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)

Platelet-derived growth factor (PDGF)-BB-stimulated glycosaminoglycan (GAG) synthesis/secretion in fetal lung fibroblasts is dependent on sequential activation of the PDGF beta-receptor, phosphatidylinositol 3-kinase (PI3K), the serine/threonine kinase Akt-1,2, and the GTPase Rab3D. Because the Akt pathway has been implicated in cell survival mechanisms, we investigated whether the pathway regulating GAG synthesis/secretion was antiapoptotic. PDGF-BB treatment protected fetal lung fibroblasts against serum starvation-induced apoptosis, whereas wortmannin, an inhibitor of PI3K, abrogated this protective effect. Transfection of constitutively active Akt into fetal lung fibroblasts also safeguarded the cells from apoptosis induced by serum starvation. To determine whether the antiapoptotic response was due, at least in part, to GAGs, we treated lung fibroblasts with beta-D-xyloside as well as with topically applied GAGs, specifically those produced by fetal lung fibroblasts. beta-D-xyloside increased GAG synthesis/secretion and diminished apoptosis. Application of sulfated GAGs, chondroitin sulfate, and heparan sulfate, but not nonsulfated hyaluronan, also resulted in diminished apoptosis. Moreover, topically applied sulfated GAGs increased Bcl-associated death promoter phosphorylation and diminished caspase-3 and -7 cleavage, indicating an antiapototic response. These data are compatible with the PDGF-BB-GAG signaling pathway regulating programmed fibroblast death in the fetal lung.
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PMID:Abrogation of apoptosis through PDGF-BB-induced sulfated glycosaminoglycan synthesis and secretion. 1546 49

We attempted to ascertain the neuroprotective effects and mechanisms of minocycline in inflammatory-mediated neurotoxicity using primary neuron/glia co-cultures treated with lipopolysaccharide (LPS). Neuronal cell death was induced by treatment with LPS for 48 h, and the cell damage was assessed using lactate dehydrogenase (LDH) assays and by counting microtubule-associated protein-2 (MAP-2) positive cells. Through terminal transferase deoxyuridine triphosphate-biotin nick end labeling (TUNEL)-staining and by measuring caspase-3 activity, we found that LPS-induced neuronal cell death was mediated by apoptosis. We determined that pre-treatment with minocycline significantly inhibited LPS-induced neuronal cell death. In addition, LPS induced inducible nitric oxide synthase (iNOS) expression significantly, resulting in nitric oxide (NO) production within glial cells, but not in neurons. Both nitric oxide synthase (NOS) inhibitors (N(G)-monomethyl-L-arginine monoacetate (L-NMMA) and S-methylisothiourea sulfate (SMT)) and minocycline inhibited iNOS expression and NO release, and increased neuronal survival in neuron/glia co-cultures. Pre-treatment with minocycline significantly inhibited the rapid and extensive production of tumor necrosis factor-alpha (TNF-alpha) mediated by LPS in glial cells. We also determined that the signaling cascade of LPS-mediated iNOS induction and NO production was mediated by TNF-alpha by using neutralizing antibodies to TNF-alpha. Consequently, our results show that the neuroprotective effect of minocycline is associated with inhibition of iNOS induction and NO production in glial cells, which is mediated by the LPS-induced production of TNF-alpha.
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PMID:Minocycline inhibits apoptotic cell death via attenuation of TNF-alpha expression following iNOS/NO induction by lipopolysaccharide in neuron/glia co-cultures. 1548 88

How perforin (PFN) delivers the granzymes during cytotoxic granule mediated apoptosis remains a mystery. A major obstacle has been the inability to visualize PFN in either monomeric or polymeric form after interaction with the target cell surface. An antibody based technique is described which detects cell surface PFN on intact cells by flow cytometry. The methodology requires the presence of calcium (Ca2+) at a concentration which supports binding but not polymerization of PFN. Functionality was ensured by showing the cell surface PFN was able to deliver GrB causing caspase-3 activation and mitochondrial depolarization. The technique demonstrates a role for heparan sulfate proteoglycans in PFN binding. Further, the variable sensitivity of effector versus target cell lines to the permeabilizing effects of PFN could not be attributed to differential binding of PFN.
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PMID:Detection of functional cell surface perforin by flow cytometry. 1591 96

The accelerated loss of lung epithelium through activation of extrinsic apoptosis is believed to play a causative role in lung pathogenesis. Previous investigations have shown that zinc is required to sustain lung epithelial cell viability under stress conditions and that depletion of intracellular zinc predisposes cells to apoptosis. In this investigation, we determined whether intracellular zinc deficiency enhanced the susceptibility of primary, differentiated cultures of human lung epithelium to death receptor-mediated apoptosis, leading to barrier dysfunction. Cultures obtained from multiple donors were exposed to stimuli that provoke death receptor-mediated apoptosis and depleted of intracellular zinc with a zinc-specific chelating agent. Transepithelial resistance, paracellular transport, caspase-8 and caspase-3 activity, and apoptosis were measured. Activation of extrinsic apoptosis or zinc chelation alone resulted in a nominal increase in caspase function and apoptosis without major evidence of barrier disruption. Activation of extrinsic apoptosis in addition to zinc depletion resulted in an abrupt decrease in transepithelial resistance, a substantial increase in apoptosis, and an increased paracellular leak. Cultures were rescued by supplementation with zinc sulfate. Further analysis revealed that exogenous zinc facilitates cell survival through activation of the phosphatidylinositol 3-kinase/Akt signaling pathway. We conclude that intracellular zinc is a vital factor in lung epithelium that protects cells from death receptor-mediated apoptosis and barrier dysfunction.
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PMID:Zinc modulates airway epithelium susceptibility to death receptor-mediated apoptosis. 1628 13

We have developed a novel double-layer zymographic method for the detection of specific processing proteases of a target proprotease using a specific fluorescent substrate. The target processing proteases were separated using sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and the gel was subsequently incubated with the target proenzyme used as the substrate. A cellulose acetate membrane was immersed in 10% glycerol and then soaked in the fluorescent substrate solution. The slab gel of the processing protease was covered with the fluorescent substrate membrane, making a double layer. The double layer was incubated at 37 degrees C, and the released fluorescent band, in which the processing protease was located, was detected using UV light. The advantages of the double-layer fluorescent zymographic method are as follows: (i) the specific detection of target proprotease using a specific substrate, (ii) a relatively rapid and sensitive method, (iii) effective detection using small amounts of crude material, and (iv) wide applications that include the detection of processing proteases and activators for target proteases. Typical examples used for the detection of the processing proteases, such as plasminogen activator, chymotrypsinogen activator, procaspase-3 processing protease and caspase-3 activators, using this new method are described in this article.
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PMID:Double-layer fluorescent zymography for processing protease detection. 1628 80

To investigate the effect of magnesium sulfate on the fetal rats of FGR and the expression of caspase-3 in the placenta of maternal rat; To explore the mechanism of using magnesium sulfate to cure the FGR. Establish model of FGR by a way of passive smoking: giving the maternal rats different agent of magnesium sulfate by subcutaneous injection: low agent group (300 mg/kg), high agent group (600 mg/kg). Concentration of magnesium sulfate was monitored. The expression of caspase-3 was measured by RT-PCR and immunohistochemistry technology. Both of the concentrations of magnesium sulfate in high and low agents group are higher than the FGR group (P < 0.01); the weight of the placenta and fetal rat in high agent group are higher than the FGR group (P < 0.05 and P < 0.01); the expression of mRNA and protein of caspase-3 in the two agent group is higher than the FGR group (P < 0.05 respectively); concentration of magnesium sulfate in the maternal rat blood correlate to the weight of fetal rat (r = 0.899, P = 0.038) and the expression of caspase-3 in the placenta of maternal rat (r = -0.747, P = 0.033; r = - 0.915, P = 0.001). The research suggests that the weight of fetal rat could be increased by treatment of magnesium sulfate. Because it would imfrmove the placental function by depressing the expression of caspase-3.
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PMID:The effects of magnesium sulfate on fetal rats of FGR and the expression of caspase-3 in the placenta of maternal rat. 1669 36

Cellular stress to ejaculated spermatozoa such as cryopreservation is known to induce caspase-derived, apoptotic signaling. Therefore, the proenzymes and active forms of caspases 1, 3, 8 and 9 were examined by western blot technique in unfrozen and frozen human spermatozoa of infertility patients and of healthy donors. Twenty-two semen samples derived from healthy donors and 26 semen samples of unselected infertility patients were divided into 3 parts, two of them were cryostored at -196 degrees C with 7% or 14% (v/v, final concentration) of glycerol. The caspases were detected by immunoblots with polyclonal rabbit-anti-caspases-antibodies after 15% sodium dodecyl sulfate-polyacrylgel electrophoresis (SDS-PAGE) under reducing conditions. For evaluation of the differences between amounts of caspase protein the luminol/H(2)O(2) method was applied. A significant increase of activated caspase-1 in donors, of caspase-8 in patients and caspase-9 in patients and donors after cryopreservation were found, whereas, the application of 14% glycerol resulted in higher amounts of activated caspase than did 7% glycerol. Possibly, glycerol may also contribute to activation of caspases via direct toxic effects to mitochondria during cryopreservation of spermatozoa. This finding strongly supports an hypothesis of a higher mitochondria-derived apoptosis-sensitivity of spermatozoa in patients than in healthy donors during cryopreservation. Inactive caspase-3 was reduced subsequent to cryopreservation in patients (p<0.05) and non-significant in donors (p<0.05). Active caspase-3 was detectable in all samples but without significant differences between the three assays. It is concluded that mechanisms associated with apoptotic processes deserve attention in cryopreservation of spermatozoa in order to conserve vital sperm functions after thawing.
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PMID:Activation of caspases in human spermatozoa during cryopreservation--an immunoblot study. 1673 10

CCL5 (RANTES (regulated on activation normal T cell expressed and secreted)) and its cognate receptor, CCR5, have been implicated in T cell activation. CCL5 binding to glycosaminoglycans (GAGs) on the cell surface or in extracellular matrix sequesters CCL5, thereby immobilizing CCL5 to provide the directional signal. In two CCR5-expressing human T cell lines, PM1.CCR5 and MOLT4.CCR5, and in human peripheral blood-derived T cells, micromolar concentrations of CCL5 induce apoptosis. CCL5-induced cell death involves the cytosolic release of cytochrome c, the activation of caspase-9 and caspase-3, and poly(ADP-ribose) polymerase cleavage. CCL5-induced apoptosis is CCR5-dependent, since native PM1 and MOLT4 cells lacking CCR5 expression are resistant to CCL5-induced cell death. Furthermore, we implicate tyrosine 339 as a critical residue involved in CCL5-induced apoptosis, since PM1 cells expressing a tyrosine mutant receptor, CCR5Y339F, do not undergo apoptosis. We show that CCL5-CCR5-mediated apoptosis is dependent on cell surface GAG binding. The addition of exogenous heparin and chondroitin sulfate and GAG digestion from the cell surface protect cells from apoptosis. Moreover, the non-GAG binding variant, (44AANA47)-CCL5, fails to induce apoptosis. To address the role of aggregation in CCL5-mediated apoptosis, nonaggregating CCL5 mutant E66S, which forms dimers, and E26A, which form tetramers at micromolar concentrations, were utilized. Unlike native CCL5, the E66S mutant fails to induce apoptosis, suggesting that tetramers are the minimal higher ordered CCL5 aggregates required for CCL5-induced apoptosis. Viewed altogether, these data suggest that CCL5-GAG binding and CCL5 aggregation are important for CCL5 activity in T cells, specifically in the context of CCR5-mediated apoptosis.
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PMID:CCL5-CCR5-mediated apoptosis in T cells: Requirement for glycosaminoglycan binding and CCL5 aggregation. 1680 36

Cathepsin D (cat D) reportedly plays an important role in certain apoptotic processes, the downstream pathways of which involve release of cytochrome c (cyt c) from mitochondria and activation of the caspase cascade. Previous studies revealed that the B-cell lymphoma 2 (Bcl-2) family members Bax or Bid play important roles in apoptotic signal transduction between cat D and mitochondria. Here, we show that glucosamine sulfate (GS) inhibits the proliferation and induces apoptosis of human chronic myelogenous leukemia K562 cells in vitro. GS interfered with the maturation of cat D. Activation of caspase-3, cleavage of poly-(ADP-ribose)-polymerase, release of cyt c, and downregulation of Bcl-xL accompanied GS-induced apoptosis, and these processes were inhibited by the cat D inhibitor pepstatin A. However, we did not detect any altered gene expression of Bcl-2, Bax, or Bid during apoptosis. Translocation of cat D from the lysosome to the cytosol was observed in GS-treated K562 cells. These findings suggest that GS-induced K562 cell apoptosis involves the translocation of cat D from the lysosome to the cytosol. Furthermore, our findings suggest that downregulation of Bcl-xL (but not Bcl-2, Bax, or Bid) connects cat D and the mitochondrial pathway, which causes the release of cyt c and activation of the caspase cascade during GS-induced apoptosis of K562 cells.
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PMID:Glucosamine sulfate-induced apoptosis in chronic myelogenous leukemia K562 cells is associated with translocation of cathepsin D and downregulation of Bcl-xL. 1685 Jan 61

TNF-alpha regulates the hypothalamo-pituitary-adrenal axis at several levels. It has been shown to modify adrenal steroidogenesis in many species, and it is supposed to act as an auto/paracrine factor. However, its significance in human adrenocortical function remains unclear. Therefore, we investigated the effect of TNF-alpha on adrenal steroidogenesis, expression of the key steroidogenic genes, apoptosis, and cell viability in the human adrenocortical cell line NCI-H295R. TNF-alpha treatment (1 nM for 48 h) decreased the basal production of cortisol, androstenedione, dehydroepiandrosterone sulfate (DHEAS), and aldosterone (14, 18, 35, and 52%, respectively), and the 8-bromo-cAMP-induced production of cortisol, androstenedione, dehydroepiandrosterone (DHEA), and DHEAS (44, 66, 58, and 48%, respectively). However, when the steroid production data were normalized by the cell number, TNF-alpha increased the basal production of cortisol, androstenedione, DHEA, DHEAS, and aldosterone (137, 121, 165, 73, and 28%, respectively), and the 8-bromo-cAMP-induced production of cortisol, DHEAS, and aldosterone (122, 121, and 256%, respectively). This was accompanied by a parallel increase in the expression of the genes encoding for the steroidogenic acute regulatory protein, 3beta-hydroxysteroid dehydrogenase 2, and 17-hydroxylase/17,20-lyase (74, 200, and 50%, respectively; quantitative real-time RT-PCR analysis). TNF-alpha increased caspase 3/7 activity (an indicator of apoptosis) and decreased cell viability dose and time dependently. The effect of TNF-alpha on apoptosis was neutralized by a monoclonal TNF-alpha antibody. These findings indicate that TNF-alpha is a potent regulator of steroidogenesis and cell viability in adrenocortical cells. TNF-alpha may have physiological and/or pathophysiological significance as an endocrine and/or paracrine/autocrine regulator of adrenocortical function.
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PMID:Tumor necrosis factor-alpha regulates steroidogenesis, apoptosis, and cell viability in the human adrenocortical cell line NCI-H295R. 1703 55


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