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NAD+ increase AND Nicotinamide

George Cătălin Marinescu, Roua-Gabriela Popescu, Anca Dinischiotu
Over 12% of the world's health resources are spent on treating diabetes, as high blood glucose is the third cause of mortality worldwide. Insulin resistance is the basis of the most common form of diabetes: type 2 diabetes. Recent animal studies report successful attempts at reversing type 2 diabetes by the administering of the NAD+ precursor nicotinamide mononucleotide (NMN). However, the current high price of this molecule urges for more efficient and cost-effective production methods. This work proposes a method for purifying NMN by Size Exclusion Chromatography (SEC) on silica with a covalently attached coating of poly(2-hydroxyethyl aspartamide) (PolyHEA) stationary phase using an isocratic elution with a denaturing mobile phase (50 mM formic acid) from a complex molecular mixture such as a fermentation broth...
March 13, 2018: Scientific Reports
Sarah J Mitchell, Michel Bernier, Miguel A Aon, Sonia Cortassa, Eun Young Kim, Evandro F Fang, Hector H Palacios, Ahmed Ali, Ignacio Navas-Enamorado, Andrea Di Francesco, Tamzin A Kaiser, Tyler B Waltz, Ning Zhang, James L Ellis, Peter J Elliott, David W Frederick, Vilhelm A Bohr, Mark S Schmidt, Charles Brenner, David A Sinclair, Anthony A Sauve, Joseph A Baur, Rafael de Cabo
The role in longevity and healthspan of nicotinamide (NAM), the physiological precursor of NAD+ , is elusive. Here, we report that chronic NAM supplementation improves healthspan measures in mice without extending lifespan. Untargeted metabolite profiling of the liver and metabolic flux analysis of liver-derived cells revealed NAM-mediated improvement in glucose homeostasis in mice on a high-fat diet (HFD) that was associated with reduced hepatic steatosis and inflammation concomitant with increased glycogen deposition and flux through the pentose phosphate and glycolytic pathways...
March 6, 2018: Cell Metabolism
Luis Rajman, Karolina Chwalek, David A Sinclair
Nicotinamide adenine dinucleotide (NAD), the cell's hydrogen carrier for redox enzymes, is well known for its role in redox reactions. More recently, it has emerged as a signaling molecule. By modulating NAD+ -sensing enzymes, NAD+ controls hundreds of key processes from energy metabolism to cell survival, rising and falling depending on food intake, exercise, and the time of day. NAD+ levels steadily decline with age, resulting in altered metabolism and increased disease susceptibility. Restoration of NAD+ levels in old or diseased animals can promote health and extend lifespan, prompting a search for safe and efficacious NAD-boosting molecules that hold the promise of increasing the body's resilience, not just to one disease, but to many, thereby extending healthy human lifespan...
March 6, 2018: Cell Metabolism
Juan Camilo Molano-Arevalo, Walter Gonzalez, Kevin Jeanne Dit Fouque, Jaroslava Miksovska, Philippe Maitre, Francisco Fernandez-Lima
Nicotinamide adenine dinucleotide (NAD) is found in all living cells where the oxidized (NAD+ ) and reduced (NADH) forms play important roles in many enzymatic reactions. However, little is known about NAD+ and NADH conformational changes and kinetics as a function of the cell environment. In the present work, an analytical workflow is utilized to study NAD+ and NADH dynamics as a function of the organic content in solution using fluorescence lifetime spectroscopy and in the gas-phase using trapped ion mobility spectrometry coupled to mass spectrometry (TIMS-MS) and infrared multiple photon dissociation (IRMPD) spectroscopy...
February 23, 2018: Physical Chemistry Chemical Physics: PCCP
Daniel S Gaul, Julien Weber, Lambertus J Van Tits, Susanna Sluka, Lisa Pasterk, Martin F Reiner, Natacha Calatayud, Christine Lohmann, Roland Klingenberg, Jürgen Pahla, Daria Vdovenko, Felix C Tanner, Giovanni G Camici, Urs Eriksson, Johan Auwerx, François Mach, Stephan Windecker, Nicolas Rodondi, Thomas F L Uuml Scher, Stephan Winnik, Christian M Matter
BACKGROUND: Sirtuin 3 (Sirt3) is a mitochondrial, nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase that reduces oxidative stress by activation of superoxide dismutase 2 (SOD2). Oxidative stress enhances arterial thrombosis. This study investigated the effects of genetic Sirt3 deletion on arterial thrombosis in mice in an inflammatory setting and assessed the clinical relevance of these findings in patients with ST-elevation myocardial infarction (STEMI). Methods and Results: Using a laser-induced carotid thrombosis model with lipopolysaccharide (LPS) challenge, in vivo time to thrombotic occlusion in Sirt3-/- mice (n = 6) was reduced by half compared to Sirt3+/+ wildtype (WT, n = 8, p<0...
February 10, 2018: Cardiovascular Research
Piotr Celichowski, Karol Jopek, Paulina Milecka, Marta Szyszka, Marianna Tyczewska, Ludwik K Malendowicz, Marcin Ruciński
Nicotinamide phosphoribosyltransferase (Nampt), also termed visfatin, catalyses the rate‑limiting step in the nicotinamide adenine dinucleotide (NAD) salvage pathway. In addition to its intracellular function (iNampt), extracellular Nampt (eNampt) also affects numerous intracellular signalling pathways. The current study investigated the role of Nampt in the regulation of the hypothalamic‑pituitary‑adrenal (HPA) axis in rats. At 1 h after intraperitoneal administration of eNampt (4 µg/100 g) in adult male rats, serum adrenocorticotropic hormone(ACTH) and aldosterone levels remained unchanged, while corticosterone levels were notably elevated compared with the control group, as determined by ELISA...
February 7, 2018: Molecular Medicine Reports
Zhenyang Yu, Jing Zhang, Meifang Hou
The redox state of NADH/NADPH balance (nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide phosphate) is crucial in cellular homeostasis. Recent studies reported that sodium halide ions (NaX, X = F-, Cl-, Br- and I-) stimulated NAD(P)H in Vibrio fischeri (VF). However, it remained unanswered whether this pattern applied in salts with other cations, e.g., K+, Mg2+ and Ca2+, whose aquatic concentrations were increased by anthropogenic activities and climate change. Currently, VF were incubated with chloride salts, including KCl, MgCl2 and CaCl2, and effects were measured in a time-dependent fashion...
February 7, 2018: Chemosphere
Yujun Hou, Sofie Lautrup, Stephanie Cordonnier, Yue Wang, Deborah L Croteau, Eduardo Zavala, Yongqing Zhang, Kanako Moritoh, Jennifer F O'Connell, Beverly A Baptiste, Tinna V Stevnsner, Mark P Mattson, Vilhelm A Bohr
Emerging findings suggest that compromised cellular bioenergetics and DNA repair contribute to the pathogenesis of Alzheimer's disease (AD), but their role in disease-defining pathology is unclear. We developed a DNA repair-deficient 3xTgAD/Polβ+/- mouse that exacerbates major features of human AD including phosphorylated Tau (pTau) pathologies, synaptic dysfunction, neuronal death, and cognitive impairment. Here we report that 3xTgAD/Polβ+/- mice have a reduced cerebral NAD+ /NADH ratio indicating impaired cerebral energy metabolism, which is normalized by nicotinamide riboside (NR) treatment...
February 20, 2018: Proceedings of the National Academy of Sciences of the United States of America
Keisuke Yaku, Keisuke Okabe, Takashi Nakagawa
Nicotinamide adenine dinucleotide (NAD) is a major co-factor that mediates multiple biological processes including redox reaction and gene expression. Recently, NAD metabolism has received considerable attention because administration of NAD precursors exhibited beneficial effects against aging-related metabolic disorders in animals. Although numerous studies have reported that NAD levels declined with aging in multiple animal tissues, the pathway and kinetics of NAD metabolism in aged organs are not completely understood...
February 9, 2018: Biomedical Chromatography: BMC
Rakesh K Singh, Leon van Haandel, Daniel P Heruth, Shui Q Ye, J Steven Leeder, Mara L Becker, Ryan S Funk
Lower plasma nicotinamide phosphoribosyltransferase (NAMPT) levels are associated with improved response to methotrexate (MTX) in patients with juvenile idiopathic arthritis (JIA). Cell-based studies confirmed that reduced cellular NAMPT activity potentiates the pharmacologic activity of MTX, however the mechanism of this interaction has yet to be defined. Therefore, in this study we investigate the mechanism of enhanced pharmacologic activity of MTX in NAMPT-deficient A549 cells. The siRNA-based silencing of NAMPT expression resulted in a greater than three-fold increase in the sensitivity to MTX (p<0...
February 2, 2018: Journal of Pharmacology and Experimental Therapeutics
Ning Zhang, Anthony A Sauve
NAD+ acts as a crucial regulator of cell physiology and as an integral participant in cellular metabolism. By virtue of a variety of signaling activities this central metabolite can exert profound effects on organism health status. Thus, while it serves as a well-known metabolic cofactor functioning as a redox-active substrate, it can also function as a substrate for signaling enzymes, such as sirtuins, poly (ADP-ribosyl) polymerases, mono (ADP-ribosyl) transferases, and CD38. Sirtuins function as NAD+-dependent protein deacetylases (deacylases) and catalyze the reaction of NAD+ with acyllysine groups to remove the acyl modification from substrate proteins...
2018: Progress in Molecular Biology and Translational Science
Xiao Hu, Weiping Zheng
Sirtuins refer to a family of intracellular enzymes that are the yeast silent information regulator 2 (sir2) protein homologs found in organisms from all the three kingdoms of life. This family of enzymes primarily catalyze the protein Nɛ-acyl-lysine deacylation reaction despite the report for a type of bacterial/fungal sirtuins to robustly catalyze a protein mono-ADP-ribosylation reaction, however, these two group transfer reactions employ the redox coenzyme β-nicotinamide adenine dinucleotide (β-NAD+) as the obligatory cosubstrate...
2018: Progress in Molecular Biology and Translational Science
Morten Dall, Melanie Penke, Karolina Sulek, Madlen Matz-Soja, Birgitte Holst, Antje Garten, Wieland Kiess, Jonas T Treebak
Dietary supplementation of nicotinamide adenine dinucleotide (NAD+) precursors has been suggested as a treatment for non-alcoholic fatty liver disease and obesity. In the liver, NAD+ is primarily generated by nicotinamide phosphoribosyltransferase (NAMPT), and hepatic levels of NAMPT and NAD+ have been reported to be dependent on age and body composition. The aim of the present study was to identify time-course-dependent changes in hepatic NAD content and NAD+ salvage capacity in mice challenged with a high-fat diet (HFD)...
February 1, 2018: Molecular and Cellular Endocrinology
Hao Xiong, Yongkang Ou, Yaodong Xu, Qiuhong Huang, Jiaqi Pang, Lan Lai, Yiqing Zheng
The sirtuin SIRT1 is a highly conserved nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylase known to have protective effects against a wide range of neurological disorders. In the present study, we discovered that C57BL/6 mice fed a long-term diet supplemented with high-dose resveratrol exhibited increased cochlear SIRT1 activity and presented a better recovery of hearing and less loss of hair cells after intense noise exposure compared with those fed a standard chew. Moreover, resveratrol attenuated cochlear SIRT1 decrease and reduced oxidative stress in the cochlea after noise exposure...
January 25, 2018: Audiology & Neuro-otology
Roberto Pellicciari, Paride Liscio, Nicola Giacchè, Francesca De Franco, Andrea Carotti, Janet Robertson, Lucia Cialabrini, Elena Katsyuba, Nadia Raffaelli, Johan Auwerx
NAD+ has a central function in linking cellular metabolism to major cell-signaling and gene-regulation pathways. Defects in NAD+ homeostasis underpin a wide range of diseases, including cancer, metabolic disorders, and aging. Although the beneficial effects of boosting NAD+ on mitochondrial fitness, metabolism, and lifespan are well established, to date, no therapeutic enhancers of de novo NAD+ biosynthesis have been reported. Herein we report the discovery of 3-[[[5-cyano-1,6-dihydro-6-oxo-4-(2-thienyl)-2-pyrimidinyl]thio]methyl]phenylacetic acid (TES-1025, 22), the first potent and selective inhibitor of human ACMSD (IC50 = 0...
January 26, 2018: Journal of Medicinal Chemistry
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
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
Mohamad A Zaini, Christine Müller, Tristan V de Jong, Tobias Ackermann, Götz Hartleben, Gertrud Kortman, Karl-Heinz Gührs, Fabrizia Fusetti, Oliver H Krämer, Victor Guryev, Cornelis F Calkhoven
Cellular metabolism is a tightly controlled process in which the cell adapts fluxes through metabolic pathways in response to changes in nutrient supply. Among the transcription factors that regulate gene expression and thereby cause changes in cellular metabolism is the basic leucine-zipper (bZIP) transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα). Protein lysine acetylation is a key post-translational modification (PTM) that integrates cellular metabolic cues with other physiological processes...
January 9, 2018: Cell Reports
Trevor Croft, Christol James Theoga Raj, Michelle Salemi, Brett S Phinney, Su-Ju Lin
Nicotinamide adenine dinucleotide (NAD+) is an essential metabolite participating in cellular redox chemistry and signaling, and the complex regulation of NAD+ metabolism is not yet fully understood. To investigate this, we established a NAD+-intermediate specific reporter system to identify factors required for salvage of metabolically-linked nicotinamide (NAM) and nicotinic acid (NA). Mutants lacking components of the NatB complex, NAT3 and MDM20, appeared as hits in this screen. NatB is an Nα-terminal-acetyltransferase responsible for acetylation of the amino terminus of specific Met-retained peptides...
January 9, 2018: Journal of Biological Chemistry
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
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