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Yang Xiao, Mandy Kwong, Anneleen Daemen, Marcia Belvin, Xiaorong Liang, Georgia Hatzivassiliou, Thomas O'Brien
Nicotinamide adenine dinucleotide (NAD) is a cofactor involved in a wide range of cellular metabolic processes and is a key metabolite required for tumor growth. NAMPT, nicotinamide phosphoribosyltransferase, which converts nicotinamide (NAM) to nicotinamide mononucleotide (NMN), the immediate precursor of NAD, is an attractive therapeutic target as inhibition of NAMPT reduces cellular NAD levels and inhibits tumor growth in vivo. However, there is limited understanding of the metabolic response to NAD depletion across cancer cell lines and whether all cell lines respond in a uniform manner...
2016: PloS One
Yoon Kyung Choi, Ji-Hee Kim, Dong-Keon Lee, Kwang-Soon Lee, Moo-Ho Won, Dooil Jeoung, Hansoo Lee, Kwon-Soo Ha, Young-Guen Kwon, Young-Myeong Kim
AIMS: The heme oxygenase-1 (HO-1)/carbon monoxide (CO) pathway induced in astrocytes after ischemic brain injury promotes vascular endothelial growth factor (VEGF) expression to maintain and repair neurovascular function. Although HO-1-derived CO has been shown to induce hypoxia-inducible factor-1α (HIF-1α)-dependent VEGF expression, the underlying mechanism independent of HIF-1α remains to be elucidated. RESULTS: HO-1 and VEGF were co-expressed in astrocytes of ischemic mouse brain tissues...
August 23, 2016: Antioxidants & Redox Signaling
Chia George Hsu, Thomas J Burkholder
The balance of ATP production and consumption is reflected in adenosine monophosphate (AMP) and nicotinamide adenine dinucleotide (NAD) content and has been associated with phenotypic plasticity in striated muscle. Some studies have suggested that AMPK-dependent plasticity may be an indirect consequence of increased NAD synthesis and SIRT1 activity. The primary goal of this study was to assess the interaction of AMP- and NAD-dependent signaling in adaptation of C2C12 myotubes. Changes in myotube developmental and metabolic gene expression were compared following incubation with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) and nicotinamide mononucleotide (NMN) to activate AMPK- and NAD-related signaling...
July 8, 2016: Journal of Physiology and Biochemistry
Gou-Chun Chen, Hui-Min Su, Yu-Shun Lin, Po-Yen Tsou, Jong-Ho Chyuan, Pei-Min Chao
α-Eleostearic acid (α-ESA), or the cis-9, trans-11, trans-13 isomer of conjugated linolenic acid, is a special fatty acid present at high levels in bitter melon seed oil. The aim of this study was to examine the effect of α-ESA on hepatic lipid metabolism. Using H4IIEC3 hepatoma cell line, we showed that α-ESA significantly lowered intracellular triglyceride accumulation compared to α-linolenic acid (LN), used as a fatty acid control, in a dose- and time-dependent manner. The effects of α-ESA on enzyme activities and mRNA profiles in H4IIEC3 cells suggested that enhanced fatty acid oxidation and lowered lipogenesis were involved in α-ESA-mediated triglyceride lowering effects...
July 2016: Journal of Nutritional Biochemistry
Antero Salminen, Anu Kauppinen, Kai Kaarniranta
AMP-activated protein kinase (AMPK) and its yeast homolog, Snf1, are critical regulators in the maintenance of energy metabolic balance not only stimulating energy production but also inhibiting energy-consuming processes. The AMPK/Snf1 signaling controls energy metabolism by specific phosphorylation of many metabolic enzymes and transcription factors, enhancing or suppressing their functions. The AMPK/Snf1 complexes can be translocated from cytoplasm into nuclei where they are involved in the regulation of transcription...
August 2016: Cellular Signalling
Kensuke Tateishi, Hiroaki Wakimoto, A John Iafrate, Shota Tanaka, Franziska Loebel, Nina Lelic, Dmitri Wiederschain, Olivier Bedel, Gejing Deng, Bailin Zhang, Timothy He, Xu Shi, Robert E Gerszten, Yiyun Zhang, Jing-Ruey J Yeh, William T Curry, Dan Zhao, Sudhandra Sundaram, Fares Nigim, Mara V A Koerner, Quan Ho, David E Fisher, Elisabeth M Roider, Lajos V Kemeny, Yardena Samuels, Keith T Flaherty, Tracy T Batchelor, Andrew S Chi, Daniel P Cahill
Heterozygous mutation of IDH1 in cancers modifies IDH1 enzymatic activity, reprogramming metabolite flux and markedly elevating 2-hydroxyglutarate (2-HG). Here, we found that 2-HG depletion did not inhibit growth of several IDH1 mutant solid cancer types. To identify other metabolic therapeutic targets, we systematically profiled metabolites in endogenous IDH1 mutant cancer cells after mutant IDH1 inhibition and discovered a profound vulnerability to depletion of the coenzyme NAD+. Mutant IDH1 lowered NAD+ levels by downregulating the NAD+ salvage pathway enzyme nicotinate phosphoribosyltransferase (Naprt1), sensitizing to NAD+ depletion via concomitant nicotinamide phosphoribosyltransferase (NAMPT) inhibition...
December 14, 2015: Cancer Cell
Xinli Li, Fuzhi Lian, Chun Liu, Kang-Quan Hu, Xiang-Dong Wang
To investigate the different effects of isocaloric high-fat diet (HFD) and high-carbohydrate diet (HCD) on hepatic steatosis and the underlying mechanisms, especially the role of microRNA-34a/silent information regulator T1 (SIRT1) axis, C57BL/6J mice (n = 12/group) were isocaloric pair-fed with Lieber-DeCarli liquid diet containing either high fat (HFLD) or high carbohydrate (HCLD) for 16 weeks. As compared to the HFLD fed mice, despite the similar final body weights, HCLD feeding: (1) induced more severe hepatic steatosis; (2) up-regulated hepatic expression of miR-34a accompanied with significant decrease of SIRT1 and nicotinamide phosphoribosyltransferase (NAMPT), SIRT1 activity and phosphorylation of AMPK; (3) up-regulated de novo lipogenesis (DNL) related proteins expression (ACC, SCD1), and down-regulated expressions of miR-122, miR-370 and miR-33; (4) decreased mRNA expressions of genes Cpt1, Pparα and Pgc1α related to fatty acid oxidation; (5) increased hepatic total cholesterol concentration and decreased expression of cholesterol metabolism related genes Abcg5, Abcg8, Abcg11, Cyp7a1 and Cyp8b1; and (6) induced higher hepatic inflammatory response accompanied with significant increased mRNA expressions of Il1β, Tnfα and Mcp1...
November 26, 2015: Scientific Reports
Chiara Zucal, Vito G D'Agostino, Antonio Casini, Barbara Mantelli, Natthakan Thongon, Debora Soncini, Irene Caffa, Michele Cea, Alberto Ballestrero, Alessandro Quattrone, Stefano Indraccolo, Alessio Nencioni, Alessandro Provenzani
BACKGROUND: Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in NAD(+) biosynthesis from nicotinamide, is one of the major factors regulating cancer cells metabolism and is considered a promising target for treating cancer. The prototypical NAMPT inhibitor FK866 effectively lowers NAD(+) levels in cancer cells, reducing the activity of NAD(+)-dependent enzymes, lowering intracellular ATP, and promoting cell death. RESULTS: We show that FK866 induces a translational arrest in leukemia cells through inhibition of MTOR/4EBP1 signaling and of the initiation factors EIF4E and EIF2A...
2015: BMC Cancer
Eirini Pantazi, Mohamed Amine Zaouali, Mohamed Bejaoui, Emma Folch-Puy, Hassen Ben Abdennebi, Ana Teresa Varela, Anabela Pinto Rolo, Carlos Marques Palmeira, Joan Roselló-Catafau
AIM: To investigate the possible involvement of Sirtuin 1 (SIRT1) in rat orthotopic liver transplantation (OLT), when Institute Georges Lopez 1 (IGL-1) preservation solution is enriched with trimetazidine (TMZ). METHODS: Male Sprague-Dawley rats were used as donors and recipients. Livers were stored in IGL-1 preservation solution for 8h at 4 °C, and then underwent OLT according to Kamada's cuff technique without arterialization. In another group, livers were stored in IGL-1 preservation solution supplemented with TMZ, at 10(-6) mol/L, for 8 h at 4 °C and then underwent OLT...
February 14, 2015: World Journal of Gastroenterology: WJG
Susanne Schuster, Melanie Penke, Theresa Gorski, Rolf Gebhardt, Thomas S Weiss, Wieland Kiess, Antje Garten
BACKGROUND: Nicotinamide phosphoribosyltransferase (NAMPT) is the key enzyme of the NAD salvage pathway starting from nicotinamide. Cancer cells have an increased demand for NAD due to their high proliferation and DNA repair rate. Consequently, NAMPT is considered as a putative target for anti-cancer therapies. There is evidence that AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) become dysregulated during the development of hepatocellular carcinoma (HCC)...
March 6, 2015: Biochemical and Biophysical Research Communications
Jeong Seok Kim, Chung-Su Yoon, Dae Ryoung Park
PURPOSE: The purpose of this study was to investigate the effect that muscle contraction induced NAD metabolism via NAMPT has on mitochondrial biogenesis. METHODS: Primary skeletal muscle cells were isolated from the gastrocnemius in C57BL/6 mice. The muscle cells were stimulated by electrical current at 1Hz for 3 minutes in conditions of normal or NAD metabolism related inhibitor treatment. NAD/NADH level, Sirt1 and mitochondria biogenesis related signal factor's changes were examined in normal or NAD metabolism related inhibitor treated cells...
September 2014: Journal of Exercise Nutrition & Biochemistry
A Alfieri, D Martone, M B Randers, G Labruna, A Mancini, J J Nielsen, J Bangsbo, P Krustrup, P Buono
We investigated whether long-term recreational football training affects the expression of health-related biochemical and molecular markers in healthy untrained subjects. Five untrained healthy men trained for 1 h 2.4 times/week for 12 weeks and 1.3 times/week for another 52 weeks. Blood samples and a muscle biopsy from the vastus lateralis were collected at T0 (pre intervention) and at T1 (post intervention). Gene expression was measured by RTqPCR on RNA extracted from muscle biopsies. The expression levels of the genes principally involved in energy metabolism (PPARγ, adiponectin, AMPKα1/α2, TFAM, NAMPT, PGC1α and SIRT1) were measured at T0 and T1...
February 2015: Molecular and Cellular Probes
Zi-Feng Zhang, Shao-Hua Fan, Yuan-Lin Zheng, Jun Lu, Dong-Mei Wu, Qun Shan, Bin Hu
Recent evidences suggest that NAD(+) depletion leads to abnormal hepatic lipid metabolism in high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD); however, the contributing mechanism is not well understood. Our previous study showed that troxerutin, a trihydroxyethylated derivative of natural bioflavonoid rutin, effectively inhibited obesity, and normalized hyperglycemia and hyperlipidemia in high-cholesterol diet-induced diabetic mice. Here we investigated whether troxerutin improved hepatic lipid metabolism via preventing NAD(+) depletion in HFD-induced NAFLD mouse model and the mechanisms underlying these effects...
September 1, 2014: Biochemical Pharmacology
Tse-Min Lu, Jia-Yun Tsai, Yen-Chung Chen, Chun-Yang Huang, Hung-Lung Hsu, Chi-Feng Weng, Chun-Che Shih, Chiao-Po Hsu
BACKGROUND: In congestive heart failure the balance between cell death and cell survival in cardiomyocytes is compromised. Sirtuin 1 (Sirt1) activates cell survival machinery and has been shown to be protective against ischemia/reperfusion injury in murine heart. The role of Sirt1 in heart failure, especially in human hearts is not clear. RESULTS: The expression of Sirt1 and other (associated) downstream molecules in human cardiomyocytes from patients with advanced heart failure was examined...
2014: Journal of Biomedical Science
Kahlilia C Morris-Blanco, Charles H Cohan, Jake T Neumann, Thomas J Sick, Miguel A Perez-Pinzon
Preserving mitochondrial pools of nicotinamide adenine dinucleotide (NAD) or nicotinamide phosphoribosyltransferase (Nampt), an enzyme involved in NAD production, maintains mitochondrial function and confers neuroprotection after ischemic stress. However, the mechanisms involved in regulating mitochondrial-localized Nampt or NAD have not been defined. In this study, we investigated the roles of protein kinase C epsilon (PKCɛ) and AMP-activated protein kinase (AMPK) in regulating mitochondrial pools of Nampt and NAD after resveratrol or ischemic preconditioning (IPC) in the cortex and in primary neuronal-glial cortical cultures...
June 2014: Journal of Cerebral Blood Flow and Metabolism
Nikolett Hart, Linda Sarga, Zsolt Csende, Lauren G Koch, Steven L Britton, Kelvin J A Davies, Zsolt Radak
Low capacity runner (LCR) rats have been developed by divergent artificial selection for treadmill endurance capacity to explore an aerobic biology-disease connection. The beneficial effects of resveratrol supplementation have been demonstrated in endurance running. In this study it was examined whether 12 weeks of treadmill exercise training and/or resveratrol can retrieve the low running performance of the LCR and impact mitochondrial biogenesis and quality control. Resveratrol regressed running performance in trained LCR (p<0...
January 2014: Dose-response: a Publication of International Hormesis Society
Hong-Sheng Zhang, Xin-Yu Chen, Tong-Chao Wu, Feng-Juan Zhang
Tat transactivating activity regulated by NAD(+) -dependent histone deacetylase sirtuin1 (SIRT1) connects HIV transcription with the metabolic state of the cell. Nicotinamide phosphoribosyltransferase (Nampt) is a rate-limiting enzyme in the mammalian NAD(+) biosynthesis. Nampt, SIRT1, and AMPK were involved in inhibiting HIV-1 transactivation through redox-regulated pathway. Tanshinone II A is a main lipid-soluble monomer derivative from the root of Salvia miltiorrhiza (Danshen) and tanshinone II A possess a variety of biological activities through redox signaling pathway...
September 2014: Journal of Cellular Physiology
Elaine Vieira, Laura Marroquí, Ana Lucia C Figueroa, Beatriz Merino, Rebeca Fernandez-Ruiz, Angel Nadal, Thomas P Burris, Ramon Gomis, Ivan Quesada
Disruption of pancreatic clock genes impairs pancreatic beta-cell function, leading to the onset of diabetes. Despite the importance of pancreatic alpha-cells in the regulation of glucose homeostasis and in diabetes pathophysiology, nothing is known about the role of clock genes in these cells. Here, we identify the clock gene Rev-erb alpha as a new intracellular regulator of glucagon secretion. Rev-erb alpha down-regulation by siRNA (60-70% inhibition) in alphaTC1-9 cells inhibited low-glucose induced glucagon secretion (p<0...
2013: PloS One
Josef Brandauer, Sara G Vienberg, Marianne A Andersen, Stine Ringholm, Steve Risis, Per S Larsen, Jonas M Kristensen, Christian Frøsig, Lotte Leick, Joachim Fentz, Sebastian Jørgensen, Bente Kiens, Jørgen F P Wojtaszewski, Erik A Richter, Juleen R Zierath, Laurie J Goodyear, Henriette Pilegaard, Jonas T Treebak
Deacetylases such as sirtuins (SIRTs) convert NAD to nicotinamide (NAM). Nicotinamide phosphoribosyl transferase (Nampt) is the rate-limiting enzyme in the NAD salvage pathway responsible for converting NAM to NAD to maintain cellular redox state. Activation of AMP-activated protein kinase (AMPK) increases SIRT activity by elevating NAD levels. As NAM directly inhibits SIRTs, increased Nampt activation or expression could be a metabolic stress response. Evidence suggests that AMPK regulates Nampt mRNA content, but whether repeated AMPK activation is necessary for increasing Nampt protein levels is unknown...
October 15, 2013: Journal of Physiology
Jun Yoshino, Caterina Conte, Luigi Fontana, Bettina Mittendorfer, Shin-ichiro Imai, Kenneth B Schechtman, Charles Gu, Iris Kunz, Filippo Rossi Fanelli, Bruce W Patterson, Samuel Klein
Resveratrol has been reported to improve metabolic function in metabolically abnormal rodents and humans, but it has not been studied in nonobese people with normal glucose tolerance. We conducted a randomized, double-blind, placebo-controlled trial to evaluate the metabolic effects of 12 weeks of resveratrol supplementation (75 mg/day) in nonobese, postmenopausal women with normal glucose tolerance. Although resveratrol supplementation increased plasma resveratrol concentration, it did not change body composition, resting metabolic rate, plasma lipids, or inflammatory markers...
November 7, 2012: Cell Metabolism
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