Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P42574 (caspase-3)
45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Selenium treatment of the doxorubicin-resistant cell line, U-1285dox, derived from human small cell carcinoma of the lung, resulted in massive apoptosis. This effect appeared maximal at 2 days after addition of selenite. The apoptosis was caspase-3 independent as revealed by Western blot analysis, activity measurement and by using caspase inhibitors. Induction of apoptosis was significantly more pronounced and occurred after addition of lower concentrations of selenite in the doxorubicin-resistant cells compared to the parental doxorubicin-sensitive cells. High levels of selenite caused necrosis in the doxorubicin-sensitive cells. Analysis of enzymatic activity (insulin reduction) of thioredoxin reductase (TrxR) and TrxR protein concentration, measured by ELISA, revealed increasing activity and protein levels after treatment with increasing concentrations of selenium. Maximum relative increase was induced up to 1 microM in both sublines and at this selenium level the concentrations of TrxR measured as insulin reducing activity or ELISA immunoreactivity were nearly identical. Increasing concentrations of selenite up to 10 microM resulted in increased activity and concentration of TrxR in the sensitive subline but decreasing levels in the resistant subline. The level of truncated Trx (tTrx) was higher in the resistant U-1285dox cells but the level did not change with increasing selenite concentrations. Our results demonstrate pronounced selective selenium-mediated apoptosis in therapy-resistant cells and suggest that redox regulation through the thioredoxin system is an important target for cancer therapy.
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PMID:Selenite-induced apoptosis in doxorubicin-resistant cells and effects on the thioredoxin system. 1503 3

Neuroblastoma, a pediatric peripheral nervous system tumor, frequently contains alterations in apoptotic pathways, producing chemoresistant disease. Insulin-like growth factor (IGF) system components are highly expressed in neuroblastoma, further protecting these cells from apoptosis. This study investigates IGF-I regulation of apoptosis at the mitochondrial level. Elevated extracellular glucose causes rapid mitochondrial enlargement coupled with an increase in the mitochondrial membrane potential (Delta Psi(M)) followed by mitochondrial membrane depolarization (MMD), uncoupling protein 3 (UCP3) downregulation, caspase-3 activation and decreased Bcl-2. MMD inhibition by Bongkrekic acid prevents high-glucose-induced loss of UCP3 and apoptosis. Glucose exposure induces caspase-9 cleavage within 30 min, and caspase-9 inhibition prevents glucose-mediated apoptosis. IGF-I prevents caspase activation and mitochondrial events leading to apoptosis. These results suggest that elevated glucose produces early initiator caspase activation, followed by Delta Psi(M) changes, in neuroblastoma cells; in turn, IGF-I prevents apoptosis by preventing downstream caspase activation, maintaining Delta Psi(M) and regulating Bcl proteins.
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PMID:Insulin-like growth factor-I regulates glucose-induced mitochondrial depolarization and apoptosis in human neuroblastoma. 1510 34

Muscle proteolysis from catabolic conditions, including chronic kidney disease, requires coordinated activation of both the apoptotic and ATP-ubiquitin-proteasome systems (Ub-P'some), including upregulation of components of the Ub-P'some system. Activation of the apoptotic system is required because caspase-3 initially cleaves myofibrils, yielding substrates for the Ub-P'some system plus a characteristic 14-kD actin fragment. The authors studied insulin deficiency, a model of accelerated muscle atrophy, to understand how regulation of the apoptotic and the Ub-P'some systems could be coordinated. As expected, phosphatidylinositol 3 kinase activity (PI3K) was suppressed in muscle; in addition to decreased insulin, the mechanism includes IRS-1 phosphorylation at serine-307. Caspase-3 activity was also increased, and the authors linked it to a low PI3K-induced activation of the apoptotic system that includes a conformational change in Bax and release of cytochrome C. Coordinated atrogin-1/MAFbx expression is required as a critical factor for Ub-P'some system-dependent muscle proteolysis in diabetes and other catabolic states. The mechanism that regulates atrogin-1/MAFbx expression is unknown. Atrogin-1/MAFbx expression increased when the authors suppressed PI3K activity in muscle cells. The forkhead transcriptional factor, a downstream substrate of PI3K, stimulated atrogin-1/MAFbx promoter transcriptional activity markedly. The authors found in diabetic muscle that mRNA of the forkhead transcriptional factor, its nuclear translocation, and binding to the atrogin-1/MAFbx promoter were increased. When PI3K activity is low, both apoptotic and Ub-P'some pathways are activated coordinately to cause muscle proteolysis. This mechanism could increase muscle atrophy in conditions with impaired insulin responsiveness.
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PMID:Regulation of muscle protein degradation: coordinated control of apoptotic and ubiquitin-proteasome systems by phosphatidylinositol 3 kinase. 1515 64

We examined the hypothesis that activation of the apoptosis cascade occurs relatively early in diabetes mellitus affecting three distinct neuronal populations that are involved in regulating gut function: (i) dorsal root ganglion (DRG), (ii) vagus nodose ganglion and (iii) colon myenteric plexus. A validated streptozotocin-induced diabetic rat model and age-matched healthy controls were studied. After 4-8 weeks of diabetes the animals were anaesthetized, fixed in situ and the relevant tissues removed. After 1 month of diabetes some animals were treated with insulin for 2 weeks to restore euglycaemia. Apoptosis was measured using immunohistochemical detection of activated caspase-3 and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL)-positive cells in adjacent sections in neurones (PGP 9.5-positive cells). The level of apoptosis was confirmed using double-label assessment of caspase-3 and TUNEL in DRG preparations. Caspase-3 immunoreactive neurones demonstrated a range in staining intensity. When all grades of staining were included, 6-8% of the DRG, nodose ganglia and myenteric neurones were immunoreactive in the preparations from diabetic rats compared with 0.2-0.5% in controls. Neurones staining positive for both caspase-3 and TUNEL accounted for 1-2% of the total neuronal population in all three preparations in diabetic rats compared with 0.1-0.2% in controls (P < 0.05). Insulin treatment reversed the percentage of TUNEL-positive neurones in diabetic rats to control levels. Activation of the apoptosis cascade occurs relatively early in diabetic autonomic neuropathy and may contribute to the pathophysiology of this disorder.
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PMID:Diabetic autonomic neuropathy: evidence for apoptosis in situ in the rat. 1519 56

We examined the effects of interleukin-1beta (IL-1beta) treatment on the distribution and degradation of lamin B in the nuclear fraction from insulin-secreting RINm5F cells. Western blot analysis indicated that IL-1beta treatment caused significant alterations in the redistribution of lamin B, specifically between the Triton X-100-soluble (membrane) and -insoluble (matrix) fractions of the nucleus. IL-1beta treatment also increased the lamin carboxymethyltransferase activity and the relative abundance of the carboxymethylated lamin in the nuclear fraction. A significant increase in the relative abundance of lamin B degradation products was also observed in the nuclear fraction from the IL-1beta-treated cells. These findings are compatible with a measurable increase in the lamin-degrading caspase-6 activity in IL-1beta-treated cells. Confocal microscopic observation of IL-1beta-treated cells suggested a significant dissociation of lamin B from the nuclear lamina and its subsequent association with the DNA-rich elements within the nucleus. N(G)-monomethyl-l-arginine, a known inhibitor of inducible nitric oxide synthetase (iNOS), markedly inhibited IL-1beta-induced iNOS gene expression, NO release, caspase-3 and caspase-6 activation, lamin B degradation, and loss of metabolic cell viability, indicating that the observed IL-1beta-induced effects on nuclear lamin B involve the intermediacy of NO. Together, our data support the hypothesis that IL-1beta treatment results in significant increase in the carboxymethylation of lamin B, which would place lamin B in a strategic location for its degradation mediated by caspases. This could possibly lead to dissolution of the nuclear envelope, culminating in the demise of the effete beta-cell.
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PMID:Interleukin-1 beta induces posttranslational carboxymethylation and alterations in subnuclear distribution of lamin B in insulin-secreting RINm5F cells. 1520 Nov 38

Metformin is an anti-diabetic drug that increases glucose utilization in insulin-sensitive tissues. The effect is in part attributable to a stimulation of AMP-activated protein kinase (AMPK). The present study demonstrates that metformin (0.5-2mM) also dose-dependently activates AMPK in insulin-producing MIN6 cells and in primary rat beta-cells, leading to increased phosphorylation of acetyl coA carboxylase (ACC). The maximal effect was reached within 12h and sustained up to 48h. After 24h exposure to metformin (0.5-1mM), rat beta-cells exhibited a reduced secretory and synthetic responsiveness to 10mM glucose, which was also the case following 24h culture with the AMPK-activator 5-amino-imidazole-4-carboxamide riboside (AICAR; 1mM). Longer metformin exposure (>24h) resulted in a progressive increase in apoptotic beta-cells as was also reported for AICAR; metformin-induced apoptosis was reduced by compound C, an AMPK-inhibitor. As with AICAR, metformin activated c-Jun-N-terminal kinase (JNK) and caspase-3 prior to the appearance of apoptosis. It is concluded that metformin-induced AMPK-activation in beta-cells reduces their glucose responsiveness and may, following sustained exposure, result in apoptosis.
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PMID:Metformin-induced stimulation of AMP-activated protein kinase in beta-cells impairs their glucose responsiveness and can lead to apoptosis. 1524 7

During development of Drosophila, cell proliferation and size are known to be regulated by insulin. Here we use Drosophila Kc cells to examine the molecular basis for the control of cell growth by insulin. Growing cells in the presence of insulin increased cell number above control levels at 16, 24, 48 and 72 h. We have demonstrated a novel anti-apoptotic effect of insulin (approximately 50%) in these cells, measured by caspase 3-like activity, which contributed to the increase in cell number. The anti-apoptotic effect was observed both in control cells and those in which apoptosis was induced by ultraviolet irradiation. An approximately 2-fold stimulation of bromodeoxyuridine incorporation demonstrated that insulin also increased Kc cell proliferation by stimulating new DNA synthesis. The ability of insulin to increase cell number, stimulate bromodeoxyuridine incorporation and reduce caspase 3-like activity was prevented by PD98059, which inhibits activation of the Drosophila extracellular signal regulated kinase (DERK) pathway, and was unaffected by wortmannin, an inhibitor of Drosophila phosphatidylinositol 3-kinase (DPI3K). Insulin also increased cell size approximately 2-fold and this was prevented by wortmannin and rapamycin, an inhibitor of Drosphilia target of rapamycin (DTOR). In summary, we show that DERK plays an important role in mediating the effect of insulin to reduce apoptosis and increase DNA synthesis whereas the DPI3K/DTOR/Dp70S6 kinase pathway mediates effects of insulin on cell size in Drosophila Kc cells.
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PMID:Insulin reduces apoptosis and increases DNA synthesis and cell size via distinct signalling pathways in Drosophila Kc cells. 1524 66

Nitric oxide (NO) contributes to cellular degeneration in various disorders, particularly in the nervous system. NO targets cell proteins such as soluble guanylyl cyclase, but its detrimental effects are generally attributed to its reaction product with superoxide, peroxynitrite. To understand the mechanisms of NO-induced cell stress, we studied the effects of the NO donors diethylenetriamine and spermine NONOate and the peroxynitrite donor 5-amino-3-(4-morpholinyl)-1,2,3-oxadiazolium chloride (SIN-1) in SH-SY5Y and NG108-15 neuroblastoma cells. All three compounds induced a dose- and time-dependent decrease in viable cells, which was not blocked by the soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. The two NONOates were approximately 15-fold more potent in SH-SY5Y than in NG108-15 cells, whereas the EC50 values of SIN-1 in SH-SY5Y and NG108-15 cells were in the same order. This led us to conclude that the mechanisms of NO and peroxynitrite did not converge. This was supported by our other findings. NONOates induced DNA fragmentation and an increase in cellular caspase-3 activity that preceded the gradual decline in cell viability. In contrast, SIN-1 induced a transient decline in ATP levels and a delayed loss of cell viability with no significant increase in caspase-3 activity or DNA laddering. Moreover, post-treatment with insulin inhibited caspase-3 activation and loss of cell viability in NONOate- but not in SIN-1-exposed cells. These findings suggest that NO is a potent toxin independent of peroxynitrite formation.
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PMID:Differential mechanisms of nitric oxide- and peroxynitrite-induced cell death. 1525 57

Diabetic patients are particularly susceptible to cardiomyopathy independent of vascular disease, and recent evidence implicates cell death as a contributing factor. Given its protective role against apoptosis, we hypothesized that dietary n-6 polyunsaturated fatty acid (PUFA) may well decrease the incidence of this mode of cardiac cell death after diabetes. Male Wistar rats were first fed a diet rich in n-6 PUFA [20% (wt/wt) sunflower oil] for 4 wk followed by streptozotocin (STZ, 55 mg/kg) to induce diabetes. After a brief period of hyperglycemia (4 days), hearts were excised for functional, morphological, and biochemical analysis. In diabetic rats, n-6 PUFA decreased caspase-3 activity, crucial for myocardial apoptosis. However, cardiac necrosis, an alternative mode of cell death, increased. In these hearts, a rise in linoleic acid and depleted cardiac glutathione could explain this "switch" to necrotic cell death. Additionally, mitochondrial abnormalities, impaired substrate utilization, and enhanced triglyceride accumulation could have also contributed to a decline in cardiac function in these animals. Our study provides evidence that, in contrast to other models of diabetic cardiomyopathy that exhibit cardiac dysfunction only after chronic hyperglycemia, n-6 PUFA feeding coupled with only 4 days of diabetes precipitated metabolic and contractile abnormalities in the heart. Thus, although promoted as being beneficial, excess n-6 PUFA, with its predisposition to induce obesity, insulin resistance, and ultimately diabetes, could accelerate myocardial abnormalities in diabetic patients.
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PMID:Brief episode of STZ-induced hyperglycemia produces cardiac abnormalities in rats fed a diet rich in n-6 PUFA. 1528 64

The pathogenesis of diabetes associated with hemochromatosis is not known. We therefore examined glucose homeostasis and beta-cell function in mouse models of hemochromatosis. Mice with targeted deletion of the hemochromatosis gene (Hfe(-/-)) on the 129/Sv genetic background exhibited a 72% increase in iron content in the islets of Langerhans compared with wild-type controls. Insulin content was decreased in Hfe(-/-) mice by 35%/pancreas and 25%/islet. Comparable decreases were seen in the mRNA levels of beta-cell-specific markers, ins1, ins2, and glucose transporter 2. By 6-8 months, islets from Hfe(-/-) mice were 45% smaller, associated with increased staining for activated caspase 3 and terminal deoxynucleotidyl transferase-mediated deoxy-UTP nick end labeling. Islets from Hfe(-/-) mice were also desensitized to glucose, with half-maximal stimulation of insulin secretion seen at 16.7 +/- 0.9 mm glucose in perifused islets from Hfe(-/-) mice compared with 13.1 +/- 0.6 mm glucose in wild-type animals. Carbonyl protein modification, a marker for oxidative stress, was increased by 58% in Hfe(-/-) islets. Despite decreased islet size, Hfe(-/-) mice exhibited enhanced glucose tolerance. Fasting serum insulin levels were comparable between Hfe(-/-) and Hfe(+/+) mice, but were 48% lower in the Hfe(-/-) mice 30 min after challenge. Similar results were seen in mice carrying an Hfe mutation analogous to the common human mutation (C282Y) and in mice fed excess dietary iron. Hfe(-/-)mice on the C57BL6 background exhibited decreased glucose tolerance at 10-12 months due to an inability to increase insulin levels as they aged. We conclude that iron excess results in beta-cell oxidant stress and decreased insulin secretory capacity secondary to beta-cell apoptosis and desensitization of glucose-induced insulin secretion. This abnormality alone, however, is insufficient to cause diabetes.
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PMID:Oxidative stress, beta-cell apoptosis, and decreased insulin secretory capacity in mouse models of hemochromatosis. 1530 12


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