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NAD AND PARP

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https://www.readbyqxmd.com/read/29351465/emerging-potential-benefits-of-modulating-nad-metabolism-in-cardiovascular-disease
#1
Daniel S Matasic, Charles Brenner, Barry London
Nicotinamide adenine dinucleotide (NAD+) and related metabolites are central mediators of fuel oxidation and bioenergetics within cardiomyocytes. Additionally, NAD+is required for the activity of multifunctional enzymes including sirtuins and poly(ADP-ribose) polymerases (PARPs) that regulate post-translational modifications, DNA damage responses, and calcium signaling. Recent research indicates that NAD+participates in a multitude of processes dysregulated in cardiovascular diseases. Therefore, supplementation of NAD+precursors including nicotinamide riboside (NR) that boost or replete the NAD+metabolome may be cardioprotective...
December 22, 2017: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/29343967/indoleamine-2-3-dioxygenase-activity-increases-nad-production-in-ifn-%C3%AE-stimulated-human-primary-mononuclear-cells
#2
Ross S Grant
IFN-γ activation of mononuclear phagocytes significantly increases indoleamine 2,3-dioxygenase (IDO) and flux through the kynurenine pathway (KP). However, the effect of IDO on NAD+ synthesis, the end product of KP metabolism, is unknown. To investigate this, primary human peripheral blood mononuclear cells were cultured up to 10 days and activated with IFN-γ in the presence or absence of a poly(ADP-ribose) polymerase (PARP) inhibitor. Day 10 macrophages had significantly higher NAD+ levels compared with monocytes...
2018: International Journal of Tryptophan Research: IJTR
https://www.readbyqxmd.com/read/29342113/mitochondria-oxidative-stress-and-the-kynurenine-system-with-a-focus-on-ageing-and-neuroprotection
#3
REVIEW
Katalin Sas, Elza Szabó, László Vécsei
In this review, the potential causes of ageing are discussed. We seek to gain insight into the main physiological functions of mitochondria and discuss alterations in their function and the genome, which are supposed to be the central mechanisms in senescence. We conclude by presenting the potential modulating role of the kynurenine pathway in the ageing processes. Mitochondrial dynamics are supposed to have important physiological roles in maintaining cell homeostasis. During ageing, a decrease in mitochondrial dynamics was reported, potentially compromising the function of mitochondria...
January 17, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29337590/novel-mechanism-for-nicotinamide-phosphoribosyltransferase-inhibition-of-tnf-%C3%AE-mediated-apoptosis-in-human-lung-endothelial-cells
#4
Radu C Oita, Sara M Camp, Wenli Ma, Ermelinda Ceco, Mark Harbeck, Patrick Singleton, Joe Messana, Xiaoguang Sun, Ting Wang, Joe G N Garcia
Nicotinamide phosphoribosyltransferase (NAMPT) exists as both intracellular (iNAMPT) and extracellular (eNAMPT) proteins. eNAMPT is secreted into the blood and functions as a cytokine/enzyme (cytozyme) that activates NFκB signaling via ligation of the TLR4 receptor, further serving as a biomarker for inflammatory lung disorders such as the acute respiratory distress syndrome (ARDS). In contrast, iNAMPT is involved in nicotinamide mononucleotide (NMN) synthesis and has been implicated in the regulation of cellular apoptosis, although the exact mechanisms for this regulation are poorly understood...
January 16, 2018: American Journal of Respiratory Cell and Molecular Biology
https://www.readbyqxmd.com/read/29332790/ultrasensitive-electrochemical-detection-of-poly-adp-ribose-polymerase-1-via-polyaniline-deposition
#5
Yong Liu, Jiahui Fan, Li Shangguan, Yuanjian Liu, Yuanqing Wei, Wei Wei, Songqin Liu
Recent findings have thrust poly ADP (ADP: adenosine diphosphate)-ribose polymerase-1 (PARP-1) into the limelight as potential chemotherapeutic target because it is closely related to the development of tumor. So, studies on its detection and inhibitors evaluation have attracted more attention. It is interesting that poly (ADP-ribose) (PAR), the catalytic product of PARP-1 in the existence of nicotinamide adenine dinucleotide (NAD+), possess twice charge density of DNA strands. PAR contain 200 units, i.e., about 400bp bases, and multiple branched strands...
April 1, 2018: Talanta
https://www.readbyqxmd.com/read/29317476/parp-inhibitor-pj34-attenuated-hepatic-triglyceride-accumulation-in-alcoholic-fatty-liver-disease-in-mice
#6
Shishun Huang, Bing Zhang, Yingli Chen, Huan Liu, Yang Liu, Xin Li, Zhiwei Bao, Zhenyuan Song, Zhigang Wang
Poly ADP ribose polymerase (PARP) is a NAD-consuming enzyme and its specific role in the pathogenesis of alcoholic fatty liver disease (AFLD) is still elusive. In current study, we applied PJ34 to inhibit hepatic PARP activity to examine the corresponding pathological alteration in AFLD in mice and the underlying molecular mechanism. We found that PJ34 decreased the intracellular TG content in hepatocyte. Moreover, PJ34 suppressed the gene expression of DGAT1 and DGAT2 and elevated the intracellular NAD+ level in hepatocyte...
January 9, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29295624/nad-deficiency-is-a-common-central-pathological-factor-of-a-number-of-diseases-and-aging-mechanisms-and-therapeutic-implications
#7
Mingchao Zhang, Weihai Ying
Increasing evidence has indicated critical roles of NAD+ in various biological functions. NAD+ deficiency has been found in models of a number of diseases such as cerebral ischemia, myocardial ischemia and diabetes, and in models of aging. Application of NAD+ or other approaches that can restore NAD+ levels are highly protective in these models of diseases and aging. NAD+ produces its beneficial effects by targeting at multiple pathological pathways, including attenuating mitochondrial alterations, DNA damage and oxidative stress by modulating such enzymes as sirtuins, glyceraldehyde-3-phosphate dehydrogenase and AP endonuclease...
January 2, 2018: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/29278652/parp1-induces-cardiac-fibrosis-by-mediating-mtor-activity
#8
Shuya Sun, Yuehuai Hu, Qiyao Zheng, Zhen Guo, Duanping Sun, Shaorui Chen, Yiqiang Zhang, Peiqing Liu, Jing Lu, Jianmin Jiang
Cardiac fibrosis is involved in nearly all forms of heart diseases, and is characterized by excessive deposition of extracellular matrix (ECM) proteins by cardiac fibroblasts (CFs). We and others have reported the possibility of poly(ADP-ribose) polymerase 1 (PARP1), the founding subtype of the PARPs enzyme family, as a novel therapeutic target of heart diseases. The cardiac fibrotic induction of mTOR (mammalian target of rapamycin) is mainly due to collagen expression, Smad3 and p53/JNK-mediated apoptosis...
December 26, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/29247608/a-macrodomain-linked-immunosorbent-assay-mlisa-for-mono-adp-ribosyltransferases
#9
Jingwen Chen, Albert Lam, Yong Zhang
ADP-ribosyltransferases (ARTs) catalyze reversible additions of mono- and poly-ADP-ribose onto diverse types of proteins by using nicotinamide adenine dinucleotide (NAD+) as a cosubstrate. In human ART superfamily, 14 out of 20 members are shown to catalyze endogenous protein mono-ADP-ribosylation and play important roles in regulating various physiological and pathophysiological processes. Identification of new modulators of mono-ARTs can thus potentially lead to discovery of novel therapeutics. In this study, we developed a macrodomain-linked immunosorbent assay (MLISA) for characterizing mono-ARTs...
December 13, 2017: Analytical Biochemistry
https://www.readbyqxmd.com/read/29203587/nampt-is-a-potent-oncogene-in-colon-cancer-progression-that-modulates-cancer-stem-cell-properties-and-resistance-to-therapy-through-sirt1-and-parp
#10
Amancio Carnero, Antonio Lucena-Cacace, Daniel Otero-Albiol, Manuel P Jimenez-Garcia, Sandra Muñoz-Galvan
PURPOSE: Colorectal cancer (CRC) is the second most common cancer in women and the third most common in men worldwide. However, despite current progress, many patients with advanced and metastatic tumors still die from the malignancy. Refractory disease often relies on nicotinamide adenine dinucleotide(NAD)-dependent mechanisms. NAD metabolism and a stable NAD regeneration circuit are required to maintain tissue homeostasis and metabolism. However, high levels of NAD confer therapy resistance to tumors...
December 4, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29196784/parp1-protects-from-benzo-a-pyrene-diol-epoxide-induced-replication-stress-and-mutagenicity
#11
Jan M F Fischer, Tabea Zubel, Kirsten Jander, Jelena Fix, Irmela R E A Trussina, Daniel Gebhard, Jörg Bergemann, Alexander Bürkle, Aswin Mangerich
Poly(ADP-ribosyl)ation (PARylation) is a complex and reversible posttranslational modification catalyzed by poly(ADP-ribose)polymerases (PARPs), which orchestrates protein function and subcellular localization. The function of PARP1 in genotoxic stress response upon induction of oxidative DNA lesions and strand breaks is firmly established, but its role in the response to chemical-induced, bulky DNA adducts is understood incompletely. To address the role of PARP1 in the response to bulky DNA adducts, we treated human cancer cells with benzo[a]pyrene 7,8-dihydrodiol-9,10-epoxide (BPDE), which represents the active metabolite of the environmental carcinogen benzo[a]pyrene [B(a)P], in nanomolar to low micromolar concentrations...
December 1, 2017: Archives of Toxicology
https://www.readbyqxmd.com/read/29073231/poly-adp-ribose-polymerases-inhibitors-prevent-early-mitochondrial-fragmentation-and-hepatocyte-cell-death-induced-by-h2o2
#12
Sandra M Martín-Guerrero, José A Muñoz-Gámez, María-Carmen Carrasco, Javier Salmerón, María Martín-Estebané, Miguel A Cuadros, Julio Navascués, David Martín-Oliva
Poly(ADP-ribose)polymerases (PARPs) are a family of NAD+ consuming enzymes that play a crucial role in many cellular processes, most clearly in maintaining genome integrity. Here, we present an extensive analysis of the alteration of mitochondrial morphology and the relationship to PARPs activity after oxidative stress using an in vitro model of human hepatic cells. The following outcomes were observed: reactive oxygen species (ROS) induced by oxidative treatment quickly stimulated PARPs activation, promoted changes in mitochondrial morphology associated with early mitochondrial fragmentation and energy dysfunction and finally triggered apoptotic cell death...
2017: PloS One
https://www.readbyqxmd.com/read/29054115/reversible-mono-adp-ribosylation-of-dna-breaks
#13
Deeksha Munnur, Ivan Ahel
ADP-ribosylation is a chemical modification of macromolecules that plays an important role in regulation of quintessential biological processes such as DNA repair, transcription, chromatin remodelling, stress response, apoptosis, bacterial metabolism and many others. ADP-ribosylation is carried out by ADP-ribosyltransferase proteins, such as poly(ADP-ribose) polymerases (PARPs) that transfer either monomer or polymers of ADP-ribose onto the molecular targets by using nicotinamide adenine dinucleotide (NAD(+) ) as a cofactor...
October 20, 2017: FEBS Journal
https://www.readbyqxmd.com/read/29029387/the-%C3%AE-nad-salvage-pathway-and-pkc-mediated-signaling-influence-localized-parp-1-activity-and-ctcf-poly-adp-ribosylation
#14
David J P Henderson, Jj L Miranda, Beverly M Emerson
Poly(ADP)ribosylation (PARylation) of the chromatin architectural protein CTCF is critical for CTCF-dependent regulation of chromatin boundary and insulator elements. Loss of CTCF PARylation results in epigenetic silencing of certain tumor suppressor genes through destabilization of nearby chromatin boundaries. We investigated the metabolic and mechanistic processes that regulate PARP-1-mediated CTCF PARylation in human cancer cell lines and discovered a key role for the expression and activity of β-NAD+ salvage enzymes, NAMPT and NMNAT-1...
September 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/28991266/macroh2a1-1-regulates-mitochondrial-respiration-by-limiting-nuclear-nad-consumption
#15
Melanija Posavec Marjanović, Sarah Hurtado-Bagès, Maximilian Lassi, Vanesa Valero, Roberto Malinverni, Hélène Delage, Miriam Navarro, David Corujo, Iva Guberovic, Julien Douet, Pau Gama-Perez, Pablo M Garcia-Roves, Ivan Ahel, Andreas G Ladurner, Oscar Yanes, Philippe Bouvet, Mònica Suelves, Raffaele Teperino, J Andrew Pospisilik, Marcus Buschbeck
Histone variants are structural components of eukaryotic chromatin that can replace replication-coupled histones in the nucleosome. The histone variant macroH2A1.1 contains a macrodomain capable of binding NAD(+)-derived metabolites. Here we report that macroH2A1.1 is rapidly induced during myogenic differentiation through a switch in alternative splicing, and that myotubes that lack macroH2A1.1 have a defect in mitochondrial respiratory capacity. We found that the metabolite-binding macrodomain was essential for sustained optimal mitochondrial function but dispensable for gene regulation...
November 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28973994/silibinin-restores-nad%C3%A2-%C2%BA-levels-and-induces-the-sirt1-ampk-pathway-in-non-alcoholic-fatty-liver
#16
Federico Salomone, Ignazio Barbagallo, Justyna Godos, Vincenzo Lembo, Walter Currenti, Diana Cinà, Roberto Avola, Nicolantonio D'Orazio, Filomena Morisco, Fabio Galvano, Giovanni Li Volti
Nicotinamide adenine dinucleotide (NAD⁺) homeostasis is emerging as a key player in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and is tightly linked to the SIRT1/5'-AMP-activated protein kinase (AMPK) pathway. Silibinin, the main component of silymarin, has been proposed as a nutraceutical for the treatment of NAFLD. In this study, we aimed to identify whether silibinin may influence the NAD⁺/SIRT1 axis. To this end, C57BL/6 mice were fed a high fat diet (HFD) for 16 weeks, and were treated with silibinin or vehicle during the last 8 weeks...
September 30, 2017: Nutrients
https://www.readbyqxmd.com/read/28970491/rev1-contributes-to-proper-mitochondrial-function-via-the-parp-nad-sirt1-pgc1%C3%AE-axis
#17
Nima Borhan Fakouri, Jon Ambæk Durhuus, Christine Elisabeth Regnell, Maria Angleys, Claus Desler, Mahdi Hasan- Olive, Ana Martín-Pardillos, Anastasia Tsaalbi-Shtylik, Kirsten Thomsen, Martin Lauritzen, Vilhelm A Bohr, Niels de Wind, Linda Hildegard Bergersen, Lene Juel Rasmussen
Nucleic acids, which constitute the genetic material of all organisms, are continuously exposed to endogenous and exogenous damaging agents, representing a significant challenge to genome stability and genome integrity over the life of a cell or organism. Unrepaired DNA lesions, such as single- and double-stranded DNA breaks (SSBs and DSBs), and single-stranded gaps can block progression of the DNA replication fork, causing replicative stress and/or cell cycle arrest. However, translesion synthesis (TLS) DNA polymerases, such as Rev1, have the ability to bypass some DNA lesions, which can circumvent the process leading to replication fork arrest and minimize replicative stress...
October 2, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28930534/regulation-of-poly-adp-ribose-polymerase-1-functions-by-post-translational-modifications
#18
Lianhua Piao, Kyoko Fujioka, Makoto Nakakido, Ryuji Hamamoto
The poly(ADP-ribose) polymerases (PARPs) catalyze poly(ADP-ribosyl)ation, a post-translational modification of proteins. This  consists of the attachment of mono- or poly-adenosine diphosphate (ADP)-ribose units from nicotinamide adenine dinucleotide (NAD(+)) to specific polar residues of target proteins. PARP1 is the most abundant and best-characterized member of the family of PARP enzymes. PARP1 plays key roles in DNA repair, as well as a wide variety of cellular processes, including transcriptional regulation, chromatin modulation, cellular signaling pathway, inflammation, cellular stress responses and so on...
January 1, 2018: Frontiers in Bioscience (Landmark Edition)
https://www.readbyqxmd.com/read/28916726/the-nqo1-bioactivatable-drug-%C3%AE-lapachone-alters-the-redox-state-of-nqo1-pancreatic-cancer-cells-causing-perturbation-in-central-carbon-metabolism
#19
Molly A Silvers, Stanislaw Deja, Naveen Singh, Robert A Egnatchik, Jessica Sudderth, Xiuquan Luo, Muhammad S Beg, Shawn C Burgess, Ralph J DeBerardinis, David A Boothman, Matthew E Merritt
Many cancer treatments, such as those for managing recalcitrant tumors like pancreatic ductal adenocarcinoma, cause off-target toxicities in normal, healthy tissue, highlighting the need for more tumor-selective chemotherapies. β-Lapachone is bioactivated by NAD(P)H:quinone oxidoreductase 1 (NQO1). This enzyme exhibits elevated expression in most solid cancers and therefore is a potential cancer-specific target. β-Lapachone's therapeutic efficacy partially stems from the drug's induction of a futile NQO1-mediated redox cycle that causes high levels of superoxide and then peroxide formation, which damages DNA and causes hyperactivation of poly(ADP-ribose) polymerase, resulting in extensive NAD(+)/ATP depletion...
November 3, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28916476/pharmacologic-ascorbate-induces-neuroblastoma-cell-death-by-hydrogen-peroxide-mediated-dna-damage-and-reduction-in-cancer-cell-glycolysis
#20
Enlong Ma, Ping Chen, Heather M Wilkins, Tao Wang, Russell H Swerdlow, Qi Chen
An ascorbate-mediated production of oxidative stress has been shown to retard tumor growth. Subsequent glycolysis inhibition has been suggested. Here, we further define the mechanisms relevant to this observation. Ascorbate was cytotoxic to human neuroblastoma cells through the production of H2O2, which led to ATP depletion, inhibited GAPDH, and non-apoptotic and non-autophagic cell death. The mechanism of cytotoxicity is different when PARP-dependent DNA repair machinery is active or inhibited. Ascorbate-generated H2O2 damaged DNA, activated PARP, depleted NAD+, and reduced glycolysis flux...
September 12, 2017: Free Radical Biology & Medicine
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