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 fibroblast cell line L929 contains a constitutively expressed NO synthase (EC 1.14.29.-) activity, which can be increased about 10-fold by tumour-necrosis factor alpha (TNF-alpha). Activities of the constitutive and the inducible enzymes are tetrahydrobiopterin-independent and can be inhibited by L-NG-nitroarginine. Induction of NO synthase by TNF-alpha was prevented by inhibitors of poly(ADP-ribose) polymerase, namely nicotinamide, 3-methoxybenzamide and 3-aminobenzamide. TNF-alpha did not lead to an increase in ADP-ribosyltransferase activity nor to a change in the pattern of ADP-ribosylated proteins. The inhibitors were only active during the first 4-5 h after exposure to TNF-alpha and they were found to suppress synthesis of protein, DNA and RNA. These data suggest that the inhibitors prevent induction of NO synthase by interference with RNA and protein synthesis. It is not yet known which reactions of these biosynthetic processes are affected by the inhibitors.
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PMID:Induction of nitric oxide synthase in L929 cells by tumour-necrosis factor alpha is prevented by inhibitors of poly(ADP-ribose) polymerase. 128 Jan 12

An ubiquitous biochemical pathway known to synthesize nitric oxide (NO) from L-arginine has been identified in many cell types. Recent studies indicate that besides activating soluble guanylate cyclase NO is likely to have effects unrelated to the known signal transduction pathway. Activation of the soluble NO synthase stimulates an endogenous ADP-ribosylation of a predominant 39 kDa protein, known to be activated by NO releasing agents. This is demonstrated using the cytosolic fraction of rat cerebellum and HL-60 cells. The ADP-ribosylation is suppressed by the known NO synthase inhibitors N-nitro-L-arginine and N-methyl-L-arginine. These observations indicate that NO derived from its physiological precursor L-arginine activates an endogenous ADP-ribosyltransferase.
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PMID:L-arginine stimulates an endogenous ADP-ribosyltransferase. 190 40

Excitotoxic amino acids, such as glutamate, may play an important role in retinal ischemia/reperfusion damage. In central neurons, excitotoxicity may be mediated by nitric oxide synthase (NOS) causing DNA damage via nitric oxide (NO). The nicked DNA activates poly-adenosine diphosphate (ADP)-ribose polymerase (PARP) and may deplete intracellular ATP resulting in cell death. PARP may also be involved in apoptosis. We used 3-aminobenzamide (3-ABA), a PARP inhibitor, to examine the possible involvement of PARP in a rat model of retinal ischemia. Retinal ischemia was induced by elevating the intraocular pressure (IOP) through the insertion of a needle into the anterior chamber of a rat eye. IOP was raised to 110 mm Hg for 60 minutes. Animals were given intracameral infusion of 0, 1, 3, 10, 30, 100 mM 3-ABA in 0.1 M PBS, pH 7.4 during ischemia. Morphologic and morphometric evaluation at 7 days after reperfusion showed that 3-ABA at 3 mM and above significantly ameliorated the ischemic/reperfusion damage to the retina. In addition, at 10 mM 3-ABA inhibited the characteristic ladder pattern in DNA gel analysis seen in apoptosis of retinal neurons after ischemia/reperfusion. Hence, PARP may be involved in retinal cell loss after ischemia/reperfusion insult probably through the apoptotic pathway.
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PMID:The effect of 3-aminobenzamide, an inhibitor of poly-ADP-ribose polymerase, on ischemia/reperfusion damage in rat retina. 914 32

Long-term potentiation (LTP) is a potential cellular mechanism for learning and memory. The retrograde messenger nitric oxide (NO) is thought to induce LTP in the CA1 region of the hippocampus via activation of soluble guanylyl cyclase (sGC) and, ultimately, cGMP-dependent protein kinase (cGK). Two genes code for the isozymes cGKI and cGKII in vertebrates. The functional role of cGKs in LTP was analyzed using mice lacking the gene(s) for cGKI, cGKII, or both. LTP was not altered in the mutant mice lineages. However, LTP was reduced by inhibition of NO synthase and NMDA receptor antagonists, respectively. The reduced LTP was not recovered by the cGK-activator 8-(4 chlorophenylthio)-cGMP. Moreover, LTP was not affected by the sGC inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]-quiloxalin-1-one. In contrast, it was effectively suppressed by nicotinamide, a blocker of the ADP-ribosyltransferase. These results show that cGKs are not involved in LTP in mice and that NO induces LTP through an alternative cGMP-independent pathway, possibly ADP-ribosylation.
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PMID:Long-term potentiation in the hippocampal CA1 region of mice lacking cGMP-dependent kinases is normal and susceptible to inhibition of nitric oxide synthase. 987 Sep 37

Although nitric oxide (NO) induces neuronal cell death under some conditions, it also can prevent apoptosis resulting from growth factor withdrawal. We investigated the molecular mechanism by which NO protects undifferentiated and differentiated PC12 cells from trophic factor deprivation-induced apoptosis. PC12 cells underwent apoptotic death in association with increased caspase-3-like activity, DNA fragmentation, poly(ADP-ribose) polymerase (PARP) cleavage, and cytochrome c release after 24 hr of serum withdrawal. The apoptosis of PC12 cells was inhibited by the addition of NO-generating donor S-nitroso-N-acetylpenicillamine (SNAP) (5-100 microM) and the specific caspase-3-like protease inhibitor Ac-Asp-Glu-Val-Asp-aldehyde (Ac-DEVD-cho) but not the YVADase (or caspase-1-like protease) inhibitor N-acetyl-Tyr-Val-Ala-Asp-aldehyde (Ac-YVAD-cho). SNAP and Ac-DEVD-cho prevented the increase in DEVDase (caspase-3-like protease) activity. The SNAP-mediated suppression of DEVDase activity was only minimally reversed by the incubation of cell lysate with dithiothreitol, indicating that NO did not S-nitrosylate caspase-3-like proteases in PC12 cells. Western blot analysis showed that NO inhibited the proteolytic activation of caspase-3. The cGMP analog 8-bromo-cGMP (8-Br-cGMP) blocked apoptotic cell death, caspase-3 activity and activation, and cytochrome c release. The soluble guanylyl cyclase inhibitor 1-H-oxodiazol-[1,2,4]-[4,3-a] quinoxaline-1-one (CODQ) significantly attenuated NO-mediated, but not 8-Br-cGMP-dependent, inhibition of apoptotic cell death, PARP cleavage, cytochrome c release, and DEVDase activity. Furthermore, the protein kinase G inhibitor KT5823 reversed both SNAP- and 8-Br-cGMP-mediated anti-apoptotic events. All these apoptotic phenomena were also suppressed by NO production through neuronal NO synthase gene transfer into PC12 cells. Furthermore, similar findings were observed in differentiated PC12 cells stimulated to undergo apoptosis by NO donors and NGF deprivation. These findings indicate that NO protects against PC12 cell death by inhibiting the activation of caspase proteases through cGMP production and activation of protein kinase G.
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PMID:Nitric oxide protects PC12 cells from serum deprivation-induced apoptosis by cGMP-dependent inhibition of caspase signaling. 1043 31

The effects of deltamethrin on the activities of nitric oxide synthase (NOS) and poly(ADP-ribose) polymerase (PARP) and the protein expression of neuronal NOS (nNOS) and PARP in rat brain were investigated in the present study. The activity of NOS was significantly increased in cortex and hippocampus at 5 h after deltamethrin treatment, and maintained at an increased level at 24 h. The activity of PARP was also elevated at the same time points in the same brain regions of treated rats. By immunohistochemical analysis, it was demonstrated that the nNOS-immunoreactive cells were markedly increased at 24 h after treatment in the cortex and hippocampus, whereas few nNOS-immunoreactive cells were observed in the same brain regions of control and treated rats at 5 h after treatment. The immunoreactivity for PARP was also increased in the same brain regions, showing the similar time course of the induction of nNOS by deltamethrin. These results indicate that deltamethrin increases the activities of NOS and PARP and initiates the protein expression of nNOS and PARP, suggesting that NOS and PARP might play important roles in neurotoxicity of deltamethrin.
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PMID:Effects of deltamethrin on nitric oxide synthase and poly(ADP-ribose) polymerase in rat brain. 1062 71

Poly(ADP-ribose) polymerase (PARP-1), a nuclear enzyme that facilitates DNA repair, may be instrumental in acute neuronal cell death in a variety of insults including, cerebral ischemia, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism, and CNS trauma. Excitotoxicity is thought to underlie these and other toxic models of neuronal death. Different glutamate agonists may trigger different downstream pathways toward neurotoxicity. We examine the role of PARP-1 in NMDA- and non-NMDA-mediated excitotoxicity. NMDA and non-NMDA agonists were stereotactically delivered into the striatum of mice lacking PARP-1 and control mice in acute (48 hr) and chronic (3 week) toxicity paradigms. Mice lacking PARP-1 are highly resistant to the excitoxicity induced by NMDA but are as equally susceptible to AMPA excitotoxicity as wild-type mice. Restoring PARP-1 protein in mice lacking PARP-1 by viral transfection restored susceptibility to NMDA, supporting the requirement of PARP-1 in NMDA neurotoxicity. Furthermore, Western blot analyses demonstrate that PARP-1 is activated after NMDA delivery but not after AMPA administration. Consistent with the theory that nitric oxide (NO) and peroxynitrite are prominent in NMDA-induced neurotoxicity, PARP-1 was not activated in mice lacking the gene for neuronal NO synthase after NMDA administration. These results suggest a selective role of PARP-1 in glutamate excitoxicity, and strategies of inhibiting PARP-1 in NMDA-mediated neurotoxicity may offer substantial acute and chronic neuroprotection.
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PMID:NMDA but not non-NMDA excitotoxicity is mediated by Poly(ADP-ribose) polymerase. 1105 Jan 21

It is suggested that the fibrillar amyloid beta peptide (A beta) in brain plays a direct role in neurodegeneration in Alzheimer's disease, probably through activation of reactive oxygen species formation. Free radicals and numerous neurotoxins elicit DNA damage that subsequently activates poly(ADP-ribose) polymerase (PARP, EC 2.4.2.30). In this study the effect of neurotoxic fragment (25-35) of full length A beta peptide on PARP activity in adult and aged rat hippocampus was investigated. In adult (4 month old) rat hippocampus the A beta 25-35 peptide significantly enhanced PARP activity by about 80% but had no effect on PARP activity in cerebral cortex and in hippocampus from aged (24-27 month old) rats. The effect of A beta peptide was reduced by half by the nitric oxide synthase inhibitor N-nitro-L-arginine. Stimulation of glutamate receptor(s) itself enhanced PARP activity by about 80% in adult hippocampus. However, A beta 25-35 did not exert any additional stimulatory effect. These results indicate that A beta, through NO and probably other free radicals, induces activation of DNA bound PARP activity exclusively in adult but not in aged hippocampus.
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PMID:Effect of amyloid beta peptide on poly(ADP-ribose) polymerase activity in adult and aged rat hippocampus. 1131 Sep 84

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes, via its metabolite MPP(+), damages of the nigrostriatal dopaminergic pathway, similar to those observed in Parkinson's disease. An intranigral injection of 10 microg MPP(+) in rat induced a decrease of about 30% of the neuronal dopamine transporter (DAT) activity 21 days after lesion. Based on the hypothesis that MPTP/MPP(+) neurotoxicity involves the nitric oxide (NO) production and/or an activation of poly(ADP-ribose) polymerase (PARP), we investigated the preventive effects of a treatment either with L-Name, a NO synthase (NOS) inhibitor or 3-aminobenzamide, a PARP inhibitor on the reduction of dopamine uptake induced by MPP(+). Rats received a daily injection i.p. of 50 mg/kg L-Name or 10 mg/kg 3-aminobenzamide 3 days before and during 21 days after the MPP(+) lesion. The results showed that inhibitors of NOS and PARP did not prevent the alteration of DAT activity induced by 10 microg MPP(+), indicating that NO and PARP were not involved in the biochemical cascade leading to the inhibition of rat DAT activity by MPP(+) in our experimental conditions.
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PMID:Impairment of the neuronal dopamine transporter activity in MPP(+)-treated rat was not prevented by treatments with nitric oxide synthase or poly(ADP-ribose) polymerase inhibitors. 1169 52

The site and mechanisms by which meningococci gain access to the CNS are unclear. In this study we determined whether production of nitric oxide (NO) is part of the host (endothelial cell) response to meningococcal cell lysate, and the consequences for endothelial cell viability. Expression of NO synthase type II (NOS-2) mRNA, protein and enzyme activity were investigated in mouse cerebrovascular endothelial cells exposed to sonicated Neisseria meningitidis. The production of nitrite peaked after 48 h of incubation, and this reflected transcriptional activation of the NOS-2 gene and increased expression of the NOS-2 protein. This endothelial response was independent of meningococcal lipopolysaccharide production. Endothelial cell death occurred as a result of NO production, and addition of a NOS inhibitor prevented cell death, but the cells did not exhibit features of apoptosis. However, inhibition of poly (ADP-ribose) polymerase (PARP) decreased the rate of cell death by more than 40%. These data indicate that N. meningitidis increases expression of NOS-2 in endothelial cells and causes cell death. Such an effect could contribute to meningococcal entry into the CNS in situ.
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PMID:Transcriptional activation of nitric oxide synthase-2, and NO-induced cell death, in mouse cerebrovascular endothelium exposed to Neisseria meningitidis. 1206 73


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