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NAD AND PARP

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https://www.readbyqxmd.com/read/27882448/sirtuins-and-their-roles-in-brain-aging-and-neurodegenerative-disorders
#1
Henryk Jęśko, Przemysław Wencel, Robert P Strosznajder, Joanna B Strosznajder
Sirtuins (SIRT1-SIRT7) are unique histone deacetylases (HDACs) whose activity depends on NAD(+) levels and thus on the cellular metabolic status. SIRTs regulate energy metabolism and mitochondrial function. They orchestrate the stress response and damage repair. Through these functions sirtuins modulate the course of aging and affect neurodegenerative diseases. SIRTSs interact with multiple signaling proteins, transcription factors (TFs) and poly(ADP-ribose) polymerases (PARPs) another class of NAD(+)-dependent post-translational protein modifiers...
November 24, 2016: Neurochemical Research
https://www.readbyqxmd.com/read/27817743/new-insights-into-the-roles-of-nad-poly-adp-ribose-metabolism-and-poly-adp-ribose-glycohydrolase
#2
Seiichi Tanuma, Akira Sato, Takahiro Oyama, Atsushi Yoshimori, Hideaki Abe, Fumiaki Uchiumi
Accumulating evidence has suggested the fundamental functions of NAD+-poly(ADP-ribose) metabolism in cellular and physiological processes, including energy homeostasis, signal transduction, DNA transaction, genomic stability and cell death or survival. The NAD+ biosynthesis and poly(ADP-ribose) [(ADP-R)n] turnover are tightly controlled by several key enzymes, such as nicotinamide phosphoribosyltransferase (NmPRT), nicotinamide mononucleotide adenylyltransferases (NMNATs), poly(ADP-ribose) polymerase (PARP), poly(ADP-ribose) glycohydrolase (PARG) and ADP-ribose pyrophosphorylase (ADPRPPL)...
2016: Current Protein & Peptide Science
https://www.readbyqxmd.com/read/27798264/nad-repletion-improves-muscle-function-in-muscular-dystrophy-and-counters-global-parylation
#3
Dongryeol Ryu, Hongbo Zhang, Eduardo R Ropelle, Vincenzo Sorrentino, Davi A G Mázala, Laurent Mouchiroud, Philip L Marshall, Matthew D Campbell, Amir Safi Ali, Gary M Knowels, Stéphanie Bellemin, Shama R Iyer, Xu Wang, Karim Gariani, Anthony A Sauve, Carles Cantó, Kevin E Conley, Ludivine Walter, Richard M Lovering, Eva R Chin, Bernard J Jasmin, David J Marcinek, Keir J Menzies, Johan Auwerx
Neuromuscular diseases are often caused by inherited mutations that lead to progressive skeletal muscle weakness and degeneration. In diverse populations of normal healthy mice, we observed correlations between the abundance of mRNA transcripts related to mitochondrial biogenesis, the dystrophin-sarcoglycan complex, and nicotinamide adenine dinucleotide (NAD(+)) synthesis, consistent with a potential role for the essential cofactor NAD(+) in protecting muscle from metabolic and structural degeneration. Furthermore, the skeletal muscle transcriptomes of patients with Duchene's muscular dystrophy (DMD) and other muscle diseases were enriched for various poly[adenosine 5'-diphosphate (ADP)-ribose] polymerases (PARPs) and for nicotinamide N-methyltransferase (NNMT), enzymes that are major consumers of NAD(+) and are involved in pleiotropic events, including inflammation...
October 19, 2016: Science Translational Medicine
https://www.readbyqxmd.com/read/27764514/sirtuins-and-their-interactions-with-transcription-factors-and-poly-adp-ribose-polymerases
#4
H Jęśko, R P Strosznajder
Sirtuins (SIRT1 to -7) are unique histone deacetylases (HDACs) whose activity depends on NAD+, thus making them capable of sensing the cellular metabolic status. Sirtuins orchestrate the stress response and damage repair, and are able to modulate the course of ageing and neurodegenerative diseases. Despite their classification as HDACs, sirtuins deacetylate a vast number of targets in many cellular compartments, and some display additional enzymatic activities including mono(ADP-ribosyl)ation. SIRTs interact with multiple signalling proteins, transcription factors and enzymes including p53, FOXOs (forkhead box subgroup O), PPARs (peroxisome proliferator-activated receptors), NF-B, and DNA-PK (DNA-dependent protein kinase)...
2016: Folia Neuropathologica
https://www.readbyqxmd.com/read/27727003/non-nad-like-poly-adp-ribose-polymerase-1-inhibitors-effectively-eliminate-cancer-in-vivo
#5
Colin Thomas, Yingbiao Ji, Niraj Lodhi, Elena Kotova, Aaron Dan Pinnola, Konstantin Golovine, Peter Makhov, Kate Pechenkina, Vladimir Kolenko, Alexei V Tulin
The clinical potential of PARP-1 inhibitors has been recognized >10years ago, prompting intensive research on their pharmacological application in several branches of medicine, particularly in oncology. However, natural or acquired resistance of tumors to known PARP-1 inhibitors poses a serious problem for their clinical implementation. Present study aims to reignite clinical interest to PARP-1 inhibitors by introducing a new method of identifying highly potent inhibitors and presenting the largest known collection of structurally diverse inhibitors...
October 4, 2016: EBioMedicine
https://www.readbyqxmd.com/read/27712995/combination-strategy-of-parp-inhibitor-with-antioxidant-prevent-bioenergetic-deficits-and-inflammatory-changes-in-cci-induced-neuropathy
#6
Prashanth Komirishetty, Aparna Areti, Ranadeep Gogoi, Ramakrishna Sistla, Ashutosh Kumar
Neuropathic pain, a debilitating pain condition and the underlying pathogenic mechanisms are complex and interwoven amongst each other and still there is scant information available regarding therapies which promise to treat the condition. Evidence indicate that oxidative/nitrosative stress induced poly (ADP-ribose) polymerase (PARP) overactivation initiate neuroinflammation and bioenergetic crisis culminating into neurodegenerative changes following nerve injury. Hence, we investigated the therapeutic effect of combining an antioxidant, quercetin and a PARP inhibitor, 4-amino 1, 8-naphthalimide (4-ANI) on the hallmark deficits induced by chronic constriction injury (CCI) of sciatic nerve in rats...
October 3, 2016: Neuropharmacology
https://www.readbyqxmd.com/read/27689878/deficiency-of-parkinson-s-disease-related-gene-fbxo7-is-associated-with-impaired-mitochondrial-metabolism-by-parp-activation
#7
Marta Delgado-Camprubi, Noemi Esteras, Marc Pm Soutar, Helene Plun-Favreau, Andrey Y Abramov
The Parkinson's disease (PD)-related protein F-box only protein 7 (Fbxo7) is the substrate-recognition component of the Skp1-Cullin-F-box protein E3 ubiquitin ligase complex. We have recently shown that PD-associated mutations in Fbxo7 disrupt mitochondrial autophagy (mitophagy), suggesting a role for Fbxo7 in modulating mitochondrial homeostasis. Here we report that Fbxo7 deficiency is associated with reduced cellular NAD(+) levels, which results in increased mitochondrial NADH redox index and impaired activity of complex I in the electron transport chain...
September 30, 2016: Cell Death and Differentiation
https://www.readbyqxmd.com/read/27686254/the-poly-adp-ribosyl-ation-of-foxo3-mediated-by-parp1-participates-in-isoproterenol-induced-cardiac-hypertrophy
#8
Jing Lu, Renwei Zhang, Huiqi Hong, Zuolong Yang, Duanping Sun, Shuya Sun, Xiaolei Guo, Jiantao Ye, Zhuoming Li, Peiqing Liu
The Forkhead box-containing protein, O subfamily 3 (FoxO3) transcription factor negatively regulates myocardial hypertrophy, and its transcriptional activity is finely conditioned by diverse posttranslational modifications, such as phosphorylation, acetylation, ubiquitination, methylation and glycosylation. Here, we introduce a novel modification of the FoxO3 protein in cardiomyocytes: poly(ADP-ribosyl)ation (PARylation) mediated by poly(ADP-ribose) polymerase-1 (PARP1). This process catalyzes the NAD(+)-dependent synthesis of polymers of ADP-ribose (PAR) and their subsequent attachment to target proteins by PARPs...
December 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27670719/expanding-functions-of-adp-ribosylation-in-the-maintenance-of-genome-integrity
#9
K Martin-Hernandez, J-M Rodriguez-Vargas, V Schreiber, F Dantzer
Cell response to genotoxic stress requires a complex network of sensors and effectors from numerous signaling and repair pathways, among them the nuclear poly(ADP-ribose) polymerase 1 (PARP1) plays a central role. PARP1 is catalytically activated in the setting of DNA breaks. It uses NAD(+) as a donor and catalyses the synthesis and subsequent covalent attachment of branched ADP-ribose polymers onto itself and various acceptor proteins to promote repair. Its inhibition is now considered as an efficient therapeutic strategy to potentiate the cytotoxic effect of chemotherapy and radiation or to exploit synthetic lethality in tumours with defective homologous recombination mediated repair...
September 23, 2016: Seminars in Cell & Developmental Biology
https://www.readbyqxmd.com/read/27668604/-poly-adp-ribose-polymerase-1-as-a-key-regulator-of-dna-repair
#10
S N Khodyreva, O I Lavrik
Poly(ADP-ribosyl)ation (PARylation) of proteins is one of the immediate cell responses to DNA damage and is catalyzed by poly(ADP-ribose) polymerases (PARPs). When bound to damaged DNA, some members of the PARP family are activated and use NAD^(+) as a source of ADP to catalyze synthesis of poly(ADP-ribose) (PAR) covalently attached to a target protein. PAR synthesis is considered as a mechanism that provides a local signal of DNA damage and modulates protein functions in response to genotoxic agents. PARP1 is the best-studied protein of the PARP family and is widely known аs a regulator of repair of damaged bases and single-strand nicks...
July 2016: Molekuliarnaia Biologiia
https://www.readbyqxmd.com/read/27663419/inhibiting-poly-adp-ribosylation-increases-fatty-acid-oxidation-and-protects-against-fatty-liver-disease
#11
Karim Gariani, Dongryeol Ryu, Keir J Menzies, Hyon-Seung Yi, Sokrates Stein, Hongbo Zhang, Alessia Perino, Vera Lemos, Elena Katsyuba, Pooja Jha, Sandrine Vijgen, Laura Rubbia-Brandt, Yong Kyung Kim, Jung Tae Kim, Koon Soon Kim, Minho Shong, Kristina Schoonjans, Johan Auwerx
BACKGROUND & AIMS: To date, no pharmacological therapy has been approved for non-alcoholic fatty liver disease (NAFLD). The aim of the present study was to evaluate the therapeutic potential of poly ADP-ribose polymerase (PARP) inhibitors in mouse models of NAFLD. METHODS: As poly ADP-ribosylation (PARylation) of proteins by PARPs consumes nicotinamide adenine dinucleotide (NAD(+)), we hypothesized that overactivation of PARPs drives NAD(+) depletion in NAFLD. Therefore, we assessed the effectiveness of PARP inhibition to replenish NAD(+) and activate NAD(+)-dependent sirtuins, hence improving hepatic fatty acid oxidation...
September 20, 2016: Journal of Hepatology
https://www.readbyqxmd.com/read/27634671/pharmacological-inhibition-of-nox4-ameliorates-alcohol-induced-liver-injury-in-mice-through-improving-oxidative-stress-and-mitochondrial-function
#12
Qian Sun, Wenliang Zhang, Wei Zhong, Xinguo Sun, Zhanxiang Zhou
BACKGROUND: Oxidative stress plays a crucial role in the development of alcoholic liver disease (ALD), however effective pharmacological treatment for oxidative injury is still lacking. The objective of this study was to determine whether inhibition of NADPH oxidase activity could reverse alcohol-induced liver injury via protecting mitochondrial functions. METHODS: C57BL/6J mice were pair-fed with Lieber-DeCarli control or ethanol diet for four week with or without administration with 30mg/kg/d GKT137831, a NOX4 inhibitor for the last two weeks...
September 12, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27567859/the-polyphenol-oleuropein-aglycone-modulates-the-parp1-sirt1-interplay-an%C3%A2-in-vitro-and-in-vivo-study
#13
Ilaria Luccarini, Daniela Pantano, Pamela Nardiello, Leonardo Cavone, Andrea Lapucci, Caterina Miceli, Chiara Nediani, Andrea Berti, Massimo Stefani, Fiorella Casamenti
Poly(ADP-ribose) polymerase-1 (PARP1) activation contributes to the cascade of events initiated by amyloid-β (Aβ) peptide eventually leading to cell death in Alzheimer's disease brain. A significant accumulation of PAR polymers and increase of PARP1 expression were detected in the cortex at the early (3.5 months) and intermediate (6 months) stage of Aβ deposition in the TgCRND8 mouse model. Our previous data highlighted the beneficial effects of oleuropein aglycone (OLE), the main polyphenol found in the olive oil, against neurodegeneration both in cultured cells and in model organisms...
September 6, 2016: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/27567805/bioenergetic-impairment-in-animal-and-cellular-models-of-alzheimer-s-disease-parp-1-inhibition-rescues-metabolic-dysfunctions
#14
Sara Martire, Andrea Fuso, Luciana Mosca, Elena Forte, Virginia Correani, Mario Fontana, Sigfrido Scarpa, Bruno Maras, Maria d'Erme
Amyloid-beta peptide accumulation in the brain is one of the main hallmarks of Alzheimer's disease. The amyloid aggregation process is associated with the generation of free radical species responsible for mitochondrial impairment and DNA damage that in turn activates poly(ADP-ribose)polymerase 1 (PARP-1). PARP-1 catalyzes the poly(ADP-ribosylation), a post-translational modification of proteins, cleaving the substrate NAD+ and transferring the ADP-ribose moieties to the enzyme itself or to an acceptor protein to form branched polymers of ADP-ribose...
August 10, 2016: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/27566573/de-novo-nad-synthesis-regulates-sirt1-foxo1-apoptotic-pathway-in-response-to-nqo1-substrates-in-lung-cancer-cells
#15
Huiying Liu, Rong Xing, Xuefang Cheng, Qingran Li, Fang Liu, Hui Ye, Min Zhao, Hong Wang, Guangji Wang, Haiping Hao
Tryptophan metabolism is essential in diverse kinds of tumors via regulating tumor immunology. However, the direct role of tryptophan metabolism and its signaling pathway in cancer cells remain largely elusive. Here, we establish a mechanistic link from L-type amino acid transporter 1 (LAT1) mediated transport of tryptophan and the subsequent de-novo NAD+ synthesis to SIRT1-FOXO1 regulated apoptotic signaling in A549 cells in response to NQO1 activation. In response to NQO1 activation, SIRT1 is repressed leading to the increased cellular accumulation of acetylated FOXO1 that transcriptionally activates apoptotic signaling...
August 23, 2016: Oncotarget
https://www.readbyqxmd.com/read/27477457/overview-on-poly-adp-ribose-immuno-biomedicine-and-future-prospects
#16
Yoshiyuki Kanai
Poly(ADP-ribose), identified in 1966 independently by three groups Strassbourg, Kyoto and Tokyo, is synthesized by poly(ADP-ribose) polymerases (PARP) from NAD(+) as a substrate in the presence of Mg(2+). The structure was unique in that it has ribose-ribose linkage. In the early-1970s, however, its function in vivo/in vitro was still controversial and the antibody against it was desired to help clear its significance. Thereupon, the author tried to produce antibody against poly(ADP-ribose) in rabbits and succeeded in it for the first time in the world...
2016: Proceedings of the Japan Academy. Series B, Physical and Biological Sciences
https://www.readbyqxmd.com/read/27471034/poly-adp-ribose-polymerases-covalently-modify-strand-break-termini-in-dna-fragments-in-vitro
#17
Ibtissam Talhaoui, Natalia A Lebedeva, Gabriella Zarkovic, Christine Saint-Pierre, Mikhail M Kutuzov, Maria V Sukhanova, Bakhyt T Matkarimov, Didier Gasparutto, Murat K Saparbaev, Olga I Lavrik, Alexander A Ishchenko
Poly(ADP-ribose) polymerases (PARPs/ARTDs) use nicotinamide adenine dinucleotide (NAD(+)) to catalyse the synthesis of a long branched poly(ADP-ribose) polymer (PAR) attached to the acceptor amino acid residues of nuclear proteins. PARPs act on single- and double-stranded DNA breaks by recruiting DNA repair factors. Here, in in vitro biochemical experiments, we found that the mammalian PARP1 and PARP2 proteins can directly ADP-ribosylate the termini of DNA oligonucleotides. PARP1 preferentially catalysed covalent attachment of ADP-ribose units to the ends of recessed DNA duplexes containing 3'-cordycepin, 5'- and 3'-phosphate and also to 5'-phosphate of a single-stranded oligonucleotide...
July 28, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27465020/emerging-therapeutic-roles-for-nad-metabolism-in-mitochondrial-and-age-related-disorders
#18
REVIEW
Sarika Srivastava
Nicotinamide adenine dinucleotide (NAD(+)) is a central metabolic cofactor in eukaryotic cells that plays a critical role in regulating cellular metabolism and energy homeostasis. NAD(+) in its reduced form (i.e. NADH) serves as the primary electron donor in mitochondrial respiratory chain, which involves adenosine triphosphate production by oxidative phosphorylation. The NAD(+)/NADH ratio also regulates the activity of various metabolic pathway enzymes such as those involved in glycolysis, Kreb's cycle, and fatty acid oxidation...
December 2016: Clinical and Translational Medicine
https://www.readbyqxmd.com/read/27374990/nad-metabolism-bioenergetics-signaling-and-manipulation-for-therapy
#19
Yue Yang, Anthony A Sauve
We survey the historical development of scientific knowledge surrounding Vitamin B3, and describe the active metabolite forms of Vitamin B3, the pyridine dinucleotides NAD(+) and NADP(+) which are essential to cellular processes of energy metabolism, cell protection and biosynthesis. The study of NAD(+) has become reinvigorated by new understandings that dynamics within NAD(+) metabolism trigger major signaling processes coupled to effectors (sirtuins, PARPs, and CD38) that reprogram cellular metabolism using NAD(+) as an effector substrate...
December 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27313049/biosensor-reveals-multiple-sources-for-mitochondrial-nad%C3%A2-%C2%BA
#20
Xiaolu A Cambronne, Melissa L Stewart, DongHo Kim, Amber M Jones-Brunette, Rory K Morgan, David L Farrens, Michael S Cohen, Richard H Goodman
Nicotinamide adenine dinucleotide (NAD(+)) is an essential substrate for sirtuins and poly(adenosine diphosphate-ribose) polymerases (PARPs), which are NAD(+)-consuming enzymes localized in the nucleus, cytosol, and mitochondria. Fluctuations in NAD(+) concentrations within these subcellular compartments are thought to regulate the activity of NAD(+)-consuming enzymes; however, the challenge in measuring compartmentalized NAD(+) in cells has precluded direct evidence for this type of regulation. We describe the development of a genetically encoded fluorescent biosensor for directly monitoring free NAD(+) concentrations in subcellular compartments...
June 17, 2016: Science
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