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)

Endometrial apoptosis increases from the proliferative phase through the secretory phase and peaks at menses. However, with the onset of pregnancy, the corpus luteum is rescued and stromal cells, instead of undergoing apoptosis, reorganize the cytoskeleton and then begin to differentiate. We hypothesized that in the presence of hormones (estradiol-17beta and medroxyprogesterone acetate), chorionic gonadotropin (hCG) as an early embryonic signal, and induction of decidualization by dibutyryl-cAMP (dbcAMP), endometrial stromal cells are rescued by the regulation of proteins that inhibit apoptosis. The percentage of cells stained with annexin V, an early apoptotic marker, increased dramatically after cytoskeletal disruption with cytochalasin D compared with non-cytochalasin-D-treated controls (P < 0.05). However, treatment of cells with hCG or dbcAMP in the presence of hormones significantly (P < 0.05) decreased the percentage of annexin-V-stained cells compared with cells treated with cytochalasin D alone. This inhibition was further confirmed by immunodetection of cleaved caspase-3 and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. The inhibition of apoptosis by hCG and dbcAMP was via the intrinsic pathway because the cytochalasin-D-treated cells stained intensely for Bax, whereas the cells treated with hormones, hCG, or dbcAMP stained predominantly for Bcl-2. Treatment of cytochalasin-D-treated cells with hormones and dbcAMP resulted in an increase in the secretion of IGF-binding protein-1 (IGFBP-1) and prolactin. Treatment of cytochalasin-D-treated cells with recombinant IGFBP-1 and prolactin also inhibited apoptosis. These data suggest that under in vitro conditions, both hCG and the induction of decidualization play a direct role in preventing uterine stromal cells from undergoing apoptosis. Furthermore, this inhibition of apoptosis may be mediated in part by IGFBP-1 and prolactin and the alteration in the expression of Bcl-2 and Bax.
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PMID:Human chorionic gonadotropin and decidualization in vitro inhibits cytochalasin-D-induced apoptosis in cultured endometrial stromal fibroblasts. 1674 Sep 72

Visceral leishmaniasis (VL) produced in BALB/c mice through intracardial administration of Leishmania donovani amastigotes was accompanied by hepatosplenomegaly with high organ parasite load and lymphadenopathy when followed up to 4-months or so. To elucidate the mechanism of immunosuppression associated with VL, we report here progressive impairment of the proliferative response of lymph node cells (lymphocytes) from infected animals (I-LNC) to in vitro stimulation with the combination of phorbol 12-myristate 13-acetate (PMA) and ionomycin (Io) that could be related to the downregulation of PKC and MAP kinase (ERK 1/2) activation process. Further, pretreatment of I-LNC with the protein phosphatase inhibitor okadaic acid (OA), but not with calyculin A or sodium orthovanadate, significantly restored their proliferative response as well as PMA-induced activation of PKC. A population of LNC (primarily T-lymphocytes) from chronically infected animals was shown to undergo apoptosis, the number of which increased considerably following PMA+ Io stimulation. The apoptotic pathway, which was followed through binding of cells to Annexin V, activation of caspase-3 and fragmentation of DNA, involved destabilization of mitochondria, probably as a result of downregulation of PKC and Bcl-2. Interestingly, prior incubation of I-LNC with OA reversed the state of cell cycle arrest (anergy) and apoptosis through progression of cells from G0/G1 to S and G2/M phases with transcriptional activation of IL-2 and IL-2R genes. Our results suggest that the cellular (immune) dysfunction in VL could be attributed to dephosphorylation of key molecules in the T-lymphocyte signaling pathway by Ser/Thr phosphatase leading to their inactivation.
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PMID:Lymph node cells from BALB/c mice with chronic visceral leishmaniasis exhibiting cellular anergy and apoptosis: involvement of Ser/Thr phosphatase. 1701 55

Unlike the tocopherols, the tocotrienols, also members of the vitamin E family, have an unsaturated isoprenoid side chain. In contrast to extensive studies on tocopherol, very little is known about tocotrienol. Because the nuclear factor-kappaB (NF-kappaB) pathway has a central role in tumorigenesis, we investigated the effect of gamma-tocotrienol on the NF-kappaB pathway. Although gamma-tocotrienol completely abolished tumor necrosis factor alpha (TNF)-induced NF-kappaB activation, a similar dose of gamma-tocopherol had no effect. Besides TNF, gamma-tocotrienol also abolished NF-kappaB activation induced by phorbol myristate acetate, okadaic acid, lipopolysaccharide, cigarette smoke, interleukin-1beta, and epidermal growth factor. Constitutive NF-kappaB activation expressed by certain tumor cells was also abrogated by gamma-tocotrienol. Reducing agent had no effect on the gamma-tocotrienol-induced down-regulation of NF-kappaB. Mevalonate reversed the NF-kappaB inhibitory effect of gamma-tocotrienol, indicating the role of hydroxymethylglutaryl-CoA reductase. Gamma-tocotrienol blocked TNF-induced phosphorylation and degradation of IkappaBalpha through the inhibition of IkappaBalpha kinase activation, thus leading to the suppression of the phosphorylation and nuclear translocation of p65. gamma-Tocotrienol also suppressed NF-kappaB-dependent reporter gene transcription induced by TNF, TNFR1, TRADD, TRAF2, TAK1, receptor-interacting protein, NIK, and IkappaBalpha kinase but not that activated by p65. Additionally, the expressions of NF-kappaB-regulated gene products associated with antiapoptosis (IAP1, IAP2, Bcl-xL, Bcl-2, cFLIP, XIAP, Bfl-1/A1, TRAF1, and Survivin), proliferation (cyclin D1, COX2, and c-Myc), invasion (MMP-9 and ICAM-1), and angiogenesis (vascular endothelial growth factor) were down-regulated by gamma-tocotrienol. This correlated with potentiation of apoptosis induced by TNF, paclitaxel, and doxorubicin. Overall, our results demonstrate that gamma-tocotrienol inhibited the NF-kappaB activation pathway, leading to down-regulation of various gene products and potentiation of apoptosis.
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PMID:Gamma-tocotrienol inhibits nuclear factor-kappaB signaling pathway through inhibition of receptor-interacting protein and TAK1 leading to suppression of antiapoptotic gene products and potentiation of apoptosis. 1711 79

Glucocorticoids induce apoptosis in chronic lymphocytic leukemia (CLL) cells through a caspase-dependent mechanism. However, their mechanism of action remains unknown. We have studied the regulation of the proapoptotic BH3-only Bcl-2 interacting mediator of cell death (BIM) in CLL cells. We demonstrate that glucocorticoids upregulate BIM at protein and mRNA levels. We have investigated the ability of different survival signals, such as 12-O-tetradecanoylphorbol 13-acetate (TPA), stromal cell-derived factor-1alpha (SDF-1alpha), interleukin 4 (IL-4) and B-cell receptor (BCR) activation, to influence the levels of BIM and its induction by glucocorticoids. TPA downregulates BIM(EL) by extracellular signal-regulated kinase (ERK)-mediated BIM phosphorylation and further proteasome-mediated degradation. However, SDF-1alpha and BCR activation induce transient BIM phosphorylation, without protein degradation. Proteasome inhibitors do not modify the levels of BIM with respect to untreated cells. However, they induce apoptosis and inhibit TPA-induced BIM(EL) degradation, leading to its accumulation. In conclusion, the results implicate BIM in glucocorticoid-induced apoptosis in CLL cells. BIM(EL) phosphorylation through the ERK pathway targets the protein for proteasomal degradation.
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PMID:Regulation of the proapoptotic BH3-only protein BIM by glucocorticoids, survival signals and proteasome in chronic lymphocytic leukemia cells. 1715 1

Silymarin consists of a family of flavonoids (silybin, isosilybin, silychristin, silydianin and taxifoline) commonly found in the dried fruit of the milk thistle plant Silybum marianum. Although silymarin's role as an antioxidant and hepatoprotective agent is well known, its role as an anticancer agent has begun to emerge. Extensive research within the last decade has shown that silymarin can suppress the proliferation of a variety of tumor cells (e.g., prostate, breast, ovary, colon, lung, bladder); this is accomplished through cell cycle arrest at the G1/S-phase, induction of cyclin-dependent kinase inhibitors (such as p15, p21 and p27), down-regulation of anti-apoptotic gene products (e.g., Bcl-2 and Bcl-xL), inhibition of cell-survival kinases (AKT, PKC and MAPK) and inhibition of inflammatory transcription factors (e.g., NF-kappaB). Silymarin can also down-regulate gene products involved in the proliferation of tumor cells (cyclin D1, EGFR, COX-2, TGF-beta, IGF-IR), invasion (MMP-9), angiogenesis (VEGF) and metastasis (adhesion molecules). The antiinflammatory effects of silymarin are mediated through suppression of NF-kappaB-regulated gene products, including COX-2, LOX, inducible iNOS, TNF and IL-1. Numerous studies have indicated that silymarin is a chemopreventive agent in vivo against a variety of carcinogens/tumor promoters, including UV light, 7,12-dimethylbenz(a)anthracene (DMBA), phorbol 12-myristate 13-acetate (PMA) and others. Silymarin has also been shown to sensitize tumors to chemotherapeutic agents through down-regulation of the MDR protein and other mechanisms. It binds to both estrogen and androgen receptors, and down-regulates PSA. In addition to its chemopreventive effects, silymarin exhibits antitumor activity against human tumors (e.g., prostate and ovary) in rodents. Various clinical trials have indicated that silymarin is bioavailable and pharmacologically safe. Studies are now in progress to demonstrate the clinical efficacy of silymarin against various cancers.
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PMID:Anticancer potential of silymarin: from bench to bed side. 1720 Nov 69

Survivin is known to be essential for cell division and to inhibit apoptosis during embryonic development and in adult cancerous tissues. However, the cardiovascular role of survivin is unknown. We observed that in cardiomyocytes cultured under conditions of serum and glucose deprivation (DEPV), the levels of survivin, Bcl-2 and extracellular signal-regulated kinase (ERK) were positively correlated with the anti-apoptotic action of a delta-opioid receptor agonist, [D-Ala2, D-Leu5]-enkephalin acetate (DADLE). By contrast, Bax translocation, mitochondrial membrane damage and reactive oxygen species (ROS) production were inversely correlated with the changes of survivin and Bcl-2. The use of RNA interference (RNAi) targeting survivin increased DEPV-induced cardiomyocyte apoptosis, whereas the anti-apoptotic effect of DADLE was blunted by survivin RNAi. Moreover, survivin transfection and overexpression provided protection against DEPV-induced cardiomyocyte apoptosis. Inhibition of ERK prevented the DADLE-induced decrease in apoptosis and Bax translocation, and increase in survivin and Bcl-2. DADLE-induced increase in survivin was also blunted by phosphoinositol 3-kinase (PI 3-kinase) inhibition. In conclusion, the present study provides the first direct evidence of an anti-apoptotic role of survivin mediating the anti-apoptotic effect of delta-opioid receptor activation in cardiomyocytes. ERK and PI 3-kinase were found to be upstream regulators of survivin. Mitochondrial membranes as well as ROS, Bcl-2 and Bax were also involved in this anti-apoptotic action.
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PMID:Survivin mediates the anti-apoptotic effect of delta-opioid receptor stimulation in cardiomyocytes. 1729 78

Bnip3 is a proapoptotic member of the Bcl-2 family of death-regulating proteins that promote the intrinsic pathway of programmed cell death. The Bnip3 death program requires membrane insertion through an N-terminal transmembrane domain that directs the protein to mitochondrial and endoplasmic reticular (ER) membranes. We have reported that simulated ischemia induces transcription of the Bnip3 gene, and Bnip3 protein is stabilized by acidosis. Bnip3 programmed death is atypical, with features of both apoptosis and necrosis. Here we demonstrate that hypoxia-reoxygenation and agents that activate protein kinase C, including calcium ionophore, phorbol 12-myristate 13-acetate, and okadaic acid, also induce Bnip3. The molecular size of Bnip3 predicted from the amino acid sequence is 21.5 kDa, but the protein typically migrates in SDS-PAGE as a 31-kDa monomer and 60-kDa dimer. Treatment of cell extracts containing Bnip3 with phosphatase yielded a series of rapidly migrating species, the smallest of which corresponded with the theoretic molecular size of Bnip3. Conversely, treatment of cells with okadaic acid eliminated the rapidly migrating species, suggesting that Bnip3 phosphorylation is a dynamic process. Elevated levels of the phosphoprotein correlated with initiation of Bnip3-dependent death, whereas the dephosphorylated species correlated with extreme acidosis.
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PMID:Regulation of Bnip3 death pathways by calcium, phosphorylation, and hypoxia-reoxygenation. 1763 46

Compounds such as S-allylmercaptocysteine, diallyl disulfide, and S-trityl-L-cysteine isolated from garlic have been known to be effective in chemoprevention. Nuclear transcription factor-kappaB (NF-kappaB) has been known to be an implicated factor in apoptotic cell death of several cancer cells. In this study, we investigated whether a sulfurcompound (named thiacremonone) isolated from garlic could modulate NF-kappaB activity and thereby induce apoptotic cell death of colon cancer cells. Treatment with different concentrations (30 - 150 microg/ml) of thiacremonone for various periods (0 - 48 h) inhibited colon cancer cell (SW620 and HCT116) growth followed by induction of apoptosis in a dose-dependent manner. We also found that thiacremonone modulated tumor necrosis factor-alpha (TNF-alpha) and tetradeanoyl phorbol acetate (TPA)-induced NF-kappaB transcriptional and DNA binding activity. Moreover, thiacremonone suppressed NF-kappaB target anti-apoptotic genes (Bcl-2, cIAP1/2, and XIAP) and inflammatory genes (iNOS and COX-2), whereas it induced apoptotic genes (Bax, cleaved caspse-3, and cleaved PARP) expression. These results suggest that a novel sulfurocompound from garlic inhibited colon cancer cell growth through induction of apoptotic cell death by modulating of NF-kappaB.
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PMID:Inhibition of cell growth and induction of apoptosis via inactivation of NF-kappaB by a sulfurcompound isolated from garlic in human colon cancer cells. 1772 Oct 42

Bromelain is a pharmacologically active compound, present in stems and immature fruits of pineapples (Ananas cosmosus), which has been shown to have anti-edematous, anti-inflammatory, anti-thrombotic and anti-metastatic properties. In the present study, antitumorigenic activity of bromelain was recorded in 7,12-dimethylbenz(a)anthracene (DMBA)-initiated and 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted 2-stage mouse skin model. Results showed that bromelain application delayed the onset of tumorigenesis and reduced the cumulative number of tumors, tumor volume and the average number of tumors/mouse. To establish a cause and effect relationship, we targeted the proteins involved in the cell death pathway. Bromelain treatment resulted in upregulation of p53 and Bax and subsequent activation of caspase 3 and caspase 9 with concomitant decrease in antiapoptotic protein Bcl-2 in mouse skin. Since persistent induction of cyclooxygenase-2 (Cox-2) is frequently implicated in tumorigenesis and is regulated by nuclear factor-kappa B (NF-kappaB), we also investigated the effect of bromelain on Cox-2 and NF-kappaB expression. Results showed that bromelain application significantly inhibited Cox-2 and inactivated NF-kappaB by blocking phosphorylation and subsequent degradation of IkappaBalpha. In addition, bromelain treatment attenuated DMBA-TPA-induced phosphorylation of extracellular signal-regulated protein kinase (ERK1/2), mitogen-activated protein kinase (MAPK) and Akt. Taken together, we conclude that bromelain induces apoptosis-related proteins along with inhibition of NF-kappaB-driven Cox-2 expression by blocking the MAPK and Akt/protein kinase B signaling in DMBA-TPA-induced mouse skin tumors, which may account for its anti-tumorigenic effects.
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PMID:Regulation of p53, nuclear factor kappaB and cyclooxygenase-2 expression by bromelain through targeting mitogen-activated protein kinase pathway in mouse skin. 1788 18

Lead is a neurotoxin that affects the developing central nervous system and may potentially induce apoptotic cell death. We investigated the effect of ascorbic acid against lead-induced neurotoxicity in the developing rat hippocampus. Female Sprague-Dawley rats were divided into three groups: control group, lead-treated group and lead plus ascorbic acid-treated group. Lead (0.2% lead acetate) was administered to female rats during pregnancy and lactation, in their drinking water. During this period, rats in the lead plus ascorbic acid-treated group received 100 mg/kg/day ascorbic acid, orally. At the end of the treatment, neuronal damage, apoptosis and blood lead levels were determined and the levels of Bax and Bcl-2 were immunodetected in the hippocampus of 21-day-old male pups. Histopathological evaluation demonstrated that ascorbic acid significantly attenuates apoptosis in the developing hippocampus and also spares hippocampal CA1, CA3 and dentate gyrus (DG) neurons. Simultaneous administration of ascorbic acid and lead lowered the level of Bax protein and increased Bcl-2 in pup hippocampus and reduced lead level in blood of dams compared with lead-treated only. Based on these results, it seems that ascorbic acid may potentially be beneficial in treating lead-induced brain injury in the developing rat brain.
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PMID:Protective effects of ascorbic acid against lead-induced apoptotic neurodegeneration in the developing rat hippocampus in vivo. 1795 57


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