Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of the present study was to investigate whether iron, which is involved in the formation of free radicals in vitro, can initiate cellular injury in human intestinal cells. The effects of various concentrations of iron were studied in preconfluent, colonic-cancerogenous cells, and also in postconfluent, differentiating cells. Cellular damage was assessed using cell proliferation (serial cell counting), tetrazolium dye (MTT) uptake, lactate dehydrogenase (LDH) release and apoptosis studies based on caspase-3 activities. Also the activities of the major antioxidative enzymes, superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) were measured after the cells had been exposed to iron. Our results indicated that preconfluent cells were more susceptible to iron toxicity, as assessed by a significant reduction in cell proliferation and MTT uptake in a concentration-dependent manner compared to the control. However, no evidence for MTT uptake was observed in postconfluent cells. Caspase-3 activity, an indicator of cell apoptosis, considerably increased in preconfluent cells at high iron levels compared to the control (p < 0.05), whereas postconfluent cells were not significantly affected. LDH release was similar for both groups and was significantly higher than the control at 900 microM iron and above. SOD activities were not affected by iron in either group, whereas GPx was considerably higher in iron-treated cells in both groups compared with the control (because of relatively high standard deviations this effect was not significant). In conclusion we suggest that iron exerts its toxic effects intracellularly especially in preconfluent Caco-2 cells, whereas only high iron doses were able to alter the viability of differentiating, enterocyte-like cells.
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PMID:Toxicological effects of iron on intestinal cells. 1512 77

Aroylhydrazone and thiosemicarbazone iron (Fe) chelators have potent antitumor activity. The aim of the current study was to examine the antitumor effects and mechanisms of action of a novel series of Fe chelators, the di-2-pyridyl thiosemicarbazones. Of 7 new chelators synthesized, 4 showed pronounced antiproliferative effects. The most active chelator was Dp44mT, which had marked and selective antitumor activity-for example, an IC(50) of 0.03 microM in neuroepithelioma cells compared with more than 25 microM in mortal fibroblasts. Indeed, this antiproliferative activity was the greatest yet observed for an Fe chelator. Efficacy was greater than it was for the cytotoxic ligand 311 and comparable to that of the antitumor agent doxorubicin. Strikingly, Dp44mT significantly (P <.01) decreased tumor weight in mice to 47% of the weight in the control after only 5 days, whereas there was no marked change in animal weight or hematologic indices. Terminal deoxyribonucleotidyl transferase (TdT)-mediated dUTP nick end-labeling (TUNEL) staining demonstrated apoptosis in tumors taken from mice treated with Dp44mT. This chelator caused a marked increase of caspase-3 activity in murine Madison-109 (M109) cells. Caspase activation was at least partially mediated by the release of mitochondrial holo-cytochrome c (h-cytc) after incubation with Dp44mT. In conclusion, Dp44mT is a novel, highly effective antitumor agent in vitro and in vivo that induces apoptosis.
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PMID:Novel di-2-pyridyl-derived iron chelators with marked and selective antitumor activity: in vitro and in vivo assessment. 1515 82

The mitochondria-targeted drugs mitoquinone (Mito-Q) and mitovitamin E (MitoVit-E) are a new class of antioxidants containing the triphenylphosphonium cation moiety that facilitates drug accumulation in mitochondria. In this study, Mito-Q (ubiquinone attached to a triphenylphosphonium cation) and MitoVit-E (vitamin E attached to a triphenylphosphonium cation) were used. The aim of this study was to test the hypothesis that mitochondria-targeted antioxidants inhibit peroxide-induced oxidative stress and apoptosis in bovine aortic endothelial cells (BAEC) through enhanced scavenging of mitochondrial reactive oxygen species, thereby blocking reactive oxygen species-induced transferrin receptor (TfR)-mediated iron uptake into mitochondria. Glucose/glucose oxidase-induced oxidative stress in BAECs was monitored by oxidation of dichlorodihydrofluorescein that was catalyzed by both intracellular H(2)O(2) and transferrin iron transported into cells. Pretreatment of BAECs with Mito-Q (1 microM) and MitoVit-E (1 microM) but not untargeted antioxidants (e.g. vitamin E) significantly abrogated H(2)O(2)- and lipid peroxide-induced 2',7'-dichlorofluorescein fluorescence and protein oxidation. Mitochondria-targeted antioxidants inhibit cytochrome c release, caspase-3 activation, and DNA fragmentation. Mito-Q and MitoVit-E inhibited H(2)O(2)- and lipid peroxide-induced inactivation of complex I and aconitase, TfR overexpression, and mitochondrial uptake of (55)Fe, while restoring the mitochondrial membrane potential and proteasomal activity. We conclude that Mito-Q or MitoVit-E supplementation of endothelial cells mitigates peroxide-mediated oxidant stress and maintains proteasomal function, resulting in the overall inhibition of TfR-dependent iron uptake and apoptosis.
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PMID:Supplementation of endothelial cells with mitochondria-targeted antioxidants inhibit peroxide-induced mitochondrial iron uptake, oxidative damage, and apoptosis. 1522 Mar 29

Heme oxygenase-1 (HO-1) is a cytoprotective protein that catalyzes the degradation of heme to biliverdin, iron, and carbon monoxide (CO). In the present study, we found that endoplasmic reticulum (ER) stress induced by a variety of experimental agents stimulated a time- and concentration-dependent increase in HO-1 mRNA and protein in vascular smooth muscle cells (SMC). The induction of HO-1 by ER stress was blocked by actinomycin D or cycloheximide and was independent of any changes in HO-1 mRNA stability. Luciferase reporter assays indicated that ER stress stimulated HO-1 promoter activity via the antioxidant response element. Moreover, ER stress induced the nuclear import of Nrf2 and the binding of Nrf2 to the HO-1 antioxidant response element. Interestingly, ER stress stimulated SMC apoptosis, as demonstrated by annexin V binding, caspase-3 activation, and DNA laddering. The induction of apoptosis by ER stress was potentiated by HO inhibition, whereas it was prevented by addition of HO substrate. In addition, exposure of SMC to exogenously administered CO inhibited ER stress-mediated apoptosis, and this was associated with a decrease in the expression of the proapoptotic protein, GADD153. In contrast, the other HO-1 products failed to block apoptosis or GADD153 expression during ER stress. These results demonstrated that ER stress is an inducer of HO-1 gene expression in vascular SMC and that HO-1-derived CO acts in an autocrine fashion to inhibit SMC apoptosis. The capacity of ER stress to stimulate the HO-1/CO system provides a novel mechanism by which this organelle regulates cell survival.
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PMID:Endoplasmic reticulum stress stimulates heme oxygenase-1 gene expression in vascular smooth muscle. Role in cell survival. 1554 73

The release of cardioactive substances during hepatic ischemia/reperfusion injury generates toxic free radicals that inflict hepatic and remote cardiac damage. The aim of the study was to determine whether TPEN, a potent iron chelator, ameliorates the apoptotic hepatic and cardiac function injuries. Three groups of isolated rat livers were studied: (1) continuously perfused with Krebs-Henseleit solution; (2) subjected to 120 min of ischemia and 15 min of reperfusion; (3) as in group 2, with TPEN administered prior to ischemia. Isolated hearts were perfused for 65 min with the effluent of the reperfused livers. Results showed that TPEN administration reduced the release of norepinephrine, epinephrine, dopamine, prostaglandin E2 and angiotensin II, decreased intrahepatic caspase-3 activity, and decreased the mean hepatocyte apoptotic index (TUNEL assay) (p = 0.001). Perfusion with post-ischemic hepatic effluent caused a transient 15-min increase in left ventricular contraction and coronary flow (p < 0.05), followed by a decrease in cardiac function at one hour. TPEN reduced the transient elevation in left ventricular contraction p < 0.05), but did not prevent the subsequent decrease in cardiac function. In conclusion, TPEN attenuates post-ischemic apoptotic hepatic injury by modulating caspase-3-like activity and reduces the cardioactive substances released from the liver.
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PMID:TPEN attenuates hepatic apoptotic ischemia/ reperfusion injury and remote early cardiac dysfunction. 1571 22

Parkinson's disease (PD) is characterized by the selective loss of dopaminergic neurons in the substantia nigra (SN). 6-Hydroxydopamine (6-OHDA), a dopaminergic neurotoxin, is detected in human brains and the urine of PD patients. Using SH-SY5Y, a human neuroblastoma cell line, we demonstrated that 6-OHDA toxicity was determined by the amount of p-quinone produced in 6-OHDA auto-oxidation rather than by reactive oxygen species (ROS). Glutathione (GSH), which conjugated with p-quinone, provided significant protection whereas catalase, which detoxified hydrogen peroxide and superoxide anions, failed to block cell death caused by 6-OHDA. Although iron accumulated in the SN of patients with PD can cause dopaminergic neuronal degeneration by enhancing oxidative stress, we found that extracellular ferrous iron promoted the formation of melanin and reduced the amount of p-quinone. The addition of ferrous iron to the culture medium inhibited caspase-3 activation and apoptotic nuclear morphologic changes and blocked 6-OHDA-induced cytotoxicity in SH-SY5Y cells and primary cultured mesencephalic dopaminergic neurons. These data suggested that generation of p-quinone played a pivotal role in 6-OHDA-induced toxicity and extracellular iron in contrast to intracellular iron was protective rather than harmful because it accelerated the conversion of p-quinone into melanin.
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PMID:p-Quinone mediates 6-hydroxydopamine-induced dopaminergic neuronal death and ferrous iron accelerates the conversion of p-quinone into melanin extracellularly. 1571 15

Hepatic fibrosis occurs after many years of iron overload in liver. An effective iron deposition model induced by ferric nitrilotriacetate (FeNTA) in cultured rat hepatocytes was assumed. It has been shown that treatment of rat hepatocytes with FeNTA lead to oxidative stress and hepatocyte apoptosis. Hepatocyte apoptosis can promote liver fibrosis. The mechanisms of hepatocyte apoptosis induced by FeNTA have not yet been fully elucidated. The present study demonstrated that FeNTA-induced hepatocyte apoptosis was related to Bax translocation, cytochrome c release, and caspase-3 activation.
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PMID:Translocation of Bax in rat hepatocytes cultured with ferric nitrilotriacetate. 1580 78

To determine the effects of vitamin supplementation on the lipid-peroxidation-mediated toxicity of iron-ions on corneal endothelial cells (CECs) leading to apoptosis, murine CECs were maintained in tissue culture medium supplemented with increasing concentrations of free iron-ions, a treatment known to lead to increased lipid-peroxidation. The concentration of anti-oxidative vitamins (ascorbic acid, tocopherol and retinoic acid) in the cell supernatant and in the cells was determined by high-pressure liquid chromatography. Apoptosis was assessed by quantification of caspase-3-like activity and by using annexin-V/propidium iodide stains for flow cytometry. Lipid-peroxidation was measured by the malondialdehyde method. Supplementation with anti-oxidative vitamins was tested for the ability to counteract the induction of apoptosis. The production of nitric oxide was assessed spectrophotometrically and the expression levels of inducible and endothelial nitric oxide synthase were determined by Western blot. Increasing levels of free iron led to a rapid loss of anti-oxidative vitamins in the supernatant and in the CECs. This was correlated with rising levels of malondialdehyde and increased apoptosis. Supplementation with ascorbic acid or alpha-tocopherol alone did not prevent lipid-peroxidation in the cells. A combination of vitamins C and E (ascorbic acid, tocopherol) or solitary supplementation with vitamin A (retinoic acid) prevented lipid-peroxidation. We thus present a novel in vitro model for testing the direct influence of pro-oxidative species on CECs. We also show that supplementation with anti-oxidative vitamins to CECs significantly prevents the generation of free-radical-induced oxidative injury and apoptosis. These findings may have important implications for the storage of human corneae prior to transplantation and for the prolongation of corneal graft survival.
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PMID:Anti-oxidative vitamins prevent lipid-peroxidation and apoptosis in corneal endothelial cells. 1583 41

In order to elucidate the mechanisms involved in apoptosis induction by iron deprivation, we compared cells sensitive (38C13) and resistant (EL4) to apoptosis induced by iron deprivation. Iron deprivation was achieved by incubation in a defined iron-free medium. We detected the activation of caspase-3 as well as the activation of caspase-9 in sensitive cells but not in resistant cells under iron deprivation. Iron deprivation led to the release of cytochrome c from mitochondria into the cytosol only in sensitive cells but it did not affect the cytosolic localization of Apaf-1 in both sensitive and resistant cells. The mitochondrial membrane potential (Deltapsi(m)) was dissipated within 24 h in sensitive cells due to iron deprivation. The antiapoptotic Bcl-2 protein was found to be associated with mitochondria in both sensitive and resistant cells and the association did not change under iron deprivation. On the other hand, under iron deprivation we detected translocation of the proapoptotic Bax protein from the cytosol to mitochondria in sensitive cells but not in resistant cells. Taken together, we suggest that iron deprivation induces apoptosis via mitochondrial changes concerning proapoptotic Bax translocation to mitochondria, collapse of the mitochondrial membrane potential, release of cytochrome c from mitochondria, and activation of caspase-9 and caspase-3.
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PMID:Iron deprivation induces apoptosis via mitochondrial changes related to Bax translocation. 1584 99

Lactoferrin, a member of the transferrin family, is iron-binding and a strongly cationic 76 kDa glycoprotein. In breast milk it is secreted in high concentrations from glandular epithelia and is also present in other exocrine fluids including saliva. In the present study, we examined the biological mechanisms of apoptosis induced by pepsin-digested-lactoferrin peptide (Lfn-p) in the human oral squamous cell carcinoma cell line SAS. We found that treatment with Lfn-p induced cell death with apoptotic nuclear changes, preceded by the cleavage of caspase-3 and poly (ADP-ribose) polymerase (PARP) in the apoptotic cells. Treatment with Lfn-p induced phosphorylation of extracellular signal-regulated kinase (ERK1/2), a member of the MAP kinase family, at early stages of apoptosis. Another MAP kinase, c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK), was also phosphorylated by treatment with Lfn-p. Pretreatment of SAS cells with SP600125, a JNK/SAPK inhibitor, diminished Lfn-induced apoptosis, as assessed by determining released lactate dehydrogenase activity. On the other hand, the MEK1 inhibitors PD98059 or U0126 showed no effect on repression of cell death, but rather an increase. These results suggest that JNK/SAPK activation may play an important role in Lfn-p-induced apoptotic cell death of human oral squamous cell carcinoma cells.
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PMID:Pepsin-digested bovine lactoferrin induces apoptotic cell death with JNK/SAPK activation in oral cancer cells. 1587 78


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