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)

Epidemiological and clinical data suggest that selenium may prevent prostate cancer, but the biological effects of selenium on normal or malignant prostate cells are not well known. We evaluated the effects of sodium selenite (Na2SeO3) or l-selenomethionine (SeMet) on monolayer and anchorage-independent growth in a series of normal primary prostate cultures (epithelial, stromal, and smooth muscle) and prostate cancer cell lines (LNCaP, PC-3, and DU145). We observed differential, dose-dependent growth inhibition and apoptosis within prostate cancer cells (compared with normal prostate cells) treated with 1-500 microM of Na2SeO3 or SeMet. Na2SeO3 more potently inhibited growth at any given concentration. The androgen-responsive LNCaP cells were the most sensitive to selenium growth suppression (IC50s at 72 h for Na2SeO3 and SeMet were 0.2 and 1.0 microM, respectively). Growth of the primary prostate cells virtually was not suppressed (IC50s at 72 h for Na2SeO3 and SeMet were 22-38 and >500 microM, respectively). We also observed that DNA condensation and DNA fragmentation (terminal deoxynucleotidyltransferase dUTP nick end labeling/fluorescence-activated cell sorting) were elevated in selenium-treated cells and that activated caspase-3 colocalized with terminal deoxynucleotidyltransferase dUTP nick end labeling-stained cells by immunofluorescence. Higher basal poly(ADP-ribose) polymerase (PARP) expression levels and PARP cleavage (a substrate for caspase-3) were observed during apoptosis in tumor cells, compared with normal cells. Selective tumor cell death was associated with an increase in sub-G0-G1 cells after propidium iodide staining and fluorescence-activated cell sorting analysis. SeMet caused an increase in arrest in the G2-M phase of the cell cycle selectively in cancer cells. Inhibition of cancer cell growth by SeMet was associated with phosphorylation of P-Tyr15-p34/cdc2, which caused growth arrest in the G2-M phase. Anchorage-independent growth of prostate cancer cells in soft agar was sensitive to selenium. Our results suggest that Na2SeO3 is the more potent inducer of apoptosis in normal and cancer prostate cells. Our SeMet results involving PARP and G2-M cell-cycle arrest (cited above) indicate that SeMet selectively induces apoptosis in cancer but not primary cells of the human prostate. Our overall findings are relevant to the molecular mechanisms of selenium actions on prostate carcinogenesis and help demonstrate the selective, dose-dependent effects of selenium (especially SeMet) on prostate cancer cell death and growth inhibition.
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PMID:Selenium effects on prostate cell growth. 1109 24

Effects of calcein acetoxymethyl ester (calcein/AM) on macromolecular synthesis, mitochondrial membrane potential, and mode of death were studied in U-937 GTB lymphoma cells. This was accomplished by measurements of (14)C-labeled thymidine and leucine incorporation, 5,5',6,6'-tetrachloro-1,1',3, 3'-tetraethylbenzimidazolyl carbocyanine iodide (JC-1) and caspase-3 activity measurements, TdT-mediated dUTP nick end labeling (TUNEL) staining, morphology, and a newly developed assay of apoptosis detection, the microculture kinetic assay (MiCK). This assay, based on absorbance measurements of cells, has been reported to reflect morphological changes in apoptosis. At 2.5 microg/mL, rapid inhibition of DNA and protein synthesis resembling that of the known inhibitors, aphidicholin and cycloheximide, was observed. Decreased mitochondrial membrane potential was evident after 1 hr of exposure and was followed by an increase in caspase-3 activity, while at 6 hr 30% of cells appeared positive with TUNEL staining. After 12 hr of exposure, viability was less than 5% as judged by morphological examination. In the MiCK assay, calcein (2.5 microg/mL) gave a rapid rise in absorbance after 3.5 hr of exposure with a peak at 5 hr, indicating maximum extent of apoptosis at that time. This was similar to the pattern generated for etoposide and doxorubicin. The results indicate that calcein, similar to cytotoxic drugs, induces a strong apoptotic response within hours of exposure.
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PMID:Apoptosis induced by calcein acetoxymethyl ester in the human histiocytic lymphoma cell line U-937 GTB. 1110 90

Alveolar macrophages (AMs) are the principal target cells of silica and occupy a key position in the pathogenesis of silica-related diseases. Silica has been found to induce apoptosis in AMs, whereas its underlying mechanisms involving the initiation and execution of apoptosis are largely unknown. The main objective of the present study was to examine the form of cell death caused by silica and the mechanisms involved. Silica-induced apoptosis in AMs was evaluated by terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling assay and cell cycle/DNA content analysis. The elevated level of reactive oxygen species (ROS), caspase-9 and caspase-3 activation, and poly(ADP-ribose) polymerase (PARP) cleavage in silica-treated AMs were also determined. The results showed that there was a temporal pattern of apoptotic events in silica-treated AMs, starting with ROS formation and followed by caspase-9 and caspase-3 activation, PARP cleavage, and DNA fragmentation. Silica-induced apoptosis was significantly attenuated by a caspase-3 inhibitor, N-acetyl-Asp-Glu-Val-Asp aldehyde, and ebselen, a potent antioxidant. These findings suggest that apoptosis is an important form of cell death caused by silica exposure in which the elevated ROS level that results from silica exposure may act as an initiator, leading to caspase activation and PARP cleavage to execute the apoptotic process.
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PMID:Reactive oxygen species and caspase activation mediate silica-induced apoptosis in alveolar macrophages. 1113 90

Excessive activation of glutamate receptors mediates neuronal death, but the intracellular signaling pathways that mediate this type of neuronal death are only partly understood. Previously, we have demonstrated that calcium/calmodulin-dependent protein kinase II-alpha(B) (CaMKII-alpha(B)) containing a nuclear localizing signal but not CaMKII-alpha is altered in retinal neurons exposed to N-methyl-D-aspartate (NMDA). The present study describes a prospective function of CaMKII-alpha(B) in signal transduction leading to apoptosis. The terminal deoxyribonucleotidyl transferase (TdT)-mediated biotin-16-dUTP nick-end labelling (TUNEL) method was used to detect fragmented DNA in fixed tissue sections of rat retina. The TUNEL assay confirmed that cell death occurs in the inner nuclear and ganglion cell layers following injection of 4 mM NMDA. A specific AIP (myristoylated autocamtide-2-related inhibitory peptide) with proven cell permeability inhibits CaMKII activity in vivo. Neuroprotection achieved by 500 microM AIP was complete when administered 2 h before and coincident with the NMDA application. Additionally, 100 microM of AIP protects only partially against the NMDA-induced excitotoxicity. The conformationally active fragment of caspase-3 (17 kDa), known to be involved in neuronal apoptosis was apparent within 30 min and at 2 h postinjection with NMDA. This activation was inhibited by 500 microM AIP when administered 2 h before and coincident with the NMDA application. The results suggest that CaMKII-alpha(B) isoform plays a role in excitotoxicity-induced neuronal apoptosis.
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PMID:Neuroprotective effect of AIP on N-methyl-D-aspartate-induced cell death in retinal neurons. 1114 4

The antitumor drug NB-506 is a glycosylated indolocarbazole derivative targeting topoisomerase I. This DNA-intercalating agent, which is currently undergoing phase I/II clinical trials, was shown to induce apoptosis in HL-60 human leukemia cells. We compared the cellular dysfunctions induced by NB-506 and the reference topoisomerase I poison camptothecin (CPT) at the nuclear, mitochondrial, and cytoplasmic levels. The two drugs NB-506 and CPT were almost equally toxic to HL-60 cells and produced similar cell cycle changes with a considerable increase in the fraction of cells with DNA content less than G1. The sub-G1 fraction, which can be considered as the apoptotic cell population, appeared more rapidly with CPT than with NB-506 but in both cases, the cell cycle perturbation was accompanied by a marked decrease in the mitochondrial transmembrane potential and the intracellular pH. In contrast, no change in the intracellular calcium concentration was detected. Treatment of HL-60 cells with NB-506 resulted in an increase in the activity of the intracellular protease caspase-3, as determined by a DEVD-based colorimetric assay and direct monitoring of poly(ADP-ribose) polymerase (PARP) cleavage by Western blot analysis. The initiator caspase-8 was also stimulated by NB-506 but, as for caspase-3, the extent of the caspase activation was weaker with NB-506 compared to CPT. With both drugs, the protease activation resulted in DNA degradation, as independently confirmed via the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay and characterization of internucleosomal DNA fragmentation. Collectively, these findings identify some of the molecular events leading to NB-506-induced apoptosis and as such, provide important mechanistic insights into the mode of action of topoisomerase I-targeted indolocarbazole antitumor drugs.
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PMID:Apoptotic response of HL-60 human leukemia cells to the antitumor drug NB-506, a glycosylated indolocarbazole inhibitor of topoisomerase 1. 1117 34

Activated caspase-3has been immunohistochemically studied in 30glioblastomas. Its distribution has been compared with that of apoptotic nuclei demonstrated by terminal dUTP nick-end labeling (TUNEL) and morphology. The best procedure for the demonstration of caspase-3 requires formalin fixation, followed by Carnoy fixation, with microwave irradiation. The number of positive cells is lower than that of apoptotic nuclei shown by TUNEL technique, especially in perinecrotic pseudo-palisadings, and there are also qualitative variations. Positive staining occurs in nuclei, cytoplasms or in both cell compartments. The interpretation of Caspase-3 positive staining is based on its crucial position in the final pathway to apoptosis and on the mechanisms by which it cleaves cytoplasmic and nuclear proteins among which inhibitory/caspase-activated DNase system is included.
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PMID:Distribution of activated caspase-3 in relation with apoptosis in human malignant gliomas. 1117 34

Cadmium (Cd) is a well-known environmental carcinogen and immunotoxin. Currently the direct cytotoxic effects of Cd on thymocytes are largely unexplored. The main objective of the present study was to investigate the apoptogenic property of Cd and the mechanisms involved, using primary cultured mouse thymocytes as a model. Cd-induced apoptosis in thymocytes was studied by TdT-mediated dUTP nick end-labeling assay and DNA gel electrophoresis. The results showed that Cd was able to cause apoptosis in mouse thymocytes in a time- and dose-dependent manner. Moreover, Cd exposure led to a rapid and sustained intracellular calcium (Ca2+) elevation, followed by caspase-3 activation and PARP cleavage, all of which preceded the characteristic DNA fragmentation. BAPTA-AM, a specific intracellular Ca2+ chelator, abolished Cd-induced Ca2+ overloading and subsequently inhibited caspase-3 activation, PARP cleavage, and apoptosis. It is believed that intracellular Ca2+ elevation may trigger caspase-3 activation either through mitochondria or through activation of Ca2+-dependent protease in Cd-treated thymocytes. Results from this study thus provide new information for a better understanding of the immunotoxic and immunomodulatory effects of Cd.
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PMID:Critical role of calcium overloading in cadmium-induced apoptosis in mouse thymocytes. 1118 Nov 7

The temporospatial expression pattern of the nuclear DNA repair enzyme redox factor-1 (ref-1), the p53-activated gene (pag) 608 and the effector caspase-3 was examined by in situ hybridization histochemistry in gerbils subjected to two 10-min episodes of unilateral common carotid artery occlusion, separated by 5h. Gene responses were correlated with the metabolic state, as revealed by regional adenosine 5'-triphosphate bioluminescent imaging, and with the degree of histological damage, as assessed by haematoxylin-eosin staining and terminal deoxynucleotidyl transferase-mediated-dUTP nick end labeling (TUNEL), in order to evaluate the role of these genes in the maturation of injury. Focal infarcts developed in the dorsolateral cerebral cortex at the bregma level and the nucleus caudate-putamen within four days after repeated unilateral ischemia, as indicated by a secondary adenosine 5'-triphosphate loss after initial adenosine 5'-triphosphate recovery and by histomorphological signs of pannecrosis. The more caudal cortex at hippocampal levels and the hippocampus (CA1>CA3 area), however, exhibited selective neuronal injury without adenosine 5'-triphosphate depletion. TUNEL+ cells appeared starting 5h after repeated unilateral ischemia. TUNEL+ cells reached maximum levels in the caudate-putamen at 12-24h, but much later in the cortex and hippocampus at two days after ischemia. Remarkably few TUNEL+ cells were noticed in the thalamus, where adenosine 5'-triphosphate state did not recover after reperfusion. Following repeated unilateral ischemia, a transient elevation of ref-1 mRNA was detected after 5h in the cerebral cortex and hippocampal CA1 area. Ref-1 mRNA levels decreased within 12-24h, before the onset of tissue damage. Subsequently, pag608 and caspase-3 mRNA levels increased, closely in parallel with the appearance of DNA fragmented cells, but slightly prior to the deterioration of adenosine 5'-triphosphate state. In the caudate-putamen, pag608 and caspase-3 mRNAs reached maximum levels already 12-24h after repeated common carotid artery occlusion, when DNA fragmentation was most prominent, and declined thereafter. In the cortex and hippocampal CA1-3 areas, where DNA damage appeared more slowly, pag608 and caspase-3 mRNAs were induced starting 24h after ischemia, and remained elevated even after two to four days. The levels of pag608 and caspase-3 mRNAs were similar at rostral and caudal levels of the cortex, as well as in the hippocampal CA1 and CA3 area, although the degree of injury differed considerably between these structures. Notably, pag608 and caspase-3 mRNAs were not elevated in the thalamus after repeated unilateral ischemia. The present report shows a close temporal association between the induction of ref-1, pag608 and caspase-3 mRNAs, the manifestation of cell injury and the secondary adenosine 5'-triphosphate depletion in infarcting brain areas, suggesting (i) that de novo responses of these genes may be involved in the maturation of cell injury and (ii) that apoptotic programs and the secondary deterioration of cerebral energy state may interfere with each other after ischemia.
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PMID:Expression of redox factor-1, p53-activated gene 608 and caspase-3 messenger RNAs following repeated unilateral common carotid artery occlusion in gerbils--relationship to delayed cell injury and secondary failure of energy state. 1118 42

The role of endogenous NO on cell survival was investigated in human melanoma cells and melanocytes. Inducible NO synthase (iNOS) was always expressed in a panel of melanoma cell lines from metastatic lesions and in normal adult melanocytes. iNOS was also detected by immunohistochemistry in melanoma cells from metastases. Release of NO by tumor cells and melanocytes was inhibited by a specific iNOS inhibitor, aminoguanidine (AMG). Inhibition of endogenous NO synthesis did not affect cell cycle progression of melanoma cells but led to cell death by apoptosis, as indicated by Annexin V/propidium iodide and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling assays. By contrast, iNOS inhibition by AMG did not promote apoptosis in normal adult melanocytes. A mitochondrial pathway was involved in melanoma apop tosis, as indicated by altered mitochondrial membrane potential (delta psi(m)) and down-regulation of Bcl-2 protein level after iNOS inhibition. AMG treatment triggered release of caspase-1, enzymatic activation of caspase-3, and degradation of poly(ADP-ribose) polymerase, one of the main caspase-3 substrates. Melanoma cell apoptosis induced by iNOS inhibition was completely blocked by peptide inhibitors of caspase-1 and caspase-3 (Ac-DEVD-CHO and AC-YVAD-CHO) or by an exogenous NO donor, sodium nitroprusside, or by addition of serum. Finally, comparison of control and AMG-treated melanoma cells by pathway-specific gene array analysis indicated that inhibition of NO synthesis led, before induction of apoptosis, to up-regulation of mRNA levels of genes involved in the apoptosis pathway such as Bax, caspase-1, caspase-3, caspase-6, gadd45beta, mdm2, and TRAIL. Taken together, these results indicate that melanoma cell survival is regulated by endogenous NO resulting from iNOS activity.
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PMID:Antiapoptotic role of endogenous nitric oxide in human melanoma cells. 1119 80

Previously we have shown decreased Fas-mediated apoptosis in cord blood lymphocyte subsets. In this study, we compared tumor necrosis factor (TNF)-alpha-induced apoptosis in T lymphocytes and their subsets between cord blood and peripheral blood from healthy young controls. The expression of TNF receptor I (TNFR-I) was assessed by flow cytometry and quantitative RT-PCR. The expression of adapter molecules TNF receptor-associated death domain (TRADD), Fas-associated death domain (FADD) and TNF-associated factor-2 (TRAF-2) and caspase 3 was analyzed by Western blotting. The activity of caspase 3 and caspase 8 was measured by colorimetric assay. The susceptibility of CD4+ and CD8+ T cells to TNF-alpha-induced apoptosis was measured by terminal deoxytidyl transferase-mediated dUTP nick end labelling (TUNEL) assay. Both CD4+ and CD8+ T cell subsets from cord blood demonstrated decreased susceptibility to TNF-alpha-induced apoptosis that was associated with decreased activation of both caspase 8 and caspase 3 as compared to T cell subsets in peripheral blood. Furthermore, expression of TNFR-I, TRADD and caspase 3 was decreased in cord blood lymphocytes as compared to peripheral blood lymphocytes. The significance of these observations is discussed.
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PMID:TNF-alpha-induced apoptosis in neonatal lymphocytes: TNFRp55 expression and downstream pathways of apoptosis. 1119 4


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