently, several groups have reported that CAPE is cytotoxic to tumor cells but not to normal cells. In this study, we investigated the mechanism of CAPE-induced apoptosis in human myeloid leukemia U937 cells. Treatment of U937 cells with CAPE decreased cell viability in a dose-dependent and time-dependent manner. DNA fragmentation assay revealed the typical ladder profile of oligonucleosomal fragments in CAPE-treated U937 cells. In addition, as evidenced by the nuclear DAPI staining experiment, we observed that the nuclear condensation, a typical phenotype of apoptosis, was found in U937 cells treated with 5 microg/ml of CAPE. Therefore, it was suggested that CAPE is a potent agent inducing apoptosis in U937 cells. Apoptotic action of the CAPE was accompanied by release of cytochrome C, reduction of Bcl-2 expression, increase of Bax expression, activation/cleavage of caspase-3 and activation/cleavage of PARP in U937 cells, but not by Fas protein, an initial mediator in the death signaling, or by phospho-eIF2 alpha and CHOP, crucial mediators in ER-mediated apoptosis. From the results, it was concluded that CAPE induces the mitochondria-mediated apoptosis but not death receptors- or ER-mediated apoptosis in U937 cells.
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PMID:Caffeic acid phenethyl ester induces mitochondria-mediated apoptosis in human myeloid leukemia U937 cells. 1806 Apr 75

The most significant complication of testicular torsion is loss of the testis, which may lead to impaired fertility. Molecular mechanisms how spermatogenesis impairs owing to testicular torsion remain unknown. This investigation, by using mouse model of testicular torsion, was undertaken to gain insight into the cellular and molecular mechanism underlying torsion-induced germ cell loss. Male mice were subjected to 2h ischemia-inducing torsion, and testes were examined at 24, 48, and 72h after the repair of torsion (reperfusion). Ischemia-reperfusion (IR) of the testes resulted in germ cell, mostly in spermatogonia, apoptosis, which was revealed by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL) technique. At 24h after torsion repair germ cell apoptosis reached peak, then decreased until 72h repair. Western blots showed that apoptotic proteins (p53, Caspase-3 and -9) gradually were upregulated at 48h reperfusion, however, anti-apoptotic proteins (Bcl-2 and BDNF) were downregulated in the relevant IR treatment. IR injury induced CHOP protein appearance with maximum expression at 24h of reperfusion. Furthermore, the germ cell apoptosis triggered downregulation of ubiquitin carboxyl-terminal hydrolase-L1 (UCH-L1) at both mRNA and protein levels. To test further whether ubiquitination was involved in IR stress, both mono- and poly-ubiquitin levels in IR stress condition were examined, which showed that both mono- and poly-ubiquitin expression significantly impaired. These results provide evidences of UCH-L1/ubiquitination signaling to the testis IR injury in vivo.
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PMID:Role of UCH-L1/ubiquitin in acute testicular ischemia-reperfusion injury. 1807 May 98

Microcystins (MCs) are a family of monocyclic heptapeptide hepatotoxins produced by freshwater species of cyanobacteria. Microcystin-LR (MCLR) is the most frequently studied and most toxic in over 80 MC congeners. Great deals of studies have demonstrated that MCLR can induce apoptosis in a wide variety of cell types. Although much evidence indicates that mitochondria play a pivotal role in MCLR-induced apoptosis, the complicated apoptosis mechanisms induced by MCLR have not been completely characterized. It is possible that there are other apoptotic pathways existing in MCLR-induced apoptosis. The present study was undertaken to determine the expression of PP2A, CHOP, Bax, Bcl-2, and p53 proteins in MCLR-induced apoptosis in FL cells. The results showed that MCLR could induce apoptosis in FL cells and the process was accompanied with the upregulation of PP2A, Bax, and p53 proteins and the downregulation of Bcl-2 proteins. In addition, the CHOP protein was upregulated at most treatment groups and decreased at the highest concentration group. These results, especially the alteration of PP2A and CHOP proteins might provide new insights into MCLR-induced apoptosis.
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PMID:Alteration of proteins expression in apoptotic FL cells induced by MCLR. 1821 37

Understanding the mechanisms governing the switch between hypoxia-induced adaptive and pathological transcription may reveal novel therapeutic targets for stroke. Using an in vitro hypoxia model that temporally separates these divergent responses, we found apoptotic signaling was preceded by a decline in c/EBP-beta activity and was associated with markers of ER-stress including transient eIF2alpha phosphorylation, and the delayed induction of the bZIP proteins ATF4 and CHOP-10. Pretreatment with the eIF2alpha phosphatase inhibitor salubrinal blocked the activation of caspase-3, indicating that ER-related stress responses are integral to this transition. Delivery of either full-length, or a transcriptionally inactive form of c/EBP-beta protected cultures from hypoxic challenge, in part by inducing levels of the anti-apoptotic protein Bcl-2. These data indicate that the pathologic response in cortical neurons induced by hypoxia involves both the loss of c/EBP-beta-mediated survival signals and activation of pro-death pathways originating from the endoplasmic reticulum.
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PMID:Loss of c/EBP-beta activity promotes the adaptive to apoptotic switch in hypoxic cortical neurons. 1843 38

This study examined whether or not the ER stress and Bcl-2 proteins are linked to the protective effect of kaempferol, a phytoestrogen, on ischemia-reperfusion (I/R)-induced cardiac damage. In order to determine if kaempferol modifies the I/R-induced response in H9c2 cardiac muscle cells, the cells were exposed to kaempferol followed by ischemia 12h/reperfusion 4h. kaempferol had a protective effect on the apoptosis induced by I/R in the cardiac muscle cells. The Kaempferol treatment significantly increased the expression level of the anti-apoptotic protein, Bcl-2, but decreased the level of the pro-apoptotic protein, bax. Kaempferol down-regulated the expressions of the endoplasmic reticulum (ER) stress proteins, GRP78, ATF-6alpha, XBP-2, IRE1-alpha, phosphor-eIF-2alpha and CHOP. In ex vivo-Langendorff experiment, the kaempferol treatment regulated the expression of ER stress proteins-CHOP and GRP78. The kaempferol also improved the post-ischemic LVEDP and LVDP significantly after 20, 30, 40 and 50 min of reperfusion compared with the untreated control hearts, which shows that kaempferol offers protection against I/R-associated cardiac dysfunction.
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PMID:Kaempferol protects ischemia/reperfusion-induced cardiac damage through the regulation of endoplasmic reticulum stress. 1856 83

Apogossypolone (ApoG2) is a semi-synthesized derivative of gossypol. The principal objective of this study was to compare stability and toxicity between ApoG2 and gossypol, and to evaluate anti-lymphoma activity of ApoG2 in vitro and in vivo. ApoG2 shows better stability when compared with a racemic gossypol and can be better tolerated by mice compared to gossypol. ApoG2 showed significant inhibition of cell proliferation of WSU-DLCL(2) and primary cells obtained from lymphoma patients, whereas it displayed no toxicity on normal peripheral blood lymphocytes. For a treatment of 72 h, the IC(50) of ApoG2 was determined to be 350 nM against WSU-DLCL2 cells. Treatment with ApoG2 at 600 mg/kg resulted in significant growth inhibition of WSU-DLCL(2) xenografts. When combined with CHOP, ApoG2 displayed even more complete inhibition of tumor growth. ApoG2 binds to purified recombinant Bcl-2, Mcl-1 and Bcl-X(L) proteins with high affinity and is shown to block the formation of heterodimers between Bcl-X(L) and Bim. For a treatment of 72 h, ApoG2 induced a maximum of 32% of apoptotic cell death. Western blot experiments showed that treatment with ApoG2 led to cleavage of caspase-3, caspase-9 and PARP. Moreover, pretreatment of DLCL(2) cells with caspase-3, -9 and broad spectrum caspase inhibitors significantly blocked growth inhibition induced by ApoG2. In conclusion, ApoG2 effectively inhibits growth of DLCL(2) cells at least partly by inducing apoptosis. It is an attractive small molecule inhibitor of the Bcl-2 family proteins to be developed further for the treatment of diffuse large cell lymphoma.
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PMID:Apogossypolone, a nonpeptidic small molecule inhibitor targeting Bcl-2 family proteins, effectively inhibits growth of diffuse large cell lymphoma cells in vitro and in vivo. 1876 31

The classification of germinal centre (GC) and non-GC is an important prognostic immunophenotype for patients with diffuse large B cell lymphoma (DLBCL) following anthracycline-based chemotherapy. The expression of the anti-apoptotic protein, Bcl-2, has been associated with an unfavourable prognosis in patients with DLBCL. Immunohistochemistry was performed using antibodies against CD10, Bcl-6, MUM-1 and Bcl-2. To establish the combined prognosis of the immunophenotype and Bcl-2 overexpression, patients were separated into four subgroups based on their gene expression profile: the Bcl-2 positive GC subgroup, Bcl-2 negative GC subgroup, Bcl-2 positive non-GC subgroup, and the Bcl-2 negative non-GC subgroup. The clinical characteristics and survival outcomes of the four patient subgroups were compared. Ninety-six patients with de novo DLBCL received R-CHOP (rituximab, cyclophosphamide, vincristine, adriamycin and prednisone) therapy. The baseline characteristics of the patient subgroups were similar. The Bcl-2 negative GC subgroup had a favourable progression-free and overall survival (OS) compared with the other three subgroups (p = 0.042, 0.043). Multivariate analysis confirmed that the Bcl-2 negative GC group was independently associated with progression-free survival and OS. The results of this study showed that the Bcl-2 negative GC patients had the most favourable prognosis among patients with DLBCL that received R-CHOP.
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PMID:Prognostic significance of the Bcl-2 negative germinal centre in patients with diffuse large B cell lymphoma treated with R-CHOP. 1915 70

This study is the first to investigate the anticancer effect of dehydrocostuslactone [DHE (3aS,6aR,9aR,9bS)-decahydro-3,6,9-tris(methylene) azuleno[4,5-b]furan-2(3H)-one)], a medicinal plant-derived sesquiterpene lactone, on hepatocellular carcinoma. Our results showed that DHE inhibits the proliferation of HepG2 and PLC/PRF/5 cells by inducing apoptosis. DHE induces up-regulation of Bax and Bak, down-regulation of Bcl-2 and Bcl-XL, and nuclear relocation of the mitochondrial factors apoptosis-inducing factor (AIF) and endonuclease G (Endo G). DHE triggered endoplasmic reticulum (ER) stress, as indicated by changes in cytosol-calcium levels, double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase phosphorylation, inositol-requiring protein 1 (IRE1) and CHOP/GADD153 up-regulation, X-box transcription factor-1 mRNA splicing, and caspase-4 activation. Enhancement of ER stress by DHE is through p38 and extracellular signal-regulated kinase 1/2-dependent manners and subsequently causes c-Jun NH(2)-terminal kinase activation, resulting in AIF and Endo G nuclear relocation. Both of IRE1 small interfering RNA transfection and 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester pretreatment inhibit DHE-mediated apoptosis, supporting the hypothesis that DHE induces cell death through ER stress. It is noteworthy that animal studies have revealed a dramatic 50% reduction in tumor volume after 45 days of treatment. This study demonstrates that DHE may be a novel anticancer agent for the treatment of liver cancer.
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PMID:Dehydrocostuslactone, a medicinal plant-derived sesquiterpene lactone, induces apoptosis coupled to endoplasmic reticulum stress in liver cancer cells. 1918 81

Oxidative stress and endoplasmic reticulum (ER) stress have been implicated in cardiovascular diseases although the interplay between the two is not clear. This study was designed to examine the influence of oxidative stress through glutathione depletion on myocardial ER stress and contractile function in the absence or presence of the heavy metal scavenger antioxidant metallothionein (MT). FVB and MT overexpression transgenic mice received the GSH synthase inhibitor buthionine sulfoximine (BSO, 30 mM) in drinking water for 2 weeks. Oxidative stress, ER stress, apoptosis, cardiac function and ultrastructure were assessed using GSH/GSSG assay, reactive oxygen species (ROS), immunoblotting, caspase-3 activity, Langendorff perfused heart function (LVDP and +/-dP/dt), and transmission electron microscopy. BSO led to a robust decrease in the GSH/GSSG ratio and increased ROS production, consolidating oxidative stress. Cardiac function and ultrastructure were compromised following BSO treatment, the effect of which was obliterated by MT. BSO promoted overt ER stress as evidenced by upregulated BiP, calregulin, phospho-IRE1 alpha and phospho-eIF2 alpha without affecting total IRE1 alpha and eIF2 alpha. BSO treatment led to apoptosis manifested as elevated expression of CHOP/GADD153, caspase-12 and Bax as well as caspase-3 activity, reduced Bcl-2 expression and JNK phosphorylation, all of which was ablated by MT. Moreover, both antioxidant N-acetylcysteine and the ER stress inhibitor tauroursodeoxycholic acid reversed the oxidative stress inducer menadione-elicited depression in cardiomyocyte contractile function. Taken together, these data suggested that ER stress occurs likely downstream of oxidative stress en route to cardiac dysfunction.
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PMID:Metallothionein alleviates oxidative stress-induced endoplasmic reticulum stress and myocardial dysfunction. 1934 29

Sarcopenia is characterized by increased regenerating myofibres and decreased myofibre size. Sarcopenia progression might be partially regulated by ageing-related signals associated with necrotic fibre disruption and nuclear apoptosis. This study sought to identify ageing-related signals in aged atrophying skeletal muscle by comparison with unloaded muscle atrophy in adults. Adult (6-month) and old (32-month) rats were used. Some adult rats were subjected to 2 weeks of hindlimb unloading (6-month-HU). Histological analysis found that regenerating fibres increased by about 30-fold only in 32-month aged soleus muscle compared with 6-month rats. The number of apoptotic DNA fragmented nuclei was increased by 3.9-fold in 6-month-HU and 2.8-fold in 32-month rats. Cleaved caspase-3 was observed at high levels on basal membranes and in nuclei in 32-month rats. By Western blot analysis additional ageing-related signals could be identified since (1) phosphorylated Bcl-2 content was increased in both cytosolic and mitochondrial fractions; (2) ER stress signal proteins caspase-12, CHOP/GADD153, and GRP78 were increased; and (3) stress-inducible chaperone HSP70 was decreased in soleus muscle from 32-month but not changed in 6-month-HU rats. We conclude that activation of ageing-related signals may mediate necrotic myofibre disruption and nuclear apoptosis induction that contribute to progression of sarcopenia.
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PMID:Differential cell death regulation between adult-unloaded and aged rat soleus muscle. 1942 51


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