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)

The present study was designed to evaluate the time course and manner of Purkinje cell death following a single ethanol dose delivered intragastrically on postnatal day (PN) 4 to rat pups. Analysis included immunolabeling of Purkinje cells with antibody specific for calbindin D28k and counting of Purkinje cells in each lobule of a mid-vermal slice. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling analysis and immunodetection for cleaved (activated) caspase-3 enzyme was used to identify apoptosis, with calbindin D28k co-immunolabeling to identify apoptotic Purkinje cells. Finally, immunodetection for cytochrome c, again with co-labeling using calbindin D28k antibody, identified intracellular release of cytochrome c from the mitochondria into the cytoplasm of Purkinje cells. The data demonstrate that a single dose of ethanol results in a significant and extensive, lobular dependent loss of Purkinje cells within 24 h after administration. Extensive loss in the early developing lobules (I-III, VIII-X) and less to no loss in the later developing lobules (IV-VII) is consistent with prior literature reports on the ethanol-induced effects on Purkinje cells at this age. Clear and consistent evidence of apoptotic Purkinje cells was identified and the pattern was transient in nature. Finally, cytochrome c is released from the mitochondria of Purkinje cells in a time course consistent with the activation of the mitochondrial pathway of apoptosis. These data support the hypothesis that ethanol-induced loss of Purkinje cells involves apoptotic mechanisms. Furthermore, the initiation of apoptosis by ethanol is consistent with ethanol-induced interruptions of Purkinje cell neurotrophic support leading to activation of the mitochondrial pathway of apoptosis.
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PMID:Time course and manner of Purkinje neuron death following a single ethanol exposure on postnatal day 4 in the developing rat. 1220 2

MST1 is a member of the Sterile-20 family of cytoskeletal, stress, and apoptotic kinases. MST1 is activated by phosphorylation at previously unidentified sites. This study examines the role of phosphorylation at several sites and effects on kinase activation. We define Thr(183) in subdomain VIII as a primary site of phosphoactivation. Thr(187) is also critical for kinase activity. Phosphorylation of MST1 in subdomain VIII was catalyzed by active MST1 via intermolecular autophosphorylation, enhanced by homodimerization. Active MST1 (wild-type or T183E), but not inactive Thr(183)/Thr(187) mutants, was also highly autophosphorylated at the newly identified Thr(177) and Thr(387) residues. Cells expressing active MST1 were mostly detached, whereas with inactive MST1, adhesion was normal. Active MKK4, JNK, caspase-3, and caspase-9 were detected in the detached cells. These cells also contained all autophosphorylated and essentially all caspase-cleaved MST1. Similar phenotypes were elicited by a caspase-insensitive D326N mutant, suggesting that kinase activity, but not cleavage of MST1, is required. Interestingly, an S327E mutant mimicking Ser(327) autophosphorylation was also caspase-insensitive, but only when expressed in caspase-3-deficient cells. Together, these data suggest a model whereby MST1 activation is induced by existing, active MST kinase, which phosphorylates Thr(183) and possibly Thr(187). Dimerization promotes greater phosphorylation. This leads to induction of the JNK signaling pathway, caspase activation, and apoptosis. Further activation of MST1 by caspase cleavage is best promoted by caspase-3, although this appears to be unnecessary for signaling and morphological responses.
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PMID:Mapping of MST1 kinase sites of phosphorylation. Activation and autophosphorylation. 1222 93

The physiological apoptosis that occurs in immature testis appears to be necessary for the maturation of this tissue. Thus, inhibition of the early apoptotic wave associated with the first round of spermatogenesis is followed by accumulation of spermatogonia and infertility later in life. To identify the cell types undergoing apoptosis in immature rat testis and to characterize the relationship between this apoptosis and progression of the first wave of spermatogenesis, sequential viable segments of seminiferous tubules from 8-, 18-, and 26-day-old rats were examined under a phase-contrast microscope. One novel observation was the existence of pronounced stage-specificity during the peak of apoptosis at the very early postnatal ages of 18 and 26 days. Increased apoptosis of pachytene spermatocytes in stages VII-VIII was the major feature that distinguished immature spermatogenesis from the corresponding adult process. The frequency of apoptosis among type A spermatogonia in immature stages IX-I was also elevated in comparison to the corresponding mature stages. The age-related peak of apoptosis was mediated by caspase 3; furthermore, stage-dependent expression of Bax in midpachytene spermatocytes was observed in the 18- and 26-day-old testis. These observations suggest that this Bax-regulated, caspase 3-mediated, increased apoptosis of midpachytene spermatocytes during the first wave of immature spermatogenesis represents a major difference in comparison to apoptosis occurring in the mature testis, and it may play an important regulatory role in establishing spermatogenesis in the rat testis.
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PMID:Increased apoptosis occurring during the first wave of spermatogenesis is stage-specific and primarily affects midpachytene spermatocytes in the rat testis. 1452 36

Carbonic anhydrase-related protein VIII (CA-RP VIII) is expressed in most non-small cell lung cancer, and especially strongly at the front of tumor progression. Screening analysis of CA-RP VIII expression in a panel of cultured lung cancer cell lines showed that a well differentiated adenocarcinoma cell line, PC-9, appeared to lack CA-RP VIII. Subsequently, CA8 cDNA was transfected with an expression vector into PC-9. Ectopic overexpression of CA-RP VIII reduced the growth of PC-9 cells on uncoated culture dishes, especially when the cultures were started at low cell density, but increased cell growth on laminin-coated dishes. Interestingly, ectopic CA-RP VIII expression markedly reduced caspase-3 activity induced by serum starvation and anti-cancer agents in PC-9 cells. The present findings suggest that CA-RP VIII expression promotes progression of lung cancer by multifarious mechanisms.
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PMID:Effect of carbonic anhydrase-related protein VIII expression on lung adenocarcinoma cell growth. 1514 May 39

The severe degeneration of the germinal epithelium and subsequent male sterility observed in mice null for the retinoic acid receptor alpha (RARalpha) gene suggested its critical role in spermatogenesis, although the etiology and progression of these abnormalities remain to be determined. Previous studies have revealed that elongated spermatids in RARalpha(-/-) testes were improperly aligned at the tubular lumen and did not undergo spermiation at stage VIII(*). We now report a distinctive failure of step 8-9 spermatids to orient properly with regard to the basal aspect of Sertoli cells, resulting in stage VIII(*)-IX(*) tubules with randomly oriented spermatids. By in situ terminal deoxynucleotidyltransferase-mediated deoxy-UTP nick end labeling (TUNEL), we noted that elongating spermatids frequently underwent apoptosis. Immunohistochemical analysis revealed that while activated caspase-3, the primary effector caspase in the apoptotic cell death machinery, was detected in the nuclei of primary spermatocytes in the first wave of spermatogenesis and occasionally in spermatogonia of both normal and mutant testes, it was not involved in the death of elongating spermatids in RARalpha(-/-) testes. Thus, sterility in RARalpha(-/-) males was associated with specific defects in spermiogenesis, which may correlate with a failure in both spermatid release and spermatid orientation to the basal aspect of Sertoli cells at stage VIII(*) in young adult RARalpha(-/-) testis. Further, the resulting apoptosis in elongating spermatids appears to involve pathways other than that mediated by activated caspase-3.
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PMID:Male sterility in mice lacking retinoic acid receptor alpha involves specific abnormalities in spermiogenesis. 1590 Dec 85

The present study was conducted to elucidate the possible molecular mechanism of germinal cell apoptosis induced by Sertoli cell damage after 1,3-dinitrobenzene (1,3-DNB), a testicular toxicant, was administered to laboratory male rats. In this study, male Sprague-Dawley rats were administered with a single oral dose of 1,3-DNB (25 mg/kg body weight). Histopathological examinations and TUNEL methods revealed a marked increase in the number of apoptotic pachytene spermatocytes in seminiferous tubules showing stages VII-VIII and IX-XI of the spermatogenic cycle at 24 h after 1,3-DNB treatment. In immunohistochemical analysis, the cytoplasm and nuclei of pachytene spermatocytes were sometimes stained with antibodies to Bax and cleaved caspase-3 at 24 h after treatment. RT-PCR analysis for apoptosis-related gene expression showed that the expression of Bax,Bcl-2, Bcl-xL, and Bcl-xs genes, which are implicated in mitochondrial pathway, was significantly upregulated in the testes of the treated rats. These results suggest that the mitochondrial pathway is mainly involved in the testicular germinal cell apoptosis in rats induced by 1,3-DNB.
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PMID:Molecular mechanism on the testicular toxicity of 1,3-dinitrobenzene in Sprague-Dawley rats: preliminary study. 1602 11

The anti-cancer efficacy of grape seed extract (GSE) against prostate cancer (PCA) via its anti-proliferative, pro-apoptotic and anti-angiogenic activities in both cell culture and animal models have recently been described by us. GSE is a complex mixture containing gallic acid (GA), catechin (C), epicatechin (EC) and several oligomers (procyanidins) of C and/or EC, some of which are esterified to GA. To determine which components are most active against PCA, an ethyl acetate extract of GSE was separated by reverse-phase high-performance liquid chromatography (HPLC) into three fractions. Fraction 1 was far more effective than others in causing growth inhibition and apoptotic death of human PCA DU145 cells. Of the components in this fraction, GA showed a very strong dose- and time-dependent growth inhibition and apoptotic death of DU145 cells, but C and procyanidins B1 (EC-C dimer), B2 (EC-EC dimer) and B3 (C-C dimer) were nearly ineffective. Mechanistic studies demonstrated a strong caspase-9, caspase-3 and poly (ADP-ribose) polymerase (PARP) cleavages by GA in DU145 cells. Procyanidin oligomers eluting in HPLC Fractions 2 and 3 were obtained in larger quantities by separating GSE into eight fractions (I-VIII) on a gel filtration column. All fractions were analyzed by HPLC-UV and negative-ion electrospray mass spectrometry. Fractions I-III contained the active compound GA and inactive components C, EC, B1 and B2. Fraction IV contained other dimers and a dimer-GA ester and was also less active than GSE in DU145 cells. Fractions V-VIII, however, caused significant growth inhibition and apoptosis with the highest activity present in the later fractions that contained procyanidin trimers and GA esters of dimers and trimers. Together, these observations identify GA as one of the major active constituents in GSE. Several procyanidins, however, and especially the gallate esters of dimers and trimers also may be efficacious against PCA and merit further investigation.
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PMID:Fractionation of grape seed extract and identification of gallic acid as one of the major active constituents causing growth inhibition and apoptotic death of DU145 human prostate carcinoma cells. 1647 70

The cumulative effects of environmental toxicants, for example, the alkylphenol, para-nonylphenol (p-NP) are of concern. Our previous study showed that p-NP reduced several testicular morphometric parameters, including sperm counts. The present study reexamined material collected in that study to determine the mechanistic basis of p-NP action on spermatogenic development in the offspring. Seven-day pregnant Sprague-Dawley rats were treated with vehicle or 100 or 250 mg/kg p-NP through gestation, lactation and afterward directly to all male offspring until 10 weeks of age. Both doses of p-NP significantly (P < 0.02) increased the number of germ cells with in situ end-labeled fragmented DNA (TUNEL positive) by 1.9-fold and 1.7-fold, respectively, and specifically in stages XII-XIV and I-III. TUNEL-labeling was, however, selective, and excluded labeling of basal cells with apoptotic morphology. Cleaved caspase-3 immunohistochemistry strongly labeled basal cells (spermatogonia and early spermatocytes) with condensed marginated chromatin but not degenerate germ cells lacking definitive nuclear material found throughout the epithelium. Only the caspase index (ratio of number of caspase positive to number of degenerate cells) of the 100-mg/kg p-NP group was significantly (p < 0.05) threefold greater than controls. Whereas both doses and either 250 or 100 mg/kg treatment alone significantly (p < 0.002) reduced the frequencies (duration) of stages I-III, VII-VIII, and late VIII-IX (spermiating and recently spermiated tubules), respectively, both doses significantly (p < 0.002) increased the frequencies of stages IV-VI and all stages containing late-stage spermatocytes (XII-XIII) and meiotic cell divisions (XIV). Thus, p-NP, an environmentally persistent xenoestrogen, insidiously alters the spermatogenic cycle and spermatogenic process in male offspring.
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PMID:Stage-related increase in the proportion of apoptotic germ cells and altered frequencies of stages in the spermatogenic cycle following gestational, lactational, and direct exposure of male rats to p-nonylphenol. 1706 34

The relationship between Bcl-2, Bax, Fas, caspase-3 and development of hemangioma and the molecular mechanism was investigated. By using immunohistochemical S-P method, proliferating cell nuclear antigen was detected. According to the classification of Mulliken in combination with PCNA expression, 27 cases were identified as proliferating hemangioma and 22 cases as involutive hemangioma. Five normal skin tissues around the tumor tissue served as controls. By using immunohistochemical technique, the expression of Bcl-2, Bax, Fax and Caspase-3 was detected. The cells expressing Bcl-2, Bax, Fax and cappase-3 were identified as hemangioma endothelia by immunohistochemical staining of VIII factor. The average absorbance (A) and average positive area rate of Bcl-2, Bax, Fas and caspase-3 expression were measured by using HPIAS-2000 imaging analysis system. The results showed that the expression of Bcl-2 in the endothelia of proliferating hemangioma was significantly higher that in involutive degenerative hemangioma endothelia and vascular endothelia of normal skin tissue (P < 0.01). The expression of Bax, Fas and Caspase-3 in the endothelia of involutive hemangioma was obviously higher than in the endothelia of proliferating hemangioma and normal skin tissue (P < 0.01). The expression of BAx and Fas in endothelia of proliferating hemangioma was higher than in those of normal skin tissue (P < 0.05). It was suggested that Bcl-2, Bax, Fas and caspase-3 might be involved in the development and involution of hemangioma. Bcl-2 could promote the growth of hemangioma by inhibiting apoptosis of endothelia. Bax, Fas and caspase-3 promote the switch of hemangioma from proliferation to involution by inducing the apoptosis of hemangioma endothelia.
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PMID:Expression and significance of Bcl-2, Bax, Fas and caspase-3 in different phases of human hemangioma. 1712 Jul 32

Glycogen synthase kinase-3, especially the beta form (GSK-3beta), plays key roles in oxidative stress-induced neuronal cell death, an important pathogenic mechanism of various neurodegenerative diseases. Although the neuroprotective effects of GSK-3beta inhibitors have been described, the optimal level of GSK-3beta inhibition for neuronal cell survival has not yet been determined. We investigated the effect of varying GSK-3beta activity on the viability of oxidative stress-injured neuronally differentiated PC12 (nPC12) cells and intracellular signals related with the GSK-3beta and caspase-3 pathways. Compared to the nPC12 control cells treated with only 100 microM H(2)O(2), treatment of 50-200 nM GSK-3beta inhibitor II or 25-500 nM GSK-3beta inhibitor VIII reduced the increased enzyme activity by about 50% and protected the cells against H(2)O(2)-induced oxidative stress. The optimal concentration of GSK-3beta inhibitor II enhanced heat shock transcription factor-1 levels, decreased levels of phosphorylated tau (Ser202) and cytosolic cytochrome c, activated caspase-3, and cleaved poly (ADP-ribose) polymerase. In contrast, higher concentrations of GSK-3beta inhibitor II (more than 500 nM) induced neuronal cell death and showed opposite effects relative to the above described intracellular signals. These results suggest that optimized inhibitor levels for modulating GSK-3beta activity may prevent apoptosis induced by oxidative stress associated with neurodegenerative diseases.
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PMID:Glycogen synthase kinase-3beta activity plays very important roles in determining the fate of oxidative stress-inflicted neuronal cells. 1715 78


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