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)

Glucocorticoid excess induces hyperglycemia, which may result in diabetes. The present experiments explored whether glucocorticoids trigger apoptosis in insulin-secreting cells. Treatment of mouse beta-cells or INS-1 cells with the glucocorticoid dexamethasone (0.1 micromol/l) over 4 days in cell culture increased the number of fractionated nuclei from 2 to 7 and 14%, respectively, an effect that was reversed by the glucocorticoid receptor antagonist RU486 (1 micromol/l). In INS-1 cells, dexamethasone increased the number of transferase-mediated dUTP nick-end labeling-staining positive cells, caspase-3 activity, and poly-(ADP-) ribose polymerase protein cleavage; decreased Bcl-2 transcript and protein abundance; dephosphorylated the proapoptotic protein of the Bcl-2 family (BAD) at serine155; and depolarized mitochondria. Dexamethasone increased PP-2B (calcineurin) activity, an effect abrogated by FK506. FK506 (0.1 micromol/l) and another calcineurin inhibitor, deltamethrin (1 micromol/l), attenuated dexamethasone-induced cell death. The stable glucagon-like peptide 1 analog, exendin-4 (10 nmol/l), inhibited dexamethasone-induced apoptosis in mouse beta-cells and INS-1 cells. The protective effect of exendin-4 was mimicked by forskolin (10 micromol/l) but not mimicked by guanine nucleotide exchange factor with the specific agonist 8CPT-Me-cAMP (50 micromol/l). Exendin-4 did not protect against cell death in the presence of cAMP-dependent protein kinase (PKA) inhibition by H89 (10 micromol/l) or KT5720 (5 micromol/l). In conclusion, glucocorticoid-induced apoptosis in insulin-secreting cells is accompanied by a downregulation of Bcl-2, activation of calcineurin with subsequent dephosphorylation of BAD, and mitochondrial depolarization. Exendin-4 protects against glucocorticoid-induced apoptosis, an effect mimicked by forskolin and reversed by PKA inhibitors.
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PMID:Dexamethasone induces cell death in insulin-secreting cells, an effect reversed by exendin-4. 1664 95

Studies in our laboratory demonstrate that vitamin D (1,25 dihydroxycholecalciferol or calcitriol) has significant antitumor activity in vitro and in vivo in murine and human squamous cell, prostate, lung, pancreatic and myeloma model systems. Calcitriol induces G0/G1 arrest, modulates p27 and p21, the cyclin-dependent kinase (cdk) inhibitors implicated in G1 arrest, and induces cleavage of caspase 3, PARP and the mitogen-activated protein kinase (MEK) in a caspase-dependent manner. Calcitriol also decreases phospho-Erk (P-Erk) and phospho-Akt (P-Akt), kinases that regulate cell survival pathways and up-regulate the pro-apoptotic signaling molecule, MEKK-1. Glucocorticoids enhance calcitriol-mediated activities pre-clinically in vitro and in vivo. Dexamethasone (dex) significantly potentiated the antitumor effect of calcitriol and decreased calcitriol-induced hypercalcemia. Both in vitro and in vivo, dex increased vitamin D receptor (VDR) ligand binding in the tumor while decreasing binding in intestinal mucosa, the site of calcium absorption. These studies demonstrated that calcitriol has significant antiproliferative activity in a number of pre-clinical model systems and form the groundwork for on-going clinical studies investigating calcitriol as an anticancer agent.
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PMID:The antitumor efficacy of calcitriol: preclinical studies. 1688 62

S100A9 is a pro-inflammatory protein expressed in infiltrating granulocytes and monocytes. We determined role of S100A9 in endotoxin (LPS)-induced uveitis (EIU) and keratitis in Wistar rats. Anti-S100A9 antibody decreased partially clinical scores, protein, and cells in the aqueous humor at 18-36 h, compared with the LPS group. S100A9-positive cells were expressed in the iris-ciliary body (ICB) and cornea at 24-48 h. Activated caspase-3 (related to apoptosis) and S100A9 co-expressed in ICB at 18-48 h after LPS injection. S100A9 was not expressed in ED2-positive cells in ICB. Dexamethasone (DEX) increased S100A9 mRNA and protein levels in the circulating blood leukocytes, but reduced S100A9 mRNA and protein levels in ICB after LPS injection. BAY 11-7085 (an inhibitor of I-kappaB phosphorylation) suppressed S100A9 mRNA in leukocytes (43.5%) and ICB (68.5%), respectively, after LPS injection. It is possible that S100A9-positive granulocytes and monocyte/macrophages may play a role in the late phase of EIU and keratitis that DEX may inhibit the migration of S100A9-positive granulocytes and monocytes from the blood into the extravascular tissues, and that nuclear factor (NF)-kappaB pathway may be involved in S100A9 expression. S100A9 could play a role in the clearance of inflammatory cells at the late phase of EIU.
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PMID:S100A9-positive granulocytes and monocytes in lipopolysaccharide-induced anterior ocular inflammation. 1710 Nov 29

Dexamethasone (DX) induces apoptosis resistance in most solid malignant tumors during co-treatment with chemotherapy agents, such as camptothecin (CAM). In this study, we investigated the mechanism by which DX reduces chemotherapy efficiency in C6-glioma. DX reduced CAM-increased DNA fragmentation and caspase-3 activation. The DX's protection was negated by RU486, an antagonist of glucocorticoid receptor (GR). DX itself increased anti-apoptotic gene, Bcl-xL expression, and its transcription factor, signaling transducer and activator of transcription 5 (Stat5), DNA binding activity and phospho-Stat5 expression. DX blocked the CAM-decreased Bcl-xL and phospho-Stat5 expression, and Stat5 binding activity. RU486 negated DX's actions. To determine whether Stat5 regulates Bcl-xL expression in CAM-induced cell death, C6-glioma was infected with an adenovirus containing a constitutively activated Stat5-GFP (Ad-Stat5ca). Overexpression of Stat5ca increased Bcl-xL and decreased CAM-induced cell death compared to control adenovirus infected cells; whereas Stat5 siRNA decreased DX-induced Bcl-xL and increased cell death. Phospho-Stat5 expression was observed in the nuclear extract by co-immunoprecipitation with an anti-GR antibody, indicating that Stat5 and GR were interactive and formed a complex in the nuclei. These results suggest that DX's prevention from CAM-induced apoptosis and RU486's antagonism of DX's protection may be through Stat5/Bcl-xL signal pathway regulated by a GR.
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PMID:Dexamethasone inhibits camptothecin-induced apoptosis in C6-glioma via activation of Stat5/Bcl-xL pathway. 1933 9

Pancreatic beta cells are very sensitive to reactive oxygen species (ROS) and this might play an important role in beta cell death in diabetes. Dexamethasone is a synthetic diabetogenic glucocorticoid, which impairs pancreatic beta cell function. Therefore we investigated the toxicity of dexamethasone in RINm5F insulin-producing cells and its dependence on the expression level of the antioxidant enzyme catalase, which inactivates hydrogen peroxide. This was correlated with oxidative stress and cell death. An increased generation of ROS was observed in dexamethasone-treated cells together with an increase in caspase-3 activity and apoptosis rate. Interestingly, exposure to dexamethasone increased the cytosolic superoxide dismutase Cu/ZnSOD protein expression and activity, whereas the mitochondrial MnSOD isoform was not affected by the glucocorticoid. Catalase overexpression in insulin-producing cells prevented all the cytotoxic effects of dexamethasone. In conclusion, dexamethasone-induced cell death in insulin-producing cells is ROS mediated. Increased levels of expression and activity of the Cu/ZnSOD might favor the generation of hydrogen peroxide in dexamethasone-treated cells. Increased ROS scavenging capacity in insulin-producing cells, through overexpression of catalase, prevents a deleterious increase in hydrogen peroxide generation and thus prevents dexamethasone-induced apoptosis.
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PMID:Protection of insulin-producing cells against toxicity of dexamethasone by catalase overexpression. 1969 81

In the setting of renal ischemia-reperfusion injury (IRI), the effect and mechanism of action of glucocorticoids are not well understood. In rat renal IRI, a single dose of dexamethasone administered before ischemia, or at the onset of reperfusion, ameliorated biochemical and histologic acute kidney injury after 24 h. Dexamethasone upregulated Bcl-xL, downregulated ischemia-induced Bax, inhibited caspase-9 and caspase-3 activation, and reduced apoptosis and necrosis of proximal tubular cells. In addition, dexamethasone decreased the number of infiltrating neutrophils and ICAM-1. We observed the protective effect of dexamethasone in neutrophil-depleted mice, suggesting a neutrophil-independent mechanism. In vitro, dexamethasone protected human kidney proximal tubular (HK-2) cells during serum starvation and IRI-induced apoptosis, but inhibition of MEK 1/2 abolished its anti-apoptotic effects in these conditions. Dexamethasone stimulated rapid and transient phosphorylation of ERK 1/2, which required the presence of the glucocorticoid receptor and was independent of transcriptional activity. In summary, in the setting of renal ischemia-reperfusion injury, dexamethasone directly protects against kidney injury by a receptor-dependent, nongenomic mechanism.
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PMID:Dexamethasone ameliorates renal ischemia-reperfusion injury. 1979 68

Dexamethasone-induced Ras protein 1 (Dexras 1), a brain-enriched member of Ras subfamily of guanosine triphosphatases, as a novel physiologic nitric oxide (NO) effector, anchor neuronal nitric oxide synthase (nNOS) that could form a ternary complex with carboxy-terminal PDZ ligand of nNOS (CAPON) and nNOS, to specific targets to enhance NO signaling. The present study was to explore the expression pattern of Dexras 1 in the development of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. Western blot and immunochemistry analysis showed that the gene and protein expression of Dexras 1 in the central nervous system (CNS) of rats increased significantly during the process of EAE compared with control groups (p < 0.01) and maintain a high level in the remission period. The protein expressions of nNOS and CAPON in hippocampus were approximately paralleled Dexras 1. Immunofluorescence revealed that both neurons and glial cells expressed the Dexras 1 in EAE CNS. Importantly, the damaged CNS in EAE-affected rats showed the codistribution between Dexras 1 and caspase 3, indicating the role of Dexras 1 played in the apoptotic process in EAE. Furthermore, colocalizations of Dexras 1 were observed in neurons and glial cells in CNS with nNOS or CAPON, supporting the ternary complex in this model. Thus, these findings suggest the postulation that Dexras 1 might participate into CNS neuronal cell death and demyelination in the whole process of EAE through regulating the NO signaling by binding to nNOS and CAPON.
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PMID:Spatiotemporal patterns of dexamethasone-induced Ras protein 1 expression in the central nervous system of rats with experimental autoimmune encephalomyelitis. 2008 51

The aim of this explore is to study the anti-inflammatory effect of Corilagin in herpes simplex virus (HSV)-1 infected microglial cells and HSV-1 infected mouse brain. The cellular model was set with microglial cells stimulated by HSV-1 and divided respectively, into virus, astragalus polysaccharides (APS), Dexamethasone and Corilagin group. A normal control group consisting of uninfected microglial cells was also included. ELISA for measuring TNF-alpha, IL-1beta and IL-10 and Greiss method for detecting NO secretion in supernatant, flow cytometry assay for examining apoptosis rate, expression of caspase-3, caspase-8, caspase-9 and caspase-12, and western-blot for measuring protein expression of cytochrome c were performed. The animal model was set up using Balb/c male mice that were intracranially inoculated with HSV-1. Animals were then divided in groups as described for the cellular model. Here, too a normal control group was included. HE staining was used to assay pathological changes in brain. As results, after Corilagin intervention, the release of TNF-alpha, IL-1beta and NO from HSV-stimulated migroglia cells was significantly inhibited. Furthermore, Corilagin induced apoptosis of HSV-stimulated microglia through all the 3 known apoptotic pathways. The animal model treated with Corilagin also displayed significant decrease of herpes simplex encephalitis induced brain pathological changes. In conclusion, Corilagin has the potential to reduce HSV-1-induced inflammatory insult to the brain, and its mode of action is through the induction of apoptosis of microglias and reduction of cytokines production.
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PMID:Effect of Corilagin on anti-inflammation in HSV-1 encephalitis and HSV-1 infected microglias. 2033 62

High systemic exposures to calcitriol are necessary for optimal antitumor effects. Human prostate cancer PC3 cells are insensitive to calcitriol treatment. Therefore, we investigated whether the inhibition of 24-hydroxylase (CYP24A1), the major calcitriol inactivating enzyme, by ketoconazole (KTZ) or RC2204 modulates calcitriol serum pharmacokinetics and biologic effects. Dexamethasone (Dex) was added to minimize calcitriol-induced hypercalcemia and as a steroid replacement for the KTZ inhibition of steroid biosynthesis cytochrome P450 enzymes. KTZ effectively inhibited time-dependent calcitriol-inducible CYP24A1 protein expression and enzyme activity in PC3 cells and C3H/HeJ mouse kidney tissues. Systemic calcitriol exposure area under the curve was higher in mice treated with a combination of calcitriol and KTZ than with calcitriol alone. KTZ and Dex synergistically potentiated calcitriol-mediated antiproliferative effects in PC3 cells in vitro; this effect was associated with enhanced apoptosis. After treatment with calcitriol and KTZ/Dex, although caspase-9 and caspase-3 were not activated and cytochrome c was not released by mitochondria, caspase-8 was activated and the truncated Bid protein level was increased. Translocation of apoptosis-inducing factor to the nucleus was observed, indicating a role of the apoptosis-inducing factor-mediated and caspase-independent apoptotic pathways. Calcitriol and KTZ/Dex combination suppressed the clonogenic survival and enhanced the growth inhibition observed with calcitriol alone in PC3 human prostate cancer xenograft mouse model. Our results show that the administration of calcitriol in combination with CYP24A1 inhibitor enhances antiproliferative effects, increases systemic calcitriol exposure, and promotes the activation of caspase-independent apoptosis pathway.
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PMID:CYP24A1 inhibition enhances the antitumor activity of calcitriol. 2059 73

Dexamethasone (Dex) provides neuroprotection against subsequent hypoxia ischemia (HI) in newborn rats, but the mechanism of this neuroprotection is not well understood. It is known that vascular endothelial growth factor A (VEGF) has neuroprotective effects. The objective of this study was to evaluate the role of the VEGF signaling pathway in the Dex-induced neuroprotection in newborn rats. Seven-day-old rat pups had the right carotid artery permanently ligated followed by 140 or 160 min of hypoxia (8% oxygen). Rat pups received two i.p. injections of either saline or Dex (0.25 mg/kg) at 24 and 4 h before HI exposure. To quantify the effects of a glucocorticoid receptor (GR) blocker, on postnatal day (PD) 6 and 15 min prior to Dex treatment rat pups received s.c. vehicle or RU486 (GR blocker, 60 mg/kg). After 24 h at PD 7, all rat pups had HI as described earlier. To quantify the effects of a VEGFR 2 blocker, at 24 h after Dex/Veh treatment (PD7), SU5416, a VEGFR 2 inhibitor or vehicle was injected intracerebroventricularly in the right hemisphere at 30 min before and 2 h after HI. Dex pre-treatment reduced brain injury and enhanced the HI-induced brain VEGF protein while a GR blocker inhibited these effects. Treatment with VEGFR 2 blocker decreased Dex-induced neuroprotection also. Dex pre-treatment enhanced the HI-induced increase in mRNA expression of VEGF splice variants and decreased the HI-induced reduction of Akt phosphorylation. Additionally, it also decreased HI-induced increase of caspase-3 activity and DNA fragments in neonatal rat brain. We conclude that Dex provides robust neuroprotection against subsequent HI in newborn rats via GR likely with the partial involvement of VEGF signaling pathway.
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PMID:Dexamethasone pre-treatment protects brain against hypoxic-ischemic injury partially through up-regulation of vascular endothelial growth factor A in neonatal rats. 2127 50


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