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: EC:2.4.2.30 (PARP)
13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The antioxidant and anticancer properties of a medicinal plant, Betula platyphylla var. japonica were investigated. The total methanol extract of B. platyphylla var. japonica had protective effects against hydrogen peroxide (H2O2) in the Chinese hamster lung fibroblast (V79-4) cell line and induced apoptotic cell death in human promyelocytic leukemia (HL-60) cells, a cancer cell line. B. platyphylla var. japonica extract significantly increased cell viability against H2O2. The extract also showed high 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity (IC50 2.4 microg/ml) and lipid peroxidation inhibitory activity (IC50 below 4.0 microg/ml). Furthermore, B. platyphylla var. japonica extract reduced the number of V79-4 cells arrested in G2/M in response to H2O2 treatment and increased the activities of several cellular antioxidant enzymes, including superoxide dismutase, catalase and glutathione peroxidase. Treatment with B. platyphylla var. japonica extract induced cytotoxicity and apoptosis in HL-60 cells, as shown by nucleosomal DNA fragmentation, increases in the subdiploid cell population, and fluorescence microscopy. B. platyphylla var. japonica extract gradually increased the expression of pro-apoptotic Bax and led to the activation of caspase-3 and cleavage of PARP. These findings suggest that B. platyphylla var. japonica exhibits potential antioxidant and anticancer properties.
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PMID:Antioxidant and anticancer activity of extract from Betula platyphylla var. japonica. 1467 57

Excessive oxidative stress has been implicated in the induction of cell death in a variety of neurodegenerative diseases. In the present study, hydrogen peroxide (H2O2)-induced cell death in rat C6 glioma cells was used as a model system for studying the molecular events associated with oxidative stress-induced cell death in glial cells. We demonstrate that exposure of C6 glioma cells to H2O2 results in apoptotic cell death in a concentration-dependent manner, and caused activation of a member of the caspase-3-like family of proteases resulting in cleavage of the DNA repair enzyme poly(ADP-ribose)polymerase, PARP. Furthermore, H2O2 induced a transient activation of the transcription factor, nuclear factor kappa B (NF(Kappa)B). Pre-treatment of cells with the antioxidant N-acetylcysteine, (NAC), prevented both the activation of NF(Kappa)B and the induction of apoptosis by H2O2, suggesting a possible role for this transcription factor in oxidant-induced apoptosis in glial cells. Exposure of the cells to H2O2 led to transient activation of both c-Jun N-terminal kinase (JNK) and p38 kinase but has no effect on extracellular regulated kinase (ERK) activity. Inhibition of p38 by SB203580 did not protect the cells against H2O2-induced apoptosis suggesting that activation of p38 is not essential for H2O2-mediated cell death in C6 glioma cells.
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PMID:Oxidative stress induces apoptosis in C6 glioma cells: involvement of mitogen-activated protein kinases and nuclear factor kappa B. 1471 69

Achacin, which belongs to the L-amino acid oxidase group, oxidizes free amino acids and produces hydrogen peroxide in cell culture systems. Morphological changes in cells incubated with achacin were similar to those of cells incubated with H(2)O(2). In both cases, the end result was cell death. To examine the mechanism of achacin-associated cytotoxicity, the H(2)O(2) scavenger catalase was added to culture media. Features typical of apoptosis, including morphological changes, DNA fragmentation, and PARP cleavage, were observed when cells were incubated with achacin in the presence of catalase. Moreover, apoptosis was inhibited by Z-VAD-fmk, a broad-spectrum caspase inhibitor. Herein, we present evidence that two pathways are involved in achacin-induced cell death. One is direct generation of H(2)O(2) through the L-amino acid oxidase activity of achacin. The other is the caspase-mediated apoptotic pathway that is induced by depletion of L-amino acids by achacin.
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PMID:Achacin induces cell death in HeLa cells through two different mechanisms. 1472 62

The massive activation of poly(ADP-ribose) polymerase-1 (PARP-1) by DNA-damaging stimuli, such as exposure to reactive oxygen species (ROS), can lead to cell injury via severe, irreversible depletion of the NAD and ATP pool, and PARP-1 inhibitors have been expected to rescue neurons from degeneration in a number of disease models. We have recently identified 2-[3-[4-(4-chlorophenyl)-1-piperazinyl] propyl]-4(3H)-quinazolinone (FR255595) as a novel and potent PARP-1 inhibitor through structure-based drug design and high-throughput screening. This compound potently inhibited PARP activity with an IC(50) value of 11 nM and was orally active and highly brain penetrable. Here, we show that prevention of PARP activation by FR255595 protects against both ROS-induced cells injury in vitro and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced nigrostriatal dopaminergic damage in an in vivo Parkinson's disease (PD) model. In cell death models in vitro, exposure of hydrogen peroxide induced cell death with PARP overactivation in PC12 cells and SH-SY5Y cells, and pre- and post-treatment with FR255595 (10(-9)-10(-5) M) significantly reduced PARP activation and cell death. In mouse MPTP model, MPTP (20 mg/kg i.p.) intoxication lead to PARP activation and cell damage in the nigrostriatal dopaminergic pathway, which was significantly ameliorated by oral administration of FR255595 (10-32 mg/kg), both in the substantia nigra and in the striatum via marked reduction of PARP activation, even with delayed treatment. These findings clearly indicate that the novel PARP-1 inhibitor FR255595 exerts neuroprotective effect through its potent PARP-1 inhibitory actions in PD model, suggesting that the drug could be an attractive candidate for several neurodegenerative disorders, including PD.
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PMID:Neuroprotective effects of a novel poly(ADP-ribose) polymerase-1 inhibitor, 2-[3-[4-(4-chlorophenyl)-1-piperazinyl] propyl]-4(3H)-quinazolinone (FR255595), in an in vitro model of cell death and in mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease. 1498 16

Oxidative stress-induced cytotoxicity is mediated in part by accelerated poly-ADP ribosylation. Peroxynitrite and hydrogen peroxide cause DNA breakage triggering the activation of the DNA nick sensor enzyme poly(ADP-ribose) polymerase-1 (PARP-1). Overactivation of PARP-1 leads to cell dysfunction and cell death mainly due to depletion of NAD(+) (the substrate of PARP-1) and ATP. PARP-1 attaches most ADP-ribose residues onto itself, leading to downregulation of enzyme activity. Here, we have investigated the role of poly(ADP-ribose) glycohydrolase (PARG), the poly(ADP-ribose)-catabolyzing enzyme in oxidative stress-induced cytotoxicity in HaCaT cells. We have found that inhibition of PARG by gallotannin (GT) (50 microM) provided significant cytoprotection to peroxynitrite- or hydrogen peroxide-treated HaCaT cells, as assessed by lactate dehydrogenase release and propidium iodide uptake (parameters of necrotic cell death) as well as caspase activation (apoptotic parameter). GT pretreatment has also inhibited the depletion of cellular NAD(+) pools in hydrogen peroxide- or peroxynitrite-treated HaCaT cells. GT caused the accumulation of poly(ADP-ribose) and concomitant inhibition in cellular PARP activity in oxidatively stressed cells. Therefore, PARG is likely to contribute to maintaining the active state of PARP-1 by continuously removing inhibitory ADP-ribose residues from PARP-1.
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PMID:Cytoprotective effect of gallotannin in oxidatively stressed HaCaT keratinocytes: the role of poly(ADP-ribose) metabolism. 1498 57

Hepatocarcinoma cells (TLT) were incubated in the presence of ascorbate and menadione, either alone or in combination. Cell death was only observed when such compounds were added simultaneously, most probably due to hydrogen peroxide (H2O2) generated by ascorbate-driven menadione redox cycling. TLT cells were particularly sensitive to such an oxidative stress due to its poor antioxidant status. DNA strand breaks were induced by this association but this process did not correspond to oligosomal DNA fragmentation (a hallmark of cell death by apoptosis). Neither caspase-3-like DEVDase activity, nor processing of procaspase-3 and cleavage of poly(ADP-ribose) polymerase (PARP) were observed in the presence of ascorbate and menadione. Cell death induced by such an association was actively dependent on protein phosphorylation since it was totally prevented by preincubating cells with sodium orthovanadate, a tyrosine phosphatase inhibitor. Finally, while H2O2, when administered as a bolus, strongly enhances a constitutive basal NF-kappaB activity in TLT cells, their incubation in the presence of ascorbate and menadione results in a total abolition of such a constitutive activity.
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PMID:Ascorbate potentiates the cytotoxicity of menadione leading to an oxidative stress that kills cancer cells by a non-apoptotic caspase-3 independent form of cell death. 1500 19

Increased reactive oxygen species (ROS) have been identified as a potential cause of remodelling and apoptotic change in fetal membrane. Vitamin C has been suggested as a therapeutic agent to prevent ROS induced chorio-amnion apoptosis. The purpose of this study was to determine whether hydrogen peroxide (HP), a ROS, initiates apoptosis in the WISH cell model and whether vitamin C would inhibit HP induced apoptosis. HP induced apoptosis in WISH cells; as assessed by cytochrome-c release from mitochondria, Poly-(ADP-ribose)-Polymerase (PARP) cleavage, nuclear matrix protein (NMP) release and DNA fragmentation analysis. HP induced dose dependent release of cytochrome-c, PARP cleavage, NMP release, and DNA fragmentation. HP also increased PGE(2)release in parallel with apoptosis in WISH cells, in a manner similar to that reported with other apoptotic agents. Vitamin C pre-incubation caused cytochrome-c release earlier, and at lower HP doses, than HP alone. It had no effect on HP induced PARP cleavage, but enhanced DNA fragmentation, and induced NMP release on its own. Vitamin C partially suppressed dose dependent HP induced PGE(2)release. We conclude that HP causes apoptosis in WISH cells and vitamin C pre-incubation does not inhibit, and may accelerate and exacerbate, HP induced apoptosis.
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PMID:Hydrogen peroxide induced apoptosis in amnion-derived WISH cells is not inhibited by vitamin C. 1502 18

Ataxia-oculomotor apraxia (AOA1) is a neurological disorder with symptoms that overlap those of ataxia-telangiectasia, a syndrome characterized by abnormal responses to double-strand DNA breaks and genome instability. The gene mutated in AOA1, APTX, is predicted to code for a protein called aprataxin that contains domains of homology with proteins involved in DNA damage signalling and repair. We demonstrate that aprataxin is a nuclear protein, present in both the nucleoplasm and the nucleolus. Mutations in the APTX gene destabilize the aprataxin protein, and fusion constructs of enhanced green fluorescent protein and aprataxin, representing deletions of putative functional domains, generate highly unstable products. Cells from AOA1 patients are characterized by enhanced sensitivity to agents that cause single-strand breaks in DNA but there is no evidence for a gross defect in single-strand break repair. Sensitivity to hydrogen peroxide and the resulting genome instability are corrected by transfection with full-length aprataxin cDNA. We also demonstrate that aprataxin interacts with the repair proteins XRCC1, PARP-1 and p53 and that it co-localizes with XRCC1 along charged particle tracks on chromatin. These results demonstrate that aprataxin influences the cellular response to genotoxic stress very likely by its capacity to interact with a number of proteins involved in DNA repair.
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PMID:Aprataxin, a novel protein that protects against genotoxic stress. 1504 83

The nuclear enzyme poly(ADP-ribose) polymerase (PARP) has been implicated in ischemia-reperfusion injury in many tissues under normothermic conditions. The purpose of this study was to determine whether PARP contributes to mechanisms of the hypothermic ischemia-reperfusion injury that occurs when kidneys are cold stored for transplantation. Cortical tissue slice PARP enzyme activity rose significantly with prolonged cold storage and was dependent on both reperfusion and preservation quality. However, prior exposure to warm ischemia abrogated this increase. PARP protein increased with cold storage but was not dependent on reperfusion. PARP enzyme activity rose quickly after reperfusion in buffer and was not different when whole blood was used. Addition of exogenous hydrogen peroxide (3 mM) to normal renal slices significantly increased PARP activity over 4 h in the cortex but not in the medulla, but the medullary basal PARP synthesis rate was five times higher than that in the cortex. However, the reactive oxygen species (ROS) inhibitors catalase (2,000 U/ml), Trolox (200 microM), and DMSO (15 mM) did not reduce reperfusion-induced PARP activity in cold-stored cortical slices. Finally, PARP inhibitors potentiated preservation injury in isolated canine proximal renal tubules. In conclusion, canine renal PARP enzyme activity rises with prolonged cold storage after reperfusion and may play a protective rather than an injurious role in hypothermic preservation for transplantation. ROS are sufficient but not necessary to activate PARP under these conditions.
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PMID:Poly(ADP-ribose) polymerase and renal hypothermic preservation injury. 1507 79

The activation of poly(ADP-ribose) polymerase-1 (PARP-1) after exposure to nitric oxide or oxygen-free radicals can lead to cell injury via severe, irreversible depletion of NAD. Genetic deletion or pharmacological inhibition of PARP-1 attenuates brain injury after focal ischemia and neurotoxicity in several neurodegenerative models in animals. FR247304 (5-chloro-2-[3-(4-phenyl-3,6-dihydro-1(2H)-pyridinyl)propyl]-4(3H)-quinazolinone) is a novel PARP-1 inhibitor that has recently been identified through structure-based drug design. In an enzyme kinetic analysis, FR247304 exhibits potent and competitive inhibition of PARP-1 activity, with a K(i) value of 35 nM. Here, we show that prevention of PARP activation by FR247304 treatment protects against both reactive oxygen species-induced PC12 cell injury in vitro and ischemic brain injury in vivo. In cell death model, treatment with FR247304 (10(-8)-10(-5) M) significantly reduced NAD depletion by PARP-1 inhibition and attenuated cell death after hydrogen peroxide (100 microM) exposure. After 90 min of middle cerebral artery occlusion in rats, poly(ADP-ribosy)lation and NAD depletion were markedly increased in the cortex and striatum from 1 h after reperfusion. The increased poly(ADP-ribose) immunoreactivity and NAD depletion were attenuated by FR247304 (32 mg/kg i.p.) treatment, and FR247304 significantly decreased ischemic brain damage measured at 24 h after reperfusion. Whereas other PARP inhibitors such as 3-aminobenzamide and PJ34 [N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-N,N-dimethylactamide] showed similar neuroprotective actions, they were less potent in in vitro assays and less efficacious in an in vivo model compared with FR247304. These results indicate that the novel PARP-1 inhibitor FR247304 exerts its neuroprotective efficacy in in vitro and in vivo experimental models of cerebral ischemia via potent PARP-1 inhibition and also suggest that FR247304 or its derivatives could be attractive therapeutic candidates for stroke and neurodegenerative disease.
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PMID:A novel and potent poly(ADP-ribose) polymerase-1 inhibitor, FR247304 (5-chloro-2-[3-(4-phenyl-3,6-dihydro-1(2H)-pyridinyl)propyl]-4(3H)-quinazolinone), attenuates neuronal damage in in vitro and in vivo models of cerebral ischemia. 1507 82


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