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)

Oxidants such as H(2)O(2) can induce a low level of apoptosis at low concentrations but at higher concentrations cause necrosis. Higher concentrations of H(2)O(2) also inhibit the induction of apoptosis by chemotherapy drugs. One theory is that, at higher concentrations, H(2)O(2) causes direct oxidative inactivation of caspase-3 activity, thus preventing the apoptotic pathway from being used. We find that treatment of recombinant caspase-3 with H(2)O(2) can partially reduce its enzymatic activity: However, the following findings show that this does not occur in the cell. (1) The inhibition by H(2)O(2) of VP-16-induced apoptosis and cellular caspase-3 activity can be overcome by adding inhibitors of poly(ADP-ribose) polymerase (PARP) at sub-stoichiometric concentrations. (2) Delayed addition of H(2)O(2) to VP-16-treated cells prevents additional caspase induction but does not inhibit the caspase activity that has already been generated. (3) H(2)O(2) is a poor inhibitor of caspase-3 activity in cell lysates. (4) Addition of H(2)O(2) to cells inhibits activation of caspase-9, which is required for activation of caspase-3. We conclude that inhibition of caspase-3 activity in the cell occurs indirectly at a step located upstream of caspase-3 activation. H(2)O(2) acts in part by inducing DNA strand breaks and activating PARP, thus depleting the cells of ATP. When this pathway is blocked, even high concentrations of H(2)O(2) can induce caspase-9 and -3 activation and cause apoptosis.
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PMID:Hydrogen peroxide inhibits activation, not activity, of cellular caspase-3 in vivo. 1103 21

The enzyme, poly(ADP-ribose) polymerase (PARP), effects repair of DNA after ischemia-reperfusion (I/R) injury to cells in nerve and muscle tissue. However, its activation in severely damaged cells can lead to ATP depletion and death. We show that PARP expression is enhanced in damaged renal proximal tubules beginning at 6-12 h after I/R injury. Intraperitoneal administration of PARP inhibitors, benzamide or 3-amino benzamide, after I/R injury accelerates the recovery of normal renal function, as assessed by monitoring the levels of plasma creatinine and blood urea nitrogen during 6 days postischemia. PARP inhibition leads to increased cell proliferation at 1 day postinjury as assessed by proliferating cell nuclear antigen and improves the histopathological appearance of kidneys examined at 7 days postinjury. Furthermore, inhibition of PARP increases levels of ATP measured at 24 h postischemia compared with those in vehicle-treated animals. Our data indicate that PARP activation is a part of the cascade of molecular events that occurs after I/R injury in the kidney. Although caution is advised, transient inhibition of PARP postischemia may constitute a novel therapy for acute renal failure.
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PMID:Inhibition of poly(ADP-ribose) polymerase attenuates ischemic renal injury in rats. 1104 68

DNA single-strand breaks induced by cell treatment with hydrogen peroxide are repaired and simultaneously trigger programmed cell death in resting human blood lymphocytes. Apoptosis is accompanied by special morphological changes in lymphocytes (15% of total cell number), internucleosomal DNA degradation, and p53 level elevation. According to morphological criteria, a major part (up to 40% of total cell number) displayed necrotic death features. Nicotinamide inhibited repair in cells with 2.5-fold elevation of the apoptotic cell proportion, whereas the fraction of cells with necrotic nuclear morphology decreased 4.5-fold. Both the inhibition of repair and the protective effect of nicotinamide against necrotic death indicate that the repair process and related poly(ADP-ribose)polymerase (PARP) activation induce a decrease in intracellular NAD+ and ATP contents below the threshold at which necrosis becomes the preferential mechanism of cell death. The mixed pattern of cell death induced by hydrogen peroxide observed in resting lymphocytes can be explained in the context of a concept of cell de-energization as a consequence of effective single-stand break repair during the first hours after removing the genotoxic agent.
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PMID:Hydrogen peroxide-induced DNA repair and death of resting human blood lymphocytes. 1111 44

Development of necrosis is a characteristic feature of glioblastoma but its pathogenesis remains poorly understood. The process of poly(ADP-ribosyl)ation in response to DNA damage is mediated by poly(ADP-ribose) polymerase (PARP) and results in NAD+ depletion. The consequent ATP and energy depletion may result in cell necrosis. Therefore PARP activation is a potential candidate for a regulatory role in the pathogenesis of necrosis in glioblastoma. This study investigated whether there might be a relationship between both PARP expression and poly(ADP-ribosyl)ation, and necrosis in glioblastoma. The pattern of expression of PARP and of poly(ADP-ribose) groups in an archival series of glioblastoma was examined using immunohistochemistry. These parameters were also studied in multicellular tumour spheroids, derived from human glioma cell lines in which central necrosis develops with increasing spheroid diameter. Poly(ADP-ribose) groups were expressed in peri-necrotic tumour cells in glioblastoma. In the spheroid model poly(ADP-ribosyl)ation was seen centrally in pre-necrotic and necrotic cells with increasing spheroid diameter. PARP was widely expressed in viable tumour cells in the glioblastoma sections. In the spheroids, PARP expression, which was initially diffuse, became confined to the outer proliferative zone with increasing diameter. The pattern of expression of poly(ADP-ribose) groups in the spheroids and in glioblastoma raises the possibility that poly(ADP-ribosyl)ation may play a role in the development of necrosis in glioma. The high basal PARP expression in both glioblastoma and the spheroids suggests that this enzyme may have additional roles in glioma cell biology.
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PMID:Expression of poly(ADP-ribose) polymerase and distribution of poly(ADP-ribosyl)ation in glioblastoma and in a glioma multicellular tumour spheroid model. 1112 19

Purines such as adenosine, inosine, and hypoxanthine are known to have potent antiinflammatory effects. These effects generally are believed to be mediated by cell surface adenosine receptors. Here we provide evidence that purines protect against oxidant-induced cell injury by inhibiting the activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP). Upon binding to broken DNA, PARP cleaves NAD+ into nicotinamide and ADP-ribose and polymerizes the latter on nuclear acceptor proteins such as histones and PARP itself. Overactivation of PARP depletes cellular NAD+ and ATP stores and causes necrotic cell death. We have identified some purines (hypoxanthine, inosine, and adenosine) as potential endogenous PARP inhibitors. We have found that purines (hypoxanthine > inosine > adenosine) dose-dependently inhibited PARP activation in peroxynitrite-treated macrophages and also inhibited the activity of the purified PARP enzyme. Consistently with their PARP inhibitory effects, the purines also protected interferon gamma + endotoxin (IFN/LPS) -stimulated RAW macrophages from the inhibition of mitochondrial respiration and inhibited nitrite production from IFN/LPS-stimulated macrophages. We have selected hypoxanthine as the most potent cytoprotective agent and PARP inhibitor among the three purine compounds, and investigated the mechanism of its cytoprotective effect. We have found that hypoxanthine protects thymocytes from death induced by the cytotoxic oxidant peroxynitrite. In line with the PARP inhibitory effect of purines, hypoxanthine has prevented necrotic cell death while increasing caspase activity and DNA fragmentation. As previously shown with other PARP inhibitors, hypoxanthine acted proximal to mitochondrial alterations as hypoxanthine inhibited the peroxynitrite-induced mitochondrial depolarization and secondary superoxide production. Our data imply that purines may serve as endogenous PARP inhibitors. We propose that, by affecting PARP activation, purines may modulate the pattern of cell death during shock, inflammation, and reperfusion injury.
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PMID:Purines inhibit poly(ADP-ribose) polymerase activation and modulate oxidant-induced cell death. 1114 97

JP-8 induces apoptosis in rat lung epithelial cells, primary mouse T lymphocytes, Jurkat T lymphoma cells, and U937 monocytic cells (Stoica et al., 2001). Here, we have observed a different mechanism of cytotoxicity in human keratinocytes grown in culture as well as when grafted onto nude mice. At lower levels of JP-8 (80 microg/ml; 1 x 10(-4) dilution), sufficient to induce apoptosis in other cell types, including lung epithelial cells (Stoica et al., 2001), no apoptosis was observed. At higher levels (>200 microg/ml; 2.5 x 10(-4) dilution), JP-8 is cytotoxic to both primary and immortalized human keratinocytes, as evidenced by the metabolism of calcein, as well as by morphological changes such as cell rounding and cell detachment. There was no evidence of activation of caspases-3, -7, or -8 either by enzyme activity or immunoblot analysis, and the stable expression of a dominant-negative inhibitor of apoptosis (FADD-DN) did not increase the survival of keratinocytes to JP-8. The pattern of poly(ADP-ribose) polymerase (PARP) cleavage was also characteristic of necrosis. PARP has been also been implicated in necrosis via its ability to lower levels of ATP in damaged cells. However, fibroblasts derived from PARP-/- mice underwent necrotic cell death similar to those derived from PARP+/+ mice, indicating that the effects of JP-8 are independent of PARP. Immunoblot analysis further revealed that exposure of keratinocytes to the toxic higher levels of JP-8 markedly downregulates the expression of the prosurvival members of the Bcl-2 family, Bcl-2 and Bcl-x(L), and upregulates the expression of antisurvival members of this family, including Bad and Bak. Bcl-2 and Bcl-x(L) have been shown to preserve mitochondrial integrity and suppress cell death. In contrast, Bak and Bad both promote cell death by alteration of the mitochondrial membrane potential, in part by heterodimerization with and inactivation of Bcl-2 and Bcl-x(L), and either inducing necrosis or activating a downstream caspase program. High intrinsic levels of Bcl-2 and Bcl-x(L) may prevent apoptotic death of keratinocytes at lower levels of JP-8, while perturbation of the balance between pro- and antiapoptotic Bcl-2 family members at higher levels may ultimately play a role in necrotic cell death in human keratinocytes. Finally, when human keratinocytes were grafted to form a human epidermis on nude mice, treatment of these grafts with JP-8 revealed cytotoxicity and altered histology in vivo.
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PMID:Mechanisms of JP-8 jet fuel cell toxicity. II. Induction of necrosis in skin fibroblasts and keratinocytes and modulation of levels of Bcl-2 family members. 1122 86

Pyridine nucleotides are critical during oxidative stress due to their roles in reductive reactions and energetics. The aim of the present study was to examine pyridine nucleotide changes in six brain regions of mice after an intracerebroventricular injection of the oxidative stress inducing agent, t-butyl hydroperoxide (t-BuOOH). A secondary aim was to investigate the correlation between NAD+ levels and DNA fragmentation. Here, we demonstrate that t-BuOOH induced a rapid oxidation of NADPH and a slow depletion of NAD+ in most brain regions. A slight increase in NADH also occurred in five brain regions. NAD+ depletion was associated with increased DNA fragmentation. This suggests the initiation of a death cascade involving poly(ADP-ribose) polymerase (PARP), NAD+, ATP depletion and consequent cell death in brain tissue. PARP activity was accelerated in some brain regions after 20 min of oxidative stress. To counteract oxidative stress induced toxicity, NAD+ levels were increased in the brain using an intraperitoneal injection of nicotinamide. A surplus of brain NAD+ prevented DNA fragmentation in some brain regions. Nicotinamide administration also resulted in higher brain NADH, NADP+ and NADPH levels in some regions. Their synthesis was further upregulated during oxidative stress. Nicotinamide as a precursor for NAD+ may provide a useful therapeutic strategy in the treatment of neurodegeneration.
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PMID:Oxidative changes in brain pyridine nucleotides and neuroprotection using nicotinamide. 1134 63

Ischemia-reperfusion induces reactive oxygen species (ROS) formation, and ROS lead to cardiac dysfunction, in part, via the activation of the nuclear poly(ADP-ribose) polymerase (PARP, called also PARS and ADP-RT). ROS and peroxynitrite induce single-strand DNA break formation and PARP activation, resulting in NAD(+) and ATP depletion, which can lead to cell death. Although protection of cardiac muscle by PARP inhibitors can be explained by their attenuating effect on NAD(+) and ATP depletion, there are data indicating that PARP inhibitors also protect mitochondria from oxidant-induced injury. Studying cardiac energy metabolism in Langendorff heart perfusion system by (31)P NMR, we found that PARP inhibitors (3-aminobenzamide, nicotinamide, BGP-15, and 4-hydroxyquinazoline) improved the recovery of high-energy phosphates (ATP, creatine phosphate) and accelerated the reutilization of inorganic phosphate formed during the ischemic period, showing that PARP inhibitors facilitate the faster and more complete recovery of the energy production. Furthermore, PARP inhibitors significantly decrease the ischemia-reperfusion-induced increase of lipid peroxidation, protein oxidation, single-strand DNA breaks, and the inactivation of respiratory complexes, which indicate a decreased mitochondrial ROS production in the reperfusion period. Surprisingly, PARP inhibitors, but not the chemically similar 3-aminobenzoic acid, prevented the H(2)O(2)-induced inactivation of cytochrome oxidase in isolated heart mitochondria, suggesting the presence of an additional mitochondrial target for PARP inhibitors. Therefore, PARP inhibitors, in addition to their important primary effect of decreasing the activity of nuclear PARP and decreasing NAD(+) and ATP consumption, reduce ischemia-reperfusion-induced endogenous ROS production and protect the respiratory complexes from ROS induced inactivation, providing an additional mechanism by which they can protect heart from oxidative damages.
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PMID:Effect of poly(ADP-ribose) polymerase inhibitors on the ischemia-reperfusion-induced oxidative cell damage and mitochondrial metabolism in Langendorff heart perfusion system. 1135 11

Cyclin-dependent kinases (cdk's) have recently been suggested to regulate human immunodeficiency virus type 1 (HIV-1) transcription. Previously, we have shown that expression of one cdk inhibitor, p21/Waf1, is abrogated in HIV-1 latently infected cells. Based on this result, we investigated the transcription of HIV-1 in the presence of chemical drugs that specifically inhibited cdk activity and functionally mimicked p21/Waf1 activity. HIV-1 production in virally integrated lymphocytic and monocytic cell lines, such as ACH(2), 8E5, and U1, as well as activated peripheral blood mononuclear cells infected with syncytium-inducing (SI) or non-syncytium-inducing (NSI) HIV-1 strains, were all inhibited by Roscovitine, a purine derivative that reversibly competes for the ATP binding site present in cdk's. The decrease in viral progeny in the HIV-1-infected cells was correlated with a decrease in the transcription of HIV-1 RNAs in cells treated with Roscovitine and not with the non-cdk general cell cycle inhibitors, such as hydroxyurea (G(1)/S blocker) or nocodazole (M-phase blocker). Cyclin A- and E-associated histone H1 kinases, as well as cdk 7 and 9 activities, were all inhibited in the presence of Roscovitine. The 50% inhibitory concentration of Roscovitine on cdk's 9 and 7 was determined to be approximately 0.6 microM. Roscovitine could selectively sensitize HIV-1-infected cells to apoptosis at concentrations that did not impede the growth and proliferation of uninfected cells. Apoptosis induced by Roscovitine was found in both latent and activated infected cells, as evident by Annexin V staining and the cleavage of the PARP protein by caspase-3. More importantly, contrary to many apoptosis-inducing agents, where the apoptosis of HIV-1-infected cells accompanies production and release of infectious HIV-1 viral particles, Roscovitine treatment selectively killed HIV-1-infected cells without virion release. Collectively, our data suggest that cdk's are required for efficient HIV-1 transcription and, therefore, we propose specific cdk inhibitors as potential antiviral agents in the treatment of AIDS.
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PMID:Inhibition of human immunodeficiency virus type 1 transcription by chemical cyclin-dependent kinase inhibitors. 1146 99

Type 1 diabetes is thought to occur as a result of the loss of insulin-producing pancreatic beta cells by an environmentally triggered autoimmune reaction. In rodent models of diabetes, streptozotocin (STZ), a genotoxic methylating agent that is targeted to the beta cells, is used to trigger the initial cell death. High single doses of STZ cause extensive beta-cell necrosis, while multiple low doses induce limited apoptosis, which elicits an autoimmune reaction that eliminates the remaining cells. We now show that in mice lacking the DNA repair enzyme alkylpurine-DNA-N-glycosylase (APNG), beta-cell necrosis was markedly attenuated after a single dose of STZ. This is most probably due to the reduction in the frequency of base excision repair-induced strand breaks and the consequent activation of poly(ADP-ribose) polymerase (PARP), which results in catastrophic ATP depletion and cell necrosis. Indeed, PARP activity was not induced in APNG(-/-) islet cells following treatment with STZ in vitro. However, 48 h after STZ treatment, there was a peak of apoptosis in the beta cells of APNG(-/-) mice. Apoptosis was not observed in PARP-inhibited APNG(+/+) mice, suggesting that apoptotic pathways are activated in the absence of significant numbers of DNA strand breaks. Interestingly, STZ-treated APNG(-/-) mice succumbed to diabetes 8 months after treatment, in contrast to previous work with PARP inhibitors, where a high incidence of beta-cell tumors was observed. In the multiple-low-dose model, STZ induced diabetes in both APNG(-/-) and APNG(+/+) mice; however, the initial peak of apoptosis was 2.5-fold greater in the APNG(-/-) mice. We conclude that APNG substrates are diabetogenic but by different mechanisms according to the status of APNG activity.
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PMID:Increased susceptibility to streptozotocin-induced beta-cell apoptosis and delayed autoimmune diabetes in alkylpurine-DNA-N-glycosylase-deficient mice. 1146 41


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