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)

SP600125 is a specific inhibitor of c-Jun N-terminal kinase (JNK) that is known to strongly induce apoptosis and block cell cycle progression in G2/M phase. In this study, we demonstrated that treatment of U937 cells with SP600125 resulted in significant G2/M cell cycle arrest that was due to decreased cyclin B1 and cdc25c protein levels. Moreover, SP600125 promoted LDH release and DNA fragmentation that was associated with caspase-3 activation and degradation of its substrates. In contrast, overexpression of the antiapoptotic protein Bcl-2 rendered leukemia cells resistant to SP600125-induced apoptosis, but more sensitive to G2/M phase arrest and endoreduplication (>4N DNA). Overexpression of Bcl-2 significantly inhibited SP600125-induced caspase-3 activation and degradation of its substrates, and sustained expression levels of the IAP-2 proteins following SP600125 treatment. The inhibitory effect of Bcl-2 on apoptosis was attenuated by treatment with the small molecule Bcl-2 inhibitor, HA14-1. These data provide important mechanistic insights related to Bcl-2-mediated resistance to SP600125-induced apoptosis, and induction of G2/M phase arrest and endoreduplication.
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PMID:Bcl-2 overexpression attenuates SP600125-induced apoptosis in human leukemia U937 cells. 1834 29

In this paper, we report the anticancer activities of Uncaria rhynchophylla extracts, a Rubiaceae plant native to China. Traditionally, Uncaria rhynchophylla has been used in the prevention and treatment of neurotoxicity. However, the cytotoxic activity of Uncaria rhynchophylla against human colon carcinoma cells has not, until now, been elucidated. We found that the methanolic extract of Uncaria rhynchophylla (URE) have cytotoxic effects on HT-29 cells. The URE showed highly cytotoxic effects via the MTT reduction assay, LDH release assay, and colony formation assay. As expected, URE inhibited the growth of HT-29 cells in a dose-dependent manner. In particular, the methanolic URE of the 500 microg/ml showed 15.8% inhibition against growth of HT-29 cells. It induced characteristic apoptotic effects in HT-29 cells, including chromatin condensation and sharking occurring 24 h when the cells were treated at a concentration of the 500 microg/ml. The activation of caspase-3 and the specific proteolytic cleavage of poly (ADP-ribose) polymerase were detected over the course of apoptosis induction. These results indicate that URE contains bioactive materials with strong activity, and is a potential chemotherapeutic agent candidate against HT-29 human colon carcinoma cells.
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PMID:Methanolic extracts of Uncaria rhynchophylla induce cytotoxicity and apoptosis in HT-29 human colon carcinoma cells. 1839 27

Pinocembrin is one of the flavonoids at the highest concentration in propolis. In this study, we investigated the neuroprotective effect of pinocembrin on ischemia/reperfusion and ischemia/reperfusion-like insults. Protection by pinocembrin was studied at the in vivo level using a model of middle cerebral artery occlusion and reperfusion in rats. Pinocembrin was administrated at the start of reperfusion. Pinocembrin markedly increased rat viability, reduced infarct volumes and neurological deficit scores in all treatment groups. Primary cortical neuronal cultures were subjected to oxygen-glucose deprivation/reoxygenation, a model of ischemia/reperfusion-like injury, and treated with pinocembrin at the start of reoxygenation. Neuronal survival rates were increased, LDH release was decreased and both neurite length and apoptosis were alleviated when pinocembrin was present during reoxygenation, and this protection was associated with the reduction of reactive oxygen species, nitric oxide and neuronal nitric oxide synthase (nNOS) and inducible NOS (iNOS), and an increase of glutathione. Moreover, DNA laddering was decreased in treatment groups of pinocembrin. Caspase-3 protein was down-regulated and PARP degradation was alleviated after pinocembrin treatments. Our results suggest that pinocembrin may be a novel therapeutic strategy to reduce cerebral ischemia/reperfusion injury, and may act by the anti-oxidative and anti-apoptotic effects.
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PMID:Pinocembrin protects rat brain against oxidation and apoptosis induced by ischemia-reperfusion both in vivo and in vitro. 1849 93

Mitochondria likely play a role in Parkinson's disease (PD) neurodegeneration. We modelled PD by creating cytoplasmic hybrid (cybrid) cell lines in which endogenous mitochondrial DNA (mtDNA) from PD or control subject platelets was expressed within human teratocarcinoma (NT2) cells previously depleted of endogenous mtDNA. Complex I activity was reduced in both PD cybrid lines and in the platelet mitochondria used to generate them. Under basal conditions PD cybrids had less ATP, more LDH release, depolarized mitochondria, less mitochondrial cytochrome c, and higher caspase 3 activity. Equivalent MPP+ exposures are more likely to trigger programmed cell death in PD cybrid cells than in control cybrid cells. Our data support a relatively upstream role for mitochondrial dysfunction in idiopathic PD.
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PMID:Mitochondrial function in Parkinson's disease cybrids containing an nt2 neuron-like nuclear background. 1849 57

Toxic effects of the mycotoxin deoxynivalenol (DON) observed in animals range from diarrhea, vomiting, gastro-intestinal inflammation to necrosis of several tissues. In the last years, DON has been tested in hepatocytes of several animal species for its cytotoxicity. However, these tests are limited to the use of animal cells. No studies using human hepatocytes are available. Further investigations with the human hepatocellular liver carcinoma cell line HepG2 might be limited due to the disadvantages of cell lines (e. g. immortalization, tumor derivation, longtime cultivation) and do not necessarily reflect the response of normal human cells. In order to overcome this problem and to be closer to the human situation, we studied the effect of DON in human primary hepatocytes and compared these data to the effects in the HepG2 cell line. Cell viability, apoptotic and necrotic cell death, albumin secretion and metabolic activity were determined. It could be demonstrated that DON has a distinct cytotoxic effect on human primary hepatocytes. Viability, protein content and albumin secretion were reduced in a dose-dependent manner. The apoptotic key enzyme caspase-3 was activated, while LDH release occurred only after long incubation time due to a secondary necrosis. Furthermore, we studied the metabolism of DON using LC-MS/MS. DON was neither metabolized by primary hepatocytes cells nor by the HepG2 cell line.
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PMID:Effects of the mycotoxin deoxynivalenol on human primary hepatocytes. 1861 82

Salidroside, a compound of natural origin, has displayed a broad spectrum of pharmacological properties. This study aimed to evaluate the inhibitory effects of salidroside on glutamate-induced cell death in a primary culture of rat hippocampal neurons as compared to brain-derived neurotrophic factor (BDNF), a usual positive control. MTT and LDH assays, together with Hoechst 33342 staining, terminal deoxynucleotidyl transferase dUTP-mediated nicked end labeling (TUNEL) assay and flow cytometric analysis using annexin-V and propidium (PI) label, indicated that salidroside pretreatment attenuated glutamate-induced apoptotic cell death in primary cultured hippocampal neurons, showing a dose-dependent pattern. Furthermore, caspase-3 activity assay and calcium measurements with Fluo 4-AM, respectively, revealed that salidroside pretreatment antagonized activation of caspase-3 and elevation of intracellular calcium level, both of which were induced by glutamate stimulation, thus adding to the understanding of how salidroside offered neuroprotection against glutamate excitotoxicity.
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PMID:Salidroside attenuates glutamate-induced apoptotic cell death in primary cultured hippocampal neurons of rats. 1868 Jul 33

Numerous reports have described the effects of quercetin in models of neurodegenerative diseases, or cancer, resulting in a very complex and sometimes paradoxical picture. Understanding how quercetin causes either protection or cell death in the same model is both tempting and essential. We used the 6-OHDA-induced toxicity model in SH-SY5Y cells, applying graded concentrations of quercetin for a variable time period and following cell viability with MTT-assay and LDH-release as well as caspase-3-like activity. We detected a time-dependent action of quercetin and distinguished an early protective effect from a late toxic one. In addition, we revealed a narrower therapeutic dose-range of quercetin than previously reported in the literature, demonstrating that the toxic effects of quercetin occurred at a concentration only 2-fold higher than the one that produced the greatest protection. We also demonstrated, to our knowledge for the first time, that quercetin itself directly inhibits caspase-3-like activity in a dose-dependent manner. Finally, single doses of quercetin failed to protect against 6-OHDA toxicity in a unilateral rat model of Parkinson's disease. In conclusion, our data may offer an explanation for the dualistic effect of quercetin reported in the literature. In fact, in most studies suggesting quercetin protection against oxidative stressors, the experimental setting failed to include prolonged exposure, and therefore the toxic effects may have been missed. This study supports previous in vivo studies that cast doubt on the efficacy of quercetin against neurodegenerative diseases due to its delayed toxicity.
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PMID:Time-dependent protective and harmful effects of quercetin on 6-OHDA-induced toxicity in neuronal SH-SY5Y cells. 1875 31

The phototoxicity of low-energy ultraviolet radiation, such as UVA, can be enhanced by the presence of photosensitizing agents. Hence, co-exposure of cells to benzo[a]pyrene (BaP), a widespread environmental carcinogen and photosensitizing agent, and UVA may synergistically induce DNA damage. In this study, exposure of cells to various concentrations of BaP for 1h followed by UVA irradiation (2J/cm(2)) increased DNA damage and decreased cell viability. Expression of apoptosis-related proteins (caspase-9, caspase-3, PARP, and Bax) and hypodiploid DNA content (sub-G(1)) were not changed. LDH release into the culture medium increased in a dose-dependent manner with BaP under UVA irradiation, suggesting that cell death due to BaP/UVA co-treatment occurred via necrosis. Intracellular reactive oxygen species (ROS) levels were increased significantly in the co-exposed cells, and treatment with the polyphenol quercetin, but not with sodium azide or N-acetylcysteine, decreased ROS levels and increased cell viability in BaP/UVA-treated cells. In conclusion, UVA irradiation combined with BaP synergistically promoted necrosis of A549 cells by increasing intracellular ROS levels, and quercetin prevented BaP-enhanced phototoxicity due to UVA irradiation.
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PMID:Quercetin prevents necrotic cell death induced by co-exposure to benzo(a)pyrene and UVA radiation. 1894 85

Some neurosteroids show neuroprotective action in in vitro and in vivo studies, but their interaction with apoptotic/necrotic processes has been only partially unraveled. The aim of the present study was to examine the effect of dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), pregnenolone (PGL) and allopregnanolone (Allo) on staurosporine-, glutamate-, and NMDA-induced damage in primary cortical neuronal culture. DHEA, DHEAS and PGL (0.1 and 1 microM) inhibited the staurosporine-evoked LDH release and decreased the number of apoptotic cells as shown by Hoechst;s staining, whereas Allo was without effect. The neurosteroids affected neither the staurosporine-evoked changes in caspase-3 activity nor the decrease in mitochondrial membrane potential. It was also shown that protective effects of DHEA, DHEAS and PGL against staurosporine-induced LDH release were attenuated by extracellular signal-regulated kinase (ERK)--mitogen-activated protein kinase (MAPK) inhibitor--PD 98059 (5 microM) but not by phosphatidylinositol-3-kinase (PI3-K) inhibitors such as LY 294002 (1 microM) or wortmannin (10 nM). The involvement of ERK2-MAPK in protective effects of neurosteroids was confirmed by Western blot study. Further study demonstrated that glutamate-induced cell damage was attenuated by DHEA, DHEAS, and PGL, but not by Allo. None of the steroids influenced NMDA-induced LDH release. The results of the present in vitro studies suggest that excitatory neurosteroids DHEA, DHEAS and PGL at physiological concentrations participate in the inhibition of cortical neuronal degeneration elicited by staurosporine and glutamate, whereas the most potent positive modulator of GABA(A) receptor--Allo--has no effect. Moreover, neurosteroids appear to attenuate the staurosporine-induced cell damage in a caspase-3 independent way and their neuroprotective mechanism of action involves the increase in ERK-MAPK phosphorylation.
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PMID:Excitatory neurosteroids attenuate apoptotic and excitotoxic cell death in primary cortical neurons. 1895 90

Macrophages express P2X(7) and other nucleotide (P2) receptors, and display the phenomena of extracellular ATP (ATP(e))-induced P2X(7)-dependent membrane permeabilization and cell death by apoptosis and necrosis. P2X(7) receptors also cooperate with toll-like receptors (TLRs) to induce inflammasome activation and IL-1beta secretion. We investigated signaling pathways involved in the induction of cell death by ATP(e) in intraperitoneal murine macrophages. Apoptosis (hypodiploid nuclei) and necrosis (LDH release) were detected 6h after an induction period of 20 min in the presence of ATP. Apoptosis was blocked by caspase 3 and caspase 9 inhibitors and by cyclosporin A. The MAPK inhibitors PD-98059, SB-203580 and SB-202190 provoked no significant effect on apoptosis, but SB-203580 blocked LDH release. Neither apoptosis nor necrosis was inhibited when both intra- and extracellular Ca(2+) were chelated during the induction period. Mepacrine, a generic PLA(2) inhibitor and BEL, an inhibitor of Ca(2+)-independent PLA(2) (iPLA(2)) blocked apoptosis, while pBPB and AACOOPF(3), inhibitors of secretory and Ca(2+)-dependent PLA(2) respectively, had no significant effect. Cycloxygenase inhibitors had no effect on apoptosis, while the inhibitors of lipoxygenase (LOX) and leukotriene biosynthesis nordihydroguaiaretic acid (NDGA), zileuton, AA-861, and MK-886 significantly decreased apoptosis. Neither NDGA nor MK-886 blocked apoptosis of 5-LOX(-/-) macrophages. CP-105696 and MK-571, antagonists of leukotriene receptors, had no significant effect on apoptosis. None of the inhibitors of PLA(2) and LOX/leukotriene pathway had a significant inhibitory effect on LDH release. Our results indicate that a Ca(2+)-independent step involving an iPLA(2) and 5-LOX are involved in the triggering of apoptosis but not necrosis by P2X(7) in macrophages.
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PMID:ATP-induced apoptosis involves a Ca2+-independent phospholipase A2 and 5-lipoxygenase in macrophages. 1898 60


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