Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.4.2.30 (PARP)
 13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypoxia decreased survival of cultured rat primary hippocampal neurons in a time dependent manner. Addition of 4 mM Na D-beta-hydroxybutyrate (bHB), a ketone body, protected the cells for 2 hr and maintained the increase in survival compared to that of controls for up to 6 hr. Trypan blue exclusion indicated that acute cell death was reduced markedly after 2-hr exposure to hypoxia in the bHB-treated group. The presence of bHB also decreased the number of neurons exhibiting condensed nuclei visualized by propidium iodide, indicative of apoptosis. The mitochondrial transmembrane potential (Em/c) was maintained for up to 2 hr exposure to hypoxia in the bHB-treated group, whereas the potential in the control group was decreased. Furthermore, cytochrome C release, caspase-3 activation, and poly (ADP-ribose) polymerase (PARP) cleavage were decreased in the bHB-treated group for the first 2 hr of exposure. These findings indicate that ketone bodies may be a candidate for widening the therapeutic window before thrombolytic therapy and at the same time decreasing apoptotic damage in the ischemic penumbra.
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PMID:D-beta-hydroxybutyrate is neuroprotective against hypoxia in serum-free hippocampal primary cultures. 1582 91

The purpose of the present study was to investigate the anti-proliferative and apoptotic effects of MCS-C2, a novel synthetic analogue of the pyrrolo[2,3-d]pyrimidine nucleoside toyocamycin and sangivamycin, in human promyelocytic leukemia (HL-60) cells. When treated with 5 microM MCS-C2, inhibited proliferation associated with apoptotic induction was found in the HL-60 cells in a concentration-dependent and time-dependent manner, plus nuclear DAPI staining revealed the typical nuclear features of apoptosis. However, MCS-C2 showed almost no antiproliferative effect and no apoptotic induction in normal lymphocyte cells used as a control when compared with those in HL-60 cancer cells. Moreover, a flow cytometric analysis of the HL-60 cells using FITC-dUTP and propidium iodide (PI) showed that the apoptotic cell population increased gradually from <1% at 0 h to 34% at 12 h after exposure to 5 microM MCS-C2. This apoptotic induction was associated with the cleavage of Bid and a release of cytochrome c from mitochondria into the cytosol, followed by the activation of caspase-3 and inactivation of poly(ADP-ribose) polymerase (PARP). However, there was no significant change in any other mitochondrial membrane proteins, such as Bcl-2 and Bax. Consequently, the current findings suggest that the mitochondrial pathway was primarily involved in the MCS-C2-induced apoptosis in the human promyelocytic leukemia HL-60 cells.
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PMID:Induction of apoptosis in human leukemia cells by MCS-C2 via caspase-dependent Bid cleavage and cytochrome c release. 1589 58

Poly(ADP-ribose) polymerase-1 (PARP-1) is an abundant nuclear enzyme of eukaryotic cells that has been implicated in response to DNA injury. PARP-1 detects single-strand DNA breaks induced by a variety of genotoxic insults. A hyperactivation of PARP-1 is believed to play a critical role in tissues undergoing cellular death by necrosis. Therefore, a radiotracer that could image PARP-1 levels with PET could provide a useful tool in measuring necrosis in a variety of pathological conditions. The phenanthridinone derivative, 2-(dimethylamino)-N-(5,6-dihydro-6-oxophenanthridin-2-yl)acetamide (PJ34), has a high affinity for PARP-1 (IC(50) = 20 nM) and is a suitable lead compound for PET radiotracer development. The synthesis of [(11)C]PJ34 was accomplished by base-catalyzed reaction of the corresponding des-methyl precursor, N-(5,6-dihydro-6-oxophenanthridin-2-yl)-2-(methylamino)acetamide with [(11)C]methyl iodide in DMF. The radiolabeling yield was 60% and the specific activity was approximately 2000 mCi/micromol (decay corrected to E.O.B.). The total radiosynthesis time was approximately 50 min. Preliminary in vivo biodistribution studies in a rodent model of diabetes indicate that [(11)C]PJ34 displays a high uptake in tissues where PARP-1 is hyperactivated. These data indicate that [(11)C]PJ34 may be a useful radiotracer for imaging tissues undergoing cellular death via necrosis.
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PMID:Synthesis and in vivo evaluation of [11C]PJ34, a potential radiotracer for imaging the role of PARP-1 in necrosis. 1598 73

In this study, the effect of (Boc-Lys (Boc)-Arg-Asp-Ser (tBu)-OtBu), a tetrapeptide derivative (PEP1261) was examined for antiproliferative potency and apoptotic induction. Synovial fibroblasts were isolated from collagen-induced arthritic (CIA) rats and exposed to peptides viz., PEP1261, and parental peptides (KRDS and RGDS). Viability of the cells decreased in the presence of PEP1261 at a lower concentration (0.1 mM) when compared to RGDS and KRDS (1 mM). The treatment of cells with peptides showed induction of apoptosis, resulting in the cleavage of caspase-3 as well as its substrate poly-(ADP-ribose) polymerase (PARP). Pretreatment of cells with caspase-3 inhibitor prevented inhibition of [(3)H] thymidine incorporation, DNA fragmentation, and cleavage of caspase-3 and PARP as confirmed by western blotting as well as annexin-V/PI-staining using flow cytometry. However, caspase-1 and caspase-2 inhibitors did not prevent the peptides from inducing apoptosis indicating that caspase-3 might have a role in the process of apoptosis induced by peptides. Treatment of synovial fibroblasts with nitric oxide donor, S-nitroso-N-acetyl-DL: -penicillamine (SNAP) (500 microM) showed significant elevation of nitric oxide levels and resulted in absence of apoptosis by preventing the inhibition of [(3)H] thymidine incorporation. This was further evidenced by annexin V/propidium iodide (PI) staining and absence of DNA fragmentation, intra cellular caspase-3 activity and PARP cleavage. In contrast, SNAP followed by PEP1261 and parental peptides-induced apoptosis by lowering the levels of nitric oxide. These results suggested that PEP1261 suppressed the proliferation and induced apoptosis in cultured synovial fibroblasts from CIA rats. This study also confirmed that PEP1261 inhibited nitric oxide level in cultured synovial fibroblasts.
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PMID:Inhibition of nitric oxide and caspase-3 mediated apoptosis by a tetrapeptide derivative (PEP1261) in cultured synovial fibroblasts from collagen-induced arthritis. 1631 20

The present study was designed to investigate the hypothesis that trans fatty acids can induce apoptosis of human umbilical vein endothelial cells (HUVEC). To test this hypothesis apoptosis was measured in HUVEC treated with 0.1, 1.0 or 5.0 mM trans elaidic acid (t-18:1) or linoelaidic acid (t,t-18:2) for 24 hours. For the detection of apoptosis, TdT-mediated dUTP nick end labelling assay (TUNEL), cell binding of annexin V and propidium iodide uptake were measured. Active Caspase-3 and cleaved PARP (poly-ADP-ribose polymerase) were also measured in the cell lysate. Moreover, cellular ability to produce ROS (reactive oxygen species) was measured by DCF fluorescence Both acids studied induce both early (annexin-positive cells) and late stages of apoptosis (cells stained by propidium iodide) in a dose-dependent manner. Also the appearance of TUNEL-positive cells was induced by both trans fatty acids tested, in a dose dependent manner. Both trans acids induce apoptosis through their effect on Caspase-3 activity and on intracellular ROS production. It is worth emphasising that linoelaidic acid proved to be a more potent inducer of apoptosis and ROS production in endothelial cells than elaidic acid. The present studies suggest that trans fatty acids may play a role in damaging and death of vascular endothelial cells in atherosclerosis.
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PMID:Trans fatty acids induce apoptosis in human endothelial cells. 1639 18

An elevated level of homocysteine (Hcy) limits the growth and induces apoptosis. However, the mechanism of Hcy-induced programmed cell death in endothelial cells is largely unknown. We hypothesize that Hcy induces intracellular reactive oxygen species (ROS) production that leads to the loss of transmembrane mitochondrial potential (Deltapsi(m)) accompanied by the release of cytochrome-c from mitochondria. Cytochrome-c release contributes to caspase activation, such as caspase-9, caspase-6, and caspase-3, which results in the degradation of numerous nuclear proteins including poly (ADP-ribose) polymerase (PARP), which subsequently leads to the internucleosomal cleavage of DNA, resulting cell death. In this study, rat heart microvascular endothelial cells (MVEC) were treated with different doses of Hcy at different time intervals. Apoptosis was measured by DNA laddering and transferase-mediated dUTP nick-end labeling (TUNEL) assay. ROS production and MP were determined using fluorescent probes (2,7-dichlorofluorescein (DCFH-DA) and 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl-benzamidazolocarbocyanin iodide (JC-1), respectively, by confocal microscopy. Differential gene expression for apoptosis was analyzed by cDNA array. The results showed that Hcy-mediated ROS production preceded the loss of MP, the release of cytochrome-c, and the activation of caspase-9 and -3. Moreover the Hcy treatment resulted in a decrease in Bcl(2)/Bax ratio, evaluated by mRNA levels. Caspase-9 and -3 were activated, causing cleavage of PARP, a hallmark of apoptosis and internucleosomal DNA fragmentation. The cytotoxic effect of Hcy was blocked by using small interfering RNA (siRNA)-mediated suppression of caspase-9 in MVEC. Suppressing the activation of caspase-9 inhibited the activation of caspase -3 and enhanced the cell viability and MP. Our data suggested that Hcy-mediated ROS production promotes endothelial cell death in part by disturbing MP, which results in subsequent release of cytochrome-c and activation of caspase-9 and 3, leading to cell death.
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PMID:Mitochondrial mechanism of microvascular endothelial cells apoptosis in hyperhomocysteinemia. 1651 65

Phospholipase A2 (PLA2) is an esterase that cleaves the sn-2 ester bond in glycerophospholipids, thereby releasing free fatty acids and lysophospholipids. In addition to the apoptotic activity of cytosolic PLA2 and Ca2+-independent PLA2, recent studies showed that secretory PLA2 (sPLA2) also play a role in apoptosis. However, the details of molecular mechanism have not been fully elucidated. Our data demonstrated that group IB PLA (IB PLA2)-exposed murine macrophage 264.7 cells showed characteristic features of apoptosis such as morphological changes, DNA laddering, staining positive for propidium iodide (PI) as well as Annexin V and activation of caspases and subsequent cleavage of poly (ADP-ribose) polymerase (PARP) in dose- and time-dependent manner. Moreover, IB PLA2 was found to elicit tumor necrosis factor (TNF)-alpha production and release of cytochrome c, suggesting that IB PLA2 exerts its apoptotic activity via the induction of TNF-alpha production and cytochrome c release, which results in triggering the activation of caspase cascade and PARP cleavage.
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PMID:Secretory phospholipase A2 induces apoptosis through TNF-alpha and cytochrome c-mediated caspase cascade in murine macrophage RAW 264.7 cells. 1656 42

The effect of oxidative stress induced by the ascorbate/menadione-redox association was examined in K562 cells, a human erythromyeloid leukaemia cell line. Our results show that ascorbate enhances menadione redox cycling, leading to the formation of intracellular reactive oxygen species (as shown by dihydrorhodamine 123 oxidation). The incubation of cells in the presence of both ascorbate/menadione and aminotriazole, a catalase inhibitor, resulted in a strong decrease of cell survival, reinforcing the role of H(2)O(2) as the main oxidizing agent killing K562 cells. This cell death was not caspase-3-dependent. Indeed, neither procaspase-3 and PARP were processed and only a weak cytochrome c release was observed. Moreover, we observed only 23% of cells with depolarized mitochondria. In ascorbate/menadione-treated cells, DNA fragmentation was observed without any sign of chromatin condensation (DAPI and TUNEL tests). The cell demise by ascorbate/menadione is consistent with a necrosis-like cell death confirmed by both cytometric profile of annexin-V/propidium iodide labeled cells and by light microscopy examination. Finally, we showed that a single i.p. administration of the association of ascorbate and menadione is able to inhibit the growth of K562 cells by about 60% (in both tumour size and volume) in an immune-deficient mice model. Taken together, these results reinforced our previous claims about a potential application of the ascorbate/menadione association in cancer therapy.
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PMID:Oxidative stress by ascorbate/menadione association kills K562 human chronic myelogenous leukaemia cells and inhibits its tumour growth in nude mice. 1682 58

Recent evidence indicates that peroxynitrite represents a major cytotoxic effector in heart diseases, but its mechanisms of action are still not known exactly. Notably, the ability of peroxynitrite to trigger cardiomyocyte apoptosis, a crucial mode of cell death in many cardiac conditions, remains poorly defined. We evaluated apoptotic and necrotic cell death in cultured H9C2 cardiomyocytes, following a brief (20 min) exposure to peroxynitrite (50-500 microM). Peroxynitrite-dependent myocardial toxicity was then investigated in a rat model of myocardial ischemia-reperfusion (MIR), where the effects of peroxynitrite were blocked by the superoxide dismutase mimetics and peroxynitrite scavenger Mn(III)-tetrakis(4-benzoic acid) porphyrin (MnTBAP). In vitro, peroxynitrite killed cardiomyocytes mostly through apoptosis (DNA fragmentation, apoptotic nuclear alterations, caspase-3 activation, and PARP cleavage), but not necrosis (propidium iodide staining and LDH release). In vivo, MIR triggered myocardial oxidative stress (malondialdehyde generation), nitrotyrosine formation, neutrophil accumulation, and the cleavage of caspase-3 and PARP, indicating ongoing myocardial apoptosis. MnTBAP suppressed these alterations, allowing a considerable reduction of myocardial injury. Thus, peroxynitrite triggers apoptosis in cardiomyocytes in vitro and in the myocardium in vivo, through a pathway involving caspase-3 activation and the cleavage of PARP. These results provide important novel information on the mechanisms of myocardial toxicity of peroxynitrite.
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PMID:Peroxynitrite is a major trigger of cardiomyocyte apoptosis in vitro and in vivo. 1693 67

FK866 is a novel anticancer agent that was previously shown to interfere with NAD superset+ biosynthesis by inhibition of nicotinamide phosphoribosyltransferase and to initiate apoptosis in cancer cells. As NAD superset+ is involved in cellular DNA repair processes, the present in vitro study on THP-1 and K562 leukemia cells was conducted to investigate the cytotoxicity of FK866 combination treatment with various cytotoxic agents: the antimetabolite Ara-C, the DNA-intercalating agent daunorubicin and the alkylating compounds 1-methyl-3-nitro-1-nitrosoguanidinium (MNNG) and melphalan. Cell viability after drug exposure was assessed by propidium iodide (PI) staining. Non-cytotoxic concentrations of FK866 (10 superset-9 M or less), applied simultaneously or 24 hours before adding cytotoxic agents, caused a depletion in the intracellular NAD superset+ and--to a lesser extent-- NADH levels in THP-1 cells. After 48 and 72 hours treatment with daunorubicin and Ara-C, respectively, increased cell death was observed in THP-1 cells that were pretreated with FK866, as compared to cells exposed to antineoplastic drugs alone. However, this effect was transient, and there was no difference in cell survival after 72 hours incubation with daunorubicin or 96 hours with Ara-C. - Non-toxic concentrations of FK866 added 8, 16, or 24 hours before starting treatment with the PARP-activating agent MNNG synergistically decreased intracellular NAD superset+ contents, and increased MNNG-induced cytotoxicity both in THP-1 and K562 cells for at least 72 hours. This effect was less pronounced when FK866 was used in combination with another alkylating agent, melphalan. The PARP inhibitor 3-aminobenzamide delayed MNNG-induced cytotoxicity by 24 hours both in cells that were pretreated with FK866 and in non-pretreated cells. 48 hours later, the protective effect of 3-aminobenzamide could no longer be observed, but FK866-pretreated cells retained increased sensitivity to MNNG. - In conclusion, the chemosensitizing effect of FK866 on cell death induced by antineoplastic drugs was particularly obvious in combination with substances like MNNG that cause NAD superset+ depletion per se. It was less pronounced and only transiently measurable in combination with daunorubicin, Ara-C, and melphalan, respectively. These results may indicate different levels of DNA damage implicated in the action of the cytotoxic agents used.
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PMID:Chemopotentiating effects of a novel NAD biosynthesis inhibitor, FK866, in combination with antineoplastic agents. 1705 66


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