UNIPROT:P42574 - FACTA Search

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Query: UNIPROT:P42574 (caspase-3)
45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cytotoxicity and apoptosis-inducing activity of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and 2-tert-butyl-4-methylphenol (BMP) and the mixture of BHA and BHT (BHA/BHT) (1:1, molar ratio) were investigated, using human promeylocytic leukemia cell lines (HL-60) and human squamous cell carcinoma cell lines (HSC-2). The 50% cytotoxic concentration (CC50) declined in the order of BHA, BHT (0.2-0.3 mM) > BHA/BHT (0.04-0.07 mM) > BMP (0.02-0.05 mM). The addition of antioxidants (N-acetyl-Lcysteine, sodium ascorbate, catalase) reduced the cytotoxicity of BHA/BHT or BMP against HSC-2 cells, but not that of BHA or BHT, whereas the addition of NADH, a quinone reductase to BMP, enhanced the cytotoxicity. These findings suggested that the cytotoxicity of BHA/BHT and BMP might be caused by reactive intermediates. BHA-induced cytotoxicity was enhanced by horseradish peroxidases, suggesting that BHA was oxidizable and produced cytotoxic BHA radicals. Internucleosomal DNA fragmentation of HL-60 cells was preferably induced by BHA/BHT and BMP, followed by BHA. The MnSOD mRNA expression in HL-60 cells assayed by reverse transcriptase-polymerase chain reaction was highly inhibited by BHA/BHT or BMP, accompanied by the change in the electrophoretic mobility of MnSOD on polyacryamide gel. These compounds activated caspase-3, 8 and 9 in HL-60 cells. Activations of caspases, particularly caspase-3, declined in the order of BHA/BHT > BHA > BMP > BHT. The most cytotoxic BMP activated caspase-3 activity to the least extent, possibly in part due to the occurrence of necrosis. The great cytotoxicity and apoptosis induction by BHA/BHT may be due to reactive intermediates derived from the interaction between BHA phenoxyl radical and BHT or BHT phenoxyl radical.
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PMID:Cytotoxicity and apoptosis induction by butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT). 1498 15

The effect of exercise on apoptosis in postmitotic tissues is not known. In this study, we investigated the effect of regular moderate physical activity (i.e., exercise training) on the extent of apoptosis in rat skeletal and cardiac muscles. Adult Sprague Dawley rats were trained (TR) 5 days weekly for 8 wk on treadmill. Sedentary rats served as controls (CON). An ELISA was used to detect mono- and oligonucleosome fragmentation as an indicator of apoptosis. Bcl-2, Bax, Apaf-1, AIF, cleaved PARP, cleaved caspase-3, cleaved/active caspase-9, heat shock protein (HSP)70, Cu/Zn-SOD, and Mn-SOD protein levels were determined by Western analyses. Bcl-2 and Bax transcript contents were estimated by RT-PCR. A spectrofluorometric assay was used to determine caspase-3 activity. DNA fragmentation in ventricles of the TR group decreased by 15% whereas that in soleus of the TR group tended to decrease (P=0.058) when compared with CON group. Protein contents of Bcl-2, HSP70, and Mn-SOD increased in both soleus and ventricle muscles of TR animals when compared with CON animals. Apaf-1 protein content in the soleus of TR animals was lower than that of CON animals. Bcl-2 mRNA levels increased in both ventricle and soleus muscles of TR animals, and Bax mRNA levels decreased in the soleus of TR animals when compared with CON animals. Furthermore, HSP70 protein content was negatively correlated to Bax mRNA content and was positively correlated to Bcl-2 protein and mRNA contents. Mn-SOD protein content was negatively correlated to the apoptotic index, and caspase-3 activity and was positively correlated to Bcl-2 transcript content and HSP70 protein content. These data suggest that exercise training attenuates the extent of apoptosis in cardiac and skeletal muscles.
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PMID:Apoptotic adaptations from exercise training in skeletal and cardiac muscles. 1513 82

Ketoconazole (KTZ) has been used as a second-line agent in hormone-refractory cancer therapy. Since transition metal complexes including those of Ru(III), show important anticancer activity with limited toxicity, we investigated the potential antitumor efficacy of Ru(II) complexed to KTZ or clotrimazole (CTZ) compared to Ru(II) alone or uncomplexed azoles. RuCl2(KTZ)2 exerted greater apoptosis- associated caspase-3 activation than RuCl2(CTZ)2, KTZ, CTZ or RuCl2(MeCN)4 against several human tumor cell monolayers. PARP cleavage and a decrease in S+G2 cells were evident after RuCl2(KTZ)2 treatment in genetically matched C8161 melanoma monolayers with unequal p53 functional status. Release of mitochondrial cytochrome c and Mn-SOD suggest mitochondria as a target of RuCl2(KTZ)2. Treatment of WM164 melanoma monolayers with 25 microM of cisplatin or RuCl2(KTZ)2 showed that the latter is more effective than cisplatin at inducing PARP fragmentation and proapoptotic Bak expression. Such results suggest that these Ru(II) and Pt(II) metal complexes are unequally effective and act through alternative signaling pathways. In studies with multicellular spheroids, which frequently are more resistant to cytotoxic anticancer drugs than monolayers, those from wt p53 C8161 melanoma underwent PARP fragmentation in response to RuCl2(KTZ)2. In contrast, spheroids of mut p53 A431 carcinoma overexpressing EGF receptor were resistant to either RuCl2(KTZ)2 or anti-EGF receptor C225 MAb. However, joint treatment with both agents restored growth arrest and apoptosis in these spheroids. In contrast to the antitumor action of cisplatin, which is known to be hampered by p53 dysfunction, we show that RuCl2(KTZ)2 is active irrespective of p53 functional status against several adherent tumor cells and synergizes with anti-EGF receptor C225 MAb to kill tumor spheroids resistant to either agent.
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PMID:Tumor apoptosis induced by ruthenium(II)-ketoconazole is enhanced in nonsusceptible carcinoma by monoclonal antibody to EGF receptor. 1538 61

Prolonged exposure to hyperoxia induces pulmonary epithelial cell death and acute lung injury. Although both apoptotic and nonapoptotic morphologies are observed in hyperoxic animal lungs, nonapoptotic cell death had only been recorded in transformed lung epithelium cultured in hyperoxia. To test whether the nonapoptotic characteristics in hyperoxic animal lungs are direct effects of hyperoxia, the mode of cell death was determined both morphologically and biochemically in human primary lung epithelium exposed to 95% O(2). In contrast to characteristics observed in apoptotic cells, hyperoxia induced swelling of nuclei and an increase in cell size, with no evidence for any augmentation in the levels of either caspase-3 activity or annexin V incorporation. These data suggest that hyperoxia can directly induce nonapoptotic cell death in primary lung epithelium. Although hyperoxia-induced nonapoptotic cell death was associated with NF-kappaB activation, it is unknown whether NF-kappaB activation plays any causal role in nonapoptotic cell death. This study shows that inhibition of NF-kappaB activation can accelerate hyperoxia-induced epithelial cell death in both primary and transformed lung epithelium. Corresponding to the reduced cell survival in hyperoxia, the levels of MnSOD were also low in NF-kappaB-deficient cells. These results demonstrate that NF-kappaB protects lung epithelial cells from hyperoxia-induced nonapoptotic cell death.
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PMID:NF-kappaB protects lung epithelium against hyperoxia-induced nonapoptotic cell death-oncosis. 1547 18

Among the critical antioxidant enzymes that protect the cells against oxidative stress are superoxide dismutases: CuZnSOD (Sod1) and MnSOD (Sod2). The latter is also implicated in apoptosis. To determine the importance of these enzymes in protection against reactive oxygen species (ROS) in the lens, we analysed DNA strand breaks in lens epithelium from transgenic and knockout (Sod1) mice following exposure to H2O2 in organ culture. Since Sod2 knockouts do not survive, comparison was made of lenses of partially-deficient (heterozygote) for Sod2 and the wild-type controls which have twice the enzyme level. Antioxidant potential of Sod2 was also studied in human lens epithelial cells (SRA01/04) in which the enzyme was up- and down-regulated by transfection with plasmids containing sense and antisense human cDNA for MnSOD. DNA strand breaks in the epithelium of Sod1 knockouts and Sod2 heterozygotes were much greater than in the corresponding wild-type or in transgenic mice over-expressing the enzymes when the lenses were exposed to H2O2. The functional role of Sod2 in apoptosis was examined in cultured human lens epithelial cells. Cells with higher enzyme levels were more resistant to the cytotoxic effects of H2O2, O2- and UV-B radiation. Furthermore, Sod2-deficient cells showed dramatic mitochondrial damage, cytochrome C leakage, caspase 3 activation and increased apoptotic cell death when they were challenged with O2-. Thus, mitochondrial enzyme (Sod2) deficiency plays an important role in the initiation of apoptosis in the lens epithelium.
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PMID:Effects of variation in superoxide dismutases (SOD) on oxidative stress and apoptosis in lens epithelium. 1564 23

Yuk-Hap-Tang (YHT) induces cell death in human cervical carcinoma HeLa cells. Caspase-3, -6 and -9 were markedly activated in HeLa cells treated with YHT. The preferred substrate for caspase-3 cysteine protease, PARP, was cleaved to its 85-kDa cleavage product. YHT increased the amount of the anti-apoptotic protein, Bcl-2, and the pro-apoptotic protein, Bax. Although p53 has been reported to accumulate in cancer cells in response to anticancer agents, the p53 expression level was not changed in HeLa cells treated with YHT. Manganese (Mn)-TBAP, a mitochondria-specific SOD mimetic agent and NAC/GSH (N-acetyl cysteine/ reduced glutathione) reduced the YHT-induced cytotoxicity and decreased the number of the YHT-induced apoptotic cells. Furthermore, YHT reduced the expression of Mn-SOD protein and its activity in HeLa cells. The data demonstrate that YHT induces the apoptosis of human cervical carcinoma HeLa cells by intervening Mn-SOD.
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PMID:Yuk-Hap-Tang induces apoptosis by intervening mn-SOD in human cervical carcinoma HeLa cells. 1567 94

Apoptosis has been implicated in the regulation of denervation-induced muscle atrophy. However, the activation of apoptotic signal transduction during muscle denervation has not been fully elucidated. The present study examined the apoptotic responses to denervation in rat gastrocnemius muscle. Following 14 days of denervation, the extent of apoptotic DNA fragmentation as determined by a cytosolic nucleosome ELISA was increased by 100% in the gastrocnemius muscle. RT-PCR and immunoblot analyses indicated that Bax was dramatically upregulated while Bcl-2 was modestly increased; however, the Bax/Bcl-2 ratio was significantly increased in denervated muscles relative to control muscles. Analyses of ELISA and immunoblots from mitochondria-free cytosol extracts showed a significant increase in mitochondria-associated apoptotic factors, including cytochrome c, Smac/DIABLO and apoptosis-inducing factor (AIF). In addition to the upregulation of caspase-3 and -9 mRNA, pro-/cleaved caspase protein and proteolytic activity levels, the X-linked inhibitor of apoptosis (XIAP) protein level was downregulated. The cleaved product of poly(ADP-ribose) polymerase (PARP) was detected in muscle samples following denervation. Although we did not find a difference in the inhibitor of DNA binding/differentiation-2 (Id2) and c-Myc protein contents between the denervated and control muscles, the protein content of tumour suppressor p53 was significantly increased in both the nuclear and the cytosolic fractions with denervation. Moreover, denervation increased the protein content of HSP70, whereas the MnSOD (a mitochondrial isoform of superoxide dismutase) protein content was diminished, which indicated that denervation might have induced cellular and/or oxidative stress. Our data show that mitochondria-associated apoptotic signalling is upregulated during muscle denervation. We interpret these findings to indicate that apoptosis has a physiologically important role in regulating denervation-induced muscle atrophy.
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PMID:Mitochondria-associated apoptotic signalling in denervated rat skeletal muscle. 1577 33

To clarify the mechanisms by which hydroquinone (HQ; 1,4-benzenediol) produces apoptosis, HQ-induced cytotoxicity, intemucleosomal DNA fragmentation, activation of superoxide dismutase (SOD), expression of Mn and Cu/ZnSOD mRNA and activation of caspase-3, -8 and -9 were investigated in the human promyelocytic leukemic cell line HL-60. Electrophoresis and activity staining of the SOD-enriched fraction showed that HQ reduced MnSOD activation more than Cu/ZnSOD activation, suggesting that it induces mitochondrial dysfunction at an early stage of apoptosis. Furthermore, the expression of MnSOD mRNA was suppressed to a greater extent than that of Cu/ZnSOD mRNA, implying that HQ causes apoptosis by inhibiting MnSOD induction. Release of cytochrome c and activation of procaspase-3 and -9, but not of procaspase-8, occurred more rapidly (as early as 6 h) in HQ-treated cells, suggesting that HQ activates the intrinsic pathway of apoptosis. Addition of the antioxidant N-acetyl-L-cysteine (NAC) significantly reduced the cytotoxicity of HQ. At a concentration that was cytotoxic to 50% of the cells (approximately 0.05 mM), HQ activated caspase-3; this effect was reduced in the presence of NAC. Interestingly, higher concentrations of HQ (0.1-0.2 mM) caused direct cell death; however, when combined with 5 mM NAC, the activation of caspase-3 was strongly enhanced, suggesting the promotion of apoptosis. The activation of caspase-3 by HQ/NAC combinations suggests that NAC, a precursor of intracellular glutathione synthesis, acts as a co-catalyst during HQ-induced apoptosis.
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PMID:Hydroquinone-induced apoptosis in HL-60 cells. 1581 34

This study examined the effect of Saeng-Ji-Hwang (SJH: Radix Rehmanniae) on cardiac muscle cells. Adriamycin-exposed H9C2 cardiac muscle cells were treated with a water extract of SJH. The adriamycin induced cell death and caspase-3 activation were significantly inhibited by SJH (2 mg/ml), which can be explained by the increase in Bcl-2 expression and the inhibition of Bax expression. Adriamycin reduced the Mn-SOD protein expression level in H9C2 cardiac muscle cells but a SJH treatment partially but significantly reversed this effect. Manganese (Mn)-TBAP or Mn-TMyM--mitochondria-specific SOD mimetic agent--reduced the adriamycin-induced cytotoxicity. It was also shown that SJH inhibits the release of H2O2 and prevents lipid peroxidation in the presence of adriamycin. This study examined the intracellular GSH level, which showed that adriamycin significantly decreased the intracellular GSH level but SJH increased it. BSO, a selective inhibitor of glutamyl cysteinyl ligase, which is a rate-limiting enzyme in GSH synthesis, did not affect the viability of the cardiac muscle cells. However, a combination of BSO with SJH in the presence of adriamycin reversed the SJH-induced protection. Overall, the results suggest that SJH-associated Mn-SOD and GSH are important factors in the mechanism of the SJH-induced protective mechanism in H9C2 cardiac muscle cells.
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PMID:Saeng-Ji-Hwang has a protective effect on adriamycin-induced cytotoxicity in cardiac muscle cells. 1582 71

During atresia of bovine follicles, granulosa cells are lost through the controlled form of cell death, apoptosis. The purpose of this study was to characterize the regulation of apoptotic death of granulosa cells in dominant bovine follicles during the first wave of follicular development. Dominant follicles were collected from Holstein heifers on days 4, 6 or 8 of the first follicular wave (n = 5/day). Regulation of apoptosis in granulosa cells was examined by annexin V and propidium iodide staining; measurement of relative levels of mRNA encoding Bcl-2, Bcl-xL and Bax; and activity of caspase-3, -8 and -9. Steady-state levels of mRNA encoding four oxidative stress-response proteins were determined. Compared with day 4, the incidence of apoptotic and nonviable granulosa cells tended to increase on day 6, and numbers of nonviable cells were higher on day 8. The ratios of relative levels of mRNA encoding Bcl-2 to Bax and Bcl-xL to Bax were higher on day 6 than days 4 and 8. Activity of caspases-3 and -9 in granulosa cells did not change among the 3 days, while caspase-8 activity decreased on day 8 compared with days 4 and 6. Amounts of GSHPx, MnSOD and Cu/ZnSOD mRNA in granulosa cells were higher on day 8 than day 6. In theca interna, amounts of Cu/ZnSOD mRNA decreased between days 4 and 6. From the decreased production of estradiol and increased numbers of apoptotic and nonviable granulosa cells, we conclude that atresia of the dominant follicle is initiated between days 4 and 6 of the first follicular wave. However, apoptosis of granulosa cells does not appear to be initiated by changes in expression of oxidative stress-response proteins.
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PMID:Regulation of apoptosis in the atresia of dominant bovine follicles of the first follicular wave following ovulation. 1598 33

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