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)

Xenon attenuates on-going neuronal injury in both in vitro and in vivo models of hypoxic-ischaemic injury when administered during and after the insult. In the present study, we sought to investigate whether the neuroprotective efficacy of xenon can be observed when administered before an insult, referred to as 'preconditioning'. In a neuronal-glial cell coculture, preexposure to xenon for 2 h caused a concentration-dependent reduction of lactate dehydrogenase release from cells deprived of oxygen and glucose 24 h later; xenon's preconditioning effect was abolished by cycloheximide, a protein synthesis inhibitor. Preconditioning with xenon decreased propidium iodide staining in a hippocampal slice culture model subjected to oxygen and glucose deprivation. In an in vivo model of neonatal asphyxia involving hypoxic-ischaemic injury to 7-day-old rats, preconditioning with xenon reduced infarction size when assessed 7 days after injury. Furthermore, a sustained improvement in neurologic function was also evident 30 days after injury. Phosphorylated cAMP (cyclic adenosine 3',5'-monophosphate)-response element binding protein (pCREB) was increased by xenon exposure. Also, the prosurvival proteins Bcl-2 and brain-derived neurotrophic factor were upregulated by xenon treatment. These studies provide evidence for xenon's preconditioning effect, which might be caused by a pCREB-regulated synthesis of proteins that promote survival against neuronal injury.
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PMID:Xenon preconditioning reduces brain damage from neonatal asphyxia in rats. 1603 70

Failure of severed adult CNS axons to regenerate could be attributed to both a reduced intrinsic capacity to grow and an heightened susceptibility to inhibitory factors of the CNS extracellular environment. A particularly interesting and useful paradigm for investigating CNS axonal regeneration is its enhancement at the CNS branch of dorsal root ganglion (DRG) neurons after conditional lesioning of their peripheral branch. Recent reports have implicated the involvement of two well-known signaling pathways utilizing separate transcription factors; the Cyclic AMP (cAMP) response element binding protein (CREB) and signal transducer and activator of transcription 3 (STAT3), in conditional lesioning. The former appears to be the pathway activated by neurotrophic factors and Bcl-2, while the latter is responsible for the neurogenic effect of cytokines [such as the leukemia inhibitory factor (LIF) and interleukin-6 (IL-6) elevated at lesion sites]. Recent findings also augmented earlier notions that modulations of the activity of another class of cellular signaling intermediate, the conventional protein kinase C (PKC), could result in a contrasting growth response by CNS neurons to myelin-associated inhibitors. We discuss these signaling pathways and mechanisms, in conjunction with other recent reports of regeneration enhancement and also within the context of what is known about aiding regeneration of injured CNS axons.
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PMID:Axonal regeneration in adult CNS neurons--signaling molecules and pathways. 1647 81

The very different effects of Cholera Toxin (CT) on cell growth and proliferation may depend on the type of ganglioside receptors in cell membranes and different signal transduction mechanisms triggered, but other functions related to the drug resistance mechanisms can not be excluded. The effect of CT treatment on the "in vitro" clonogenicity, the Population Doubling Time (PDT), apoptosis, PKA activation and Bax and Bcl-2 expression was evaluated in WEHI-3B cell line and its CT-resistant subclone (WEHI-3B/CTRES). In WEHI-3B parental cells the dramatic accumulation of cAMP induced by CT correlated well with PKA activation, increased PDT value, inhibition of clonogenicity and apoptosis. H-89 treatment inhibited PKA activation by CT but did not protect the cells from apoptosis and growth inhibition. In WEHI-3B/CTRES no significant CT-dependent accumulation of cAMP occurred with any increase of PKA activity and PDT. In CT resistant cells (WEHI-3B/CTRES), Bcl-2 expression was down regulated by both CT or drug treatment (eg., ciprofloxacin, CPX) although these cells were protected from CT-dependent apoptosis but not from drug-induced apoptosis. Differently from other cell models described, down regulation of Bcl-2 is proved to be independent on cAMP accumulation and PKA activation. Our observations support the implication of cAMP dependent kinase (PKA) in the inhibition of WEHI-3B cells growth and suggest that, in WEHI-3B/CTRES, Bcl-2 expression could be modulated by CT in the absence of cAMP accumulation. Also in consideration of many contradictory data reported in literature, our cell models (of one sensitive parental cell strain and two clones with different uncrossed specific resistance to CT and CPX) provides a new and interesting tool for better investigating the relationship between the CT signal transduction mechanisms and Bcl-2 expression and function.
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PMID:Bcl-2 down modulation in WEHI-3B/CTRES cells resistant to Cholera Toxin (CT)-induced apoptosis. 1654 Nov 29

Impaired survival signaling may represent a central mechanism in neurodegeneration. 6-Hydroxydopamine (6-OHDA) is an oxidative neurotoxin used to injure catecholaminergic cells of the central and peripheral nervous systems. Although 6-OHDA elicits phosphorylation of several kinases, downstream transcriptional effects that influence neuronal cell death are less defined. The cAMP response element (CRE) is present in the promoter sequences of several important neuronal survival factors. Treatment of catecholaminergic neuronal cell lines (B65 and SH-SY5Y) with 6-OHDA resulted in repression of basal CRE transactivation. Message levels of CRE-driven genes such as brain-derived neurotrophic factor and the survival factor Bcl-2 were decreased in 6-OHDA-treated cells, but message levels of genes lacking CRE sequences were not affected. Repression of CRE could be reversed by delayed treatment with cAMP several hours after initiation of 6-OHDA injury. Furthermore, restoration of CRE-driven transcription was associated with significant neuroprotection. In contrast to observations in other model systems, the mechanism of CRE repression did not involve decreased phosphorylation of its binding protein CREB. Instead, total CREB and phospho-CREB (pCREB) were increased in the cytoplasm and decreased in the nucleus of 6-OHDA-treated cells. 6-OHDA also decreased nuclear pCREB in dopaminergic neurons of primary mouse midbrain cultures. Co-treatment with cAMP promoted/restored nuclear localization of pCREB in both immortalized and primary culture systems. Increased cytoplasmic pCREB was observed in degenerating human Parkinson/Lewy body disease substantia nigra neurons but not in age-matched controls. Notably, cytoplasmic accumulation of activated upstream CREB kinases has been observed previously in both 6-OHDA-treated cells and degenerating human neurons, supporting a potential role for impaired nuclear import of phosphorylated signaling proteins.
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PMID:Functional repression of cAMP response element in 6-hydroxydopamine-treated neuronal cells. 1662 93

Glucocorticoid excess induces hyperglycemia, which may result in diabetes. The present experiments explored whether glucocorticoids trigger apoptosis in insulin-secreting cells. Treatment of mouse beta-cells or INS-1 cells with the glucocorticoid dexamethasone (0.1 micromol/l) over 4 days in cell culture increased the number of fractionated nuclei from 2 to 7 and 14%, respectively, an effect that was reversed by the glucocorticoid receptor antagonist RU486 (1 micromol/l). In INS-1 cells, dexamethasone increased the number of transferase-mediated dUTP nick-end labeling-staining positive cells, caspase-3 activity, and poly-(ADP-) ribose polymerase protein cleavage; decreased Bcl-2 transcript and protein abundance; dephosphorylated the proapoptotic protein of the Bcl-2 family (BAD) at serine155; and depolarized mitochondria. Dexamethasone increased PP-2B (calcineurin) activity, an effect abrogated by FK506. FK506 (0.1 micromol/l) and another calcineurin inhibitor, deltamethrin (1 micromol/l), attenuated dexamethasone-induced cell death. The stable glucagon-like peptide 1 analog, exendin-4 (10 nmol/l), inhibited dexamethasone-induced apoptosis in mouse beta-cells and INS-1 cells. The protective effect of exendin-4 was mimicked by forskolin (10 micromol/l) but not mimicked by guanine nucleotide exchange factor with the specific agonist 8CPT-Me-cAMP (50 micromol/l). Exendin-4 did not protect against cell death in the presence of cAMP-dependent protein kinase (PKA) inhibition by H89 (10 micromol/l) or KT5720 (5 micromol/l). In conclusion, glucocorticoid-induced apoptosis in insulin-secreting cells is accompanied by a downregulation of Bcl-2, activation of calcineurin with subsequent dephosphorylation of BAD, and mitochondrial depolarization. Exendin-4 protects against glucocorticoid-induced apoptosis, an effect mimicked by forskolin and reversed by PKA inhibitors.
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PMID:Dexamethasone induces cell death in insulin-secreting cells, an effect reversed by exendin-4. 1664 95

During tumor growth and invasion, the endothelial cells from a relatively quiescent endothelium start proliferating. The exact mechanism of switching to a new angiogenic phenotype is currently unknown. We have examined the role of intracellular cAMP in this process. When a non-transformed capillary endothelial cell line was treated with 2 mM 8Br-cAMP, cell proliferation was enhanced by approximately 70%. Cellular morphology indicated enhanced mitosis after 32-40 h with almost one-half of the cell population in the S phase. Bcl-2 expression and caspase-3, -8, and -9 activity remained unaffected. A significant increase in the Glc(3)Man(9)GlcNAc(2)-PP-Dol biosynthesis and turnover, Factor VIIIC N-glycosylation, and cell surface expression of N-glycans was observed in cells treated with 8Br-cAMP. Dol-P-Man synthase activity in the endoplasmic reticulum membranes also increased. A 1.4-1.6-fold increase in HSP-70 and HSP-90 expression was also observed in 8Br-cAMP treated cells. On the other hand, the expression of GRP-78/Bip was 2.3-fold higher compared to that of GRP-94 in control cells, but after 8Br-cAMP treatment for 32 h, it was reduced by 3-fold. GRP-78/Bip expression in untreated cells was 1.2-1.5-fold higher when compared with HSP-70 and HSP-90, whereas that of the GRP-94 was 1.5-1.8-fold lower. After 8Br-cAMP treatment, GRP-78/Bip expression was reduced 4.5-4.8-fold, but the GRP-94 was reduced by 1.5-1.6-fold only. Upon comparison, a 2.9-fold down-regulation of GRP-78/Bip was observed compared to GRP-94. We, therefore, conclude that a high level of Glc(3)Man(9)GlcNAc(2)-PP-Dol, resulting from 8Br-cAMP stimulation up-regulated HSP-70 expression and down-regulated that of the GRP-78/Bip, maintained adequate protein folding, and reduced endoplasmic reticulum stress. As a result capillary endothelial cell proliferation was induced.
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PMID:Potentiation of angiogenic switch in capillary endothelial cells by cAMP: A cross-talk between up-regulated LLO biosynthesis and the HSP-70 expression. 1669 4

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

Evidence from epidemiological studies suggests that plant-based diets can reduce the risk of prostate cancer. However, very little information is available concerning the use of botanicals in preventing prostate cancer. As a first step toward developing botanicals as prostate cancer preventives, we examined the effect of Nexrutine on human prostate cancer cells. Nexrutine is a herbal extract developed from Phellodendron amurense. Phellodendron extracts have been used traditionally in Chinese medicine for hundreds of years as an antidiarrheal, astringent, and anti-inflammatory agent. The present study investigated its potential antitumor effect on human prostate cancer cells. Our results suggest that it inhibits tumor cell proliferation through apoptosis induction and inhibition of cell survival signaling. The results of the present study indicate that Nexrutine treatment 1) inhibits the proliferation of both androgen-responsive and androgen-independent human prostate cancer cells through induction of apoptosis; 2) reduces levels of pAkt, phosphorylated cAMP response-binding protein (pCREB) and CREB DNA-binding activity; and 3) induces apoptosis in prostate cancer cells stably overexpressing Bcl-2. Further, Akt kinase activity was reduced in cells treated with Nexrutine, and ectopic expression of myristoylated Akt protected from Nexrutine induced inhibition of proliferation, implicating a role for Akt signaling.
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PMID:Akt-and CREB-mediated prostate cancer cell proliferation inhibition by Nexrutine, a Phellodendron amurense extract. 1682 98

This study aimed to elucidate whether the effect of cilostazol to suppress apoptotic cell death is directly coupled to cAMP-dependent protein kinase activation in human umbilical vein endothelial cells (HUVECs). After exposure of HUVECs to LPS (1 microgml(-1)) for 18 h, the endothelial cells irregularly aggregated with loss of cobblestone appearance, which was reversed by cilostazol (1-100 microM), as well as by cilostamide (cilostazol analog), and cilostazol metabolites (OPC-13015 and OPC-31213), respectively. LPS-stimulated production of reactive oxygen species (ROS) was significantly reduced by cilostazol (0.1-10 microM). In line with these, LPS (1 microgml(-1))- and TNF-alpha (200 ngml(-1))-induced DNA fragmentation, assessed by agarose gel electrophoresis, was significantly reduced by treatment with cilostazol (10 microM) as well as by dibutyryl cAMP (100 microM). This effect was reversed by cAMP-dependent protein kinase inhibitor, Rp-cAMPs (200 microM). Further, LPS (1 microgml(-1))-induced decrease in Bcl-2 and increase in Bax protein expression were fully reversed by cilostazol (10 microM) and dibutyryl cAMP (100 microM), all of which were antagonized by Rp-cAMPs (200 microM). Taken together, cilostazol effectively protected HUVECs from LPS- and TNF-alpha-induced cell death associated with oligonucleosomal DNA fragmentation via activation of cAMP-dependent protein kinase.
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PMID:Protection from apoptotic cell death by cilostazol, phosphodiesterase type III inhibitor, via cAMP-dependent protein kinase activation. 1682 80

Glutamate treatment depletes hippocampal HT22 cells of glutathione, which renders the cells incapable to reduce reactive oxygen species and ultimately cumulates in cell death by oxidative stress. HT22 cells resistant to glutamate displayed increased phosphorylation of cAMP-response-element binding (CREB) and decreased ERK1/2 suggestive of differences in signal transmission. We investigated the amount of candidate G-protein-coupled receptors involved in this resistance and found an increase in mRNA for receptors activated by the vasoactive intestinal peptide VIP (VPAC2, 12.6-fold) and glutamate like the metabotropic glutamate receptor mGlu1 (5.3-fold). Treating cells with VIP and glutamate led to the same changes in protein phosphorylation observed in resistant cells and induced the proto-oncogene Bcl-2. Bcl-2 overexpression protected by increasing the amount of intracellular glutathione and Bcl-2 knockdown by small interfering RNAs (siRNA) increased glutamate susceptibility of resistant cells. Other receptors upregulated in this paradigm might represent useful targets in the treatment of neurological diseases associated with oxidative stress.
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PMID:Induction of Bcl-2 by functional regulation of G-protein coupled receptors protects from oxidative glutamate toxicity by increasing glutathione. 1705 Jan 65


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