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 aim of this study was to investigate the role of inducible nitric oxide (NO) synthase (iNOS) and NO on the modulation of the inflammatory response caused by splanchnic ischemia and reperfusion. A severe model of mesenteric ischemia and reperfusion was produced by subjecting mice to 45 min occlusion followed by reperfusion of the superior mesenteric artery and celiac trunk. In this experimental protocol, wild-type mice treated with GW274150 (5 mg/kg i.p.), a novel, potent, and selective inhibitor of iNOS activity, and mice lacking of the gene for iNOS (iNOS 'knock-out', iNOS-KO) exhibited no difference in the rate of mortality in comparison with wild-type control mice. In a second study, using a less severe model of mesenteric injury obtained by occlusion of the superior mesenteric artery only for 45 min, we evaluated the survival rate. Under these conditions, wild-type mice treated with GW274150 and iNOS-KO mice showed a significant difference in the rate of mortality in comparison with wild-type. Therefore, wild-type mice treated with GW274150 and iNOS-KO mice when compared with wild-type littermates showed a significant reduction of the mesenteric injury, upregulation of P-selectin and intercellular adhesion molecule-1, and neutrophil infiltration, as well as a significant inhibition of the degree of oxidative and nitrosative damage, indicated by malondialdehyde levels, formation of nitrotyrosine and poly(ADP-ribose)polymerase (PARP), respectively. Plasma levels of the proinflammatory cytokines tumour necrosis factor-alpha, interleukin (IL) 6, and IL-1beta were also significantly reduced in iNOS-KO mice in comparison with control wild-type mice. Wild-type mice treated with GW274150 and iNOS-KO mice were also found to have reduced activation of the transcriptional factor nuclear factor-kappaB in the ileum. These results suggest that the induction of iNOS and NO production are essential for the upregulation of the inflammatory response in splanchnic ischemia/reperfusion and participate in end organ damage under these conditions.
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PMID:Role of induced nitric oxide in the initiation of the inflammatory response after postischemic injury. 1216 82

1. In the presence of genotoxic stress poly(ADP-ribose) polymerase-1 (PARP-1) leads to NAD(+) and ATP depletion, participating in the pathogenesis of several disorders including inflammation. Accordingly, chemical inhibitors of PARP-1 are efficacious anti-inflammatories, albeit the underlying molecular mechanisms are still under debate. 2. This study investigated the effect of the PARP-1 inhibitors 6(5H)-phenanthridinone and benzamide as well as that of benzoic acid, an inactive analogue of benzamide, on development of experimental allergic encephalomyelitis (EAE) in rats. Both 6(5H)-phenanthridinone and benzamide attenuated development of EAE, reducing clinical score, neuroimmune infiltration and expression of inflammatory mediators such as inducible nitric oxide synthase, interleukin-1beta and -2, cyclooxygenase-2, tumour necrosis factor-alpha and interferon-gamma in the spinal cord of myelin-immunized rats. Importantly, no evidence of NAD(+) and ATP depletion as well as poly(ADP-ribose) formation was detected in the spinal cord. 3. By contrast, a robust formation of poly(ADP-ribose) occurred in B- and T-cell areas in lymph nodes of myelin-immunized rats and was suppressed by the treatment with 6(5H)-phenanthridinone and benzamide. In cultures of activated rat lymphocytes, 6(5H)-phenanthridinone and benzamide reduced the DNA-binding activity of NF-kappaB and AP-1 and transcription of pro-inflammatory cytokines such as interleukin-2, interferon-gamma and tumour necrosis factor-alpha. 4. Notably, benzoic acid did not reproduce the in vivo and in vitro effects of its parent compound. 5. These findings indicate that PARP-1 promotes transcriptional activation in lymphocytes and inhibitors of its enzymatic activity are useful for the treatment of autoimmune disorders of the central nervous system.
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PMID:Inhibitors of poly(ADP-ribose) polymerase-1 suppress transcriptional activation in lymphocytes and ameliorate autoimmune encephalomyelitis in rats. 1241 6

We investigated the mechanism of augmentation of nitric oxide (NO) production in the murine macrophage cell line RAW264.7 after gamma-irradiation. The cells treated with interferon-gamma (IFN-gamma) or lipopolysaccharide (LPS) showed enhanced NO production by gamma-irradiation in a dose-dependent manner, accompanying the induction of inducible nitric oxide synthase (iNOS) expression. Nuclear factor kappa B (NF-kappaB) activation was induced 1 h after gamma-irradiation dose-dependently, which was detected by the degradation of I-kappaB. Inhibitors of I-kappaB degradation, MG132 and N(alpha)-p-tosyl-L-lysine chloromethyl ketone (TLCK), suppressed the further increase by gamma-irradiation in IFN-gamma-induced NO production, showing that gamma-irradiation induced NO production via NF-kappaB activation. Although NF-kappaB is known to be a redox-sensitive transcription factor, the antioxidant agents N-acetyl-cysteine (NAC) and 6-hydroxy-2,5,7,8-tetramethyl-chroman-2-carboxylic acid (trolox) showed no suppression and treatment with H(2)O(2) showed only slight enhancement of IFN-gamma-induced NO production. The DNA damaging agents camptothecin and etoposide enhanced IFN-gamma-induced NO production and showed I-kappaB degradation, indicating that the increase in NO production was due to direct DNA damage. Furthermore, 3-aminobenzamide (3AB) and benzamide, inhibitors of poly (ADP-ribose) polymerase (PARP) that are activated upon recognition of DNA strand breaks, suppressed the further increase by gamma-irradiation in IFN-gamma-induced NO production and the I-kappaB degradation by gamma-irradiation. We concluded that (1) the increase in NO production was due to direct DNA damage by gamma-irradiation, and that (2) PARP activation through DNA damage induced NF-kappaB activation, leading to iNOS expression and NO production.
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PMID:gamma-Irradiation-induced DNA damage enhances NO production via NF-kappaB activation in RAW264.7 cells. 1258 60

Airway inflammation is a central feature of asthma and chronic obstructive pulmonary disease. Reactive oxygen species (ROS) contribute to inflammation by damaging DNA, which, in turn, results in the activation of poly(ADP-ribose) polymerase-1 (PARP-1) and depletion of its substrate, nicotinamide adenine dinucleotide. Here we show that prevention of PARP-1 activation protects against both ROS-induced airway epithelial cell injury in vitro and airway inflammation in vivo. H(2)O(2) induced the generation of ROS, PARP-1 activation and concomitant nicotinamide adenine dinucleotide depletion, and release of lactate dehydrogenase in A549 human airway epithelial cells. These effects were blocked by the PARP-1 inhibitor 3-aminobenzamide (3-AB). Furthermore, 3-AB inhibited both activation of the proinflammatory transcription factor nuclear factor-kappaB and expression of the interleukin-8 gene induced by H(2)O(2) in these cells. In a murine model of allergen-induced asthma, 3-AB prevented airway inflammation elicited by ovalbumin. Moreover, PARP-1 knockout mice were resistant to such ovalbumin-induced inflammation. These protective effects were associated with an inhibition of expression of the inducible nitric oxide synthase. These results implicate PARP-1 activation in airway inflammation, and suggest this enzyme as a potential target for the development of new therapeutic strategies in the treatment of asthma as well as other respiratory disorders such as chronic obstructive pulmonary disease.
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PMID:Gene knockout or pharmacological inhibition of poly(ADP-ribose) polymerase-1 prevents lung inflammation in a murine model of asthma. 1259 58

1. Inflammatory bowel disease (IBD) is characterized by oxidative and nitrosative stress, leukocyte infiltration, and increased expression of the adhesion molecules intercellular adhesion molecule 1 (ICAM-1) in the colon. Recent evidence also suggests that the cyclopentenone prostaglandin (PG) 15-deoxy-delta(12,14)-PGJ(2) (15d- PGJ(2)) functions as an early anti-inflammatory signal. 2. The aim of the present paper is to investigate the effects of 15d-PGJ(2) in rats subjected to experimental colitis. 3. Colitis was induced in rats by intra-colonic instillation of dinitrobenzene sulphonic acid (DNBS). 15d-PGJ(2) was administered daily as intraperitoneal injection (20 or 40 microg kg(-1)). On day 4, animals were sacrificed and tissues were taken for histological and biochemical analysis. 4. 15d-PGJ(2) significantly reduced the degree of haemorrhagic diarrhoea and weight loss caused by administration of DNBS. 15d-PGJ(2) also caused a substantial reduction of (i) the degree of colonic injury, (ii) the rise in myeloperoxidase (MPO) activity (mucosa), (iii) the increase in the tissue levels of malondialdehyde (MDA) and (iv) of the pro-inflammatory cytokines tumour necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta). 5. Furthermore, 15d-PGJ(2) reduced the increase in immunohistochemical staining for (i) inducible nitric oxide synthase (iNOS), (ii) nitrotyrosine and (iii) poly (ADP-ribose) polymerase (PARP), as well as (iv) the increased expression of ICAM-1 caused by DNBS in the colon. 6. Electrophoresis mobility shift assay (EMSA) of inflamed colon revealed that 15d- PGJ(2) also caused a substantial reduction of the activation of nuclear factor-kappaB (NF-kappaB). Furthermore, 15d-PGJ(2) stimulates the activation of heat shock protein 72 (hsp72) in the inflamed colon, as assessed by Western blot analysis. 7. In conclusion, 15d-PGJ(2) reduces the development of experimental colitis.
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PMID:The cyclopentenone prostaglandin 15-deoxy-delta(12,14)- PGJ2 attenuates the development of colon injury caused by dinitrobenzene sulphonic acid in the rat. 1259 22

Excessive release of proinflammatory products by activated glia causes neurotoxicity and participates in the pathogenesis of neurodegenerative disorders. Recently, poly(ADP-ribose) polymerase-1 (PARP-1) has been shown to play a key role in nuclear factor kappa B (NF-kappaB)-driven expression of inflammatory mediators by glia during the neuroimmune response. Here we report the novel finding that the enzymatic activity of PARP-1 promotes, in an beta-nicotinamide adenine dinucleotide-dependent fashion, the DNA binding of NF-kappaB in microglia exposed to lipopolysaccharides, interferon-gamma or beta-amyloid 1-40. Consistently, we found that targeting NF-kappaB-dependent glial activation with pharmacological inhibitors of PARP-1 enzymatic activity reduces expression of inflammatory mediators such as inducible nitric oxide synthase, interleukin 1beta, tumor necrosis factor alpha and amyloid precursor protein, and reduces the neurotoxic potential of activated glia in vitro. Importantly, pharmacological inhibition of lipopolysaccharide-induced poly(ADP-ribose) formation in vivo suppresses neuroinflammation and related neural cell death. Our findings build on prior published reports in PARP-1 null mice and highlight the importance of PARP-1 enzymatic activity in transcriptional control during glial activation, identifying PARP-1 activity-dependent regulation of NF-kappaB as a novel pharmacological target for therapeutic intervention in the treatment of acute and chronic neurodegenerative disorders.
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PMID:Poly(ADP-ribose) polymerase-1 activity promotes NF-kappaB-driven transcription and microglial activation: implication for neurodegenerative disorders. 1267 7

Experimental intoxication models are used to study the more common sporadic form of Parkinson's disease (PD). 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyrimidine (MPTP) animal models of PD provide a valuable and predictive tool to probe the molecular mechanisms of dopamine neuronal cell death in PD. MPTP is a powerful neurotoxin that induces neuronal degeneration in the substantia nigra pars compacta and produces PD-like symptoms in several mammalian species tested, a feat not yet accomplished in genetically engineered mice expressing human genetic mutations. The mechanisms of MPTP-induced neurotoxicity are not yet fully understood but involve activation of N-methyl-D-aspartate (NMDA) receptors by glutamate, production of NO by nNOS and iNOS, oxidative injury to DNA, and activation of the DNA damage-sensing enzyme poly (ADP-ribose) polymerase (PARP). Recent experiments indicate that translocation of a mitochondrial protein apoptosis inducing factor (AIF) from mitochondria to the nucleus depends on PARP activation and plays an important role in excitotoxicity-induced cell death. This article briefly reviews the experimental findings regarding excitotoxicity, PARP activation, and AIF translocation in MPTP toxicity and dopaminergic neuronal cell death.
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PMID:Apoptosis inducing factor and PARP-mediated injury in the MPTP mouse model of Parkinson's disease. 1284 82

The present study describes the role of RhoA as a negative regulator of iNOS expression via the inactivation of NF-kappaB in transformed brain cell lines [C(6) glioma, human astrocytoma (T98G, A172), neuroblastoma (NEB), and immortal rat astrocytes]. Treatment with lovastatin resulted in the induction of LPS/IFN-gamma-mediated iNOS mRNA and increased nitric oxide (NO) production. The addition of mevalonate and geranylgeranylpyrophosphate (GGPP) reversed the lovastatin-mediated effect, whereas FPP had no effect. An inhibitor of geranylgeranyltransferase inhibitor (GGTI 298) further induced the cytokine and lovastatin-mediated iNOS expression, suggesting the involvement of geranylgeranylated proteins in the regulation of iNOS. Bacterial toxin B (inactivates RhoA, B, and C; CDC42; Rac proteins), C3 ADP-ribosyltransferase (C3) toxin from C. botulinum (inactivates RhoA, B, and C proteins), and Y-27632 (selective inhibitor of Rho-associated kinases) increased the LPS/IFN-gamma-mediated iNOS expression. Lovastatin treatment induced NO by increasing NF-kappaB translocation and its association with the CREB-binding protein (CBP/p300) via the downregulation of RhoA. Inhibition of RhoA resulted in increased activation of IKKalpha. Cotransfection studies with dominant-negative form of RhoA and iNOS-luciferase or NF-kappaB-luciferase reporter constructs further support these observations. Taken together, these studies show that downregulation of RhoA by lovastatin resulted in increased iNOS expression via the activation of NF-kappaB-CBP/p300 pathway in transformed brain cells.
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PMID:Rho A negatively regulates cytokine-mediated inducible nitric oxide synthase expression in brain-derived transformed cell lines: negative regulation of IKKalpha. 1457 7

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors that are related to retinoid, steroid and thyroid hormone receptors. The PPAR-gamma receptor subtype appears to play a pivotal role in the regulation of cellular proliferation and inflammation. The thiazolidinedione rosiglitazone (Avandia) is a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist, that was recently approved by the Food and Drug Administration for treatment of type II diabetes mellitus. In the present study, we have investigated the effects of rosiglitazone in animal models of acute inflammation (carrageenan-induced paw oedema and carrageenan-induced pleurisy). We report here for the first time that rosiglitazone (given at 1, 3 or 10 mg/kg i.p. concomitantly with carrageenan injection in the paw oedema model, or at 3, 10 or 30 mg/kg i.p. 15 min before carrageenan administration in the pleurisy model) exerts potent anti-inflammatory effects (e.g. inhibition of paw oedema, pleural exudate formation, mononuclear cell infiltration and histological injury) in vivo. Furthermore, rosiglitazone reduced: (1) the increase in the staining (immunohistochemistry) for nitrotyrosine and poly (ADP-ribose) polymerase (PARP), (2) the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), intercellular adhesion molecules-1 (ICAM-1) and P-selectin in the lungs of carrageenan-treated rats. In order to elucidate whether the protective effect of rosiglitazone is related to activation of the PPAR-gamma receptor, we also investigated the effect of a PPAR-gamma antagonist, bisphenol A diglycidyl ether (BADGE), on the protective effects of rosiglitazone. BADGE (30 mg/kg i.p.) administered 30 min prior to treatment with rosiglitazone significantly antagonized the effect of the PPAR-gamma agonist and thus abolished the anti-inflammatory effects of rosiglitazone. We propose that rosiglitazone and other potent PPAR-gamma agonists may be useful in the therapy of inflammation.
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PMID:Rosiglitazone, a ligand of the peroxisome proliferator-activated receptor-gamma, reduces acute inflammation. 1470 29

Inappropriate expression of inducible nitric oxide synthase (iNOS) and unregulated production of nitric oxide (NO) may contribute to neuronal cell death implicated in neurological disorders such as Alzheimer's disease. In this study, we have investigated the molecular mechanisms underlying nitrosative cell death induced by NO in cultured rat pheochromocytoma (PC12) cells. Incubation of PC12 cells with the NO donor sodium nitroprusside (SNP) resulted in apoptotic death as revealed by the decrease of mitochondrial transmembrane potential (deltapsi(m)), cleavage of poly(ADP-ribose) polymerase (PARP), and induction of p21(Waf1/Cip1). It has been reported that the expression of cyclooxygenase-2 (COX-2) and peroxisome proliferator-activated receptor-gamma (PPARgamma) is elevated in Alzheimer's disease, and certain nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce the risk and delay the onset of Alzheimer's disease. Treatment of PC12 cells with a proapoptotic dose of SNP induced expression of both COX-2 and PPARgamma. Addition of the PPARgamma antagonist GW9662 to the media augmented the NO-induced cytotoxicity. Although cotreatment of PGE(2) (50 micro M) and SNP (0.4 mM) aggravated the NO-induced cytotoxicity, preincubation of the same concentration of PGE(2) was cytoprotective. Taken together, the above findings suggest that the proinflammatory mediators such as PGE(2) and PPARgamma may regulate the nitrosative stress-induced apoptotic cell death.
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PMID:Induction of cyclooxygenase-2 and peroxisome proliferator-activated receptor-gamma during nitric oxide-induced apoptotic PC12 cell death. 1503 6


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