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) synthase or polymerase (PARS and PARP, respectively) is a cytotoxic enzyme which causes cellular damage. Nicotinamide, a compound of vitamin B complex, has been reported to exert an inhibitory effect on PARS or PARP. The present study tests the effects of nicotinamide on acute lung injury and associated alterations following ischaemia/reperfusion (I/R) of the isolated perfused rat's lung. I/R increased the lung weight (LW) to body weight ratio, LW gain, protein and dye tracer leakage, pulmonary arterial pressure and capillary permeability. The insult also increased nitrate/nitrite, methyl guanidine, tumour necrosis factor-alpha and interleukin-1beta in lung perfusate, while it decreased adenosine triphosphate content with an increase in PARP activity in lung tissue. Most of the I/R-induced changes were abrogated by post-treatment (30 min after I/R) with nicotinamide (100 mg.kg(-1) body weight). However, the increase in pulmonary arterial pressure was enhanced by nicotinamide post-treatment. Following I/R, the inducible nitric oxide synthase (iNOS) mRNA expression was enhanced. Nicotinamide reduced the iNOS expression. The results suggest that nicotinamide exerted a protective effect on the acute lung injury caused by ischaemia/reperfusion. The mechanisms may be mediated through the inhibition on the poly (adenosine diphosphate-ribose) polymerase activity, inducible nitric oxide synthase expression and the subsequent suppression of nitric oxide, free radicals and pro-inflammatory cytokines with restoration of adenosine triphosphate.
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PMID:Nicotinamide abrogates acute lung injury caused by ischaemia/reperfusion. 1750 97

Compounds such as S-allylmercaptocysteine, diallyl disulfide, and S-trityl-L-cysteine isolated from garlic have been known to be effective in chemoprevention. Nuclear transcription factor-kappaB (NF-kappaB) has been known to be an implicated factor in apoptotic cell death of several cancer cells. In this study, we investigated whether a sulfurcompound (named thiacremonone) isolated from garlic could modulate NF-kappaB activity and thereby induce apoptotic cell death of colon cancer cells. Treatment with different concentrations (30 - 150 microg/ml) of thiacremonone for various periods (0 - 48 h) inhibited colon cancer cell (SW620 and HCT116) growth followed by induction of apoptosis in a dose-dependent manner. We also found that thiacremonone modulated tumor necrosis factor-alpha (TNF-alpha) and tetradeanoyl phorbol acetate (TPA)-induced NF-kappaB transcriptional and DNA binding activity. Moreover, thiacremonone suppressed NF-kappaB target anti-apoptotic genes (Bcl-2, cIAP1/2, and XIAP) and inflammatory genes (iNOS and COX-2), whereas it induced apoptotic genes (Bax, cleaved caspse-3, and cleaved PARP) expression. These results suggest that a novel sulfurocompound from garlic inhibited colon cancer cell growth through induction of apoptotic cell death by modulating of NF-kappaB.
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PMID:Inhibition of cell growth and induction of apoptosis via inactivation of NF-kappaB by a sulfurcompound isolated from garlic in human colon cancer cells. 1772 Oct 42

The influence of de novo synthesis of nicotinamide adenine dinucleotide (NAD) through the kynurenine (KYN) pathway of tryptophan (TRP) degradation on gene transcription of inducible nitric oxide synthase (iNOS) and nitric oxide (NO) production in chicken interferon gamma (ChIFN-gamma)-stimulated and non-stimulated chicken macrophage cell line HD11 was investigated. Interferon gamma up regulation of iNOS transcription and NO production was dependent on an undisturbed flow through the KYN pathway. Inhibition of indoleamine-2,3-dioxygenase, the rate-limiting enzyme of TRP catabolism, by 1-methyl-l-tryptophan (1-mTRP) down regulated both iNOS gene transcription and NO production. Addition of KYN to 1-mTRP-treated, ChIFN-gamma-stimulated macrophages circumvented the down regulation of iNOS transcription and NO production. Inhibition of poly(ADP-ribose) polymerase (PARP), a nuclear enzyme involved in DNA repair, replication and transcription, which cleaves NAD into nicotinamide and ADP-ribose, down regulated iNOS gene transcription and NO production in ChIFN-gamma-stimulated HD11 cells. Our results suggest that prevention of NAD depletion in HD11 cells by ChIFN-gamma-mediated induction of IDO facilitates iNOS transcription and NO production. This effect is most likely a result of PARP1 automodification in the presence of NAD, known to facilitate transcription by changing chromatin structure and to allow NFkappaB binding to iNOS promoter which is hindered by direct protein-protein interaction between NFkappaB and unmodified PARP1.
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PMID:The role of tryptophan metabolism in iNOS transcription and nitric oxide production by chicken macrophage cells upon treatment with interferon gamma. 1808 71

It was previously shown that nitric oxide produced by inducible nitric oxide synthase (iNOS) and peroxynitrite are responsible for cyclophosphamide (CP)-induced cystitis. Since endogenous production of peroxynitrite is known to lead to poly(ADP-ribose) polymerase (PARP) activation, in this study, the aim was to evaluate whether the PARP activation pathway is also included in the pathogenesis of CP-induced bladder ulceration in rats. A total of 48 male albino Wistar rats were divided into 5 groups. Group 1 served as control and was given 2 ml saline; four groups received a single dose of CP (200 mg/kg) with the same time intervals. Group 2 received CP only; Group 3, selective iNOS inhibitor 1400W (20 mg/kg); Group 4, peroxynitrite scavenger ebselen (30 mg/kg); and Group 5, PARP inhibitor 3-aminobenzamide (20 mg/kg). CP injection resulted in severe cystitis with continuous macroscopic hemorrhage, strong edema, inflammation, and ulceration. Moreover, bladder iNOS activation and urine nitrite-nitrate levels were dramatically increased. Histologically, 1400W protected bladder against CP damage and decreased urine nitrite-nitrate levels and bladder iNOS induction. Ebselen has shown similar histologic results with 1400W without changing urinary nitrite-nitrate level and iNOS activity. Furthermore in the 3-aminobenzamide group, beneficial effects had also occurred including decreased ulceration. These results suggest that PARP activation involves pathogenesis of CP-induced bladder ulceration. Furthermore, PARP is not only important for ulceration but also for bladder edema, hemorrhage, and inflammation because of broken uroepithelial cellular integrity.
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PMID:Effects of poly(ADP-ribose) polymerase inhibition in bladder damage caused by cyclophosphamide in rats. 1829 39

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by selective degeneration of motor neurons. Mutations in copper/zinc superoxide dismutase (SOD1) account for 20% cases of familial ALS (fALS), but the underlying pathogenetic mechanisms are largely unknown. Using SOD1(G93A) mice model of ALS, we demonstrated that mutation in SOD1 caused a significant increase in the level of plasma homocysteine (Hcy). To investigate whether Hcy-lowering therapy is beneficial to this disease, we applied folic acid (FA) and vitamin B12 which are important factors involved in the Hcy metabolism to assess the neuroprotective effect of FA and B12 in the SOD1(G93A) mice. Our results showed FA or FA+B12 treatment significantly delayed the disease onset and prolonged the lifespan, accompanied by the significant reduction of motor neuron loss. Furthermore, we found that FA or FA+B12 treatment significantly attenuated the plasma Hcy level, suppressed the activation of microglia and astrocytes, and inhibited the expression of inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-alpha) in spinal cord. Moreover, FA or FA+B12 treatment decreased the levels of cleaved caspase-3 and poly(ADP-ribose)polymerase (PARP) but up-regulated the level of anti-apoptotic protein Bcl-2. However, B12 treatment alone did not show any significant benefit to this disease. These results provide evidence to demonstrate that elevated Hcy is involved in the pathogenesis of fALS and FA therapy may have therapeutic potential for the treatment of the disease.
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PMID:Folic acid protects motor neurons against the increased homocysteine, inflammation and apoptosis in SOD1 G93A transgenic mice. 1843 68

Malignant melanoma is the most deadly form of skin cancer due to its highly metastatic nature. Untargeted therapies are ineffective for treating metastatic disease, leading to the development of agents specifically inhibiting proteins or pathways deregulated in melanoma. The deregulation of inducible nitric oxide synthase (iNOS) is one such event occurring in melanoma, and is correlated with poor survival. Current iNOS inhibitors, such as PBIT [S,S'-1,4-phenylenebis(1,2-ethanediyl)bis-isothiourea], require high concentrations for clinical efficacy causing systemic toxicity. To develop more potent agents effective at significantly lower concentrations, a novel isosteric analogue of PBIT was synthesized, called PBISe [S,S'-1,4-phenylenebis(1,2-ethanediyl)bis-isoselenourea], in which sulfur was replaced with selenium. PBISe kills melanoma cells >10-fold more effectively than PBIT, and cultured cancer cells are 2- to 5-fold more sensitive than normal cells. Like PBIT, PBISe targets iNOS but also has new inhibitory properties acting as an Akt3 pathway inhibitor and mitogen-activated protein kinase (MAPK) cascade activator, which causes decreased cancer cell proliferation and increased apoptosis. Inhibition of cellular proliferation mediated by PBISe induced a G2-M phase cell cycle block linked to excessively high MAPK activity causing decreased cyclin D1 and increased p21 as well as p27 levels. PBISe promotes apoptosis by inhibiting Akt3 signaling, elevating cleaved caspase-3 and PARP levels. Compared with PBIT, PBISe reduced tumor development by 30% to 50% in mice inducing a 2-fold increase in apoptosis with negligible associated systemic toxicity. Collectively, these results suggest that PBISe is a potent chemotherapeutic agent with novel properties enabling the targeting of iNOS, Akt3, and MAPK signaling, thereby promoting melanoma cell apoptosis and inhibition of proliferation.
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PMID:PBISe, a novel selenium-containing drug for the treatment of malignant melanoma. 1848 17

The present study is aimed at evaluating the functional and neuroprotective effect of benzamide, a poly-(ADP-ribose) polymerase (PARP) inhibitor on delayed neuronal death (DND) in hippocampus CA1 region and memory impairment following global cerebral ischemia (GCI) in a mouse model. GCI was induced by bilateral common carotid artery occlusion (BCAo) for 20 min followed by reperfusion for 9 days. Postischemic continuous treatment with benzamide (160 mg/kg b w i.p. for 9 days) significantly reversed the GCI-induced anterograde memory impairment in passive avoidance step through and elevated plus maze tasks. The observed memory impairment in vehicle treated ischemia group was found to be well correlated with DND and downregulation of cholinergic muscarinic receptor-1 expression, which was possibly mediated by inflammation and apoptosis, as revealed from inducible nitric oxide synthase (iNOS) expression and number of TUNEL positive neurons in hippocampus CA1 region. It is clear from the present experiment that benzamide treatment significantly decreases the iNOS expression and number of apoptotic neurons and thereby improves the neuronal survival and memory during GCI. Our present findings provide compelling evidence that multiple doses of benzamide treatment is a promising therapeutic approach for cerebrovascular and neurodegenerative diseases, which deserves further clinical evaluation.
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PMID:Benzamide protects delayed neuronal death and behavioural impairment in a mouse model of global cerebral ischemia. 1850 76

Gene transcription is highly regulated to ensure that specific genes are expressed at the appropriate times, places and levels in response to various genetic and environmental stimuli. Activation of some genes occurs by relief of basal repression controls, whereas termination of active transcription can involve feedback inhibition. We describe our characterization of aldosterone-triggered de-repression of the epithelial Na(+) channel-alpha subunit (ENaCalpha) gene in renal collecting duct cells in a process that involves a novel nuclear repressor complex, consisting of a histone H3 K79 methyltransferase and the putative transcription factor AF9, that regulates targeted histone H3 K79 methylation at the ENaCalpha promoter. As an example of feedback inhibition, we describe our work characterizing how the end product, nitric oxide, feedback inhibits inducible nitric oxide synthase (iNOS) gene transcription by S-nitrosylating its transactivator poly(ADP-ribose) polymerase (PARP-1) and, thereby, decreasing its ability to act at the iNOS promoter.
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PMID:New mechanisms for transcriptional repression of ENaC And iNOS. 1852 88

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

Among the most readily available chemical warfare agents, sulfur mustard (SM) has been the most widely used chemical weapon. The toxicity of SM as an incapacitating agent is of much greater importance than its ability to cause lethality. Oxidative stress is the first and key event in the pathogenesis of SM toxicity. The involvement of inducible nitric oxide (iNOS) in SM toxicity, however, also leads to elevated nitrosative stress; thus, the damage caused by SM is nitro-oxidative stress because of peroxynitrite (ONOO-) production. Once ONOO- is formed, it activates nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) leading to pro-inflammatory gene expression thereby promoting inflammation; additionally, ONOO- directly exerts harmful effects by damaging all biomolecules including lipids, proteins and DNA within cells. DNA damage is sensed by an important DNA repair enzyme, poly (ADP-ribose) polymerase (PARP); this enzyme repairs molecular damage by using nicotinamide adenine dinucleotide (NAD+) as a substrate. Over-activation of PARP, due to severe DNA damage, consumes vast amounts of the respiratory coenzyme NAD+ leading to a cellular energy crisis. This pathophysiologic mechanism eventually results in cellular dysfunction, apoptosis or necrosis. Therefore, classic antioxidants may have limited beneficial effects on SM toxicity. Melatonin is a multifunctional indolamine which counteracts virtually all pathophysiologic steps and displays significant beneficial effects against ONOO--induced cellular toxicity. Melatonin has the capability of scavenging both oxygen and nitrogen-based reactants including ONOO- and blocking transcriptional factors which induce pro-inflammatory cytokines. The delayed toxicity of SM, however, currently has no mechanistic explanation. We propose that epigenetic aberrations may be responsible for delayed detrimental effects of mustard poisoning. Therefore, as a putative epigenetic modulator, melatonin may also be beneficial to subjects with delayed toxicity of SM.
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PMID:The use of melatonin to combat mustard toxicity. REVIEW. 1898 75


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