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)

Glucose toxicity is an important initiator of cardiovascular disease, contributing to the development of insulin resistance, impaired contractile function, abnormal energy metabolism, cardiomyocyte and endothelial cell death, coronary heart disease, and heart failure. High blood glucose can, however, paradoxically protect the heart against a variety of insults, including ischemia, hypoxia, and calcium overload. To provide information on the underlying basis of these divergent actions of high glucose, the present study examined the hypothesis that the adverse effects of high glucose are linked to impaired insulin signaling, leading to a reduction in the levels of cytoprotective factors, and that the beneficial effects of high glucose occur in the absence of insulin and result in an improvement in Akt signaling. This hypothesis was evaluated by using an in vitro cardiomyocyte model that is amenable to manipulations in glucose and insulin. Prolonged exposure of the isolated neonatal cardiomyocyte to medium containing insulin and high glucose led to increased susceptibility to angiotensin II-mediated apoptosis, an effect associated with reduced levels of phospho-Akt and an increased Bax/Bcl-2 ratio. By contrast, exposure to high glucose levels in the absence of insulin rendered the cardiomyocyte resistant to angiotensin II-mediated apoptosis. Because the beneficial effects of high glucose were associated with elevations in phospho-Akt and Bcl-2 content, the cardioprotective activity of high glucose resembles the actions of insulin. Hence, the activation state of Akt is largely determined by the activity of insulin and other growth factors. Because high glucose diminishes insulin signaling, it reduces phospho-Akt levels and renders the cell susceptible to damaging insults. In the absence of insulin, however, the natural activity of high glucose is unmasked. As a result, Akt signaling is increased and the cell is rendered resistant to cell death.
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PMID:Proapoptotic and antiapoptotic effects of hyperglycemia: role of insulin signaling. 1841 25

The underlying molecular mechanism whereby hyperglycemia causes endothelial cell apoptosis is not well understood. This study aims to elucidate the role of survival factor VEGF involved in the apoptosis of endothelial cells induced by elevated glucose. The present study confirmed that high concentration of glucose (25 mmol/l) significantly increased the apoptotic cell number in cultured primary human umbilical vein endothelial cells (HUVEC). Up-regulation of Bax/Bcl-2 ratio and activation of caspase-3 induced by high glucose suggested that mitochondria apoptosis pathway was involved. High glucose significantly reduced VEGF expression in HUVEC both at mRNA and protein levels. p42/44 MAPK phosphorylation was transitory attenuated when exposed to high glucose and preceded VEGF reduction, thus suggesting down-regulation of VEGF through inhibition of p42/44 MAPK. Addition of VEGF prevented HUVEC apoptosis from high glucose exposure. Moreover, elevated reactive oxygen species (ROS) generation, calcium overload, Bax/Bcl-2 ratio, caspase-3 activation in HUVEC induced by high glucose were reversed by pre-challenge with VEGF. This may represent a mechanism for the anti-apoptotic effect of VEGF. These results suggest that down-regulation of VEGF plays a critical role in apoptosis of endothelial cells induced by high glucose and restoration of VEGF might have benefits in the early stage of diabetic endothelial dysfunction.
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PMID:Critical effect of VEGF in the process of endothelial cell apoptosis induced by high glucose. 1878 Jan 85

We assessed the expression of Bcl-2 family members at both mRNA and protein levels as well as the Caspase-3 activity, in order to investigate the occurrence of apoptosis in hippocampus of STZ-induced diabetic rats. We selected twenty-four Wistar rats; half of them were made diabetic by intraperitoneal injection of a single 60 mg/kg dose of streptozotocin (STZ, IP), while the others received normal saline and served as controls. The expressions of Bcl-2, Bcl-x(L), and Bax mRNA and proteins were measured using RT-PCR and western blotting, respectively. Caspases-3 activity was determined by using the Caspase-3/CPP32 Fluorometric Assay Kit. The result showed that mRNA and protein levels of Bcl-2 and Bcl-x(L) were lower in hippocampus of diabetic group than that of the control group, whereas expressions of Bax in hippocampus of diabetic rats were higher than that of controls at both mRNA and protein levels (P < .01). Hyperglycemia was found to raise 6.9-fold hippocampal caspase-3 activity in diabetic group compared with control group (P < .001). Therefore, the induction of diabetes is associated with increased ratios of Bax/Bcl-2, Bax/Bcl-x(L), and increased caspase-3 activity in hippocampus which shows that apoptosis is favored in hippocampal region.
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PMID:Evaluation of Bcl-2 family gene expression and Caspase-3 activity in hippocampus STZ-induced diabetic rats. 1892 82

Growth factor stimulation and oncogenic transformation lead to increased glucose metabolism that may provide resistance to cell death. We have previously demonstrated that elevated glucose metabolism characteristic of stimulated or cancerous cells can stabilize the anti-apoptotic Bcl-2 family protein Mcl-1 through inhibition of GSK-3. Here we show that the pro-apoptotic Bcl-2 family protein, Puma, is also metabolically regulated. Growth factor deprivation led to the loss of glucose uptake and induction of Puma. Maintenance of glucose uptake after growth factor withdrawal by expression of the glucose transporter, Glut1, however, suppressed Puma up-regulation and attenuated growth factor withdrawal-induced activation of Bax, DNA fragmentation, and cell death. Conversely, glucose deprivation led to Puma induction even in the presence of growth factor. This regulation of Puma expression was a central component in cell death as a consequence of growth factor or glucose deprivation because Puma deficiency suppressed both of these cell death pathways. Puma induction in growth factor or glucose withdrawal was dependent on p53 in cell lines and in activated primary T lymphocytes because p53 deficiency suppressed Puma induction and delayed Bax and caspase activation, DNA fragmentation, and loss of clonogenic survival. Importantly, although p53 levels did not change or were slightly reduced, p53 activity was suppressed by elevated glucose metabolism to inhibit Puma induction after growth factor withdrawal. These data show that p53 is metabolically regulated and that glucose metabolism initiates a signaling mechanism to inhibit p53 activation and suppress Puma induction, thus promoting an anti-apoptotic balance to Bcl-2 family protein expression that supports cell survival.
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PMID:Glucose metabolism attenuates p53 and Puma-dependent cell death upon growth factor deprivation. 1899 Jun 90

Hyperglycemia initiates a sequence of events that leads to the development of diabetic retinopathy. We explored the effect of re-institution of good blood glucose control on apoptosis and apoptosis related genes (Bax and Bcl-2) in the retina of diabetic rats. Fifty male Wistar rats randomly divided into five groups : normal control group (CON), diabetic rats with high blood glucose levels for 8 months group (DM) ,diabetic rats with good blood glucose control for 8 months group (DM(1)),diabetic rats with poor blood glucose control for 2 month followed by good blood glucose control for six additional months group (DM(2)), rats with poor blood glucose control for 4 months followed by good blood glucose levels for four additional months group (DM(3)). Expression of Bax and Bcl-2 in the retina was studied by immunohistochemistry and the apoptotic cells were stained using the TUNEL method. The apoptotic cell, expression of Bax and Bcl-2 and the ratio of Bax to Bcl-2 in the retina was increased in DM group compared with normal rats' (P < 0.01). There was no significant difference in apoptotic cells and the ratio of Bax to Bcl-2 between DM(1) group and CON group. The number of TUNEL positive cells and Bax to Bcl-2 ratio was partially reversed in DM(2) group. But glucose control had no effect on the apoptotic cells and the expression of Bax and Bcl-2 in DM(3) group. There was a positive correlation between apoptotic cells and Bax/Bcl-2 ratio in the retina (r = 0.808, P < 0.01). Good blood glucose control at early stage can decrease the number of apoptotic cells in the retina; the decreased apoptosis is correlated with the down-regulation of Bax to Bcl-2 ratio.
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PMID:The timing of re-institution of good blood glucose control affects apoptosis and expression of Bax and Bcl-2 in the retina of diabetic rats. 1899 Oct 18

Diabetic nephropathy, the leading cause of end-stage renal disease, is characterized by a proapoptotic and prooxidative environment. The mechanisms by which lifestyle interventions, such as exercise, benefit diabetic nephropathy are unknown. We hypothesized that exercise inhibits early diabetic nephropathy via attenuation of the mitochondrial apoptotic pathway and oxidative damage. Type 2 diabetic db/db and normoglycemic wild-type mice were exercised for an hour everyday at a moderate intensity for 7 wk, following which renal function, morphology, apoptotic signaling, and oxidative stress were evaluated. Exercise reduced body weight, albuminuria, and pathological glomerular expansion in db/db mice independent of hyperglycemic status. Changes in renal morphology were also related to reduced caspase-3 (main effector caspase in renal apoptosis), caspase-8 (main initiator caspase of the "extrinsic" pathway) activities, and TNF-alpha expression. A role for the mitochondrial apoptotic pathway was unlikely as both caspase-9 activity (initiator caspase of this pathway) and expression of regulatory proteins such as Bax and Bcl-2 were unchanged. Kidneys from db/db mice also produced higher levels of superoxides and had greater oxidative damage concurrent with downregulation of superoxide dismutase (SOD) 1 and 3. Interestingly, although exercise also increased superoxides, there was also upregulation of multiple SODs that likely inhibited lipid (hydroperoxides) and protein (carbonyls and nitrotyrosine) oxidation in db/db kidneys. In conclusion, exercise can inhibit progression of early diabetic nephropathy independent of hyperglycemia. Reductions in caspase-3 and caspase-8 activities, with parallel improvements in SOD expression and reduced oxidative damage, could underlie the beneficial effects of exercise in diabetic kidney disease.
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PMID:Moderate exercise attenuates caspase-3 activity, oxidative stress, and inhibits progression of diabetic renal disease in db/db mice. 1914 89

Diabetic vascular complications are related to a combination of oxidative stress and hyperglycemia. Here we investigate the effect and mechanism of soy isoflavones on oxidative stress-induced endothelial cell injury. Oxidative stress was modeled in primary cultured human umbilical vein endothelial cells by incubation with H(2)O(2) and high glucose. Genistein and daidzein protected the cells against H(2)O(2)-induced apoptosis and their protective actions were abolished by ICI 182780, an estrogen receptor antagonist. The inhibition of cell proliferation by oxidative stress was prevented by genistein and daidzein under normal glucose conditions, but they were less effective at high glucose levels. Genistein and daidzein upregulated the estrogen receptor ERbeta and increased Bcl-2 expression. Silencing of Bcl-2 with siRNA abolished the protection of genistein. Moreover, inhibition of the PI3K and Rho A/Rho kinase pathways by wortmannin and Y-27632 altered the effects of genistein and daidzein on cell survival. We conclude that oxidative stress-induced apoptosis and cell proliferation inhibition can be prevented by soy isoflavones via the regulation of ERbeta and Bcl-2/Bax expression and modulation of cell survival signaling, such as the PI3K pathway. These findings imply that multiple mechanisms are involved in the beneficial effects of soy isoflavone supplements for diabetic endothelial injury.
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PMID:Multiple mechanisms of soy isoflavones against oxidative stress-induced endothelium injury. 1939 15

Retinal capillary cells undergo apoptosis before pathology characteristic of retinopathy can be observed, and the appearance of apoptotic capillary cell can predict the development of pathology. The purpose of this study is to investigate the effect of reversal of hyperglycemia on retinal capillary cell apoptosis, and identify the apoptosis encoding genes. Streptozotocin-diabetic rats were maintained either in poor glycemic control (PC, glycated hemoglobin, GHb >11%) or in good glycemic control (GC, GHb <6%) for 12 months, or allowed to be in PC for 6 months followed by GC for 6 additional months (PC-GC). Capillary cell apoptosis was determined in the trypsin-digested retinal microvasculature by TUNEL staining, and the genes encoding apoptosis were identified by Oligo GEArray rat apoptosis microarray that profiles 113 genes. Six months of good glycemic control that followed 6 months of poor control failed to attenuate the number of TUNEL-positive capillary cells in the retinal microvasculature. Twenty-three retinal genes, mainly from TNF ligand and receptor, caspase, Bcl-2 and death domain subfamilies that were upregulated by least a two-fold in PC rats remain upregulated after reversal of hyperglycemia. Thus, the continued activation of apoptosis plays a major role in the resistance of retinopathy to halt after re-institution of good glycemic control, and the regulation apoptosis machinery could help retard the progression of diabetic retinopathy.
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PMID:Metabolic memory in diabetes - from in vitro oddity to in vivo problem: role of apoptosis. 1946 16

Hyperglycemia, which occurs under the diabetic condition, is widely recognized as the causal link between diabetes and its serious complications. Diabetic neuropathies, which are among the most frequent complications of diabetes, affect sensory, motor, and autonomic nerves. The exact molecular mechanisms of high glucose-induced toxicity on neuronal cells, is still unclear. We previously reported that high glucose can induce apoptosis in PC12 cells, as evidenced by DNA fragmentation and high Bax/Bcl-2 ratio. The present study examined the involvement of caspase-3, the executioner, and two initiators of apoptosis, caspase-8 and caspase-9, during high glucose-induced apoptosis in PC12 cells, a neuronal cell line. Cells were exposed to high glucose with or without z-VAD-fmk, a pan-caspase inhibitor. Cell viability was measured by MTT assay. Caspase activity was determined spectrophotometrically using enzyme specific substrates. To correlate and confirm the caspase activity with changes in protein expression, procaspase-8, -9, and -3 were evaluated by Western blot analysis. The DNA-fragmentation was determined by DNA ladder using gel electrophoresis. The PC12 cell viability on high glucose exposure was decreased compared to controls, which was reversed by z-VAD-fmk. The activities of caspase-8, -9, and -3 were significantly increased in treated cells compared to controls. Moreover, high glucose exposure induced a significant decrease in protein levels of procaspases, indicating conversion of pro-form into the mature caspases. Finally, DNA fragmentation (Ladder) was shown in treated cells by high glucose. Based on the current data, it could be concluded that high glucose-induced apoptosis in PC12 cells is mediated, in part, by activation of caspase-8, -9, and -3 dependent pathways.
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PMID:Involvement of caspase-8, -9, and -3 in high glucose-induced apoptosis in PC12 cells. 1946 86

Activation of circulating monocytes by hyperglycemia is bound to play a role in inflammatory and atherosclerosis. In this study, we examined whether flavonoids (catechin, EGCG, luteolin, quercetin, rutin) - phytochemicals that may possible belong to a new class of advanced glycation end products (AGEs) inhibitors - can attenuate high glucose (15 mmol/L, HG)-induced inflammation in human monocytes. Our results show that all flavonoids significantly inhibited HG-induced expression of proinflammatory genes and proteins, including TNF-alpha, interleukin-1beta (IL-1beta), and cyclooxygenase (COX)-2, at a concentration of 20 microM. Flavonoids also prevented oxidative stress in activated monocytes, as demonstrated by their inhibitory effects on intracellular reactive oxygen species (ROS) and N(epsilon)-(carboxymethyl)lysine formation caused by HG. These inhibitory effects may involve inhibition of nuclear factor-kappaB activation and may be supported by downregulation of the following: i) PKC-dependent NADPH oxidase pathway; ii) phosphorylation of p38 mitogen-activated protein kinase and extracellular signal-regulated protein kinase, and iii) mRNA expression of receptor of AGEs. In addition, we found for the first time that lower levels of Bcl-2 protein under HG conditions could be countered by the action of flavonoids. Our data suggest that, along with their antioxidant activities, flavonoids possess anti-inflammatory properties and might therefore have additional protective effects against glycotoxin-related inflammation.
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PMID:Naturally occurring flavonoids attenuate high glucose-induced expression of proinflammatory cytokines in human monocytic THP-1 cells. 1955 21


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