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

---

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

Reactive nitrogen species are thought to be involved in both hypoxic-ischemic and cytokine-induced brain injury, including periventricular leukomalacia (PVL), the major pathological substrate of cerebral palsy in premature infants. PVL appears to be the result of perinatal inflammatory events and hypoxic-ischemic injury to the cerebral white matter. The chronic disturbance of myelination resulting from PVL suggests that developing oligodendrocytes (OLs) are involved in its pathogenesis. We hypothesized that nitric oxide (NO) could participate in the pathogenesis of PVL through a toxic effect on developing OLs. Using primary cultures of highly enriched OLs we found that NO is toxic to developing OLs (O4+, O1-, MBP-), with an EC50 value of 236 +/- 125 microm of DETANOnoate. Peroxynitrite formation does not appear to be involved in NO toxicity in developing OLs, as determined by the failure of peroxynitrite scavengers as well as superoxide dismutase overexpression to prevent NO-induced toxicity. Similarly, several pathways involving PARP, excitotoxicity, guanylyl cyclase and caspase activation were not related to NO toxicity to developing OLs. NO toxicity to OLs resulted in ATP depletion and loss of mitochondrial membrane potential (DeltaPsi) in developing OLs. Apoptosis-inducing factor (AIF) has been shown to be involved in caspase-independent cell death, and we found that AIF translocated from mitochondria into the nucleus upon NO exposure. In conclusion, we suggest that the vulnerability of developing OLs to NO involves mitochondrial dysfunction and translocation of AIF from mitochondria to nuclei.
...
PMID:Nitric oxide-induced cell death in developing oligodendrocytes is associated with mitochondrial dysfunction and apoptosis-inducing factor translocation. 1537 92

Peroxynitrite, which has been implicated in secondary neuronal damage resulting from spinal cord injury, is capable of mediating several toxic interactions including inducing DNA strand breaks and activating the nuclear enzyme, poly (ADP-ribose) polymerase (PARP). In the present study we have tested the hypothesis that peroxynitrite-induced cell death in spinal cord injury is due to activation of PARP. Initially we examined whether peroxynitrite exerts toxic effects on primary cultures of spinal cord neurons and then determined whether the spinal cord neuronal cell death triggered by peroxynitrite was associated with PARP activation. Peroxynitrite dose-dependently reduced the viability of spinal cord neurons in vitro. Furthermore, peroxynitrite exposure markedly increased the number of DNA strand breaks in primary spinal cord neurons, resulting in activation of PARP. To identify whether PARP activation plays a direct role in peroxynitrite-induced neurotoxicity we assessed the effects of the PARP inhibitors, nicotinamide, 3-aminobenzamide and 5-iodo-6-amino-1,2 benzopyrone on cell viability in spinal cord neurons exposed to peroxynitrite. The presence of the PARP inhibitors in the cultures not only inhibited peroxynitrite-induced PARP activity in spinal cord neurons but also protected the cells from the deleterious actions of peroxynitrite. Therefore, our results demonstrate that peroxynitrite exerts toxic effects on spinal cord neurons in vitro at least in part through a PARP-dependent pathway.
...
PMID:Poly(ADP-ribose) polymerase activity contributes to peroxynitrite-induced spinal cord neuronal cell death in vitro. 1545 94

Dysregulation of nitric oxide (NO) and increased oxidative and nitrosative stress are implicated in the pathogenesis of heart failure. Peroxynitrite is a reactive oxidant that is produced from the reaction of nitric oxide with superoxide anion and impairs cardiovascular function through multiple mechanisms, including activation of matrix metalloproteinases (MMPs) and nuclear enzyme poly(ADP-ribose) polymerase (PARP). Recent studies suggest that the neutralization of peroxynitrite or pharmacological inhibition of MMPs and PARP are promising new approaches in the experimental therapy of various forms of myocardial injury. In this article, the role of nitrosative stress and downstream mechanisms, including activation of MMPs and PARP, in various forms of heart failure are discussed and novel emerging therapeutic strategies offered by neutralization of peroxynitrite and inhibition of MMPs and PARP in these pathophysiological conditions are reviewed.
...
PMID:Nitrosative stress and pharmacological modulation of heart failure. 1592 5

Ischemia and reperfusion injury leads to a complex pathophysiological process, which in turn results in the generation of free radicals. Peroxynitrite, a highly reactive species causes DNA single strand breaks, which activates the nuclear enzyme, poly (ADP-ribose) polymerase (PARP). The activation of PARP leads to an energy consuming inefficient repair cycle with subsequent depletion of NAD(+) and ATP pools and necrotic cell death. The present review overviews the pathophysiological role of the peroxynitrite-PARP pathway in cardiac ischemia/reperfusion injury with special reference to the therapeutic potential of PARP inhibitors in the treatment of this disease.
...
PMID:Role of nitrosative stress and poly(ADP-ribose) polymerase activation in myocardial reperfusion injury. 1602 18

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.
...
PMID:Peroxynitrite is a major trigger of cardiomyocyte apoptosis in vitro and in vivo. 1693 67

Overproduction of oxidants and free radicals in ageing tissues induces nitro-oxidative stress, which has recently been implicated in the pathogenesis of cardiovascular dysfunction associated with ageing. Peroxynitrite, a strong cytotoxic oxidant damages proteins and DNA and activates several pathways causing tissue injury, including the peroxynitrite-poly(ADP-ribose) polymerase (PARP) pathway. In this study, we investigated the effectiveness of the peroxynitrite decomposition catalyst FP15 on ageing-associated cardiac and vascular dysfunction. Young and ageing rats were treated with vehicle or FP15 intraperitoneally. Using a microtip Millar pressure catheter we performed left ventricular blood pressure analysis to assess systolic and diastolic function. Endothelium-dependent and -independent vasorelaxation of isolated aortic rings were investigated by using acetylcholine and sodium nitroprusside. Ageing animals showed a marked reduction of systolic and diastolic cardiac function and loss of endothelium-dependent relaxant responsiveness of aortic rings. FP15-treatment significantly improved cardiac performance and endothelial function. Immunohistochemical staining confirmed that FP15 effectively reduced nitrosative stress and prevented the activation of PARP in the aortic wall of ageing rats. Our results demonstrate the importance of endogenous peroxynitrite-overproduction in the pathogenesis of ageing-associated cardiovascular dysfunction. Pharmacological decomposition of peroxynitrite by FP15 may represent a novel therapeutic utility to improve cardiac and vascular dysfunction associated with ageing.
...
PMID:The peroxynitrite decomposition catalyst FP15 improves ageing-associated cardiac and vascular dysfunction. 1711 20

Throughout the last 2 decades, experimental evidence from in vitro studies and preclinical models of disease has demonstrated that reactive oxygen and nitrogen species, including the reactive oxidant peroxynitrite, are generated in parenchymal, endothelial, and infiltrating inflammatory cells during stroke, myocardial and other forms of reperfusion injury, myocardial hypertrophy and heart failure, cardiomyopathies, circulatory shock, cardiovascular aging, atherosclerosis and vascular remodeling after injury, diabetic complications, and neurodegenerative disorders. Peroxynitrite and other reactive species induce oxidative DNA damage and consequent activation of the nuclear enzyme poly(ADP-ribose) polymerase 1 (PARP-1), the most abundant isoform of the PARP enzyme family. PARP overactivation depletes its substrate NAD(+), slowing the rate of glycolysis, electron transport, and ATP formation, eventually leading to functional impairment or death of cells, as well as up-regulation of various proinflammatory pathways. In related animal models of disease, peroxynitrite neutralization or pharmacological inhibition of PARP provides significant therapeutic benefits. Therefore, novel antioxidants and PARP inhibitors have entered clinical development for the experimental therapy of various cardiovascular and other diseases. This review focuses on the human data available on the pathophysiological relevance of the peroxynitrite-PARP pathway in a wide range of disparate diseases, ranging from myocardial ischemia/reperfusion injury, myocarditis, heart failure, circulatory shock, and diabetic complications to atherosclerosis, arthritis, colitis, and neurodegenerative disorders.
...
PMID:Role of the peroxynitrite-poly(ADP-ribose) polymerase pathway in human disease. 1853 82

Nitric oxide (NO) induces cell proliferation or cell death, depending on the cell type involved, the isoform of nitric oxide synthase activated, and its cellular localisation. In neurons, the damaging effect of NO is usually attributed to the highly toxic peroxynitrite, formed by its reaction with superoxide. Peroxynitrite induces DNA damage and consequently the activation of poly (ADP-ribose) polymerase (PARP). This study set out to examine the contribution of peroxynitrite to the damage induced in cerebellar granule neurons (CGNs) by treatment with the NO donor S-nitroso-N-acetylpenicillamine (SNAP), for short (6 h) or prolonged (24 h) exposures. The Alamar blue assay was used to quantify CGN viability, which was also assessed by morphological examination. SNAP (10 microM-1 mM) induced a concentration- and time-dependent reduction of CGN viability, with associated damage to cell bodies and neurite processes evident following 100 microM SNAP treatments. Damage from 6 h exposures was prevented by the presence of haemoglobin (a NO scavenger), uric acid (a peroxynitrite scavenger), melatonin (a non-specific antioxidant), and by cyclosporin A (a permeability transition pore blocker). It was reduced by the PARP-1 inhibitor 3,4-dihydro-5-[4-(1-piperidinyl)butoxyl]-1(2H)-isoquinolinone (DPQ), whilst superoxide dismutase (SOD) potentiated the effects. Following 24 h exposure to SNAP, damage was only partially blocked by haemoglobin, melatonin, cyclosporin A and DPQ, but was not affected by uric acid or SOD. The data suggest that short exposure to NO induces neuronal damage through peroxynitrite produced by its interaction with superoxide, whereas a longer exposure to NO can induce damage partly by a mechanism which is independent of peroxynitrite formation.
...
PMID:Prolonged exposures of cerebellar granule neurons to S-nitroso-N-acetylpenicillamine (SNAP) induce neuronal damage independently of peroxynitrite. 1864 53

Overactivation of poly(adenosine diphosphate-ribose) polymerase (PARP), an enzyme involved in cellular response to DNA injury resulting from oxidative and nitrosative stress, is considered to play a key role in the pathogenesis of diabetes complications by promoting numerous vascular dysfunctions. In this study, we examined the ability of metformin, which was reported to possess intrinsic vasculoprotective properties independently of its antihyperglycemic effects, to inhibit PARP activation induced by high glucose concentrations in bovine aortic endothelial cells; and we investigated the potential mechanisms involved in this inhibition. The PARP activity was measured by cellular enzyme-linked immuno-specific assay (CELISA) method; cell poly(ribosyl)ated protein polymer accumulation was evaluated by immunofluorescence. Peroxynitrite anion productions were determined using dihydrorhodamine 123 fluoroprobe; and expression of p47phox subunit of nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase was analyzed by Western blot in the absence and presence of protein kinase C and NAD(P)H oxidase inhibitors (calphostin and diphenyleneiodonium chloride, respectively). Our data showed that a therapeutically relevant concentration of metformin (5.10(-5) mol/L) was able to abolish PARP activation, to reduce poly(ribosyl)ated protein polymer accumulation, to decrease intracellular peroxynitrite anion level, and to reverse the overexpression of p47phox in bovine aortic endothelial cells stimulated by 25 mmol/L glucose in a similar manner to that of calphostin or diphenyleneiodonium chloride. Taken together, these results suggest that metformin could inhibit glucose-induced PARP activation through blockade of a protein kinase C-dependent NAD(P)H oxidase activation pathway. We propose that some of the beneficial effects of metformin on vascular endothelial cell functions in diabetes may be related to its inhibitory effect on PARP overactivation and its deleterious consequences.
...
PMID:Metformin suppresses high glucose-induced poly(adenosine diphosphate-ribose) polymerase overactivation in aortic endothelial cells. 1930 74

Diabetic retinopathy and retinopathy of prematurity are blinding disorders that follow a pathological pattern of ischemic retinopathy and affect premature infants and working-age adults. Yet, the treatment options are limited to laser photocoagulation. The goal of this study is to elucidate the molecular mechanism and examine the therapeutic effects of inhibiting tyrosine nitration on protecting early retinal vascular cell death and late neovascularization in the ischemic retinopathy model. Ischemic retinopathy was developed by exposing neonatal mice to 75% oxygen [postnatal day (p) 7-p12] followed by normoxia (21% oxygen) (p12-p17). Peroxynitrite decomposition catalyst 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron III chloride (FeTPPS) (1 mg/kg), the nitration inhibitor epicatechin (10 mg/kg) or the thiol donor N-acetylcysteine (NAC, 150 mg/kg) were administered (p7-p12) or (p7-p17). Vascular endothelial cells were incubated at hyperoxia (40% oxygen) or normoxia (21% oxygen) for 48 h. Vascular density was determined in retinal flat mounts labeled with isolectin B4. Expression of vascular endothelial growth factor, caspase-3, and poly(ADP ribose) polymerase (PARP), activation of Akt and p38 mitogen-activated protein kinase (MAPK), and tyrosine nitration of the phosphatidylinositol (PI) 3-kinase p85 subunit were analyzed by Western blot. Hyperoxia-induced peroxynitrite caused endothelial cell apoptosis as indicated by expression of cleaved caspase-3 and PARP leading to vaso-obliteration. These effects were associated with significant tyrosine nitration of the p85 subunit of PI 3-kinase, decreased Akt activation, and enhanced p38 MAPK activation. Blocking tyrosine nitration of PI 3-kinase with epicatechin or NAC restored Akt phosphorylation, and inhibited vaso-obliteration at p12 and neovascularization at p17 comparable with FeTPPS. Early inhibition of tyrosine nitration with use of epicatechin or NAC can represent safe and effective vascular-protective agents in ischemic retinopathy.
...
PMID:Early intervention of tyrosine nitration prevents vaso-obliteration and neovascularization in ischemic retinopathy. 1981 13


<< Previous 1 2 3 Next >>

---