Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:EXPT03226 (vitamin E)
 17,558 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The implication of oxidative damage and/or intact mitochondrial function in physiological Fas-based cytotoxicity has been tested using the cytolytic hybridoma d11S and the CD8(+) CTL clone KB5.C20, previously stimulated to express Fas ligand (FasL) on their surface, as effectors and U937 or U937-rho0 cells (depleted of mitochondrial DNA) as targets. Immobilized anti-Fas mAb, which induced death of U937 cells, inhibited the growth of U937-rho0 cells but without inducing cell death. By contrast, FasL-expressing effectors readily killed both targets, with induction of DNA fragmentation, in 20 h assays. These results demonstrate the lack of involvement of mitochondrial-derived free radicals and/or intact mitochondrial function in physiological Fas-based cytotoxicity. Supplementation of Fas-sensitive cells (Jurkat, U937, L1210Fas) with a polyunsaturated fatty acid, which induces cell death through the generation of lipid free radicals, resulted in the potentiation of Fas-based cytotoxicity. This potentiating effect, but not Fas-based cytotoxicity itself, was eliminated by the physiological antioxidant vitamin E. On the other hand, the IL-1beta-converting enzyme (ICE)-like protease tetrapeptide inhibitor Ac-YVAD-cmk partially inhibited Fas-based cytotoxicity, while the specific inhibitor of CPP32/Yama Ac-DEVD-CHO was a much more effective inhibitor of Fas-induced apoptosis. It was concluded that Fas-induced cytotoxicity was clearly dependent on ICE-like protease activation, and especially on that of CPP32 in Fas-sensitive cells, including mitochondrial DNA-depleted ones.
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PMID:Role of oxidative damage and IL-1 beta-converting enzyme-like proteases in Fas-based cytotoxicity exerted by effector T cells. 875 63

Alpha-Tocopheryl succinate (alpha-TOS), but not a-tocopherol, triggered apoptosis in Jurkat T cells. Apoptosis was induced by alpha-TOS in a time- and concentration-dependent mode, and signs of apoptosis were visible at concentrations of alpha-TOS as low as 30 microM, and within 3-5 h after addition of the ester. Employing a specific fluorogenic substrate, caspase-3 was found to be activated rapidly in response to alpha-TOS at 50 microM. We also found that Jurkat T cells challenged with alpha-TOS, when exposed to the lysosomotropic weak base acridine orange, showed decreased lysosomal uptake of the dye. This is suggestive of the involvement of lysosomal destabilisation in apoptosis of the cells. Apoptosis of Jurkat T cells induced with alpha-TOS also involved a drop in the mitochondrial membrane potential, although this phenomenon occurred after the initiation of lysosomal rupture. All apoptotic features observed with alpha-TOS were very similar to those found when cross-linking of the Fas receptor triggered apoptosis. These findings are consistent with the recent idea that vitamin E can contribute to elimination of malignant cells by the induction of apoptosis, and can be of (patho)physiological significance.
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PMID:alpha-tocopheryl succinate-induced apoptosis in Jurkat T cells involves caspase-3 activation, and both lysosomal and mitochondrial destabilisation. 1009 76

In this study, we show that N-acetylcysteine (NAC), a precursor of glutathione and an intracellular free radical scavenger, almost completely prevented hepatocyte growth factor (HGF)-suppressed growth of Sarcoma 180 and Meth A cells, and HGF-induced apoptosis, assessed by DNA fragmentation, and increase in caspase-3 activity, in Sarcoma 180 cells. The reduced form of glutathione also prevented HGF-suppressed growth of the cells as effective as NAC. Ascorbic acid partially prevented the effect of HGF, but other antioxidants such as superoxide dismutase, catalase, and vitamin E, and the free radical spin traps N-t-butyl-alpha-phenylnitrone and 3,3,5, 5-tetramethyl-1-pyrroline-1-oxide did not have protective effects. HGF caused morphological changes of the cells, many cells showing condensation and rounding, and enhanced the generation of intracellular reactive oxygen species (ROS) as judged by flow cytometric analysis using 2',7'-dichlorofluorescein diacetate. NAC completely prevented both HGF-induced morphological changes and the enhancement of ROS generation in the cells. However, NAC did not prevent the HGF-induced scattering of Madin-Darby canine kidney cells. To our knowledge, this is the first report that HGF stimulates the production of ROS, and our results suggest the involvement of oxidative stress in the mechanism by which HGF induces growth suppression of tumor cells.
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PMID:Involvement of oxidative stress in tumor cytotoxic activity of hepatocyte growth factor/scatter factor. 1022 23

Apoptosis may play an important role in atherogenesis. Oxidized low-density lipoprotein (oxLDL) promotes apoptosis in the arterial wall in addition to several other proatherogenic effects. Tocopherol supplements have been suggested to protect against coronary heart disease (CHD) in epidemiological studies. The effects of oxLDL and alpha- and gamma-tocopherol on apoptotic signaling pathways are poorly understood. Thus, the goal of the study was to investigate these pathways in the presence of copper-oxidized LDL and tocopherols in human coronary smooth muscle cells (SMC). We showed that oxLDL-mediated apoptosis, assessed by DNA fragmentation, terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) assay, and caspase activation stimulated several transcription factors and proapoptotic dynamic movements of the Bcl-2 family proteins through the mitogen-activated protein kinase (MAPK) and Jun kinase pathways. alpha-Tocopherol and gamma-tocopherol significantly reduced these molecular events and cell death effectors caspase-3 and -8. Under our experimental conditions, alpha-tocopherol was significantly more effective than gamma-tocopherol, and oxLDL-mediated apoptosis increased c-Jun, cyclic AMP-responsive element-binding, Ets-like element kinase-dependent 7, and activating transcription factor-2 proteins as well as nuclear activity of the activated protein-1 complex in human coronary SMC. Moreover, our results demonstrate that tocopherols may exert their antiatherogenic effects at least in part via reduction of the MAPK and JunK cascade together with a protective profile of apoptotic genes of the Bcl-2 family. These data are consistent with the beneficial effects of tocopherols on atherogenesis seen in experimental studies and on CHD in epidemiological surveys.
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PMID:Modulation by alpha- and gamma-tocopherol and oxidized low-density lipoprotein of apoptotic signaling in human coronary smooth muscle cells. 1075 58

Tamoxifen (TAM) is widely used in the treatment of breast cancer. The cytostatic effects of TAM have been attributed to the antagonism of estrogen receptor (ER) and inhibition of estrogen-dependent proliferative events. However, the mechanism by which TAM is also effective against certain ER-negative breast tumors remains to be elucidated. Here we report that TAM induced the activity of caspase-3-like proteases in ER-negative breast cancer cell lines MDA-MB-231 and BT-20, as evidenced by the cleavage of fluorogenic tetrapeptide substrate and of poly(ADP-ribose) polymerase. The activation of caspase-3-like proteases preceded TAM-induced chromatin condensation and nuclear fragmentation, the typical apoptotic morphologies. Pretreatment of cells with a specific inhibitor of caspase-3, acetyl-Asp-Glu-Val-Asp-aldehyde, or with a general inhibitor of caspases, benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, prevented TAM-induced apoptosis. TAM also stimulated c-Jun NH2-terminal kinase (JNK) 1 activity, and interfering with the JNK pathway by over-expressing a DN JNK1 mutant attenuated TAM-induced apoptosis. In addition, treatment of cells with a lipid-soluble antioxidant vitamin E blocked TAM-induced caspase-3 and JNK1 activation as well as apoptosis, whereas water-soluble antioxidants N-acetyl L-cysteine and glutathione had little effect. Thus, this study demonstrates that TAM induces apoptosis in ER-negative breast cancer cells through caspase-3 and JNK1 pathways, which are probably initiated at the cell membrane by an oxidative mechanism.
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PMID:Activation of caspase-3 and c-Jun NH2-terminal kinase-1 signaling pathways in tamoxifen-induced apoptosis of human breast cancer cells. 1108 19

The Swedish double mutation (KM670/671NL) of amyloid precursor protein (APPsw) is associated with early-onset familial Alzheimer's disease (FAD) and results in from three- to sixfold increased beta-amyloid production. The goal of the present study was to elucidate the effects of APPsw on mechanisms of apoptotic cell death. Therefore, PC12 cells were stably transfected with human APPsw. Here we report that the vulnerability of APPsw-bearing PC12 cells to undergo apoptotic cell death was significantly enhanced after exposure to hydrogen peroxide compared to human wild-type APP-bearing cells, empty vector-transfected cells, and parent untransfected cells. In addition, we have analyzed the potential influence of several mechanisms that can interfere with the execution of the apoptotic cell death program: the inhibition of cell death by the use of caspase inhibitors and the reduction of oxidative stress by the use of (+/-)-alpha-tocopherol (vitamin E). Interestingly, oxidative stress-induced cell death was significantly attenuated in APPsw PC12 cells by pretreatment with caspase-3 inhibitors but not with caspase-1 inhibitors. In parallel, caspase-3 activity was markedly elevated in APPsw PC12 after stimulation with hydrogen peroxide for 6 hr, whereas caspase-1 activity was unaltered. In addition, oxidative stress-induced cell death could be reduced after pretreatment of APPsw cells with (+/-)-alpha-tocopherol. The protective potency of (+/-)-alpha-tocopherol was even greater than that of caspase-3 inhibitors. Our findings further emphasize the role of mutations in the amyloid precursor protein in apoptotic cell death and may provide the fundamental basis for further efforts to elucidate the underlying processes caused by FAD-related mutations.
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PMID:Elevated vulnerability to oxidative stress-induced cell death and activation of caspase-3 by the Swedish amyloid precursor protein mutation. 1128 46

After 12, 18, and 24 h of oral administration of carbon tetrachloride (as a 1:1 mixture with mineral oil: 4 ml/kg body weight) to rats, the activity of caspase-3-like protease in the liver increased significantly compared to that in the control group that was given mineral oil (4 ml/kg). In plasma, the activity of caspase-3 was barely detectable in the control rat, but increased significantly 24 h after drug administration along with a dramatic increase in glutamate oxaloacetate transaminase. These results indicate that carbon tetrachloride causes apoptosis in the liver by activating caspase-3, which is released to plasma by secondary necrosis. After 18 and 24 h of carbon tetrachloride administration, the liver concentration of hydrophilic vitamin C was decreased significantly, while that of hydrophobic vitamin E was not affected. The plasma concentration of vitamins C and E was not influenced significantly. These results suggest that carbon tetrachloride induces oxidative stress mainly in the aqueous phase of the liver cell.
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PMID:Evaluation of oxidative stress during apoptosis and necrosis caused by carbon tetrachloride in rat liver. 1134 7

24-Hydroxycholesterol, the main cholesterol elimination product of the brain is increased in serum of Alzheimer patients. This oxysterol behaves neurotoxic towards the human neuroblastoma cell line, SH-SY5Y. Here we demonstrate, that 24-hydroxycholesterol-induced neurotoxicity in differentiated SH-SY5Y cells was due to apoptosis, as indicated by DNA-fragmentation, caspase-3 activation and a decrease of the mitochondrial membrane potential. Free radicals were generated, resulting in the death of 75% of the cells within 48h; neurotoxicity in differentiated SH-SY5Y cells was partially prevented by physiological concentrations of vitamin E (50-100 microM) in that 75% of the cells survived. Physiological concentrations of estradiol-17beta (1-100nM) elicited a protective effect in differentiated cells, which was not significant; however, in undifferentiated cells a significant protection was noted by this steroid hormone. Vitamin C and melatonin did not prevent 24-hydroxycholesterol-induced neurotoxicity. These in vitro data support the in vivo observed beneficial effects reported as circumstantial evidence of vitamin E and estradiol-17beta treatment in the prevention and therapy of neurodegenerative disease.
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PMID:Neurotoxicity of 24-hydroxycholesterol, an important cholesterol elimination product of the brain, may be prevented by vitamin E and estradiol-17beta. 1147 14

Necrosis and apoptosis coexist in the thyroid during goitre development and involution, but little is known about their respective causes. To test the possible role of free radicals, we analysed separately necrosis and apoptosis in male Wistar rats with depressed or normal antioxidant protection. Vitamin E-deficient and -sufficient rats were made goitrous with perchlorate in drinking water; involution was induced by repeated injection of NaI, without or with methimazole. Increase of thyroid malondialdehyde concentration and decrease of glutathione peroxidase activity confirmed the depressed antioxidant protection in vitamin E-deficient rats. Plasma thyroxine and TSH levels were not modified. Necrosis (swollen cells) and apoptosis (pyknotic cells) were quantified on histological sections. In vitamin E-sufficient rats, dead cells were very rare in control thyroids, increased 3-fold in goitre and still further during involution. Necrotic epithelial cells predominated in the goitre and their number declined after iodide supplementation, without or with methimazole. In contrast, the number of apoptotic cells and the caspase-3 activity were increased in goitre and further increased after involution, with two-thirds of pyknotic cells being observed in the interstitium. Apoptosis was prevented by methimazole. Vitamin E deficiency significantly increased total cell death and epithelial cell necrosis and induced the occurrence of much cell debris in the follicular lumen during involution, with no modification of the apoptotic reaction. These results show that the type of cell death is differentially regulated during goitre development and involution: necrosis is related to the oxidative status of the cells, while apoptosis comes with iodine-induced involution.
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PMID:Cell necrosis and apoptosis are differentially regulated during goitre development and iodine-induced involution. 1183 55

Dolichyl monophosphate (Dol-P) is involved in the attachment of carbohydrate chains to proteins in the formation of N-linked glycoprotein. We found that this compound induces apoptosis in human leukemia U937 cells. During this apoptotic execution, the increase of plasma membrane fluidity (5-20 min), reduction in mitochondrial transmembrane potential (delta psi m) and translocation of apoptosis-inducing factor (1-3 hr), caspase-3-like protease activation (2-4 hr), chromatin condensation and DNA ladder formation (3-4 hr) were observed successively. In this study, we examined mitochondrial morphological changes by electron microscopy and delta psi m by JC-1 from immediately after treatment of Dol-P. After 5 min of treatment, we observed clearly that mitochondrial cristae began to be disrupted ultrastructurally and almost all the cristae were disintegrated after 1 hr of treatment. The delta psi m of Dol-P treated cells was reduced to 34% as compared with that of control cells immediately after treatment and was quartered within 1 hr. The reduction in delta psi m was not inhibited by cyclosporin A, N-acetyl-L-cysteine and vitamin E. These results indicate that mitochondrial disruption is one of the first triggering events of Dol-P-induced apoptosis.
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PMID:Disruption of mitochondria is an early event during dolichyl monophosphate-induced apoptosis in U937 cells. 1202 7


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