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)

Evidence suggests that inactivation of cell-damaging mechanisms and/or activation of cell-survival mechanisms may provide effective preventive or therapeutic interventions to reduce cerebral ischemia/reperfusion (I/R) injuries. Docosahexaenoic acid (DHA) is an essential polyunsaturated fatty acid in the central nervous system that has been shown to possess neuroprotective effects. We examined whether different preadministrative protocols of DHA have effects on brain injury after focal cerebral I/R and investigated the potential neuroactive mechanisms involved. Sprague-Dawley rats were intraperitoneally pretreated with DHA once 1 h or 3 days being subjected to focal cerebral I/R or daily for 6 weeks before being subjected to focal cerebral I/R. Reduction of brain infarction was found in all three DHA-pretreated groups. The beneficial effect of DHA on the treatment groups was accompanied by decreases in blood-brain barrier disruption, brain edema, malondialdehyde (MDA) production, inflammatory cell infiltration, interleukin-6 (IL-6) expression and caspase-3 activity. Elevation of antioxidative capacity, as evidenced by decreased MDA level and increased superoxide dismutase activity and glutathione level, was detected only in the chronic daily-administration group. The two single-administration groups showed increased phosphorylation of extracellular-signal-regulated kinase (ERK). Elevation of Bcl-2 expression was detected in the chronic daily-administration and 3-day-administration groups. In vitro study demonstrated that DHA attenuated IL-6 production from stimulated glial cells involving nuclear factor kappaB inactivation. Therefore, the data suggest that the neuroprotective mechanisms of DHA pretreatment are, in part, mediated by attenuating damaging mechanisms through reduction of cytotoxic factor production and by strengthening survival mechanisms through ERK-mediated and/or Bcl-2-mediated prosurvival cascade.
 ...
PMID:Protective effect of docosahexaenoic acid against brain injury in ischemic rats. 1880 85

Incidence of cerebral vascular disease (CVD) is higher in patients with diabetes mellitus (DM) than that in individuals without DM, and neuronal apoptosis determines the severity of cerebral infarction. However, there is no effective therapy for CVD. Granulocyte-colony stimulating factor (G-CSF), a potent hematopoietic factor, could inhibit apoptosis of hematopoietic progenitor cells. However, its effect on neuronal cells is still unclear. In this study, we investigated the anti-apoptosis properties of G-CSF in neurons following focal cerebral ischemia in diabetic rats. The diabetic condition was generated in rats by intravenous injection of streptozotocin. After 6 weeks, diabetic rats underwent middle cerebral artery occlusion (MCAO) and received subcutaneous administration of G-CSF (50 microg/kg) daily for 7, 14 or 21 days. We analyzed the changes in neurological severity scores, infarct volume, number of apoptotic neurons, and the expression of G-CSF receptor, phosphorylated signal transducer and activator of transcription 3 (pSTAT3), cellular inhibitor of apoptosis protein 2 (cIAP2), Bcl-2, and Bax in the brain tissue. Bax is a pro-apoptotic member of the Bcl-2 protein family. The DM rats treated with G-CSF not only showed the reduced infarct volume and decreased apoptosis cell number, but also presented improved neurological scores. The G-CSF also increased the expression of pSTAT3, Bcl-2, and cIAP2 proteins as well as Bcl-2 mRNA, but inhibited Bax protein expression in the brain. These results indicate that G-CSF partially increases neuronal survival by affecting apoptosis pathways. G-CSF provides a potential treatment for stroke and other neurological dysfunction accompanied by neuronal apoptosis.
 ...
PMID:Granulocyte-colony stimulating factor inhibits neuronal apoptosis in a rat model of diabetic cerebral ischemia. 1883 93

Bcl-2 homology domain 3 (BH3)-only pro-apoptotic proteins may play an important role in upstream cell death signaling pathways underlying ischemic brain injury. Puma is a potent BH3-only protein that can be induced via p53, FoxO3a and endoplasmic reticulum stress pathways and is upregulated by global cerebral ischemia. To more completely define the contribution of Puma to ischemic brain injury we measured the expressional response of Puma to transient focal cerebral ischemia in mice and also compared infarct volumes in puma-deficient versus puma-expressing mice. Real-time quantitative PCR determined puma mRNA levels were significantly increased 8h after 90min middle cerebral artery (MCA) occlusion in the ipsilateral cortex, while expression remained unchanged contralaterally. Puma protein levels were also increased in the ischemic cortex over the same period. However, cortical and striatal infarct volumes were not significantly different between puma-deficient and puma-expressing mice at 24h, and no differences between genotypes were found for post-ischemic neurological deficit scores. These data demonstrate that focal cerebral ischemia is associated with puma induction but suggest that Puma does not contribute significantly to lesion development in the present model.
 ...
PMID:Effects of transient focal cerebral ischemia in mice deficient in puma. 1915 65

Many natural polyphenolic compounds have been shown to attenuate reactive oxygen/nitrogen species (ROS/RNS) formation and protect against ischemia/reperfusion injury both in vitro and in vivo. 2,3,5,4'-tetrahydroxystilbene-2-O-beta-D-glucoside (TSG), an active component of the rhizome extract from Polygonum multiflorum, exhibits antioxidative and anti-inflammatory effects. Here, we used an in vitro ischemic model of oxygen-glucose deprivation followed by reperfusion (OGD-R) and an in vivo ischemic model of middle cerebral artery occlusion (MCAO) to investigate the neuroprotective effects of TSG on ischemia/reperfusion brain injury and the related mechanisms. We demonstrated that OGD-R-induced neuronal injury, intracellular ROS generation, and mitochondrial membrane potential dissipation were reversed by TSG. The elevation of H2O2-induced [Ca2+]i was also attenuated by TSG. Inhibition of the c-Jun N-terminal kinase (JNK) and Bcl-2 family-related apoptotic signaling pathway was involved in the neuroprotection afforded by TSG. Meanwhile, TSG inhibited iNOS mRNA expression induced by OGD-R, which may be mediated by the activation of SIRT1 and inhibition of NF-kappaB activation. In vivo studies further demonstrated that TSG significantly reduced the brain infarct volume and the number of positive cells by TUNEL staining in the cerebral cortex compared to the MCAO group. Our study indicates that TSG protects against cerebral ischemia/reperfusion injury through multifunctional cytoprotective pathways.
 ...
PMID:Protection by tetrahydroxystilbene glucoside against cerebral ischemia: involvement of JNK, SIRT1, and NF-kappaB pathways and inhibition of intracellular ROS/RNS generation. 1927 42

Previous work has demonstrated that ischemic preconditioning neuroprotection is associated with inhibition of JNK pathway activation. The present study was designed to examine the hypothesis that the suppression of JNK3 activation by preconditioning is mediated by NMDA receptors and crosstalk between ERK1/2 and JNK3. Preconditioning (3 min ischemia) 2 days before global cerebral ischemia (8-min) markedly decreased neuronal degeneration in hippocampus CA1, an effect abolished by pretreatment with the NMDA receptor antagonist, MK-801. Furthermore, preconditioning abolished cerebral ischemia-induced JNK3 activation and enhanced ERK1/2 activation, an effect reversed by MK-801. Due to the inverse relationship between ERK1/2 and JNK3 activation following preconditioning, we hypothesized that ERK1/2 may regulate JNK3 activation following preconditioning. In support of this contention, pretreatment with the MEK inhibitor, PD98059 significantly attenuated preconditioning-induced ERK1/2 phosphorylation, and strongly reversed preconditioning down-regulation of JNK3 phosphorylation. This finding suggests that ERK1/2 signaling is responsible for preconditioning-induced down-regulation of JNK3 activation. Western blot analysis and immunohistochemistry further demonstrated that preconditioning, in an NMDA-dependent manner, enhanced activation of the pro-survival factors, p-CREB and Bcl-2, while attenuating activation of putative pro-death factors, p-c-Jun and Fas-L in the hippocampus CA1. As a whole, the study demonstrates that preconditioning attenuation of pro-death JNK3 in the hippocampus CA1 following global cerebral ischemia is mediated by NMDA receptor-induced crosstalk between ERK1/2 and JNK3. The ERK1/2-mediated reduction of JNK3 activation leads to enhanced pro-survival signaling (P-CREB and Bcl-2 induction) and attenuation of pro-death signaling (p-c-Jun and Fas-L), with subsequent induction of ischemic tolerance.
 ...
PMID:Preconditioning neuroprotection in global cerebral ischemia involves NMDA receptor-mediated ERK-JNK3 crosstalk. 1937 93

Neural progenitor cells (NPCs) have the potential to survive brain ischemia and participate in neurogenesis after stroke. However, it is not clear how survival responses are initiated in NPCs. Using embryonic mouse NPCs and the in vitro oxygen and glucose deprivation (OGD) model, we found that angiopoietin-1 (Ang1) could prevent NPCs from OGD-induced apoptosis, as evidenced by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and annexin V labeling. Ang1 significantly elevated tunica intima endothelial kinase 2 (Tie2) autophosphorylation level, suggesting the existence of functional Tie2 receptors on NPCs. NPCs under OGD conditions exhibited reduction of Akt phosphorylation, decrease of the Bcl-2/Bax ratio, activation of caspase-3, cleavage of PARP, and downregulation of beta-catenin and nestin. Ang1 reversed the above changes concomitantly with significant rising of survival rates of NPCs under OGD, but all these effects of Ang1 could be blocked by either soluble extracellular domain of Tie2 Fc fusion protein (sTie2Fc) or the phosphoinositide 3-kinase (PI3K) inhibitor 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one (LY294002). Our findings suggest the existence of an Ang1-Tie2-PI3K signaling axis that is essential in initiation of survival responses in NPCs against cerebral ischemia and hypoxia.
 ...
PMID:An Ang1-Tie2-PI3K axis in neural progenitor cells initiates survival responses against oxygen and glucose deprivation. 1940 99

Brain ischemia is one of the most common causes of death and the leading cause of adult disability in the world. Brain ischemic preconditioning (BIP) refers to a transient, sublethal ischemia which results in tolerance to later, otherwise lethal, cerebral ischemia. Many attempts have been made to understand the molecular and cellular mechanisms underlying the neuroprotection offered by ischemic preconditioning. Many studies have shown that neuroprotective mechanisms may involve a series of molecular regulatory pathways including activation of the N-methyl-D-aspartate (NMDA) and adenosine receptors; activation of intracellular signaling pathways such as mitogen activated protein kinases (MAPK) and other protein kinases; upregulation of Bcl-2 and heat shock proteins (HSPs); and activation of the ubiquitin-proteasome pathway and the autophagic-lysosomal pathway. A better understanding of the processes that lead to cell death after stroke as well as of the endogenous neuroprotective mechanisms by which BIP protects against brain ischemic insults could help to develop new therapeutic strategies for this devastating neurological disease. The purpose of the present review is to summarize the neuroprotective mechanisms of BIP and to discuss the possibility of mimicking ischemic preconditioning as a new strategy for preventive treatment of ischemia.
 ...
PMID:The neuroprotective mechanism of brain ischemic preconditioning. 1961 92

Curcumin, a member of the curcuminoid family of compounds, is a yellow colored phenolic pigment obtained from the powdered rhizome of C. longa Linn. Recent studies have demonstrated that curcumin has protective effects against cerebral ischemia/reperfusion injury. However, little is known about its mechanism. In the present study, we tested the effects of curcumin in focal cerebral ischemia in rats and the possible mechanisms. Adult male Sprague-Dawley rats were treated with curcumin (100, 300 and 500 mg/kg) administered intraperitoneally after 60 min of occlusion (beginning of reperfusion). Neurological score and infarct volume were assessed at 24 and 72 h. Oxidative stress was evaluated by malondialdehyde assay and the apoptotic mechanisms were studied by Western blotting. Curcumin treatment significantly reduced infarct volume and improved neurological scores at different time points compared with the vehicle-treated group. Curcumin treatment decreased malondialdehyde levels, cytochrome c, and cleaved caspase 3 expression and increased mitochondrial Bcl-2 expression. Inhibition of oxidative stress with curcumin treatment improves outcomes after focal cerebral ischemia. This neuroprotective effect is likely exerted by antiapoptotic mechanisms.
 ...
PMID:Curcumin improves outcomes and attenuates focal cerebral ischemic injury via antiapoptotic mechanisms in rats. 1977 61

Apoptosis is one of the major characteristics of delayed neuronal degeneration in neuronal injury following cerebral ischemia. Hypoxia-induced apoptosis may be co-regulated by HIF-1alpha as well as many other factors. In recent years, numerous studies concerning panaxynol (PNN) have been reported. However, whether PNN can show anti-hypoxia properties is still unknown. In this study, the protective effects of PNN on OGD-induced neuronal apoptosis and potential mechanisms were investigated. Pretreatment of the cells with PNN for 24h following exposure to OGD resulted in a significant elevation of cell survival determined by MTT assay, LDH assay, Hoechst staining and flow cytometric assessment. In addition to enhancing the expression of HIF-1alpha, PNN also normalized the caspase-3 expression/activation and increased the Bcl-2/Bax ratio. In our study, the increased level of HIF-1alpha with decreased cellular apoptosis suggested an important role for HIF-1alpha in hypoxic neurons. These results indicated that the neuroprotective effects of PNN on hypoxic neurons were at least partly due to up-regulation of HIF-1alpha and raised the possibility that PNN might reduce neurodegenerative disorders and ischemic brain diseases.
 ...
PMID:Panaxynol protects cortical neurons from ischemia-like injury by up-regulation of HIF-1alpha expression and inhibition of apoptotic cascade. 1980 Mar 26

4-hydroxybenzyl alcohol (4-HBA), one of the major active phenolic constituents of Gastrodia elata Blume, a very important traditional Chinese medicinal herb, has been shown to be an effective agent against the central and peripheral nervous disorders. In this study, we attempted to explore the possible mechanisms underlying the neuroprotection against transient focal cerebral ischemia by 4-HBA.4-HBA (25, 50 mg/kg) was given 30 min before focal ischemia in rats caused by middle cerebral artery occlusion (1 h of occlusion, 24 h of reperfusion). Under the treatment of 50 mg/kg 4-HBA, total (100.76+/-2.90 mm(3)), cortical (64.91+/-1.46 mm(3)), and sub-cortical (38.77+/-2.78 mm(3)) infarct volumes were significantly decreased in comparison to ischemia-reperfusion values. Neurological evaluation and Nissl-staining of the 4-HBA group were improved significantly compared to the untreated ischemia group. TUNEL-positive cells were reduced significantly in 4-HBA treated group. Results of immunofluorescence staining analysis and Western immunoblot indicated that 4-HBA increased the expression of Bcl-2 and inhibited the activation of caspase-3 ultimately inhibiting apoptosis. These results suggested that 4-HBA ameliorated ischemic injury induced by transient focal cerebral ischemia in rats, and this neuroprotective effect may be partly related to attenuate apoptosis pathway.
 ...
PMID:Neuroprotective effect of 4-hydroxybenzyl alcohol against transient focal cerebral ischemia via anti-apoptosis in rats. 1985 70


<< Previous 1 2 3 4 5 6 7 8 9 10