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)

Poly (ADP-ribose) synthabse (PARS) or polymerase (PARP) is a cytotoxic enzyme causing cellular damage. Niacinamide inhibits PARS or PARP. The present experiment tests the effects of niacinamide (NCA) on organ dysfunction and acute lung injury (ALI) following lipopolysaccharide (LPS). LPS was administered to anesthetized rats and to isolated rat lungs. In anesthetized rats, LPS caused systemic hypotension and increased biochemical factors, nitrate/nitrite (NOx), methyl guanidine (MG), tumor necrosis factoralpha (TNFalpha), and interleukin-1beta (IL-1beta). In isolated lungs, LPS increased lung weight (LW) to body weight ratio, LW gain, protein and dye tracer leakage, and capillary permeability. The insult also increased NOx, MG, TNFalpha, and IL-1beta in lung perfusate, while decreased adenosine triphosphate (ATP) content with an increase in PARP activity in lung tissue. Pathological examination revealed pulmonary edema with inflammatory cell infiltration. These changes were abrogated by posttreatment (30 min after LPS) with NCA. Following LPS, the inducible NO synthase (iNOS) mRNA expression was increased. NCA reduced the iNOS expression. Niacinamide exerts protective effects on the organ dysfunction and ALI caused by endotoxin. The mechanisms may be mediated through the inhibition on the PARP activity, iNOS expression and the subsequent suppression of NO, free radicals, and proinflammatory cytokines with restoration of ATP.
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PMID:Niacinamide abrogates the organ dysfunction and acute lung injury caused by endotoxin. 1787 64

Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear protein that, once activated by genotoxic agents, modulates the activity of several nuclear proteins including itself. Previous studies have established that PARP-1 inhibition may provide benefit in the treatment of different diseases, particularly those involving a hypoxic situation, in which an increased oxidative and nitrosative stress occurs. One of the most important transcription factors involved in the response to the hypoxic situation is the hypoxia-inducible factor-1 (HIF-1). The activity of HIF-1 is determined by the accumulation of its alpha subunit which is regulated, in part, by oxidative stress (ROS) and nitric oxide (NO), both of them highly dependent on PARP-1. Besides, HIF-1alpha can be induced by iron chelators such as deferoxamine (DFO). In this sense, the therapeutical use of DFO to strengthen the post-hypoxic response has recently been proposed. Taking into account the increasing interest and potential clinical applications of PARP inhibition and DFO treatment, we have evaluated the impact of PARP-1 on HIF-1alpha accumulation induced by treatment with DFO. Our results show that, in DFO treated cells, PARP-1 gene deletion or inhibition decreases HIF-1alpha accumulation. This lower HIF-1alpha stabilization is parallel to a decreased inducible NO synthase induction and NO production, a higher response of some antioxidant enzymes (particularly glutathione peroxidase and glutathione reductase) and a lower ROS level. Taken together, these results suggest that the absence of PARP-1 modulates HIF-1 accumulation by reducing both NO and oxidative stress.
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PMID:PARP-1 modulates deferoxamine-induced HIF-1alpha accumulation through the regulation of nitric oxide and oxidative stress. 1845 42

Oxidative stress and zinc release are both known to contribute to neuronal death after hypoglycemia; however, the cause-effect relationships between these events are not established. Here we found, using a rat model of profound hypoglycemia, that the neuronal zinc release and translocation that occur immediately after hypoglycemia are prevented by the nitric oxide synthase inhibitor 7-nitroindazole but not by overexpression of superoxide dismutase-1 (SOD-1). However, overexpression of SOD-1 prevented activation of poly(ADP-ribose) polymerase-1 (PARP-1) and neuronal death, suggesting that zinc release is upstream of superoxide production. Accordingly, zinc-induced superoxide production was blocked in neuronal cultures by the NADPH oxidase inhibitor apocynin and by genetic deficiency in the p47(phox) subunit of NADPH oxidase. A key role for the vesicular zinc pool in this process was suggested by reduced superoxide formation and neuronal death in mice deficient in zinc transporter 3. Together, these findings suggest a series of events in which nitric oxide production triggers vesicular zinc release, which in turn activates NADPH oxidase and PARP-1. This sequence may also occur in other central nervous system disorders in which zinc, nitric oxide, and oxidative stress have been linked.
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PMID:Sequential release of nitric oxide, zinc, and superoxide in hypoglycemic neuronal death. 1854 58

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.
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PMID:Prolonged exposures of cerebellar granule neurons to S-nitroso-N-acetylpenicillamine (SNAP) induce neuronal damage independently of peroxynitrite. 1864 53

Goniothalamin is a styryllactone synthesized by plants of the genus Goniothalamus. The biological activities of this molecule, particularly its anti-protozoan, anti-fungal, and larvicidal properties, have received considerable attention. In this work, we investigated the action of the natural and synthetic enantiomers (R)-goniothalamin (1) and (S)-goniothalamin (ent-1) on cell viability, nitric oxide synthase (NOS) expression and activity, and the expression of selected proteins involved in apoptosis and autophagy in renal cancer cells. Both compounds were cytotoxic and decreased the mitochondrial function of renal cancer cells. However, the enantiomers differentially affected the expression/activity profiles of some signaling pathway mediators. Ent-1 (4 nM) was more potent than 1 (6.4 microM) in inhibiting constitutive NOS activity (54% and 59% inhibition, respectively), and both enantiomers decreased the protein expression of neuronal and endothelial NOS, as assessed by western blotting. Ent-1 and 1 caused down-regulation of Ras and TNFR1 and inhibition of protein serine/threonine phosphatase 2A (PP2A). Compound 1 markedly down-regulated Bcl2, an anti-apoptotic protein, and also induced PARP cleavage. Despite inducing an expressive down-regulation of Bax, ent-1 was also able to induce PARP cleavage. These results suggest that these compounds caused apoptosis in renal cancer cells. Interestingly, ent-1 enhanced the expression of LC3, a typical marker of autophagy. NFkappaB was down-regulated in 1-treated cells. Overall, these results indicate that the anti-proliferative activity of the two enantiomers on renal cancer cells involved distinct signaling pathways, apoptosis and autophagy as dominant responses towards 1 and ent-1, respectively.
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PMID:Cytotoxicity of goniothalamin enantiomers in renal cancer cells: involvement of nitric oxide, apoptosis and autophagy. 1877 61

Inducible nitric oxide synthase (iNOS) inhibition was recently shown to exert no effect on allergen challenge in human asthma, raising serious concerns about the role of the protein in the disease. The present study investigated the role of iNOS in ovalbumin-induced eosinophilia from the perspective of its relationship with poly(ADP-ribose) polymerase-1 (PARP-1) and oxidative DNA damage. A mouse model of ovalbumin-induced eosinophilia was used to conduct the studies. iNOS-associated protein nitration and tissue damage were partially responsible for allergen-induced eosinophilia. iNOS expression was required for oxidative DNA damage and PARP-1 activation upon allergen challenge. PARP-1 was required for iNOS expression and protein nitration, and this requirement was connected to nuclear factor-kappaB. PARP-1 was an important substrate for iNOS-associated by-products after ovalbumin-challenge. PARP-1 nitration blocked its poly(ADP-ribosyl)ation activity. Interleukin-5 re-establishment in ovalbumin-exposed PARP-1(-/-) mice reversed eosinophilia and partial mucus production without a reversal of iNOS expression, concomitant protein nitration or associated DNA damage. The present results demonstrate a reciprocal relationship between inducible nitric oxide synthase and poly(ADP-ribose) polymerase-1 and suggest that expression of inducible nitric oxide synthase may be dispensable for eosinophilia after interleukin-5 production. Inducible nitric oxide synthase may be required for oxidative DNA damage and full manifestation of mucus production. Such dispensability may explain, in part, the reported ineffectiveness of inducible nitric oxide synthase inhibition in preventing allergen-induced inflammation in humans.
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PMID:Reciprocal regulation of iNOS and PARP-1 during allergen-induced eosinophilia. 1882 81

Here we overview the role of reactive nitrogen species (nitrosative stress) and associated pathways in the pathogenesis of diabetic vascular complications. Increased extracellular glucose concentration, a principal feature of diabetes mellitus, induces a dysregulation of reactive oxygen and nitrogen generating pathways. These processes lead to a loss of the vascular endothelium to produce biologically active nitric oxide (NO), which impairs vascular relaxations. Mitochondria play a crucial role in this process: endothelial cells placed in increase extracellular glucose respond with a marked increase in mitochondrial superoxide formation. Superoxide, when combining with NO generated by the endothelial cells (produced by the endothelial isoform of NO synthase), leads to the formation of peroxynitrite, a cytotoxic oxidant. Reactive oxygen and nitrogen species trigger endothelial cell dysfunction through a multitude of mechanisms including substrate depletion and uncoupling of endothelial isoform of NO synthase. Another pathomechanism involves DNA strand breakage and activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP). PARP-mediated poly(ADP-ribosyl)ation and inhibition of glyceraldehyde-3-phosphate dehydrogenase importantly contributes to the development of diabetic vascular complications: it induces activation of multiple pathways of injury including activation of nuclear factor kappa B, activation of protein kinase C and generation of intracellular advanced glycation end products. Reactive species generation and PARP play key roles in the pathogenesis of 'glucose memory' and in the development of injury in endothelial cells exposed to alternating high/low glucose concentrations.
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PMID:Role of nitrosative stress in the pathogenesis of diabetic vascular dysfunction. 1921 Jul 48

A respiratory inhibitor, antimycin A (AA), induced an apoptotic-like cell death characterized by nuclear and DNA fragmentation in human leukemia HL-60 cells. This cell death was significantly restricted by a nitric oxide synthase (NOS) inhibitor, N(G)-monomethyl-L-arginine (L-NMMA), and a poly(ADP-ribose) polymerase (PARP) inhibitor, 5-aminoisoquinoline (AIQ). Indeed, NO production and PARP overactivation were detected in the cells treated with AA. On the one hand, L-NMMA partly eliminated NO production and on the other, AIQ and L-NMMA also restricted PARP activation. Excessive signals related to PARP overactivation induce the translocation of an apoptosis-inducing factor (AIF) from the mitochondria to the nuclei, resulting in DNA fragmentation. In AA-treated cells, the nuclear translocation of AIF occurred. This translocation was restricted by pretreatment with AIQ and L-NMMA. Although pretreatment with ascorbic acid eliminated the reactive oxygen species (ROS) generation induced by the blockade of complex III by AA, the pretreatment did not protect the cells from AA-induced cell death. Furthermore, cytochrome c release or caspase-3 activation was not observed in the cells treated with AA. These results suggest that AA-induced cell death does not depend on respiratory inhibition and the succeeding cascades, but on NO production, PARP overactivation and AIF translocation.
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PMID:Antimycin A-induced cell death depends on AIF translocation through NO production and PARP activation and is not involved in ROS generation, cytochrome c release and caspase-3 activation in HL-60 cells. 1922 86

New discoveries in the last decade significantly altered our view on mitochondria. They are no longer viewed as energy-making slaves but rather individual cells-within-the-cell. In particular, it has been suggested that many important cellular mechanisms involving specific enzymes and ion channels, such as nitric oxide synthase (NOS), ATP-dependent K+ (KATP) channels, and poly-(APD-ribose) polymerase (PARP), have a distinct, mitochondrial variant. Unfortunately, exploring these parallel systems in mitochondria have technical limitations and inappropriate methods often led to inconsistent results. For example, the intriguing possibility that mitochondria are significant sources of nitric oxide (NO) via a unique mitochondrial NOS variant has attracted intense interest among research groups because of the potential for NO to affect functioning of the electron transport chain. Nonetheless, conclusive evidence concerning the existence of mitochondrial NO synthesis is yet to be presented. This review summarizes the experimental evidence gathered over the last decade in this field and highlights new areas of research that reveal surprising dimensions of NO production and metabolism by mitochondria.
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PMID:Mitochondrial nitric oxide synthase: current concepts and controversies. 1927 61

Icariside II (IS) isolated from the roots of Epimedium koreanum Nakai was known to have antioxidant activity and inhibit melanogenesis and hypoxia inducible factor. We report here for the first time that IS induces apoptosis through its anti-inflammatory effects in PC-3 prostate cancer cells. IS exerted cytotoxicity against PC-3 cells with IC(50) of approximately 20 microM. IS suppressed both constitutive and arachidonic acid (AA)-induced cyclooxygenase-2 (COX-2) expression as well as reduced prostaglandin E2 (PGE2) levels in PC-3 cells even at a low concentrations (5 and 10 microM). Additionally, IS increased sub G1 apoptotic portion and exhibited terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL)-positive apoptotic bodies in PC-3 cells at higher concentrations (20 and 40 microM). Furthermore, IS attenuated the mitochondrial membrane potential, released cytochrome C into cytosol, activated caspase-9, -8, and -3 expressions and cleaved poly (ADP-ribose) polymerase (PARP) in PC-3 cells. Consistently, COX-2, inducible NO synthase (iNOS), and vascular endothelial growth factor (VEGF) expressions were suppressed while in parallel inducing apoptosis in hormone-independent prostate carcinoma cells PC-3. Moreover, exogeneous PGE2 inhibited IS induced PARP cleavage in PC-3 cells and also knockdown of COX-2 by siRNA potentiated IS induced PARP cleavage, thereby implicating the critical role of COX-2 pathway in IS induced apoptosis. Taken together, these findings demonstrate that IS initiates the inhibition of COX-2/PGE(2) pathway and then induces apoptosis mainly via mitochondrial dependent pathway in PC-3 prostate cancer cells as a potent cancer chemotherapeutic agent.
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PMID:Cyclooxygenase-2/prostaglandin E2 pathway mediates icariside II induced apoptosis in human PC-3 prostate cancer cells. 1928 54


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