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)

The pattern of cell death in the immature brain differs from that seen in the adult CNS. During normal development, more than half of the neurons are removed through apoptosis, and mediators like caspase-3 are highly upregulated. The contribution of apoptotic mechanisms in cell death appears also to be substantial in the developing brain, with a marked activation of downstream caspases and signs of DNA fragmentation. Mitochondria are important regulators of cell death through their role in energy metabolism and calcium homeostasis, and their ability to release apoptogenic proteins and to produce reactive oxygen species. We find that secondary brain injury is preceded by impairment of mitochondrial respiration, signs of membrane permeability transition, intramitochondrial accumulation of calcium, changes in the Bcl-2 family proteins, release of proapoptotic proteins (cytochrome C, apoptosis inducing factor) and downstream activation of caspase-9 and caspase-3 after hypoxia-ischemia. These data support the involvement of mitochondria-related mechanisms in perinatal brain injury.
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PMID:Mitochondrial impairment in the developing brain after hypoxia-ischemia. 1537 74

To investigate the effect of benzamide and nicotinamide, well known inhibitors of poly(ADP-ribose) polymerase, in Chinese hamster V79 cells at the physiological condition of cell growth, we have tested the ability of the inhibitors to induce apoptosis. Apoptosis was detected by nuclear fragmentation, nucleosomal ladder formation, cytochrome-c release from the mitochondria and caspase-3 activation. Benzamide treatment alone increased nuclear fragmentation in dose (2.5-10 mM) and time (4-48 h)-dependent manner. Such treatment also increased nucleosomal ladders. However, 5 mM benzamide pre-treatment inhibited the nucleosomal ladders induced by gamma-irradiation indicating the role of poly(ADP-ribose) polymerase was different in irradiated cells and in un-irradiated cells. Release of cytochrome-c from the mitochondria and caspase-3 activity were also increased by such treatment. Treatment with 200 microM of aurin tricarboxylic acid (ATA), an inhibitor of DNases, inhibited the nucleosomal ladders induced by benzamide or gamma-irradiation without changing the cytochrome-c release or caspase-3 activation. This result showed that ATA inhibited the nucleosomal ladders possibly by inhibiting DNase(s) involved in apoptosis.
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PMID:Induction of apoptosis by benzamide and its inhibition by aurin tricarboxylic acid (ATA) in Chinese hamster V79 cells. 1545 Apr 10

Visual cortex ablation in newborn rats causes a rapid and almost complete degeneration of neurones in the dorsal lateral geniculate nucleus (dLGN), as a consequence of the axotomy of geniculo-cortical fibres. Death of dLGN neurones occurs by apoptosis and is partially prevented (approximately 50%) by intraocular delivery of brain-derived neurotrophic factor (BDNF). Here we investigated the molecular mechanisms of BDNF-mediated neuroprotection. We found that exogenous administration of BDNF partially decreases (approximately 50%) the up-regulation of apoptotic proteins (phosphorylated c-Jun, cytochrome C and cleaved caspase 3), that occurs in dLGN neurones following visual cortex ablation at postnatal day 7. These results demonstrate that the neuroprotective action of BDNF on axotomised dLGN neurones involves the partial blockade of well-characterised apoptotic pathways.
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PMID:BDNF down-regulates the caspase 3 pathway in injured geniculo-cortical neurones. 1548 79

TNFalpha-related apoptosis inducing ligand (TRAIL) has been shown to induce apoptosis in prostate cancer cells. However, some prostate cancer cells, such as LNCaP are resistant to TRAIL. In addition to the involvement of several pathways in the TRAIL-resistance of LNCaP, it has been shown that mitochondrial response to TRIAL is low in these cells. Therefore, in this study, using in vitro cell free and reconstitution models, we have demonstrated that mitochondria from these cells are capable of responding to apoptotic stimuli. Furthermore, experiments to determine the influence of cytochrome c on apoptotic response noted that incubation of cytosol with exogenous cytochrome c induced truncation of Bid. We have demonstrated that truncation of Bid by exogenous cytochrome c is mediated through the activation of caspases-9 and -3. Incubation of cytosol with recombinant caspases-9 and -3 in the absence or presence of inhibitors showed that activation of caspase-9, leading to the activation of caspase-3 was necessary for the truncation of Bid. Published results indicate that in apoptotic cells cytochrome c is released from the mitochondria in two installments, an early small amount and a late larger amount. Our results suggest that the initial release of cytochrome generates tBid that is capable of translocation into the mitochondria causing further release of cytochrome c. Thus, in addition to providing functional explanation for the biphasic release of cytochrome c from mitochondria, we demonstrate the presence of a feedback amplification of mitochondrial apoptotic signal.
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PMID:Mitochondria from TRAIL-resistant prostate cancer cells are capable of responding to apoptotic stimuli. 1549 15

The aim was to investigate the mechanism of arsenic trioxide (ATO) inducing apoptosis of K562 cells that express P210Bcr-Abl. Apoptosis was analyzed by cell proliferation assay, morphological changes, DNA-PI staining and cell cycle analysis. ELISA kits were also used to analyze the concentration of cytosolic cytochrome C and activation of caspase-3. Transcriptional levels of Bcl-XL and Bcr-Abl were assayed by semiquantitative reverse transcription polymerase chain reaction (RT-PCR). The results showed that K562 cells were induced to apoptosis after exposure to 2.5 micromol/L ATO for at least 48 hours, and the cell cycle of K562 cells was arrested at the G2/M phase. Caspase-3 was activated and there was a cytosolic accumulation of cytochrome C. ATO could only reduce the transcriptional level of Bcl-XL, but could not down-regulate the Bcr-Abl transcriptional level. In conclusion, ATO can induce K562 cells to apoptosis. The signal pathway mediated by the cytosolic translocation of mitochondria cytochrome C is one of the mechanisms for ATO inducing apoptosis. And the decrease of Bcl-XL may induce more apoptosis.
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PMID:[The mechanism of arsenic trioxide-inducing apoptosis of K562 cells]. 1549 10

Extracts from European mistletoe or Viscum album L. have been reported to exert cytotoxic and immunomodulatory effects in vitro and in vivo. The mechanism of this anti-tumoral activity is however, largely unknown. In this study we tested the hypothesis that IscadorQu, an aqueous fermented extract from the European mistletoe grown on oaks, induces tumor regression by cell cycle inhibition and/or interference with apoptotic signaling pathways in cancer cells. Also a possible effect on angiogenesis, which is a prerequisite for tumor growth in vivo, is studied in endothelial cell cultures. Furthermore, we examined which apoptotic signaling route is activated by staining cells for specific pro-apoptotic proteins. To characterize these properties, 6 different human cancer cell lines, one epidermis derived cell line and 2 endothelial cell cultures were incubated with different concentrations of IscadorQu. Cell cycle kinetics parameters were measured by bromodeoxyuridine (BrdU) pulse labeling and tubulin staining. Apoptotic responses were detected by M30 CytoDeath or Annexin V/propidium iodide assays. Characterization of the apoptotic pathway was performed by staining cells for active caspase 3, active caspase 8, cytochrome C and chloromethyl-X-rosamine. The results of this study show that sensitivity to IscadorQu treatment varies strongly between different cell lines. In sensitive cell lines, including tumor and endothelial cell cultures, IscadorQu caused early cell cycle inhibition followed by apoptosis in a dose-dependent manner. Apoptosis was induced by activating the mitochondrial but not the death receptor-dependent pathway.
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PMID:Differential effects of Viscum album extract IscadorQu on cell cycle progression and apoptosis in cancer cells. 1554 86

Apoptotic cell death has been observed in many in vivo and in vitro models of ischemia. However, the molecular pathways involved in ischemia-induced apoptosis remain unclear. We have examined the role of Bcl-2 family of proteins in mediating apoptosis of PC12 cells exposed to the conditions of oxygen and glucose deprivation (OGD) or OGD followed by restoration of oxygen and glucose (OGD-restoration, OGD-R). OGD decreased mitochondrial membrane potential and induced necrosis of PC12 cells, which were both prevented by the overexpression of Bcl-2 proteins. OGD-R caused apoptotic cell death, induced cytochrome C release from mitochondria and caspase-3 activation, decreased mitochondrial membrane potential, and increased levels of pro-apoptotic Bax translocated to the mitochondrial membrane, all of which were reversed by overexpression of Bcl-2. These results demonstrate that the cell death induced by OGD and OGD-R in PC12 cells is potentially mediated through the regulation of mitochondrial membrane potential by the Bcl-2 family of proteins. It also reveals the importance of developing therapeutic strategies for maintaining the mitochondrial membrane potential as a possible way of reducing necrotic and apoptotic cell death that occurs following an ischemic insult.
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PMID:Role of Bcl-2 family of proteins in mediating apoptotic death of PC12 cells exposed to oxygen and glucose deprivation. 1556 17

Among the critical antioxidant enzymes that protect the cells against oxidative stress are superoxide dismutases: CuZnSOD (Sod1) and MnSOD (Sod2). The latter is also implicated in apoptosis. To determine the importance of these enzymes in protection against reactive oxygen species (ROS) in the lens, we analysed DNA strand breaks in lens epithelium from transgenic and knockout (Sod1) mice following exposure to H2O2 in organ culture. Since Sod2 knockouts do not survive, comparison was made of lenses of partially-deficient (heterozygote) for Sod2 and the wild-type controls which have twice the enzyme level. Antioxidant potential of Sod2 was also studied in human lens epithelial cells (SRA01/04) in which the enzyme was up- and down-regulated by transfection with plasmids containing sense and antisense human cDNA for MnSOD. DNA strand breaks in the epithelium of Sod1 knockouts and Sod2 heterozygotes were much greater than in the corresponding wild-type or in transgenic mice over-expressing the enzymes when the lenses were exposed to H2O2. The functional role of Sod2 in apoptosis was examined in cultured human lens epithelial cells. Cells with higher enzyme levels were more resistant to the cytotoxic effects of H2O2, O2- and UV-B radiation. Furthermore, Sod2-deficient cells showed dramatic mitochondrial damage, cytochrome C leakage, caspase 3 activation and increased apoptotic cell death when they were challenged with O2-. Thus, mitochondrial enzyme (Sod2) deficiency plays an important role in the initiation of apoptosis in the lens epithelium.
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PMID:Effects of variation in superoxide dismutases (SOD) on oxidative stress and apoptosis in lens epithelium. 1564 23

It has been shown that deletion of the gene encoding the inducible form of nitric oxide synthase (iNOS) results in a reduction of ischemia-induced apoptotic cell death, suggesting the detrimental role of iNOS. The signaling pathways by which iNOS mediates apoptotic cell death under ischemic conditions remain unclear. Understanding the molecular mechanisms of iNOS-mediated apoptotic cell death in ischemia may offer opportunities for potential therapeutic intervention. In the current study, undifferentiated rat pheochromocytoma PC12 cells, exposed to oxygen and glucose deprivation (OGD) followed by reperfusion (adding back oxygen and glucose, OGD-R), were used as an in vitro model of ischemia. The iNOS expression and activity were increased during OGD-R. OGD-R-induced apoptosis was demonstrated by the increase of LDH release, cytosolic release of cytochrome C and caspase-3 activity. Inhibition of iNOS activity by selective iNOS inhibitors, aminoguanidine and 1400W, reduces OGD-R-induced apoptotic cell death, as demonstrated by the decrease of LDH release, cytochrome C release, and caspase-3 activity. These results suggest the critical role of iNOS in mediating apoptosis under ischemic conditions, likely through the induction of caspase-3 activity.
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PMID:Inhibitors of iNOS protects PC12 cells against the apoptosis induced by oxygen and glucose deprivation. 1566 23

Early contractile dysfunction and the later death of cardiomyocytes are two major problems that can follow myocardial infarction or major cardiovascular surgery that demands ischemic arrest of the heart. Here, we found that 24 h of hypoxia and 1 h of reoxygenation induced the expression of the chaperone ORP150 in cultured rat cardiomyocytes. Inhibition of its induction using an adenovirus to express anti-sense ORP150 significantly enhanced the hypoxia-reoxygenation-induced cardiomyocyte death; cell death was reduced by overexpressing ORP150. Decreased levels of ORP150 expression also enhanced caspase-3 and -8 activation, cytochrome-c release, and DNA fragmentation, suggesting that this chaperone regulates apoptotic cell death. In contrast, increasing the expression of ORP150 in the cardiomyocytes had the opposite effect on the expression of these molecules. Moreover, apoptotic cell death initiated by myocardial ischemia-reperfusion (I/R) was significantly inhibited in vivo by transfecting an ORP150 expression plasmid into whole rat heart using the hemagglutinating virus of Japan (HVJ)-liposome method. Interestingly, ORP150 seemed to preserve calcium homeostasis in cardiomyocytes that underwent ischemia-reoxygenation in vitro. Calpain activity in the cardiomyocytes was enhanced by anti-sense ORP150 and suppressed by sense ORP150. Finally, we examined the functional recovery of rat hearts that overexpressed ORP150 or GFP protein and were subjected to I/R; we found that ORP150 preserved early contractile function after transient ischemia. Our results indicated cytoprotective roles for ORP150 in rat heart and suggested a therapeutic role for the protein both in preventing cardiomyocyte death and in preserving contractile function after ischemic damage.
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PMID:150-kDa oxygen-regulated protein attenuates myocardial ischemia-reperfusion injury in rat heart. 1573 11


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