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)

The cellular and molecular basis of brain stem death remains an enigma. As the origin of a "life-and-death" signal that reflects the progression toward brain stem death, the rostral ventrolateral medulla (RVLM) is a suitable neural substrate for mechanistic delineation of this phenomenon. Here, we evaluated the hypothesis that heat shock proteins (HSPs) play a neuroprotective role in the RVLM during brain stem death and delineated the underlying mechanisms, using a clinically relevant animal model that employed the organophosphate pesticide mevinphos (Mev) as the experimental insult. In Sprague-Dawley rats, proteomic, Western blot, and real-time PCR analyses demonstrated that Mev induced de novo synthesis of HSP60 or HSP70 in the RVLM without affecting HSP90 level. Loss-of-function manipulations of HSP60 or HSP70 in the RVLM using anti-serum or antisense oligonucleotide potentiated Mev-elicited cardiovascular depression alongside reduced nitric-oxide synthase (NOS) I/protein kinase G signaling, enhanced NOS II/peroxynitrite cascade, intensified nucleosomal DNA fragmentation, elevated cytoplasmic histone-associated DNA fragments or activated caspase-3, and augmented the cytochrome c/caspase-3 cascade of apoptotic signaling in the RVLM. Co-immunoprecipitation experiments further revealed a progressive increase in the complex formed between HSP60 and mitochondrial or cytosolic Bax or mitochondrial Bcl-2 during Mev intoxication, alongside a dissociation of the cytosolic HSP60-Bcl-2 complex. We conclude that HSP60 and HSP70 confer neuroprotection against Mev intoxication by ameliorating cardiovascular depression via an anti-apoptotic action in the RVLM. The possible underlying intracellular processes include enhancing NOS I/protein kinase G signaling and inhibiting the NOS II/peroxynitrite cascade. In addition, HSP60 exerts its effects against apoptosis by blunting Mev-induced activation of the Bax/cytochrome c/caspase-3 cascade.
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PMID:Heat shock protein 60 or 70 activates nitric-oxide synthase (NOS) I- and inhibits NOS II-associated signaling and depresses the mitochondrial apoptotic cascade during brain stem death. 1715 Sep 54

Two mechanisms of brain cell death coexist, necrosis and apoptosis. We investigated the correlation between the apoptotic index and the expression of apoptosis modulators and stress response in an ultraviolet-induced cortical microinfarct. Adult rat neocortex was exposed to an ultraviolet beam and brains removed at different intervals after injury were paraffin-embedded and processed for TUNEL assay and immunohistochemistry against apoptotic modulators Bax and Bcl-2, and stress protein HSP70. During the 12-72h postirradiation period, apoptotic nuclei decreased from 11% to 4% in the infarcted area whereas only 1.2% of such nuclei was seen in the perilesional area. While Bcl-2 was always negative in the lesion focus, Bax was positive at all survival times, mainly in glial cells. HSP70 was expressed over a broad area of the ipsilateral hemisphere from 3h after brain injury, firstly in neurons and progressively in glial cells and finally in endothelium. At longer survival times, positive cells could be also seen in the contralateral hemisphere. Apoptosis seems to play only a quantitatively modest role in the progression of brain damage in penumbra areas despite the wide expression of pro-apoptotic factors. On the other hand HSP70 appears to be one of the main protective responses to injury stress.
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PMID:Spatio-temporal distribution of apoptosis and the modulators thereof following a cortical microinfarct in rat brain. 1716 79

Cerebral ischemia (stroke) triggers a complex series of biochemical and molecular mechanisms that impairs the neurologic functions through breakdown of cellular integrity mediated by excitotoxic glutamatergic signalling, ionic imbalance, free-radical reactions, etc. These intricate processes lead to activation of signalling mechanisms involving calcium/calmodulin-dependent kinases (CaMKs) and mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK). The distribution of these transducers bring them in contact with appropriate molecular targets leading to altered gene expression, e.g. ERK and JNK mediated early gene induction, responsible for activation of cell survival/damaging mechanisms. Moreover, inflammatory reactions initiated at the neurovascular interface and alterations in the dynamic communication between the endothelial cells, astrocytes and neurons are thought to substantially contribute to the pathogenesis of the disease. The damaging mechanisms may proceed through rapid nonspecific cell lysis (necrosis) or by active form of cell demise (apoptosis or necroptosis), depending upon the severity and duration of the ischemic insult. A systematic understanding of these molecular mechanisms with prospect of modulating the chain of events leading to cellular survival/damage may help to generate the potential strategies for neuroprotection. This review briefly covers the current status on the molecular mechanisms of stroke pathophysiology with an endeavour to identify potential molecular targets such as targeting postsynaptic density-95 (PSD-95)/N-methyl-d-aspartate (NMDA) receptor interaction, certain key proteins involved in oxidative stress, CaMKs and MAPKs (ERK, p38 and JNK) signalling, inflammation (cytokines, adhesion molecules, etc.) and cell death pathways (caspases, Bcl-2 family proteins, poly (ADP-ribose) polymerase-1 (PARP-1), apoptosis-inducing factor (AIF), inhibitors of apoptosis proteins (IAPs), heat shock protein 70 (HSP70), receptor interacting protein (RIP), etc., besides targeting directly the genes itself. However, selecting promising targets from various signalling cascades, for drug discovery and development is very challenging, nevertheless such novel approaches may lead to the emergence of new avenues for therapeutic intervention in cerebral ischemia.
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PMID:Molecular targets in cerebral ischemia for developing novel therapeutics. 1722 14

The hypothesis tested in the study suggests that mechanisms of the earlier described delayed or accelerated tumor progression may be regulated by the antiapoptotic and proapoptotic cellular programs activated in stress reactions of transformed cells to the host normal cellular environment. Therefore, spontaneously transformed hamster cell line STHE, its bcl-2-transduced line STHE-Bcl-2, and 64 of their descendant tumor cell variants naturally selected in two in vivo regimes (local tumor growth versus dissemination) were examined. The role of Bcl-2 and the possible activation of endogenous death-signaling Bax, Ras, and HSP90/HSP70 stress proteins in STHE (Bcl-2+/-) tumor cell variants were studied in dynamics of in vivo tumor progression. The data demonstrate: (1) Immediate in vivo activation of Bax and of HSP90/HSP70 stress proteins in disseminated STHE cells on the background of accelerated tumor progression; (2) No immediate activation of Bax and the gradual downregulation of Bcl-2 in STHE-Bcl-2 cells on the background of delayed tumor progression; (3) Alternative and mutually suppressive character of Bcl-2 and Bax expression in both regimes of tumor progression; (4) In the later stages of tumor progression, the regular transit of the initial Bcl-2 antiapoptotic, Bax-suppressing program, and the delayed tumor progression towards Bcl-2 loss, activation of Bax, and acceleration of tumor progression. Thus, the delay of tumor progression is apparently determined by the ability of Bcl-2-expressing tumor cells to extinguish the cell-damaging environmental stress signals and Bax activation, while its acceleration correlates with Bcl-2 loss, activation of proapoptotic Bax, and tumor cells damage.
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PMID:Alternative production of Bcl-2 and Bax by tumor cells determines the rates of in vivo tumor progression: suggested mechanisms. 1729 4

Ghrelin is a novel brain-gut peptide and the endogenous ligand of growth hormone secretagogue receptor 1a (GHSR-1a). Evidences have been shown that ghrelin inhibited cell apoptosis in cardiocytes, endotheliocytes, osteoblasts, and so on. Recently, it was reported that ghrelin inhibited neuronal apoptosis of hypothalamus and hippocampus. However, little is known about the effects of ghrelin on cortical neurons during focal ischemia/reperfusion injury. In the present study, we showed that ghrelin (i.v.) prevented cortical neurons from injury induced by ischemia/reperfusion in vivo and by LPS, glutamate, NMDA and H(2)O(2) in vitro. We found that the expression of ghrelin's receptor (GHSR-1a) in rat cerebral cortex were obviously decreased by ischemia/reperfusion injury and increased by ghrelin (i.v.). Ghrelin up-regulated the expression of Bcl-2/Bax and HSP70, and inhibited caspase8, 9, 3 through GHSR-1a, which was contributed to the neuroprotective mechanism of ghrelin. Ghrelin might be an important regulator in therapeutic strategy of cortex injury.
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PMID:Ghrelin protects cortical neuron against focal ischemia/reperfusion in rats. 1756 May 44

Cancer thermotherapy and radiofrequency ablation (RFA) have been adopted as modalities for treating various kinds of cancer. We have previously demonstrated that bone morphogenetic protein-4 (BMP-4) is up-regulated in colonic adenocarcinoma. Here, we investigated whether an increase of BMP-4 expression changes cellular response to heat treatment in human colon cancer HCT116 cells. BMP-4 overexpressing HCT116 cells generated by stable transfection showed a significantly increased survival rate and a decreased apoptotic rate in comparison to empty vector controls after heat treatment at 45 degrees C for 20min. The expression levels and pattern of HSP90, HSP70, and HSP27 after heat treatment were similar between these two cell lines. There was no difference in expression levels of Bcl-2 and Bax in these two cell lines and their expression remained unchanged after heat treatment. Both activities of the extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) were stimulated by heat in these cells. Comparatively, BMP-4 overexpressing cells had an intense and prolonged ERK activation, while a less intense and short JNK activation. Correspondingly, treatment of BMP-4 overexpressing cells with noggin, a BMP-4 antagonist, resulted in a reduction of heat-activated ERK but an increase of heat-activated JNK and significantly increased heat-induced apoptotic rate. These results indicate that BMP-4 can protect colon cancer cells from heat-induced apoptosis through enhancing the activation of ERK as well as inhibiting the activation of JNK.
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PMID:Bone morphogenetic protein-4 inhibits heat-induced apoptosis by modulating MAPK pathways in human colon cancer HCT116 cells. 1764 Jul 99

In the present study, the protective effect of melatonin on sodium arsenite (arsenite)-induced apoptosis was investigated. Local infusion of arsenite elevated lipid peroxidation and depleted glutathione content in the infused substantia nigra (SN), as well as reduced striatal dopamine content. Systemic administration of melatonin diminished arsenite-induced oxidative injury. Furthermore, melatonin attenuated arsenite-induced increases in heat shock protein 70 and heme oxygenase-1 as well as phosphorylation of p38 mitogen-activated protein kinase and elevations in cyclooxygenase II and inducible nitric oxide synthase expression. Inhibition by melatonin of arsenite-induced apoptosis was determined by its attenuation of DNA fragmentation and terminal deoxytransferase-mediated dUTP-nick end labeling's positive cells in the infused SN of melatonin-treated rats. Melatonin reduced arsenite-induced apoptosis through mitochondrial and endoplasmic reticulum (ER) pathways. In the mitochondrial pathway, systemic melatonin inhibited arsenite-induced elevations in Bcl-2 and cytosolic cytochrome c as well as arsenite-induced reductions in procaspase-3 levels and elevations in active caspase-3 levels in the infused SN. Regarding the ER pathway, melatonin attenuated arsenite-induced elevations in activating transcription factor-4, CCAAT/enhancer binding protein (C/EBP) homologues protein, X-bon binding protein (XBP-1) and cytosolic immunoglobulin binding protein (BIP) as well as reductions in procaspase 12 levels. Moreover, aggregation of alpha-synuclein was reduced in the arsenite-infused SN of melatonin-treated rats. Our in vitro data showed that melatonin ameliorated arsenite-induced lipid peroxidation. Taken together, our data suggest that melatonin is neuroprotective against arsenite-induced oxidative injury in the nigrostriatal dopaminergic system of rat brain. Furthermore, the neuroprotective effects by melatonin on arsenite-induced apoptosis were mediated via inhibiting both mitochondrial and ER pathways. Accordingly, melatonin may be therapeutically useful for the treatment of arsenite-induced apoptosis in central nervous system.
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PMID:Melatonin attenuates arsenite-induced apoptosis in rat brain: involvement of mitochondrial and endoplasmic reticulum pathways and aggregation of alpha-synuclein. 1764 94

Previous observations in heat-shocked pig islets revealed the ambivalent character of the stress response simultaneously inducing processes of protection and apoptosis. To clarify whether the proapoptotic character of the stress response is reduced in heat-exposed islets still embedded in their native environment, hyperthermia was performed in the present study either as whole body hyperthermia (WBH) prior to pancreas resection or as in vitro heat shock (HS) after isolation. HS (42 degrees C/45 min) was induced in donors 12 h before isolation (WBH, n = 32) or in freshly isolated islets prior to 12 h of culture at 37 degrees C (in vitro HS, n = 25). Islets continuously incubated at 37 degrees C served as controls (n = 34). Proinflammatory treatment was performed with H2O2, DETA-NO, or a combination of IL-1beta, TNF-alpha, and IFN-gamma. Quality assessment included islet yield, viability staining, static glucose incubation, and nude mouse transplantation. WBH was significantly less effective than in vitro HS to induce HSP70 overexpression and to increase islet resistance against inflammatory mediators. Although characterized by an unaltered Bax to Bcl-2 ratio, islets subjected to WBH partially failed to restore sustained normoglycemia in diabetic nude mice. The inflammatory response observed in the pancreas of WBH-treated rats was associated with significantly reduced viability that seems to have a higher predictive value for posttransplant outcome compared to islet in vitro function or mitochondrial activity. In contrast, in vitro HS significantly decreased transcript levels of Bcl-2, but did not affect posttransplant function compared to sham-treated islets. These findings suggest that WBH is primarily associated with increased necrosis as a secondary tissue type-specific effect of pancreas damage while in vitro HS mainly induces apoptosis.
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PMID:Effect of pretransplant preconditioning by whole body hyperthermia on islet graft survival. 1801 60

Lithium is a major drug used for the treatment of bipolar mood disorder and has recently been shown to have neuroprotective properties. In this study we investigated the neuroprotective effects of lithium in gerbils subjected to global cerebral ischemia, an animal model of stroke. The ischemia-induced exploratory behavior changes, measured by open field testing, were largely suppressed by lithium treatment for 7 days prior to ischemic onset. Similarly, memory impairments, measured by T-maze testing, were prevented by lithium pretreatment. This is believed to be the first report of lithium-induced protection against hyperactivity in a novel open field and memory impairment in a gerbil model of global ischemia. These behavioral benefits were associated with an increase in viable cells as measured by hematoxylin and eosin staining and a decrease in apoptotic TUNEL-positive cells in the CA1 hippocampal area of ischemic gerbils. Moreover, the lithium-induced neuroprotection was accompanied by down-regulation of pro-apoptotic p53 in the CA1 but up-regulation of anti-apoptotic Bcl-2 and heat shock protein 70 (HSP70) in the ischemic brain. These results underscore the ability of lithium to improve functional behavioral outcome in gerbil and rodent cerebral ischemic models and further indicate the potential therapeutic use of lithium in certain human stroke conditions.
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PMID:Lithium reduces ischemia-induced hippocampal CA1 damage and behavioral deficits in gerbils. 1802 86

Ischaemic pre-conditioning has a powerful protective potential against ischaemia-induced cell death, and acidosis is an important feature of ischaemia and can lead to apoptosis. Here we tested whether pre-conditioning with acidosis, that is, acidic pre-conditioning (APC), may protect coronary endothelial cells (EC) against apoptosis induced by simulated ischaemia. For pre-conditioning, EC were exposed fo 40 min. to acidosis (pH 6.4) followed by a 14-hrs recovery period (pH 7.4) and finally treated for 2 hrs with simulated ischaemia (glucose-free anoxia at pH 6.4). Cells undergoing apoptosis were visualized by chromatin staining or by determination of caspase-3 activity Simulated ischaemia in untreated EC increased caspase-3 activity and the number of apoptotic cell (31.3 +/- 1.3%versus 3.9 +/- 0.6% in control). APC significantly reduced the rate of apoptosis (14.2 +/- 1.3%) and caspase-3 activity. Western blot analysis exploring the under lying mechanism leading to this protection revealed suppression of the endoplasmic reticulum- (reduced cleavage of caspase-12) and mitochondria-mediated (reduced cytochrome C release) pathways of apoptosis. These effects were associated with an over-expression of the anti-apoptotic protein Bcl-xL 14 hrs after APC, whereas no effect on the expression of Bcl-2, Bax, Bak, procaspase-12, reticulum-localized chaperones (GRP78, calreticulin), HSP70, HSP32 and HSP27 could be detected. Knock-down of Bcl-xL by siRNA-treatment prevented the protective effect of APC. In conclusion, short acidic pre-treatment can protect EC against ischaemic apoptosis. The mechanism of this protection consists of suppression of the endoplasmic reticulum- and mitochondria-mediated pathways. Over-expression of the anti apoptotic protein Bcl-xL is responsible for the increased resistance to apoptosis during ischaemic insult.
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PMID:Acidic pre-conditioning suppresses apoptosis and increases expression of Bcl-xL in coronary endothelial cells under simulated ischaemia. 1805 90


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