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)

Nucleated cells are more resistant to complement-mediated cell death than anucleated cells such as erythrocytes. There are few reports concerning the metabolic response of nucleated cells subjected to sub-lethal complement attack. It is possible that the rate of utilization of specific metabolic fuels by the cell is increased to enhance cell defence. We have measured the maximum activity of hexokinase, citrate synthase, glucose 6-phosphate dehydrogenase and glutaminase in rat mesenteric lymphocytes exposed to sub-lethal concentrations of activated complement (present in zymosan-activated serum, ZAS). These enzymes were carefully selected as they indicate changes of flux in glycolysis, TCA cycle, pentose phosphate pathway and glutaminolysis, respectively. The only enzyme activity to change on exposure of lymphocytes to ZAS was glutaminase, which was enhanced approximately by two-fold. Although rates of both glutamine and glucose utilization were enhanced by exposure to ZAS, only the rate of oxidation of glutamine was increased. Complement kills anucleated cells by simple osmotic lysis. However, it is likely that some nucleated cells will display characteristics of an ordered death mechanism and we have demonstrated that the concentration of lymphocyte ATP is dramatically decreased by activated complement. Nevertheless, the extent of cell death could be significantly reduced by the addition of inhibitors of the nuclear enzyme poly (ADP-ribose) polymerase (PARP). We conclude that glutamine metabolism is not only important for lymphocyte proliferative responses but is also important for cell defence from sub-lethal concentrations of activated complement. The rapid rate of complement-induced lymphocyte death reported here is suggested to be a consequence of over-activation of the nuclear enzyme PARP and ATP depletion.
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PMID:Sub-lethal concentrations of activated complement increase rat lymphocyte glutamine utilization and oxidation while lethal concentrations cause death by a mechanism involving ATP depletion. 1212 93

The DNA repair enzyme, poly(ADP-ribose) polymerase-1 (PARP1), contributes to cell death during ischemia/reperfusion when extensively activated by DNA damage. The cell death resulting from PARP1 activation is linked to NAD+ depletion and energy failure, but the intervening steps are not well understood. Because glycolysis requires cytosolic NAD+, the authors tested whether PARP1 activation impairs glycolytic flux and whether substrates that bypass glycolysis can rescue cells after PARP1 activation. PARP1 was activated in mouse cortical astrocyte and astrocyte-neuron cocultures with the DNA alkylating agent, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Studies using the 2-deoxyglucose method confirmed that glycolytic flux was reduced by more than 90% in MNNG-treated cultures. The addition of 5 mmol/L of alpha-ketoglutarate, 5 mmol/L pyruvate, or other mitochondrial substrates to the cultures after MNNG treatment reduced cell death from approximately 70% to near basal levels, while PARP inhibitors and excess glucose had negligible effects. The mitochondrial substrates significantly reduced cell death, with delivery delayed up to 2 hours after MNNG washout. The findings suggest that impaired glycolytic flux is an important factor contributing to PARP1-mediated cell death. Delivery of alternative substrates may be a promising strategy for delayed treatment of PARP1-mediated cell death in ischemia and other disorders.
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PMID:Tricarboxylic acid cycle substrates prevent PARP-mediated death of neurons and astrocytes. 1214 62

Double-stranded (ds) RNA-induced sequence-specific interference with gene expression, RNA interference (RNAi), has been extensively used in invertebrates, allowing for efficient and high-throughput gene silencing and gene function analysis. In vertebrates, however, use of RNAi to study gene function has been limited due to non-specific effects induced by double-stranded RNA (dsRNA)-dependent protein kinase and interferon activation. dsRNA-induced specific inhibition of vertebrate gene expression has only been shown in embryonic and non-differentiated mammalian cells. In this report, we demonstrate dsRNA-induced specific interference of gene expression and gene function in partially as well as fully differentiated mouse neuroblastoma cells. Specific silencing was observed in the expression of an integrated transgene coding for green fluorescent protein and a variety of endogenous genes. Moreover, we show that RNAi-mediated inhibition of poly (ADP-ribose) polymerase (PARP) expression induced cellular resistance to oxygen-glucose deprivation, consistent with the role of PARP in ischemia-induced brain damage. Our results indicate that RNAi can be used as a powerful tool to study gene function in neural cells.
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PMID:Specific interference with gene expression and gene function mediated by long dsRNA in neural cells. 1246 5

To study the effect of extracellular acidosis on apoptosis and necrosis during ischemia and reoxygenation, we exposed human post-mitotic NT2-N neurones to oxygen and glucose deprivation (OGD) followed by reoxygenation. In some experiments, pH of the cell medium was lowered to 5.9 during either OGD or reoxygenation or both. Staurosporine, used as a positive control for apoptosis, caused Poly(ADP-ribose)-polymerase (PARP) cleavage and nuclear fragmentation, but no PARP cleavage and little fragmentation were seen after OGD. Low molecular weight DNA fragments were found after staurosporine treatment, but not after OGD. No protective effect of caspase inhibitors was seen after 3 h of OGD and 21 h of reoxygenation, but after 45 h of reoxygenation caspase inhibition induced a modest improvement in 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide (MTT) cleavage. While acidosis during OGD accompanied by neutral medium during reoxygenation protected the neurones (MTT: 228 +/- 117% of neutral medium, p < 0.001), acidosis during reoxygenation only was detrimental (MTT: 38 +/- 25%, p < 0.01). We conclude that apoptotic mechanisms play a minor role after OGD in NT2-N neurones. The effect of acidosis on neuronal survival depends on the timing of acidosis, as acidosis was protective during OGD and detrimental during reoxygenation.
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PMID:Acidosis has opposite effects on neuronal survival during hypoxia and reoxygenation. 1260 26

Excessive activation of poly(ADP-ribose) polymerase-1 (PARP-1), a nuclear enzyme catalyzing the transfer of ADP-ribose units from NAD to acceptor proteins, induces cellular energy failure by NAD and ATP depletion and has been proposed to play a causative role in a number of pathological conditions, including ischemia/reperfusion injury. In this study, we used an in vitro enzyme activity assay to characterize a series of newly synthesized isoquinolinone derivatives as potential PARP-1 inhibitors. Several compounds displayed powerful inhibitory activity: thieno[2,3-c]isoquinolin-5-one (TIQ-A) displayed a submicromolar IC50 of 0.45 +/- 0.1 microM, whereas the 5-hydroxy and 5-methoxy TIQ-A derivatives had IC50 values of 0.39 +/- 0.19 and 0.21 +/- 0.12 microM, respectively. We then examined the neuroprotective effects of the newly characterized compounds in cultured mouse cortical cells exposed to 60 min of oxygen and glucose deprivation (OGD). When PARP-1 inhibitors were present in the incubation medium during OGD and the subsequent 24-h recovery period, they significantly attenuated neuronal injury. TIQ-A provided neuroprotection even when added to the culture 30 min after OGD and was able to reduce the early activation of PARP induced by OGD as detected by flow cytometry. When the IC50 values observed in the PARP-1 activity assay for selected compounds were compared with their IC50 values for the neuroprotective activity, a significant correlation (r = 0.93, P < 0.01) was observed. Our results suggest that TIQ-A and its derivatives are a new class of neuroprotectants that may be helpful in studies aimed at understanding the involvement of PARP-1 in physiology and pathology.
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PMID:Novel isoquinolinone-derived inhibitors of poly(ADP-ribose) polymerase-1: pharmacological characterization and neuroprotective effects in an in vitro model of cerebral ischemia. 1260 24

Poly(ADP-ribose) polymerases (PARPs) are a group of protein-modifying and nucleotide-polymerizing enzymes able to catalyze the transfer of multiple ADP-ribose units from NAD to substrate proteins. In the human genome, 16 different genes encoding for members of this emerging family of enzymes have been identified. Known family members are PARP-1, PARP-2, PARP-3, vPARP, tankyrase 1 and tankyrase 2, each of them with a possible specific role in cell biology. The most studied member of the family is PARP-1, which is abundantly present in the nucleus and is involved in the maintenance of genomic stability. In pathological conditions, highly reactive radical species may cause DNA damage and PARP-1 hyperactivation. This may lead to necrotic cell death through massive NAD consumption. We show that following middle cerebral artery occlusion, rats treated with PARP inhibitors displayed reduced brain infarct volumes. Similarly, PARP inhibitors reduced neuronal death induced by oxygen-glucose deprivation (OGD) or excitotoxins in primary cultures of murine cortical cells. On the contrary, PARP inhibitors did not attenuate the OGD-induced selective loss of CA1 pyramidal cells in rat organotypic hippocampal slices. In addition, they were not neuroprotective against transient bilateral carotid occlusion in gerbils. We observed that post-ischemic brain damage was predominally necrotic in cultured cortical cells, whereas a caspase-dependent apoptotic process was responsible for the CA1 pyramidal cell loss in hippocampal slices. Hence, it appears reasonable to propose PARP inhibitors as useful therapeutic agents in pathological brain conditions were necrosis predominates.
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PMID:Poly(ADP-ribose) polymerase as a key player in excitotoxicity and post-ischemic brain damage. 1262 50

Poly(ADP-ribose) polymerase-1 (PARP-1) is a member of the PARP enzyme family consisting of PARP-1 and a growing family of additional, novel poly(ADP-ribosylating) enzymes. PARP-1 is one of the most abundant nuclear proteins, and it functions as a DNA nick sensor enzyme. Upon binding to DNA breaks, activated PARP cleaves NAD(+) into nicotinamide and ADP-ribose and polymerizes the latter onto nuclear acceptor proteins including histones, transcription factors and PARP itself. Overactivation of PARP in response to oxidant- and free radical-mediated excessive DNA single strand breaks promotes cell dysfunction and necrotic-type cell death in a variety of pathophysiological conditions. Emerging data indicate that high circulating glucose in diabetes mellitus is able to induce free radical and oxidant generation in the cardiovascular system with the concomitant activation of PARP. This process results in acute loss of the ability of the endothelium to release nitric oxide (endothelial dysfunction) and leads to a severe functional impairment of the heart (diabetic cardiomyopathy). Accordingly, pharmacological inhibition of PARP protects against diabetic cardiovascular dysfunction. Surprisingly, PARP inhibition not only prevents the development of diabetic endothelial dysfunction, but also restores normal vascular function in established diabetes. In addition to the direct cytotoxic pathway regulated by DNA injury and PARP activation, PARP also modulates the course of cardiovascular inflammation and injury by regulating the activation of NF-kappaB, and the expression of a number of proinflammatory genes. The research into the role of PARP in diabetic cardiovascular injury is now supported by novel tools, such as new classes of potent inhibitors of PARP, as well as genetically engineered animals lacking the gene for PARP. Inhibitors of PARP may become useful in the experimental therapy of diabetic vascular complications. (c) 2002 Prous Science. All rights reserved.
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PMID:PARP as a Drug Target for the Therapy of Diabetic Cardiovascular Dysfunction. 1267 3

A class of poly(ADP-ribose) polymerase (PARP-1) inhibitors, the imidazobenzodiazepines, are presented in this text. Several derivatives were designed and synthesized with ionizable groups (i.e., tertiary amines) in order to promote the desired pharmaceutical characteristics for administration in ischemic injury. Within this series, several compounds have excellent in vitro potency and our computational models accurately justify the structure-activity relationships (SARs) and highlight essential hydrogen bonding residues and hydrophobic pockets within the catalytic domain of PARP-1. Administration of these compounds (5q, 17a and 17e) in the mouse model of streptozotocin-induced diabetes results in maintainance of glucose levels. Furthermore, one such inhibitor (5g, IC(50)=26 nM) demonstrated significant reduction of infarct volume in the rat model of permanent focal cerebral ischemia.
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PMID:Design and synthesis of poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors. Part 4: biological evaluation of imidazobenzodiazepines as potent PARP-1 inhibitors for treatment of ischemic injuries. 1290 15

A transient, sublethal ischemic interval confers resistance to a subsequent, otherwise lethal ischemic insult, in a process termed ischemic preconditioning. Poly(ADP-ribose) polymerase-1 (PARP-1) normally functions in DNA repair, but extensive PARP-1 activation is a major cause of ischemic cell death. Because PARP-1 can be cleaved and inactivated by caspases, we investigated the possibility that caspase cleavage of PARP-1 could contribute to ischemic preconditioning. Murine cortical cultures were treated with glucose deprivation combined with 0.5 mm 2-deoxyglucose and 5 mm azide ("chemical ischemia") to model the reversible energy failure that occurs during transient ischemia in vivo. Cortical cultures preconditioned with 15 min of chemical ischemia showed increased resistance to subsequent, longer periods of chemical ischemia. These cultures were also more resistant to the PARP-1 activating agent, N-methyl-N'-nitro-N-nitrosoguanidine, suggesting reduced capacity for PARP-1 activation after preconditioning. Immunostaining for the 89 kDa PARP-1 cleavage fragment and for poly(ADP-ribose) formation confirmed that PARP-1 was cleaved and PARP-1 activity was attenuated in the preconditioned neurons. Preconditioning also produced an increase in activated caspase-3 peptide and an increase in caspase-3 activity in the cortical cultures. A cause-effect relationship between caspase activation, PARP-1 cleavage, and ischemic preconditioning was supported by studies using the caspase inhibitor Ac-Asp-Glu-Val-Asp-aldehyde (DEVD-CHO). Cultures treated with DEVD-CHO after preconditioning showed reduced PARP-1 cleavage and reduced resistance to subsequent ischemia. These findings suggest a novel interaction between the caspase- and PARP-1-mediated cell death pathways in which sublethal caspase activation leads to PARP-1 cleavage, thereby increasing resistance to subsequent ischemic stress.
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PMID:Ischemic preconditioning by caspase cleavage of poly(ADP-ribose) polymerase-1. 1295 57

In this report, we show that hyperglycemia-induced overproduction of superoxide by the mitochondrial electron transport chain activates the three major pathways of hyperglycemic damage found in aortic endothelial cells by inhibiting GAPDH activity. In bovine aortic endothelial cells, GAPDH antisense oligonucleotides activated each of the pathways of hyperglycemic vascular damage in cells cultured in 5 mM glucose to the same extent as that induced by culturing cells in 30 mM glucose. Hyperglycemia-induced GAPDH inhibition was found to be a consequence of poly(ADP-ribosyl)ation of GAPDH by poly(ADP-ribose) polymerase (PARP), which was activated by DNA strand breaks produced by mitochondrial superoxide overproduction. Both the hyperglycemia-induced decrease in activity of GAPDH and its poly(ADP-ribosyl)ation were prevented by overexpression of either uncoupling protein-1 (UCP-1) or manganese superoxide dismutase (MnSOD), which decrease hyperglycemia-induced superoxide. Overexpression of UCP-1 or MnSOD also prevented hyperglycemia-induced DNA strand breaks and activation of PARP. Hyperglycemia-induced activation of each of the pathways of vascular damage was abolished by blocking PARP activity with the competitive PARP inhibitors PJ34 or INO-1001. Elevated glucose increased poly(ADP-ribosyl)ation of GAPDH in WT aortae, but not in the aortae from PARP-1-deficient mice. Thus, inhibition of PARP blocks hyperglycemia-induced activation of multiple pathways of vascular damage.
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PMID:Inhibition of GAPDH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells. 1452 35


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