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: EC:3.4.22.56 (caspase-3)
35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Coptidis rhizoma (CR) is a herb used in many traditional prescriptions against diabetes mellitus in Asia for centuries. Our purpose was to determine the protective effect and its action mechanism of CR on the cytotoxicity of pancreatic beta-cells. Nitric oxide (NO) is believed to play a key role in the process of pancreatic beta-cell destruction leading to insulin-dependent diabetes mellitus (IDDM). Exposure of RINm5F cells to chemical NO donor such as S-nitroso-N-acetylpenicillamine (SNAP) induced apoptotic events such as the disruption of mitochondrial membrane potential (Deltapsim), cytochrome c release from mitochondria, activation of caspase-3, poly (ADP-ribose) polymerase cleavage and DNA fragmentation. Also, exposure of SNAP led to LDH release into medium, one of the necrotic events. However, pretreatment of RINm5F cells with CR extract protected both apoptosis and necrosis through the inhibition of Deltapsim disruption in SNAP-treated RINm5F cells. In addition, rat islets pretreated with CR extract retained the insulin-secretion capacity even after the treatment with IL-1beta. These results suggest that CR may be a candidate for a therapeutic or preventing agent against IDDM.
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PMID:Protective effect of Coptidis Rhizoma on S-nitroso-N-acetylpenicillamine (SNAP)-induced apoptosis and necrosis in pancreatic RINm5F cells. 1558 68

Malignant insulinoma is a critical cancer form with a poor prognosis. Because cure by surgery is infrequent, effective chemotherapy is in demand. Induction of cell death in tumor cells by proteasome inhibitors is emerging as a potential strategy in cancer therapy. Here we investigated whether inhibition of the proteasome has an antitumorigenic potential in insulinoma cells. Exposure of mouse betaTC3 insulinoma cells to the proteasome inhibitor N-Acetyl-Leu-Leu-Nle-CHO (ALLN) reduced cell viability, activated caspase-3, induced apoptosis, and suppressed insulin release. Treatment with ALLN also resulted in phosphorylation of c-jun N-terminal kinase (JNK) and an increase in in vitro phosphorylation of c-jun. In insulinoma cells with impaired JNK signaling, ALLN-induced apoptosis was significantly suppressed. Another proteasome inhibitor, lactacystin, also stimulated JNK activation, caused activation of caspase-3, suppressed cell viability, and induced apoptosis in betaTC3 and rat INS-1E cells. Both ALLN and lactacystin caused a marked decrease in the cellular amount of the JNK scaffold protein JNK-interacting protein 1/islet-brain-1. In primary pancreatic rat islet cells, proteasome inhibition reduced insulin secretion but had no impact on cell viability and even partially protected against the toxic effect of proinflammatory cytokines. Our findings demonstrate that proteasome inhibitors possess antitumorigenic and antiinsulinogenic effects on insulinoma cells.
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PMID:Antitumorigenic effect of proteasome inhibitors on insulinoma cells. 1561 49

Loss of protein and lean body mass occurs commonly in patients with chronic kidney disease (CKD). CKD or conditions associated with CKD will stimulate muscle loss, but the cellular mechanisms by which these conditions cause muscle atrophy are largely undefined. In animal models of uremia and other catabolic conditions or in peritoneal dialysis patients, there is evidence that the ubiquitin-proteasome proteolytic system is activated to degrade actomyosin and myofibrillar proteins in muscle. Before the ubiquitin system can degrade muscle proteins, however, an initial cleavage of actomyosin and myofibrils must occur. Caspase-3 performs this initial cleavage of actomyosin and leaves a footprint of its activity, accumulation of a 14-kDa actin fragment in muscle. A critical step in stimulating the ubiquitin-proteasome system in muscle was recently discovered, the activation of a specific E3 ubiquitin-conjugating enzyme, atrogin-1. Both caspase-3 and the ubiquitin system, including atrogin-1, are activated when insulin signaling is impaired, and specifically when phosphatidylinositol 3 kinase activity is suppressed. Strategies that prevent a decrease in phosphatidylinositol 3 kinase activity or inhibit caspase-3 activity could lead to treatments that prevent muscle wasting in CKD patients.
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PMID:Strategies for suppressing muscle atrophy in chronic kidney disease: mechanisms activating distinct proteolytic systems. 1564 2

Despite new approaches, treatment options for malignant gliomas are still limited, calling for further development of therapeutic strategies. The peroxisome proliferator-activated receptor (PPAR)gamma, a member of the nuclear hormone receptor family, represents a possible new target for neoplastic therapies. Synthetic PPARgamma agonists were developed and are already in clinical use for the treatment of type II diabetes, since PPARgamma plays a crucial role in lipid metabolism and regulation of insulin sensitivity. Beyond these metabolic effects, PPARgamma agonists exhibit antineoplastic effects in various malignant tumor cells. Here, we investigated the antineoplastic effects of the nonthiazolidinedione tyrosine-based PPARgamma ligand (S)-2-(1-carboxy-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}ethylamino)benzoic acid methyl ester (GW7845) in rat and human glioma cells. GW7845 reduced cellular viability of rat C6 glioma and human glioma cells in a time-dependent manner. Analysis of GW7845-treated tumor cells revealed induction of apoptotic cell death as determined by terminal deoxynucleotidyl transferase dUTP nick-end labeling staining and cleaved caspase-3 activation. Furthermore, GW7845 reduced proliferation of C6 glioma cells as measured by Ki-67 immunore-activity. There was also a reduction of migration and invasion, assessed by Boyden chamber and spheroid experiments. Together, these data indicate that the PPARgamma agonist GW7845 may be of potential use in treatment of malignant gliomas.
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PMID:The nonthiazolidinedione tyrosine-based peroxisome proliferator-activated receptor gamma ligand GW7845 induces apoptosis and limits migration and invasion of rat and human glioma cells. 1566 44

Insulin receptor substrates (Irs-proteins) integrate signals from the insulin and insulin-like growth factor-1 (IGF1) receptors with other processes to control cellular growth, function, and survival. Here, we show that Irs2 promoted the maturation and survival of photoreceptors in the murine retina immediately after birth. Irs2 was mainly localized to the outer plexiform layer as well as to photoreceptor inner segments. It was also seen in ganglion cells and inner plexiform layer but in smaller amounts. Compared with control littermates, Irs2 knock-out mice lose 10% of their photoreceptors 1 week after birth and up to 50% by 2 weeks of age as a result of increased apoptosis. The surviving photoreceptor cells developed short organized segments, which displayed proportionally diminished but otherwise normal electrical function. However, IGF1-stimulated Akt phosphorylation was barely detected, and cleaved/activated caspase-3 was significantly elevated in isolated retinas of Irs2-/- mice. When diabetes was prevented, which allowed the Irs2-/- mice to survive for 2 years, most photoreceptor cells were lost by 16 months of age. Because apoptosis is the final common pathway in photoreceptor degeneration, pharmacological strategies that increase Irs2 expression or function in photoreceptor cells could be a general treatment for blinding diseases such as retinitis pigmentosa.
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PMID:Insulin receptor substrate 2 is essential for maturation and survival of photoreceptor cells. 1568 62

Recently, we identified thioredoxin-interacting protein (TXNIP) as the most dramatically glucose-induced gene in our human islet microarray study. TXNIP is a regulator of the cellular redox state, but its role in pancreatic beta-cells and the mechanism of its regulation by glucose remain unknown. We therefore generated a stable transfected beta-cell line (INS-1) overexpressing human TXNIP and found that TXNIP overexpression induced apoptosis as assessed by Bax, Bcl2, caspase-3, and cleaved caspase-9 as well as Hoechst staining. Interestingly, islets of insulin-resistant/diabetic mice (AZIP-F1, BTBRob/ob) demonstrated elevated TXNIP expression, suggesting that TXNIP may play a role in glucotoxicity and the beta-cell loss observed under these conditions. Furthermore, we found that glucose-induced TXNIP transcription is not dependent on glucose metabolism and is mediated by a distinct carbohydrate response element (ChoRE) in the human TXNIP promoter consisting of a perfect nonpalindromic repeat of two E-boxes. Transfection studies demonstrated that this ChoRE was necessary and sufficient to confer glucose responsiveness. Thus, TXNIP is a novel proapoptotic beta-cell gene elevated in insulin resistance/diabetes and up-regulated by glucose through a unique ChoRE and may link glucotoxicity and beta-cell apoptosis.
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PMID:Thioredoxin-interacting protein is stimulated by glucose through a carbohydrate response element and induces beta-cell apoptosis. 1570 78

The fibrotic and antiapoptotic effects of insulin-like growth factors (IGF) are mediated by type I IGF receptor (IGF-1R). IGFs could play a role in intestinal stricturing and in the maintenance of inflammation in Crohn's disease (CD). We aimed to describe IGF-1R expression in CD intestinal lesions, to compare it to other intestinal inflammatory diseases and to correlate it with fibrosis and apoptosis. IGF-1R expression and apoptosis (active caspase-3) were studied by immunohistochemistry. Surgical intestinal specimens [17 CD, nine controls, six diverticulitis and four ulcerative colitis (UC)] were used. IGF-1R was expressed transmurally mainly by inflammatory cells (IC) and smooth muscle cells, both in diseased intestine and controls. IGF-1R positive IC were increased in the mucosa and the submucosa of CD (P < 0.007), and in involved areas compared to uninvolved areas (P = 0.03). In UC, the number of IGF-1R positive IC was only increased in the mucosa, and was not different from controls in the submucosa. In diverticulitis, the number of IGF-1R positive IC did not differ from controls. In CD submucosa, IGF-1R expression in IC was inversely correlated with apoptosis in uninvolved areas (P = 0.01). Expression of IGF-1R in submucosal fibroblast-like cells, subserosal adipocytes and hypertrophic nervous plexi was specific for CD. We have shown a transmural altered expression of IGF-1R in CD. This may suggest a role for IGF-1R in the maintenance of chronic inflammation and stricture formation in CD.
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PMID:Altered expression of type I insulin-like growth factor receptor in Crohn's disease. 1573 Mar 99

We have previously shown that hippocampal neuronal apoptosis accompanied by impaired cognitive functions occurs in type 1 diabetic BB/Wor rats. To differentiate the contribution by insulin deficiency vs. that by hyperglycemia on neuronal apoptosis, we examined the activities of various apoptotic pathways in hippocampi from type 1 diabetic BB/Wor rats (hyperglycemic and insulinopenic) and type 2 diabetic BBZDR/Wor rats (hyperglycemic and hyperinsulinemic). DNA fragmentation was demonstrated by LM-PCR in type 1 diabetic BB/Wor rats, but was not detectable in duration- and hyperglycemia-matched type 2 BBZDR/Wor rats. Of various apoptotic pathways, Fas activations, 8-OHdG expression, and caspase-12 were demonstrated in type 1 diabetic BB/Wor rats only. In contrast, perturbations of the IGF and NGF systems and PARP activation were demonstrated in type 1 and to a lesser extent in type 2 diabetes. Expressions of Bax and active caspase-3 were significantly increased in type 1, but not in type 2, diabetic rats. These data suggest a lesser apoptogenic stress in type 2 vs. type 1 diabetes. These differences translated into a more profound neuronal loss in the hippocampus of type 1 rats. The results demonstrate that caspase-dependent apoptotic activities dominate in type 1 diabetes, whereas PARP-mediated caspase-independent apoptotic stress is present in both type 1 and type 2 diabetes. The findings suggest that insulin deficiency plays a compounding role to that of hyperglycemia in neuronal apoptosis underpinning primary diabetic encephalopathy.
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PMID:The role of impaired insulin/IGF action in primary diabetic encephalopathy. 1577 48

The role of regucalcin, a regulatory protein in intracellular signaling pathway, in cell death was investigated by using the cloned rat hepatoma H4-II-E cells overexpressing regucalcin. The hepatoma cells (wild-type) and stable regucalcin/pCXN2 transfectants were cultured for 72 h in a medium containing 10% fetal bovine serum (FBS) to obtain subconfluent monolayers. After culture for 72 h, cells were further cultured for 24-72 h in a medium containing either vehicle, insulin (10(-8) or 10(-7) M) or insulin-like growth factor-I (IGF-I; 10(-9) or 10(-8) M) in the absence of FBS. The number of wild-type cells was significantly decreased by culture for 24, 48, or 72 h in the presence of insulin (10(-8) or 10(-7) M) or IGF-I (10(-9) or 10(-8) M). Agarose gel electrophoresis showed the presence of low-molecular-weight deoxyribonucleic acid (DNA) fragments of adherent wild-type cells cultured with insulin or IGF-I. The effect of insulin or IGF-I in stimulating cell death and DNA fragmentation in hepatoma cells (wild-type) was significantly prevented in transfectants overexpressing regucalcin. Meanwhile, epinephrine (10(-6) or 10(-5) M) or transforming growth factor-beta1 (10(-13) or 10(-12) M) did not cause cell death of hepatoma cells. Insulin-induced decrease in the number of wild-type cells was significantly prevented by culture with caspase-3 inhibitor (10(-8) M), although the effect of IGF-I was not inhibited. The effect of insulin or IGF-I in inducing the death of hepatoma cells (wild-type) was significantly prevented in the presence of N omega-nitro-L-arginine methylester (NAME), an inhibitor of nitric oxide synthase. Genistein (10(-6) M), an inhibitor of protein tyrosine kinase, or vanadate (10(-5) M), an inhibitor of protein tyrosine phosphatase, caused a significant decrease in the number of hepatoma cells (wild-type). The effect of insulin in inducing the death of wild-type cells was not seen in the presence of genistein or vanadate. The effect of IGF-I on the death of wild-type cells was observed in the presence of genistein or vanadate. The effect of genistein on cell death was significantly prevented in transfectants. Such effect was not seen with vanadate. This study demonstrates that insulin or IGF-I stimulates cell death and apoptosis in the hepatoma cells, and that overexpression of regucalcin has a suppressive effect on cell death induced by insulin or IGF-I that is mediated through different signaling pathway.
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PMID:Overexpression of regucalcin suppresses cell death and apoptosis in cloned rat hepatoma H4-II-E cells induced by insulin or insulin-like growth factor-I. 1588 Jun 94

beta-cells die by apoptosis in type 1 diabetes as a result of autoimmune attack mediated by cytokines, and in type 2 diabetes by various perpetrators including human islet amyloid polypeptide (hIAPP). The cascade of apoptotic events induced by cytokines and hIAPP is mediated through caspases and reactive oxygen species. The baculovirus p35 protein is a potent anti-apoptotic agent shown to be effective in a variety of species and able to inhibit a number of apoptotic pathways. Here, we aimed at determining the protective potential of p35 in beta-cells exposed to cytokines and hIAPP, as well as the effects of p35 on beta-cell function. The p35 gene was introduced into betaTC-tet cells, a differentiated murine beta-cell line capable of undergoing inducible growth-arrest. Both proliferating and growth-arrested cells expressing p35 manifested increased resistance to cytokines and hIAPP, compared with control cells, as judged by cell viability, DNA fragmentation, and caspase-3 activity assays. p35 was significantly more protective in growth-arrested, compared with proliferating, cells. No significant differences were observed in proliferation and insulin content between cells expressing p35 and control cells. In contrast, p35 manifested a perturbing effect on glucose-induced insulin secretion. These findings suggest that p35 could be incorporated as part of a multi-pronged approach of immunoprotective strategies to provide protection from recurring autoimmunity for transplanted beta-cells, as well as in preventive gene therapy in type 1 diabetes. p35 may also be protective from beta-cell damage caused by hIAPP in type 2 diabetes.
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PMID:Baculovirus p35 increases pancreatic beta-cell resistance to apoptosis. 1589 16


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