Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Triptolide, a major active component extracted from the root of Tripterygium wilfordii Hook f, has been shown to possess potent immunosuppressive and anti-inflammatory properties. In the present report, we reported that triptolide increased the generation of reactive oxygen species (ROS) and nitric oxide (NO) and induced apoptosis of RAW 264.7 cells in a dose-dependent manner (5-25 ng/ml). The antioxidant, reduced glutathione (GSH), significantly inhibited triptolide-induced apoptosis and inhibited the degradation of Bcl-2 protein, disruption of mitochondrial membrane potential, release of cytochrome c from mitochondria into the cytosol, activation of caspase-3, and cleavage of poly-(ADP-ribose)-polymerase. The inducible nitric oxide synthase-specific inhibitor 1400w blocked triptolide-induced apoptosis, but did not alter mitochondria disruption and caspase-3 activation. These results, for the first time, implicated that the increased endogenous ROS and NO co-mediated triptolide-induced apoptosis in macrophages. ROS initiated triptolide-induced apoptosis by the mitochondria signal pathway, while the apoptotic cell death mediated by NO was not via mitochondria collapse and caspase-3 activation. In addition, combining mathematical calculation and computer simulation based on our conventional experimental results, we set and validated the apoptotic model and provided more dynamic processes of triptolide-induced apoptotic cascade in macrophages.
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PMID:The roles of endogenous reactive oxygen species and nitric oxide in triptolide-induced apoptotic cell death in macrophages. 1710 29

Reactive oxygen species (ROS) generated after exposure to hypoxia and reoxygenation (H/R) play a pivotal role in the stimulation of cell death. In this study, we explored H/R-induced cytotoxicity in human lymphocytes. Compared to cells under normoxic conditions, H/R-treated cells exhibited significantly decreased viability and increased DNA breakage. Western blotting analysis demonstrated that H/R-induced the accumulation of p53 and p63 proteins. H/R also led to the activation of caspase-3 and -9, accompanied by the cleavage of PARP (poly(ADP-ribose)polymerase). Because apoptosis is usually accompanied by ROS generation and collapse of the mitochondrial membrane potential (MMP, Deltapsi(m)), we examined ROS and MMP levels in H/R-treated lymphocytes. Cells subjected to H/R exhibited significantly increased ROS and decreased MMP, compared with normoxic cells. Taken together, these results indicate that H/R treatment of human lymphocytes induces rapid ROS generation and MMP collapse, which triggers apoptosis.
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PMID:Hypoxia/reoxygenation-induced cytotoxicity in cultured human lymphocytes. 1712 11

AlphaB-crystallin homology, heat stress induction and chaperone activity suggested that a previously encloned gene product is a novel small heat shock protein (Hsp16.2). Suppression of Hsp16.2 by siRNA sensitized cells to hydrogen peroxide or taxol induced cell-death. Over-expressing of Hsp16.2 protected cells against stress stimuli by inhibiting cytochrome c release from the mitochondria, nuclear translocation of AIF and endonuclease G, and caspase 3 activation. Recombinant Hsp16.2 protected mitochondrial membrane potential against calcium induced collapse in vitro indicating that Hsp16.2 stabilizes mitochondrial membrane systems. Hsp16.2 formed self-aggregates and bound to Hsp90. Inhibition of Hsp90 by geldanamycin diminished the cytoprotective effect of Hsp16.2 indicating that this effect was Hsp90-mediated. Hsp16.2 over-expression increased lipid rafts formation as demonstrated by increased cell surface labeling with fluorescent cholera toxin B, and increased Akt phosphorylation. The inhibition of PI-3-kinase-Akt pathway by LY-294002 or wortmannin significantly decreased the protective effect of the Hsp16.2. These data indicate that the over-expression of Hsp16.2 inhibits cell death via the stabilization of mitochondrial membrane system, activation of Hsp90, stabilization of lipid rafts and by the activation of PI-3-kinase-Akt cytoprotective pathway.
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PMID:Inhibition of cell death by a novel 16.2 kD heat shock protein predominantly via Hsp90 mediated lipid rafts stabilization and Akt activation pathway. 1713 96

Desferrioxamine (DFX), which is an iron chelator, mimics hypoxia by enhancing HIF1-alpha accumulation and upregulating inflammatory mediators. DFX is usually beneficial, with preventive effects related primarily to its ability to scavenge reactive oxygen species. However, toxic effects on skeletal and ocular organs have been reported. The cytokinesis block micronucleus test and alkaline single-cell gel (Comet) assay were used to evaluate the genotoxic effects of DFX on human blood lymphocytes. Cultured human lymphocytes treated with 130microM DFX for various periods of time showed significant differences in the incidence of micronucleated binucleate cells, as well as in the length and moment of the comet tail. Western blot analysis using antibodies to proteins involved in the p53-mediated response to DNA damage revealed that p53 was accumulated and DNA damage checkpoint kinases were activated in lymphocytes treated with DFX. On the other hand, the p53 downstream target proteins p21 and bax were not affected, which indicates that DFX does not promote the transactivational activity of p53. Apoptosis assays demonstrated DFX-induced apoptosis of lymphocytes via the caspase cascade. The observed increase in the sub-G1 fraction and enhanced caspase-3 activity indicate that DFX can promote apoptosis in human lymphocytes, and these results were confirmed by protein immunoblot analysis. As apoptotic cell death is preceded by the collapse of the mitochondrial membrane potential, we also measured the mitochondrial membrane potential (Deltapsi(m)) using DiOC6, which is a fluorescent membrane potential probe. The fluorescence intensity of DiOC6 in lymphocytes was significantly reduced in a time-dependent manner after DFX treatment. Taken together, these results indicate that DFX activates p53-mediated checkpoint signals and induces apoptosis via mitochondrial damage in human peripheral blood lymphocytes.
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PMID:Desferrioxamine (DFX) has genotoxic effects on cultured human lymphocytes and induces the p53-mediated damage response. 1714 76

Ultraviolet (UV) irradiation is a DNA-damaging agent that triggers apoptosis through both the membrane death receptor and mitochondrial apoptotic signaling pathways. Bid, a pro-apoptotic Bcl-2 family member, is important in most cell types to apoptosis in response to DNA damage. In this study, a recombinant plasmid, YFP-Bid-CFP, comprised of yellow and cyan fluorescent protein and a full length Bid, was used as a fluorescence resonance energy transfer analysis (FRET) probe. Using the FRET technique based on YFP-Bid-CFP, we found that Bid activation was initiated at 9+/-1 h after UV irradiation, and the average duration of the activation was 75+/-10 min. Bid activation coincided with a collapse of the mitochondrial membrane potential with an average duration of 50+/-10 min. When cells were pretreated with Z-IETD-fmk (caspase-8 specific inhibitor) the process of Bid activation was completely inhibited, but the apoptosis was only partially affected. Z-DEVD-fmk (caspase-3 inhibitor) and Z-FA-fmk (non asp specific inhibitor) did not block Bid activation. Furthermore, the endogenous Bid activation with or without Z-IETD-fmk in response to UV irradiation was confirmed by Western blotting. In summary, using the FRET technique, we observed the dynamics of Bid activation during UV-induced apoptosis and found that it was a caspase-8 dependent event.
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PMID:Fluorescence resonance energy transfer analysis of bid activation in living cells during ultraviolet-induced apoptosis. 1721 57

Magnolol, a compound extracted from the Chinese medicinal herb Magnolia officinalis, has several biological effects. However, its protective effects against endothelial injury remain unclear. In this study, we examined whether magnolol prevents oxidized low density lipoprotein (oxLDL)-induced vascular endothelial apoptosis. Incubation of oxLDL with magnolol (2.5-20 microM) inhibited copper-induced oxidative modification via diene formation, thiobarbituric acid reactive substances (TBARS) assay and electrophoretic mobility assay. Apoptotic cell death as characterized by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) stain. We measured the production of reactive oxygen species (ROS) by using the fluorescent probe 2',7'-dichlorofluorescein acetoxymethyl ester (DCF-AM), and observed the activity of antioxidant enzymes. Furthermore, several apoptotic signaling pathways which showed NF-kappaB activation, increased cytosolic calcium, alteration of mitochondrial membrane potential, cytochrome c release and activation of caspase 3 were also investigated. We demonstrated that magnolol prevented the copper-induced oxidative modification of LDL. Magnolol attenuated the oxLDL-induced ROS generation and subsequent NF-kappaB activation. Furthermore, intracellular calcium accumulation and subsequent mitochondrial membrane potential collapse, cytochome c release and activation of caspase 3 caused by oxLDL were also inhibited by magnolol. Our results suggest that magnolol may have clinical implications in the prevention of atherosclerotic vascular disease through decreasing the oxLDL-induced ROS production.
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PMID:Protective effects of magnolol against oxidized LDL-induced apoptosis in endothelial cells. 1721 33

A sustained increase in the cytosolic Ca(2+) concentration ([Ca(2+)](i)) can cause cell death. In this study, we found that, in cultured porcine aortic smooth muscle cells, endoplasmic reticulum (ER) stress, triggered by depletion of Ca(2+) stores by thapsigargin (TG), induced an increase in the [Ca(2+)](i) and cell death. However, the TG-induced death was not related to the [Ca(2+)](i) increase but was mediated by targeting of activated Bax to mitochondria and the opening of mitochondrial permeability transition pores (PTPs). Once the mitochondrial PTPs had opened, several events, including collapse of the mitochondrial membrane potential, cytochrome c release, and caspase-3 activation, occurred and the cells died. TG-induced cell death was completely inhibited by the pan-caspase inhibitor Z-VAD-fmk and was enhanced by the Ca(2+) chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), suggesting the existence of a Ca(2+)-dependent anti-apoptotic mechanism. After TG treatment, Ca(2+)-sensitive mitogen-activated protein kinase (MAPK) activation was induced and acted as a downstream effector of phosphatidylinositol 3-kinase (PI 3-kinase). The protective effect of Z-VAD-fmk on TG-induced cell death was reversed by BAPTA, PD-098059 (an MAPK kinase inhibitor), or LY-294002 (a PI 3-kinase inhibitor). Taken together, our data indicate that ER stress simultaneously activate two pathways, the mitochondrial caspase-dependent death cascade and the Ca(2+)-dependent PI 3-kinase/MAPK anti-apoptotic machinery. The Bax activation and translocation, but not the [Ca(2+)](i) increase, may activate mitochondrial PTPs, which, in turn, causes activation of caspases and cell death, whereas Ca(2+)-dependent MAPK activation counteracts death signaling; removal of Ca(2+) activated a second caspase-independent death pathway.
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PMID:Dual effect of thapsigargin on cell death in porcine aortic smooth muscle cells. 1721 71

Chloroacetaldehyde, a metabolite of the anticancer drug ifosfamide, may be responsible for serious adverse effects like encephalopathy in ifosfamide chemotherapy. In this study, we demonstrate that chloroacetaldehyde, but not ifosfamide, induces cell death in human osteosarcoma Saos-2 cells and we investigated the mechanism by which this occurs. Chloroacetaldehyde above 30 micromol/l induced significant cell death in a time-dependent manner. Thiol compounds such as N-acetyl cysteine, glutathione and dithiothreitol protected the cells against chloroacetaldehyde-induced cell death, although other nonthiol compounds and the antioxidative enzymes superoxide dismutase and catalase did not, suggesting that reactive oxygen species might not mediate cell death. In cells exposed to chloroacetaldehyde, levels of both total thiols and glutathione were significantly reduced. Chloroacetaldehyde also collapsed the mitochondrial membrane potential of these cells, induced the release of cytochrome c from mitochondria to the cytosol and significantly reduced cellular ATP levels during the course of death. The mitochondrial potential collapse was also prevented by thiol compounds. Flow cytometric analyses by means of annexin-V and propidium iodide double staining and immunofluorescence staining of active caspase-3 revealed that cells subjected to a lethal dose of chloroacetaldehyde displayed features characteristic of necrosis and that caspase-3 was not activated in response to chloroacetaldehyde. Taken together, these findings suggest that Saos-2 cells exposed to chloroacetaldehyde die by necrosis resulting from a decrease in intracellular thiols, disruption of the mitochondrial membrane potential and the depletion of cellular ATP.
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PMID:Necrotic pathway in human osteosarcoma Saos-2 cell death induced by chloroacetaldehyde. 1741 23

Several studies have shown how pentacyclic triterpenes can inhibit proliferation and induce apoptosis of some tumor cell lines; however, its effect on astrocytic tumors, one of the most malignant forms of cancer, has rarely been reported. The aim of this study was to examine how the pentacyclic triterpenes, oleanolic acid and maslinic acid, isolated from olive juice, affected astrocytoma cell morphology and survival. Cell proliferation was inhibited in 1321N1 astrocytoma cells by using 1 to 50 micromol/L of either oleanolic acid or maslinic acid, with an average IC(50) of 25 micromol/L. Growth inhibition led to morphologic and cytoskeletal alterations associated with the loss of stellate morphology and characterized by a retraction of the cytoplasm and collapse of actin stress fibers. Using 4',6-diamidino-2-phenylindole and Annexin V, we showed that astrocytoma cell death induced by oleanolic acid or maslinic acid were mainly due to apoptotic events. Furthermore, we showed that caspase-3 is activated as a consequence of triterpene treatment. Finally, we found that exposure of the cells to oleanolic acid or maslinic acid resulted in a significant increase of intracellular reactive oxygen species, followed by loss of mitochondrial membrane integrity. Importantly, enzymatic scavengers, such as catalase, or phenolic antioxidants, such as butylated hydroxytoluene, rescued cells from the triterpene-mediated apoptosis, suggesting that the potential therapeutic effect of these acidic triterpenes is dependent on oxidative stress. Our data show that acidic triterpenes play a major role in 1321N1 astrocytoma morphology and viability and support the conclusion that oleanolic acid and maslinic acid may thus be promising new agents in the management of astrocytomas.
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PMID:Acidic triterpenes compromise growth and survival of astrocytoma cell lines by regulating reactive oxygen species accumulation. 1744 87

Previous studies have suggested that Ginkgo biloba extract (EGb761) has a protective potentiality against apoptosis of neurons or neuron-like cells induced by MPTP. In this study, the effects of EGb761 on PC12 cells injured by paraquat (PQ), a neurotoxin, were tested. The results showed that after incubation of PC12 cells with EGb761 prior to PQ exposure, the PQ-induced decrease of cell viability was significantly reversed, the collapse of mitochondrial membrane potential (MMP) was attenuated and the percentage of apoptotic cells was reduced. Moreover, EGb761 pretreatment evidently increased the numbers of tyrosine hydroxylase (TH) positive and bcl-2 positive cells and degraded the number of caspase-3 positive cells in PQ-injured PC12 cells, in comparison to the treatment with PQ alone. This study indicates that EGb761 has a neuroprotective effect on paraquat-induced apoptosis of PC12 cells. The mechanism underlying the protective effects of EGb761 in PQ-injured PC12 cells might be related to the increase of bcl-2 activation, maintenance of MMP stability and decrease of caspase-3 activation through mitochondria-dependent pathway. The results from this study provide an experimental basis for the potential use of EGb761 in treatment of Parkinson's disease.
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PMID:Protective effects of Ginkgo biloba extract on paraquat-induced apoptosis of PC12 cells. 1750 17


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