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 mechanism by which beta-amyloid protein (A beta) causes degeneration in cultured neurons is not completely understood, but several lines of evidence suggest that A beta-mediated neuronal death is associated with an enhanced production of reactive oxygen species (ROS) and oxidative damage. In the present study, we address whether supplementation of glucose-containing culture media with energy substrates, pyruvate plus malate (P/M), protects rat primary neurons from A beta-induced degeneration and death. We found that P/M addition attenuated cell death evoked by beta-amyloid peptides (A beta(25-35) and A beta(1-40)) after 24 hr treatment and that this effect was blocked by alpha-ciano-3-hydroxycinnamate (CIN), suggesting that it requires mitochondrial pyruvate uptake. P/M supply to control and A beta-treated neuronal cultures increases cellular reducing power, as indicated by the ability to reduce the dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). The early increases in ROS levels, measured by dichlorofluorescein (DCF) fluorescence, and caspase-3 activity that follow exposure to A beta were notably reduced in the presence of P/M. These results place activation of caspase-3 most likely downstream of oxidative damage to the mitochondria and indicate that mitochondrial NAD(P) redox status plays a central role in the neuroprotective effect of pyruvate. Inhibition of respiratory chain complexes and mitochondrial uncoupling did not block the early increase in ROS levels, suggesting that A beta could initiate oxidative stress by activating a source of ROS that is not accesible to the antioxidant defenses fueled by mitochondrial substrates.
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PMID:Pyruvate protection against beta-amyloid-induced neuronal death: role of mitochondrial redox state. 1283 69

The purpose of this study was to investigate the potential neuroprotective effects of myricetin (flavonoid) and fraxetin (coumarin) on rotenone-induced apoptosis in SH-SY5Y cells, and the possible signal pathway involved in a neuronal cell model of Parkinson's disease. These two compounds were compared to N-acetylcysteine. The viability of cells was assessed by 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and cytotoxicity was assayed by lactate dehydrogenase (LDH) released into the culture medium. Parameters related to apoptosis, such as caspase-3 activity, the cleavage of poly(ADP-ribose) polymerase and the levels of reactive oxygen species were also determined. Rotenone caused a time- and dose-dependent decrease in cell viability and the degree of LDH release was proportionally to the effects on cell viability. Cells were pretreated with fraxetin, myricetin and N-acetylcysteine at different concentrations for 30 min before exposure to rotenone. Cytotoxicity of rotenone (5 microM) for 16 h was significantly diminished as well as the release of LDH into the medium, by the effect of fraxetin, myricetin and N-acetylcysteine, with fraxetin (100 microM) and N-acetylcysteine (100 microM) being more effective than myricetin (50 microM). Rotenone-induced apoptosis in SH-SY5Y cells was detected by an increase in caspase-3 activity and in the cleavage of poly(ADP-ribose) polymerase. After exposing these cells to rotenone, a significant increase in reactive oxygen species preceded apoptotic events. Fraxetin (100 microM) and N-acetylcysteine (100 microM) not only reduced rotenone-induced reactive oxygen species formation, but also attenuated caspase-3 activity and poly(ADP-ribose) polymerase cleavage at 16 h against rotenone-induced apoptosis. The effect of fraxetin in both experiments was similar to that of N-acetylcysteine. These results demonstrated the protective action of fraxetin and suggest that it can reduce apoptosis, possibly by decreasing free radical generation in SH-SY5Y cells. Myricetin at 100 microM was without any preventive effect.
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PMID:Effect of fraxetin and myricetin on rotenone-induced cytotoxicity in SH-SY5Y cells: comparison with N-acetylcysteine. 1286 Apr 76

Sanguinarine, derived from the root of Sanguinaria canadensis and other poppy fumaria species, possesses strong antimicrobial, anti-inflammatory, and antioxidant properties. We earlier showed that sanguinarine kills human epidermoid carcinoma A431 cells via an induction of apoptosis [N. Ahmad et al., Clin. Cancer Res., 6: 1524-1528, 2000]. In this study, using immortalized human keratinocytes (HaCaT cells), we provide information about mechanism of the antiproliferative effect of sanguinarine. Sanguinarine [0.1 (M-2 (M)] treatment to HaCaT cells was found to inhibit in a dose-dependent manner the cell proliferation and induce apoptosis, as measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and ELISA, respectively. Sanguinarine treatment also resulted in a significant cleavage of poly(ADP-ribose) polymerase in HaCaT cells. Because mitochondrial pathway is critical for the regulation of apoptosis, we studied the involvement and regulation of mitochondrial events in sanguinarine-mediated apoptosis of HaCaT cells. As shown by the immunoblot analysis, our data clearly demonstrated that sanguinarine treatment to HaCaT cells resulted in a dose-dependent (a) increase in the level of Bax with a concomitant decrease in Bcl-2 levels and (b) increase in Bax/Bcl-2 ratio. Sanguinarine also resulted in significant increases in the proapoptotic members of Bcl-2 family proteins, i.e., Bak and Bid. This was accompanied by increase in (a) protein expression of cytochrome c and apoptotic protease-activating factor-1 and (b) activity and protein expression of caspase-3, caspase-7, caspase-8, and caspase-9. Taken together, our data showed the involvement of mitochondrial pathway and Bcl-2 family proteins during sanguinarine-mediated apoptosis of immortalized keratinocytes. We suggest that sanguinarine could be developed as a drug for the management of hyperproliferative skin disorders, including skin cancer.
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PMID:Activation of prodeath Bcl-2 family proteins and mitochondrial apoptosis pathway by sanguinarine in immortalized human HaCaT keratinocytes. 1291 70

The protective effect of Acanthopanax senticosus (AS) against ethanol (EtOH)-induced apoptosis of the human neuroblastoma cell line SK-N-MC was investigated via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometric analysis, DNA fragmentation assay, reverse transcription-polymerase chain reaction (RT-PCR), and caspase-3 assay. It was shown that cells treated with EtOH exhibit classical apoptotic features, while cells pre-treated with Acanthopanax senticosus prior to EtOH exposure showed decreased occurrence of apoptotic features. In addition, Acanthopanax senticosus pre-treatment was shown to inhibit EtOH-induced increase in caspase-3 mRNA expression and activity. These results suggest that Acanthopanax senticosus may exert a protective effect against EtOH-induced apoptosis of human neuroblastoma cells.
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PMID:Protective effect of Acanthopanax senticosus against ethanol-induced apoptosis of human neuroblastoma cell line SK-N-MC. 1294 69

Current treatments for childhood brain tumor medulloblastoma (MB), radiation and chemotherapy, lead to undesirable side effects. Identification of antitumor agents that reduce the toxicity will thus have significant therapeutic value. In this study, we investigated all-trans-retinoic acid (ATRA) as an antitumor agent. Although high concentrations (1-10 microM) of retinoic acid derivatives are generally needed for significant antitumor effects in many cancer cells, we observed that pharmacologically relevant concentrations of ATRA were effective in inducing cell death in human MB cells. Using 10-fold lower concentrations (100-500 nM), we found that ATRA inhibits MB (DAOY, D283, D425, and D458) cell proliferation as determined by cell viability [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] and bromodeoxyuridine incorporation assays. Furthermore, 100 nM ATRA was potent in inhibiting the anchorage-independent growth of the sensitive cell lines (D283, D425, and D458) in soft agar assays. We also demonstrate that the ATRA-induced decrease in cell viability was due to increased cell death by apoptosis, which was accompanied by a 20-fold induction of caspase-3 activity in the most sensitive cell line, D458. By contrast, induction of caspase-3 was only 2-fold in the relatively insensitive DAOY cells. Furthermore, ATRA-induced cell death in D283, D425, and D458 cells was accompanied by activation of caspase-3, a key executioner of apoptosis. We also demonstrate that activated caspase-3 resulted in cleavage of 116-kDa poly(ADP-ribose) polymerase 1 to its signature fragments (85 and 29 kDa). Pretreatment with a specific caspase-3 inhibitor, DEVD-CHO, significantly reduced ATRA-induced apoptotic cell death. Thus, we demonstrate for the first time that low concentrations of ATRA inhibit MB cell proliferation and induce apoptotic cell death in part by activating caspase-3/poly(ADP-ribose) polymerase 1 effector pathway, and we show that retinoic acids and novel retinoids are potential antitumor agents in MB therapy.
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PMID:All-trans-retinoic acid-induced apoptosis in human medulloblastoma: activation of caspase-3/poly(ADP-ribose) polymerase 1 pathway. 1451 26

To clarify the role of the Golgi apparatus in photodynamic therapy-induced apoptosis, its signaling pathway was studied after photodynamic treatment of human cervix carcinoma cell line HeLa, in which a photosensitizer, 2,4,5,7-tetrabromorhodamine 123 bromide (TBR), was incorporated into the Golgi apparatus. Laser scanning microscopic analysis of TBR-loaded HeLa cells confirmed that TBR was exclusively located in the Golgi apparatus. HeLa cells incubated with TBR for 1 h were then exposed to visible light using an Xe lamp. Light of wavelength below 670 nm was eliminated with a filter. Morphological observation of nuclei stained with Hoechst 33342 revealed that apoptosis of cells was induced by exposure to light. Electron spin resonance spectrometry showed that light-exposed TBR produced both singlet oxygen (1O2) and superoxide anion (O2-). Apoptosis induction by TBR was inhibited by pyrrolidine dithiocarbamate, an O2- scavenger, but not by NaN3, a quencher of 1O2. Furthermore, TBR-induced apoptosis was inhibited by aurintricarboxylic acid and ZnCl2, which are known as inhibitors of deoxyribonuclease (DNase) gamma, and (acetoxymethyl)-1,2-bis(o-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid, a chelator of Ca2+, but not by acetyl Asp-Glu-Val-Asp-aldehyde, an inhibitor of caspase-3. These results suggested that O2- was responsible for TBR-induced apoptosis, and Ca(2+)-dependent and caspase-3-independent nuclease such as DNase gamma played an important role in apoptotic signaling triggered by Golgi dysfunction.
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PMID:Ca(2+)-dependent and caspase-3-independent apoptosis caused by damage in Golgi apparatus due to 2,4,5,7-tetrabromorhodamine 123 bromide-induced photodynamic effects. 1455 10

Loss of cardiomyocytes by apoptosis is proposed to cause heart failure. Angiotensin II (ANG II), an important neurohormonal factor during heart failure, can induce cardiomyocyte apoptosis. Inasmuch as hexarelin has been reported to have protective effects in this process, we examined whether hexarelin can prevent cardiomyocytes from ANG II-induced cell death. Cultured cardiomyocytes from neonatal rats were stimulated with ANG II. Apoptosis was evaluated using fluorescence microscopy, TdT-mediated dUTP nick-end labeling (TUNEL) method, flow cytometry, DNA laddering, and analysis of cell viability by (3,4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). It was found that incubation with 0.1 micromol/l ANG II for 48 h increased cardiomyocyte apoptosis. Administration of 0.1 micromol/l hexarelin significantly decreased this ANG II-induced apoptosis and DNA fragmentation and increased myocyte viability. To further investigate the underlying mechanisms, caspase-3 activity assay and mRNA expression of Bax, Bcl-2, and growth hormone secretagogue receptor (GHS-R; the supposed hexarelin binding site) were examined. GHS-R mRNA was abundantly expressed in cardiomyocytes and was upregulated after administration of hexarelin. These results suggest that hexarelin abates cardiomyocytes from ANG II-induced apoptosis possibly via inhibiting the increased caspase-3 activity and Bax expression induced by ANG II and by increasing the expression of Bcl-2, which is depressed by ANG II. Whether the upregulated expression of GHS-R induced by hexarelin is associated with this antiapoptotic effect deserves further investigation.
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PMID:Hexarelin protects rat cardiomyocytes from angiotensin II-induced apoptosis in vitro. 1461 77

Insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1), a member of the IGFBP super family, is down-regulated at the mRNA level in several solid cancers. We hypothesize that IGFBP-rP1 has a tumor-suppressive effect on prostate cancer growth and its inactivation is through CpG hypermethylation. We tested this hypothesis through expression analysis of IGFBP-rP1, transfection studies, growth analysis, and CpG methylation in prostate cancer cells and tissues. In situ hybridization revealed IGFBP-rP1 mRNA expression was detected in the stroma and epithelium of benign prostatic hyperplasia tissues but was either weak or lost in prostate cancer tissues. The mRNA expression for IGFBP-rP1 was lacking in DU145, LNCaP, ND-1, and PC-3 prostate cancer cell lines, and after demethylation (5-aza-dC treatment), the expression was restored suggesting that methylation inactivated IGFBP-rP1 expression in prostate cancer cells. We further tested whether transfection of IGFBP-rP1 can modulate prostate cancer cells growth. We transfected PC-3 cell lines with IGFBP-rP1 cDNA (PC-3-rP1) and Northern blotting confirmed mRNA transcript of IGFBP-rP1 in these PC-3-rP1 clones. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed growth rate was significantly lower in PC-3-rP1 cells than in the nontransfected control. In addition, the medium obtained from PC-3-rP1 cells reduced the growth rate in both PC-3-rP1 and control PC-3 cells. A soft agar colony-forming assay revealed that colony formation was markedly decreased in PC-3-rP1 cells. The number of apoptotic cells and caspase-3 expression were increased in the PC-3-rP1 cells as compared with control PC-3 cells. This is the first study that suggests inactivation of IGFBP-rP1 is through CpG methylation, and tumor-suppressive activity of IGFBP-rP1 is through induction of apoptosis in an IGF-I independent manner in prostate cancer.
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PMID:Restoration of insulin-like growth factor binding protein-related protein 1 has a tumor-suppressive activity through induction of apoptosis in human prostate cancer. 1463 96

Ginseng radix, the root of Panax ginseng C. A. MEYER (Araliaceae), is one of the best-known Oriental medicinal herbs with numerous therapeutic applications. To investigate whether Ginseng radix possesses a protective effect against 1-methyl-4-phenylpyridine (MPP(+))-induced cytotoxicity in neuronal cells, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometry, DNA fragmentation assay, reverse transcription-polymerase chain reaction (RT-PCR), Western blotting, and caspase-3 enzyme assay were performed on PC12 neuronal cells. Cells treated with MPP(+) exhibited various apoptotic features, while cell pretreated with Ginseng radix prior to MPP(+) exposure showed a decrease in the occurrence of apoptotic features. These results suggest that Ginseng radix may exert a protective effect against MPP(+)-induced apoptosis in PC12 cells.
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PMID:Protective effect of aqueous extract of Ginseng radix against 1-methyl-4-phenylpyridinium-induced apoptosis in PC12 cells. 1464 68

A potent inhibitor of serine/threonine kinases, staurosporine exerts antiproliferative and apoptotic effects in many cancer cells, although the exact mechanism of its action is still unclear. This study examines the effects of staurosporine on Chang liver cells, an immortalized non-tumor cell line, in comparison with those caused in HuH-6 and HepG2 cells, two human hepatoma cell lines. Our results provide evidence that staurosporine promotes apoptosis in Chang liver cells as observed by flow cytometric analysis and acridine orange/ethidium bromide staining. The effect appeared already after 8 h of treatment and increased with treatment time and dose. After 48 h of exposure to 200 nM staurosporine clear apoptotic signs were observed in about 50% of the cells. Western blotting analysis showed that in Chang liver cells staurosporine induced a marked decrease in the levels of the antiapoptotic factors Bcl-2 (-75%) and Bcl-XL (-50%). Staurosporine also caused loss of mitochondrial transmembrane potential, release of cytochrome c from mitochondria and activation of caspase-3. The involvement of caspases in staurosporine-induced cell death was also suggested by the observation that the addition of z-VAD-fmk, a general inhibitor of caspases, suppressed apoptosis. In HuH-6 and HepG2 cells treatment with staurosporine induced the arrest of cells in G2/M phase of cell cycle. This effect was not modified by z-VAD-fmk and was not accompanied by the appearance of biochemical signs of apoptosis. We conclude that staurosporine induced apoptosis in Chang liver cells by a mitochondria-caspase-dependent pathway which was closely correlated with a decrease in Bcl-2 and Bcl-XL levels, while in HuH-6 and HepG2 hepatoma cells the drug caused only an antiproliferative effect.
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PMID:Staurosporine-induced apoptosis in Chang liver cells is associated with down-regulation of Bcl-2 and Bcl-XL. 1501 Aug 57


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