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)

Oxidative stress in the brain has been increasingly associated with the development of numerous human neurological diseases. Microglia, activated upon neuronal injury or inflammatory stimulation, are known to release superoxide anion (*O(2) (-)), hydrogen peroxide (H(2)O(2)), and nitric oxide (NO), thereby further contributing to oxidative neurotoxicity. The reaction of NO and *O(2) (-), forming the toxic peroxynitrite (ONOO(-)), has been proposed to play a pathogenic role in neuronal injury. However, the interactions between H(2)O(2) and NO during oxidative stress, which may promote or diminish cell death, is less clear. In this study, we explored oxidative neurotoxicity induced by H(2)O(2) plus NO in primary cultures of rat cerebral cortex neurons. As the mechanisms may involve reactions between H(2)O(2) and NO, we monitored the production of ONOO(-)and reactive oxygen species (ROS) throughout the experiments. Results indicated that the NO donor S-nitroso-N-acetyl-D, L-penicillamine (SNAP) and H(2)O(2) by themselves elicited neuronal death in a concentration- and time-dependent manner. Sublytic concentrations of H(2)O(2) plus SNAP were sufficient to induce neuronal apoptosis as determined by DNA laddering and fluorescent staining of apoptotic nuclei. Transient ONOO(-)increase was accompanied by rapid H(2)O(2) decay and NO production, whereas ROS slowly decreased following treatment. Furthermore, p38 mitogen-activated protein kinase (MAPK) activation and the cleavage of caspase-3 were observed. Conversely, inhibition of p38 MAPK and caspase-3 significantly reduced apoptotic death induced by H(2)O(2) plus SNAP. These data suggest that H(2)O(2) and NO act synergistically to induce neuronal death through apoptosis in which activation of p38 MAPK and caspase-3 is involved.
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PMID:Oxidative neurotoxicity in rat cerebral cortex neurons: synergistic effects of H2O2 and NO on apoptosis involving activation of p38 mitogen-activated protein kinase and caspase-3. 1270 12

We examined the mechanism of 17beta-estradiol (estrogen)-mediated inhibition of apoptosis in C6 (rat glioma) cells following exposure to hydrogen peroxide (H(2)O(2)). Cells were preincubated with 4 microM estrogen for 2 h and then exposed to 100 microM H(2)O(2) for 24 h. Exposure to H(2)O(2) caused significant increases in intracellular calcium (Ca(2+)), as determined by fura-2, which was attenuated by preincubation with estrogen. H(2)O(2) and ionomycin caused cell death in a dose-dependent manner, as measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Preincubation with estrogen restored viability in cells exposed to H(2)O(2) but not in cells exposed to ionomycin. Western blot analysis showed an increase in Bax/Bcl-2 ratio, calpain activity, and caspase-3 activity following treatment with H(2)O(2), and estrogen pretreatment decreased levels of all three. Cell morphology, as evaluated by Wright staining, indicated apoptosis in cells treated with H(2)O(2), and pretreatment with estrogen reduced apoptosis. Results from MTT and Wright staining were further supported by the terminal deoxyribonucleotidyl transferase (TdT)-mediated dUTP Nick End Labeling (TUNEL) assay. These results indicate a role for estrogen in preventing apoptosis in C6 glial cells exposed to H(2)O(2). Our results suggest that estrogen may have a protective role in minimizing glial cell apoptosis in neurological diseases such as demyelinating disease or central nervous system trauma.
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PMID:Estrogen attenuates oxidative stress-induced apoptosis in C6 glial cells. 1270 34

Previous experiments have shown that emodin is highly active in suppressing the proliferation of several tumor cell lines. However, it is not clear that emodin can induce growth inhibition of hepatoma cells. We have found that emodin induces apoptotic responses in the human hepatocellular carcinoma cell lines (HCC) Mahlavu, PLC/PRF/5 and HepG2. The addition of emodin to these three cell lines led to inhibition of growth in a time- and dose-dependent manner. Emodin generated reactive oxygen species (ROS) in these cells which brought about a reduction of the intracellular mitochondrial transmembrane potential (DeltaPsim), followed by the activation of caspase-9 and caspase-3, leading to DNA fragmentation and apoptosis. Our findings demonstrate that ROS and the resulting oxidative stress play a pivotal role in apoptosis. Preincubation of hepatoma cell lines with the hydrogen peroxide-scavenging enzyme, catalase (CAT) and cyclosporin A (CsA), partially inhibited apoptosis. These results demonstrate that enhancement of generation of ROS, DeltaPsim disruption and caspase activation may be involved in the apoptotic pathway induced by emodin.
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PMID:Induction of apoptosis in hepatocellular carcinoma cell lines by emodin. 1271 64

This study was designed to isolate new genes related to apoptosis in rat pheochromocytoma (PC12) cells treated with hydrogen peroxide (H2O2), and to characterize the roles of the genes using both in vitro and in vivo models of oxidative injury. cDNA libraries were prepared from H2O2-treated and -untreated PC12 cells, and a ribosomal protein S9 (RPS9) clone was isolated by a differential screening method. Increase of RPS9 expression in both H2O2-treated PC12 and neuroblastoma (Neuro-2A) cells was shown by Northern blot analysis. Viability of the antisense-transfected Neuro-2A (RPS9-AS) cells following H2O2 treatment was significantly reduced in a dose-dependent manner. In an in vivo model of transient forebrain ischemia, an increase in RPS9 expression was prominent by 1 day postischemia in the granule cell layer neurons of the dentate gyrus. Both activation of caspase-3 and significant recovery of viability following pretreatment with cycloheximide were shown in RPS9-AS cells treated with H2O2. These data suggest that RPS9 plays a protective role in oxidative injury of neuronal cells.
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PMID:Alterations in mRNA expression of ribosomal protein S9 in hydrogen peroxide-treated neurotumor cells and in rat hippocampus after transient ischemia. 1271 47

The intracellular generation of hydrogen peroxide (H(2)O(2)) by 6-formylpterin and its effects on the cell surface exposure of phosphatidylserine (PS) as a marker of cell death were examined in human peripheral blood leukocytes, and the effects were compared with those of exogenously administered H(2)O(2). Neutrophils, monocytes and lymphocytes were isolated from fresh blood, and cultured for 24 h in vitro. In neutrophils, the intracellular H(2)O(2) generation was observed when the cells were incubated with 100-500 microM 6-formylpterin, and the PS exposure due to spontaneous apoptosis was inhibited. The underlying mechanism of the inhibition was attributed to the suppression of both activation and activity of caspase-3. On the other hand, exogenously administered 100 microM H(2)O(2) did not affect the PS exposure. The intracellular H(2)O(2) generation was also observed in monocytes and lymphocytes. In monocytes, 500 microM 6-formylpterin induced more PS exposure than 100 microM H(2)O(2) did. In lymphocytes, up to 500 microM 6-formylpterin did not induce conspicuous PS exposure, while 100 microM H(2)O(2) induced severe PS exposure. These findings indicated that the resistance against an internal and external source of H(2)O(2) are different among leukocytes, for example, lymphocytes are poorly resistant against external H(2)O(2) but highly resistant against internal one.
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PMID:Effects of 6-formylpterin as an internal source of hydrogen peroxide on cell death of human peripheral blood leukocytes. 1273 36

To understand the basis of oligodendrocyte (OL) susceptibility to oxidative injury, purified rat OL cultures at different stages of maturation were exposed to nitric oxide (NO) donors with fast or slow kinetics of release and to tert-butyl-hydroperoxide, a membrane-permeant organic hydroperoxide. OL precursors (pre-OL) displayed the highest vulnerability to both oxygen or nitrogen reactive species, whereas mature OLs were uniquely vulnerable to long-lasting levels of NO. Cell death occurred by necrosis as well as apoptosis associated with increased caspase-3 activity and, only in the case of pre-OLs, with a decreased expression of the anti-apoptotic protein bcl-2. Pre-OLs were also more susceptible than mature OLs to lipid peroxidation, as measured by F2-isoprostane content in culture media. Finally, pre-OLs, but not mature OLs, expressed high levels of the mitochondrial scavenging enzyme Mn superoxide dismutase, suggesting that pre-OLs may efficiently convert anion superoxide into hydrogen peroxide and, paradoxically, be more predisposed than mature OLs to a toxic imbalance between hydrogen peroxide production and detoxification processes. These data suggest that susceptibility to lipid peroxidation, expression of the scavenging enzyme Mn superoxide dismutase and of the anti-apoptotic protein bcl-2, may contribute to the maturation-dependent vulnerability of OLs to oxidant injury.
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PMID:Differential lipid peroxidation, Mn superoxide, and bcl-2 expression contribute to the maturation-dependent vulnerability of oligodendrocytes to oxidative stress. 1276 90

Opening of the mitochondrial permeability transition pore has been recognized to be involved in cell death. The present study investigated the effect of beta-carbolines (harmaline and harmalol) on the MPP(+)-induced change in the mitochondrial membrane permeability and cell death in differentiated PC12 cells. beta-Carbolines and antioxidants (superoxide dismutase, catalase, ascorbate or rutin) prevented the loss of cell viability in PC12 cells treated with 250 microM MPP(+), while the effects of N-acetylcysteine and dithiothreitol were not observed. beta-Carbolines reduced the condensation and fragmentation of nuclei caused by MPP(+) in PC12 cells. beta-Carbolines alone did not exhibit a significant cytotoxic effect on PC12 cells. beta-Carbolines (50 microM) inhibited the decrease in mitochondrial transmembrane potential, cytochrome c release, activation of caspase-3, formation of reactive oxygen species (ROS) and depletion of GSH caused by MPP(+) in PC12 cells. beta-Carbolines reduced the hydrogen peroxide- or SIN-1-induced cell death in PC12 cells. The results suggest that beta-carbolines may attenuate the MPP(+)-induced viability loss in PC12 cells by inhibition of change in the mitochondrial membrane permeability and by antioxidant effect.
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PMID:N-methylated beta-carbolines protect PC12 cells from cytotoxic effect of MPP+ by attenuation of mitochondrial membrane permeability change. 1280 96

Treatment with 0.2 mM hydrogen peroxide (H(2)O(2)) or with 0.5 mM cisplatin caused caspase-9 and caspase-3 activation and death by apoptosis in U-937 human promonocytic cells. However, treatment with 2 mM H(2)O(2), or incubation with the glutathione suppressor DL-buthionine-(S,R)-sulfoximine (BSO) prior to treatment with cisplatin, suppressed caspase activation and changed the mode of death to necrosis. Treatment with 2 mM H(2)O(2) caused a great decrease in the intracellular ATP level, which was partially prevented by 3-aminobenzamide (3-ABA). Correspondingly, 3-ABA restored the activation of caspases and the execution of apoptosis. By contrast, BSO plus cisplatin did not decrease the ATP levels, and the generation of necrosis by this treatment was not affected by 3-ABA. On the other hand, while all apoptosis-inducing treatments and treatment with 2 mM H(2)O(2) caused Bax translocation from the cytosol to mitochondria as well as cytochrome c release from mitochondria to the cytosol, treatment with BSO plus cisplatin did not. Treatment with cisplatin alone caused Bid cleavage, while BSO plus cisplatin as well as 0.2 and 2 mM H(2)O(2) did not. Bcl-2 overexpression reduced the generation of necrosis by H(2)O(2), but not by BSO plus cisplatin. These results indicate the existence of different apoptosis/necrosis regulatory mechanisms in promonocytic cells subjected to different forms of oxidative stress.
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PMID:The selection between apoptosis and necrosis is differentially regulated in hydrogen peroxide-treated and glutathione-depleted human promonocytic cells. 1286 96

Anthocyanidins are the aglycon nucleuses of anthocyanins, which are reddish pigments widely spread in colored fruits and vegetables. To investigate their anti-cancer effect, induction of apoptosis was tested in human promyelocytic leukemia cells (HL-60), which is a valid model for testing antileukemic or general antitumoral compounds. Of six anthocyanidins representing the aglycons of most of anthocyanins, only those with an ortho-dihydroxyphenyl structure on the B-ring induce apoptosis, suggesting that the ortho-dihydroxyphenyl structure of anthocyanidins may contribute to the induction of apoptosis. Delphinidin, the most potent inducer, causes apoptosis in a time- and dose-dependent manner. The efficacious induction of apoptosis was observed at 100 micro M for 6 h. Concomitant with the apoptosis, delphinidin stimulates JNK pathway activation including JNK phosphorylation and c-jun gene expression, and activates caspase-3. Antioxidants including N-acetyl-L-cysteine (NAC) and catalase effectively block delphinidin-induced JNK phosphorylation, caspase-3 activation, and DNA fragmentation. Moreover, anthocyanidins directly cause HL-60 cells to generate intracellular hydrogen peroxide. Thus, anthocyanidins may trigger an apoptotic death program through an oxidative stress-involved JNK signaling pathway. The induction of apoptosis by anthocyanins may be the pivotal mechanism by which its chemopreventive action against cancer is based.
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PMID:Anthocyanidins induce apoptosis in human promyelocytic leukemia cells: structure-activity relationship and mechanisms involved. 1288 7

Takrisodokyeum (TRSDY), a Chinese herbal medicine, has been known to exert anti-tumoral activity in Korea. However, its molecular mechanism of action is not understood. In this study, we found that TRSDY induced apoptosis in HL-60 cells as evidenced by both a characteristic ladder pattern of discontinuous DNA fragments and an increase of annexin V+/PI- stained cell population. Our data demonstrated that TRSDY-induced apoptotic cell death was accompanied by activation of caspase-3 and cleavages of its substrates, poly(ADP-ribose) polymerase (PARP) and RhoGDP dissociation inhibitor (RhoGDI-2; also called D4-GDI) in a time- and concentration-dependent manner. Caspase-3 inhibitor, but not caspase-1 inhibitor, prevented TRSDY-induced apoptosis. Furthermore, treatment with TRSDY increased the production of intracellular hydrogen peroxide and pretreatment of cells with anti-oxidants conferred complete protection against hydrogen peroxide generation and subsequent caspase-3 activation. Taken together, these results suggest that TRSDY induces hydrogen peroxide generation, which, in turn, causes activation of caspase-3, degradation of PARP and D4-GDI, and eventually leads to apoptotic cell death.
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PMID:Induction of apoptosis by takrisodokyeum through generation of hydrogen peroxide and activation of caspase-3 in HL-60 cells. 1289 15


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