|
1
|
Bi SZ, Sun WD, Zhu XJ, Lai SY, An-Liu, Zhang CY, Li JH. Nicotinamide N-methyltransferase in cardiovascular Diseases: Mechanistic insights and therapeutic potential. Eur J Med Chem 2025; 295:117790. [PMID: 40412299 DOI: 10.1016/j.ejmech.2025.117790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2025] [Revised: 05/13/2025] [Accepted: 05/20/2025] [Indexed: 05/27/2025]
Abstract
Cardiovascular diseases (CVDs), including conditions like ischemic heart disease, heart failure (HF), and atherosclerosis (AS), have complex pathogenesis that involves both behavioral and metabolic factors. Nicotinamide N-methyltransferase (NNMT) is an enzyme involved in the methylation of nicotinamide (NAM), and its increased activity is associated with disruptions in the NAD+ and methionine cycles. These disruptions are considered significant risk factors for cardiovascular diseases, though the specific mechanisms of NNMT remain unclear. This review discusses the role of NNMT in cardiovascular diseases by modulating NAD+ and methionine metabolism, including mechanisms such as NAD+ depletion, mitochondrial energy crisis, SIRTs deactivation, PARP hyperactivation, as well as hyperhomocysteinemia and epigenetic dysregulation. NNMT is linked to diseases such as atherosclerosis, pulmonary arterial hypertension, heart failure, and coronary heart disease, playing a critical role in their progression. Moreover, the potential of NNMT as a therapeutic target for cardiovascular diseases is explored. RNAi therapies, NNMT small-molecule inhibitors, and exercise therapies are promising treatment approaches, but there are limitations in current research, including discrepancies between animal models and human tissue expression, the dual role of NNMT, and the dose-dependent effects of NNMT inhibitors. Future studies should further clarify NNMT's mechanisms and assess its feasibility as a therapeutic target, aiming to develop more effective treatments and enhance prevention and treatment strategies for cardiovascular diseases.
Collapse
Affiliation(s)
- Shuang-Zhou Bi
- Physical Education College, Jiangxi Normal University, Nanchang, 330022, Jiangxi Province, China
| | - Wei-Dong Sun
- Physical Education College, Jiangxi Normal University, Nanchang, 330022, Jiangxi Province, China
| | - Xiao-Juan Zhu
- Physical Education College, Jiangxi Normal University, Nanchang, 330022, Jiangxi Province, China
| | - Shi-Yan Lai
- Physical Education College, Jiangxi Normal University, Nanchang, 330022, Jiangxi Province, China
| | - An-Liu
- Physical Education College, Jiangxi Normal University, Nanchang, 330022, Jiangxi Province, China
| | - Chen-Ying Zhang
- Physical Education College, Jiangxi Normal University, Nanchang, 330022, Jiangxi Province, China
| | - Jiang-Hua Li
- Physical Education College, Jiangxi Normal University, Nanchang, 330022, Jiangxi Province, China.
| |
Collapse
|
|
2
|
Dettlaff-Pokora A, Swierczynski J. High Concentrations of Circulating 2PY and 4PY-Potential Risk Factor of Cardiovascular Disease in Patients with Chronic Kidney Disease. Int J Mol Sci 2025; 26:4463. [PMID: 40362700 PMCID: PMC12072460 DOI: 10.3390/ijms26094463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2025] [Revised: 05/05/2025] [Accepted: 05/06/2025] [Indexed: 05/15/2025] Open
Abstract
Recently published data indicate that elevated circulating concentrations of N1-methyl-2-pyridone-5-carboxamide (2PY, also described as Met2PY) and N1-methyl-4-pyridone-5-carboxamide (4PY, also described as Met4PY), terminal catabolites of nicotinamide adenine dinucleotide (NAD+), are associated with cardiovascular disease (CVD) risk in humans. Previously, we and the others have shown that patients with advanced stages of chronic kidney disease (CKD) exhibit several-fold higher circulating 2PY and 4PY concentrations compared to healthy subjects or patients in the early stages of the disease. It is also well documented that patients with advanced CKD stages exhibit markedly elevated CVD risk, which is the main cause of premature death (in these patients). Therefore, we hypothesize that high concentrations of circulating 2PY and 4PY are important factors that may contribute to cardiovascular events and, ultimately, premature death in CKD patients. However, further, accurately controlled clinical research is needed to provide definitive answers concerning the role of 2PY and 4PY in CVD risk in CKD patients. Moreover, we are dealing with some issues related to the use of NAD+ precursors (NAD+ boosters) as drugs (also in CKD patients) and/or supplements. Due to the increase in circulating 2PY and 4PY levels during treatment with NAD+ boosters, these precursors should be used with caution, especially in patients with increased CVD risk.
Collapse
Affiliation(s)
- Agnieszka Dettlaff-Pokora
- Department of Biochemistry, Faculty of Medicine, Medical University of Gdańsk, Dębinki 1, 80-211 Gdańsk, Poland
| | - Julian Swierczynski
- Institute of Nursing and Medical Rescue, State University of Applied Sciences in Koszalin, 75-582 Koszalin, Poland;
| |
Collapse
|
|
3
|
Sun WD, Zhu XJ, Li JJ, Mei YZ, Li WS, Li JH. Nicotinamide N-methyltransferase (NNMT): a novel therapeutic target for metabolic syndrome. Front Pharmacol 2024; 15:1410479. [PMID: 38919254 PMCID: PMC11196770 DOI: 10.3389/fphar.2024.1410479] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Accepted: 05/21/2024] [Indexed: 06/27/2024] Open
Abstract
Metabolic syndrome (MetS) represents a constellation of metabolic abnormalities, typified by obesity, hypertension, hyperglycemia, and hyperlipidemia. It stems from intricate dysregulations in metabolic pathways governing energy and substrate metabolism. While comprehending the precise etiological mechanisms of MetS remains challenging, evidence underscores the pivotal roles of aberrations in lipid metabolism and insulin resistance (IR) in its pathogenesis. Notably, nicotinamide N-methyltransferase (NNMT) has recently surfaced as a promising therapeutic target for addressing MetS. Single nucleotide variants in the NNMT gene are significantly correlated with disturbances in energy metabolism, obesity, type 2 diabetes (T2D), hyperlipidemia, and hypertension. Elevated NNMT gene expression is notably observed in the liver and white adipose tissue (WAT) of individuals with diabetic mice, obesity, and rats afflicted with MetS. Knockdown of NNMT elicits heightened energy expenditure in adipose and hepatic tissues, mitigates lipid accumulation, and enhances insulin sensitivity. NNMT catalyzes the methylation of nicotinamide (NAM) using S-adenosyl-methionine (SAM) as the donor methyl group, resulting in the formation of S-adenosyl-l-homocysteine (SAH) and methylnicotinamide (MNAM). This enzymatic process results in the depletion of NAM, a precursor of nicotinamide adenine dinucleotide (NAD+), and the generation of SAH, a precursor of homocysteine (Hcy). Consequently, this cascade leads to reduced NAD+ levels and elevated Hcy levels, implicating NNMT in the pathogenesis of MetS. Moreover, experimental studies employing RNA interference (RNAi) strategies and small molecule inhibitors targeting NNMT have underscored its potential as a therapeutic target for preventing or treating MetS-related diseases. Nonetheless, the precise mechanistic underpinnings remain elusive, and as of yet, clinical trials focusing on NNMT have not been documented. Therefore, further investigations are warranted to elucidate the intricate roles of NNMT in MetS and to develop targeted therapeutic interventions.
Collapse
Affiliation(s)
| | | | | | | | | | - Jiang-Hua Li
- Key Lab of Aquatic Training Monitoring and Intervention of General Administration of Sport of China, Physical Education College, Jiangxi Normal University, Nanchang, China
| |
Collapse
|
|
4
|
Fashe MM, Le TV, Gower MN, Mulrenin IR, Dorman KF, Smith S, Fallon JK, Dumond JB, Boggess KA, Lee CR. Impact of Pregnancy on the Pharmacokinetics and Metabolism of Nicotinamide in Humans. Clin Pharmacol Ther 2024; 115:556-564. [PMID: 38093631 PMCID: PMC11250906 DOI: 10.1002/cpt.3146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Accepted: 12/11/2023] [Indexed: 12/17/2023]
Abstract
In pre-eclampsia models, nicotinamide (NAM) has protective effects in pre-eclampsia and is being evaluated as a therapeutic nutraceutical in clinical studies. NAM undergoes extensive hepatic metabolism by NAM N-methyltransferase to methylnicotinamide (MNA), which is subsequently metabolized to methyl-2-pyridone-5-carboxamide (M2PY) by aldehyde oxidase. However, the pharmacokinetics of NAM and its major metabolites has never been studied in pregnant individuals. Blood samples were collected before and 1, 2, 4, 8, and 24 hours after single 1 g oral NAM dose in healthy pregnant (gestational age 24-33 weeks) and nonpregnant female volunteers (n = 6/group). Pooled urine was collected from 0 to 8 hours. NAM, MNA, and M2PY area under the concentration-time curve (AUC) data were analyzed by noncompartmental analysis. No difference in the plasma AUC0→24 of NAM (median (25%-75%): 463 (436-576) vs. 510 (423, 725) μM*hour, P = 0.430) and its intermediate metabolite MNA (89.1 (60.4, 124.4) vs. 83.8 (62.7, 93.7) μM*hour, P = 0.515) was observed in pregnant and nonpregnant volunteers, respectively; however, the terminal metabolite M2PY AUC0 → 24 was significantly lower in pregnant individuals (218 (188, 254) vs. 597 (460, 653) μM*hour, P < 0.001). NAM renal clearance (CLR ; P = 0.184), MNA CLR (P = 0.180), and total metabolite formation clearance (P = 0.405) did not differ across groups; however, M2PY CLR was significantly higher in pregnant individuals (10.5 (9.3-11.3) vs. 7.5 (6.4-8.5) L/h, P = 0.002). These findings demonstrate that the PK of NAM and systemic exposure to its intermediate metabolite MNA are not significantly altered during pregnancy, and systemic exposure to NAM's major metabolite M2PY was reduced during pregnancy due to increased renal elimination.
Collapse
Affiliation(s)
- Muluneh M. Fashe
- Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Tien V. Le
- Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Megan N. Gower
- Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Ian R. Mulrenin
- Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Karen F. Dorman
- Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Spenser Smith
- Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - John K. Fallon
- Center for Nanotechnology in Drug Delivery and Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Julie B. Dumond
- Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Kim A. Boggess
- Department of Obstetrics & Gynecology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Craig R. Lee
- Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| |
Collapse
|
|
5
|
Ferrell M, Wang Z, Anderson JT, Li XS, Witkowski M, DiDonato JA, Hilser JR, Hartiala JA, Haghikia A, Cajka T, Fiehn O, Sangwan N, Demuth I, König M, Steinhagen-Thiessen E, Landmesser U, Tang WHW, Allayee H, Hazen SL. A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk. Nat Med 2024; 30:424-434. [PMID: 38374343 PMCID: PMC11841810 DOI: 10.1038/s41591-023-02793-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Accepted: 12/22/2023] [Indexed: 02/21/2024]
Abstract
Despite intensive preventive cardiovascular disease (CVD) efforts, substantial residual CVD risk remains even for individuals receiving all guideline-recommended interventions. Niacin is an essential micronutrient fortified in food staples, but its role in CVD is not well understood. In this study, untargeted metabolomics analysis of fasting plasma from stable cardiac patients in a prospective discovery cohort (n = 1,162 total, n = 422 females) suggested that niacin metabolism was associated with incident major adverse cardiovascular events (MACE). Serum levels of the terminal metabolites of excess niacin, N1-methyl-2-pyridone-5-carboxamide (2PY) and N1-methyl-4-pyridone-3-carboxamide (4PY), were associated with increased 3-year MACE risk in two validation cohorts (US n = 2,331 total, n = 774 females; European n = 832 total, n = 249 females) (adjusted hazard ratio (HR) (95% confidence interval) for 2PY: 1.64 (1.10-2.42) and 2.02 (1.29-3.18), respectively; for 4PY: 1.89 (1.26-2.84) and 1.99 (1.26-3.14), respectively). Phenome-wide association analysis of the genetic variant rs10496731, which was significantly associated with both 2PY and 4PY levels, revealed an association of this variant with levels of soluble vascular adhesion molecule 1 (sVCAM-1). Further meta-analysis confirmed association of rs10496731 with sVCAM-1 (n = 106,000 total, n = 53,075 females, P = 3.6 × 10-18). Moreover, sVCAM-1 levels were significantly correlated with both 2PY and 4PY in a validation cohort (n = 974 total, n = 333 females) (2PY: rho = 0.13, P = 7.7 × 10-5; 4PY: rho = 0.18, P = 1.1 × 10-8). Lastly, treatment with physiological levels of 4PY, but not its structural isomer 2PY, induced expression of VCAM-1 and leukocyte adherence to vascular endothelium in mice. Collectively, these results indicate that the terminal breakdown products of excess niacin, 2PY and 4PY, are both associated with residual CVD risk. They also suggest an inflammation-dependent mechanism underlying the clinical association between 4PY and MACE.
Collapse
Affiliation(s)
- Marc Ferrell
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Systems Biology and Bioinformatics Program, Department of Nutrition, Case Western Reserve University, Cleveland, OH, USA
| | - Zeneng Wang
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - James T Anderson
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Xinmin S Li
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Marco Witkowski
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Department of Cardiology, Angiology and Intensive Care, Deutsches Herzzentrum der Charité, Campus Benjamin Franklin, Berlin, Germany
| | - Joseph A DiDonato
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - James R Hilser
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Department of Biochemistry & Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Jaana A Hartiala
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Arash Haghikia
- Department of Cardiology, Angiology and Intensive Care, Deutsches Herzzentrum der Charité, Campus Benjamin Franklin, Berlin, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany
- Berlin Institute of Health (BIH), Berlin, Germany
- Friede Springer Cardiovascular Prevention Center at Charité, Berlin, Germany
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Tomas Cajka
- West Coast Metabolomics Center, University of California, Davis, Davis, CA, USA
- Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Oliver Fiehn
- West Coast Metabolomics Center, University of California, Davis, Davis, CA, USA
| | - Naseer Sangwan
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Ilja Demuth
- Department of Endocrinology and Metabolism, Charité - Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health Center for Regenerative Therapies, Berlin, Germany
| | - Maximilian König
- Department of Endocrinology and Metabolism, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | | | - Ulf Landmesser
- Department of Cardiology, Angiology and Intensive Care, Deutsches Herzzentrum der Charité, Campus Benjamin Franklin, Berlin, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany
- Berlin Institute of Health (BIH), Berlin, Germany
- Friede Springer Cardiovascular Prevention Center at Charité, Berlin, Germany
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - W H Wilson Tang
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Department of Cardiovascular Medicine, Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Hooman Allayee
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Department of Biochemistry & Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Stanley L Hazen
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
- Department of Cardiovascular Medicine, Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, OH, USA.
| |
Collapse
|
|
6
|
Liang J, Huang F, Song Z, Tang R, Zhang P, Chen R. Impact of NAD+ metabolism on ovarian aging. Immun Ageing 2023; 20:70. [PMID: 38041117 PMCID: PMC10693113 DOI: 10.1186/s12979-023-00398-w] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 11/21/2023] [Indexed: 12/03/2023]
Abstract
Nicotinamide adenine dinucleotide (NAD+), a crucial coenzyme in cellular redox reactions, is closely associated with age-related functional degeneration and metabolic diseases. NAD exerts direct and indirect influences on many crucial cellular functions, including metabolic pathways, DNA repair, chromatin remodeling, cellular senescence, and immune cell functionality. These cellular processes and functions are essential for maintaining tissue and metabolic homeostasis, as well as healthy aging. Causality has been elucidated between a decline in NAD levels and multiple age-related diseases, which has been confirmed by various strategies aimed at increasing NAD levels in the preclinical setting. Ovarian aging is recognized as a natural process characterized by a decline in follicle number and function, resulting in decreased estrogen production and menopause. In this regard, it is necessary to address the many factors involved in this complicated procedure, which could improve fertility in women of advanced maternal age. Concerning the decrease in NAD+ levels as ovarian aging progresses, promising and exciting results are presented for strategies using NAD+ precursors to promote NAD+ biosynthesis, which could substantially improve oocyte quality and alleviate ovarian aging. Hence, to acquire further insights into NAD+ metabolism and biology, this review aims to probe the factors affecting ovarian aging, the characteristics of NAD+ precursors, and the current research status of NAD+ supplementation in ovarian aging. Specifically, by gaining a comprehensive understanding of these aspects, we are optimistic about the prominent progress that will be made in both research and therapy related to ovarian aging.
Collapse
Affiliation(s)
- Jinghui Liang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Obstetric & Gynecologic Diseases, Beijing, 100730, China
| | - Feiling Huang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Obstetric & Gynecologic Diseases, Beijing, 100730, China
| | - Zhaoqi Song
- School of Medical Technology and Engineering, Fujian Medical University, Fuzhou, Fujian, China
| | - Ruiyi Tang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Obstetric & Gynecologic Diseases, Beijing, 100730, China
| | - Peng Zhang
- Beijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute, MOE Key Laboratory of Major Diseases in Children, Rare Disease Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China.
| | - Rong Chen
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Obstetric & Gynecologic Diseases, Beijing, 100730, China.
| |
Collapse
|
|
7
|
She J, Sheng R, Qin ZH. Pharmacology and Potential Implications of Nicotinamide Adenine Dinucleotide Precursors. Aging Dis 2021; 12:1879-1897. [PMID: 34881075 PMCID: PMC8612620 DOI: 10.14336/ad.2021.0523] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 05/23/2021] [Indexed: 12/21/2022] Open
Abstract
Coenzyme I (nicotinamide adenine dinucleotide, NAD+/NADH) and coenzyme II (nicotinamide adenine dinucleotide phosphate, NADP+/NADPH) are involved in various biological processes in mammalian cells. NAD+ is synthesised through the de novo and salvage pathways, whereas coenzyme II cannot be synthesised de novo. NAD+ is a precursor of coenzyme II. Although NAD+ is synthesised in sufficient amounts under normal conditions, shortage in its supply due to over consumption and its decreased synthesis has been observed with increasing age and under certain disease conditions. Several studies have proved that in a wide range of tissues, such as liver, skin, muscle, pancreas, and fat, the level of NAD+ decreases with age. However, in the brain tissue, the level of NADH gradually increases and that of NAD+ decreases in aged people. The ratio of NAD+/NADH indicates the cellular redox state. A decrease in this ratio affects the cellular anaerobic glycolysis and oxidative phosphorylation functions, which reduces the ability of cells to produce ATP. Therefore, increasing the exogenous NAD+ supply under certain disease conditions or in elderly people may be beneficial. Precursors of NAD+ have been extensively explored and have been reported to effectively increase NAD+ levels and possess a broad range of functions. In this review article, we discuss the pharmacokinetics and pharmacodynamics of NAD+ precursors.
Collapse
Affiliation(s)
- Jing She
- Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Neuropsychiatric Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China
| | - Rui Sheng
- Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Neuropsychiatric Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China
| | - Zheng-Hong Qin
- Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Neuropsychiatric Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China
| |
Collapse
|
|
8
|
Roles of Nicotinamide N-Methyltransferase in Obesity and Type 2 Diabetes. BIOMED RESEARCH INTERNATIONAL 2021; 2021:9924314. [PMID: 34368359 PMCID: PMC8337113 DOI: 10.1155/2021/9924314] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 07/20/2021] [Indexed: 11/28/2022]
Abstract
Type 2 diabetes (T2D) is thought to be a complication of metabolic syndrome caused by disorders of energy utilization and storage and characterized by insulin resistance or deficiency of insulin secretion. Though the mechanism linking obesity to the development of T2D is complex and unintelligible, it is known that abnormal lipid metabolism and adipose tissue accumulation possibly play important roles in this process. Recently, nicotinamide N-methyltransferase (NNMT) has been emerging as a new mechanism-of-action target in treating obesity and associated T2D. Evidence has shown that NNMT is associated with obesity and T2D. NNMT inhibition or NNMT knockdown significantly increases energy expenditure, reduces body weight and white adipose mass, improves insulin sensitivity, and normalizes glucose tolerance and fasting blood glucose levels. Additionally, trials of oligonucleotide therapeutics and experiments with some small-molecule NNMT inhibitors in vitro and in preclinical animal models have validated NNMT as a promising therapeutic target to prevent or treat obesity and associated T2D. However, the exact mechanisms underlying these phenomena are not yet fully understood and clinical trials targeting NNMT have not been reported until now. Therefore, more researches are necessary to reveal the acting mechanism of NNMT in obesity and T2D and to develop therapeutics targeting NNMT.
Collapse
|
|
9
|
Pollard CL, Gibb Z, Swegen A, Lawson EF, Grupen CG. Nicotinic acid supplementation at a supraphysiological dose increases the bioavailability of NAD + precursors in mares. J Anim Physiol Anim Nutr (Berl) 2021; 105:1154-1164. [PMID: 34117670 DOI: 10.1111/jpn.13589] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 04/07/2021] [Accepted: 05/04/2021] [Indexed: 11/29/2022]
Abstract
NAD+ deficiency has recently been linked with increased occurrences of congenital abnormalities and embryonic death in human and animal subjects. Early embryonic death is a major component of pregnancy loss in mares and very little is known regarding the requirement for NAD+ in horses. The aim of this study was to quantify NAD+ and its metabolites in the plasma and urine of mares after orally administering an acute dose of nicotinic acid and determine the absorption, metabolism and excretion of this essential precursor for NAD+ biosynthesis. Nicotinic acid (5 g per os) was administered to four mares via a dosing syringe. Blood samples were collected at 0, 0.25, 0.5, 1, 2, 4, 6 and 22 h, and urine samples were collected at 0, 3, 6 and 22 h. The samples were processed and analysed by mass spectrometry. A general additive model was applied to all metabolite concentration values followed by a post-hoc multiple comparisons test. Nicotinic acid was rapidly absorbed into peripheral blood within 15 min of administration and the concentrations of nicotinic acid, nicotinamide (NAM), nicotinuric acid, nicotinic acid mononucleotide and nicotinic acid adenine dinucleotide (NaAD) increased significantly in plasma at 30 min. The concentrations of NAM, nicotinic acid riboside and NaAD increased significantly in urine at 3 h. The levels of NAM and NaAD remained significantly elevated in plasma at 22 h, sixfold and ninefold greater, respectively, than the basal levels at 0 h. While the extracellular levels of NAD+ in the samples remained undetected, the large, sustained elevation of NaAD levels in plasma indicates that the NAD+ levels were boosted within the cellular compartments. The results show that nicotinic acid supplementation increases the bioavailability of NAD+ precursors in mares, which is proposed to be beneficial during periods of peak NAD+ demand, such as during early embryo development.
Collapse
Affiliation(s)
- Charley-Lea Pollard
- Sydney School of Veterinary Science, Faculty of Science, The University of Sydney, Camden, NSW, Australia
| | - Zamira Gibb
- Priority Research Centre for Reproductive Science, University of Newcastle, Callaghan, NSW, Australia
| | - Aleona Swegen
- Priority Research Centre for Reproductive Science, University of Newcastle, Callaghan, NSW, Australia.,Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, UK
| | - Edwina F Lawson
- Priority Research Centre for Reproductive Science, University of Newcastle, Callaghan, NSW, Australia
| | - Christopher G Grupen
- Sydney School of Veterinary Science, Faculty of Science, The University of Sydney, Camden, NSW, Australia
| |
Collapse
|
|
10
|
Yokouchi C, Nishimura Y, Goto H, Sato M, Hidoh Y, Takeuchi K, Ishii Y. Reduction of fatty liver in rats by nicotinamide via the regeneration of the methionine cycle and the inhibition of aldehyde oxidase. J Toxicol Sci 2021; 46:31-42. [PMID: 33408299 DOI: 10.2131/jts.46.31] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Nonalcoholic fatty liver disease, which has been rapidly increasing in the world in recent years, is roughly classified into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis. This study was based on our previous reports that stated that the combination treatment of N1-methylnicotinamide (MNA) and hydralazine (HYD) improves fatty liver in NAFL model rats. This finding was attributed to the MNA metabolism inhibition by HYD, which is a strong inhibitor of aldehyde oxidase (AO); this results in an increase in hepatic MNA and improved fatty liver. We hypothesized that orally administered nicotinamide (NAM), which is the precursor of MNA and is a form of niacin, would be efficiently metabolized by nicotinamide N-methyltransferase in the presence of exogenous S-adenosylmethionine (SAM) in NAFL rats. To address this issue, NAFL model rats were orally administered with NAM, SAM, and/or HYD. As a result, liver triglyceride (TG) and lipid droplet levels were barely altered by the administration of NAM, SAM, NAM+SAM, or NAM+HYD. By contrast, the triple combination of NAM+SAM+HYD significantly reduced hepatic TG and lipid droplet levels and significantly increased hepatic MNA levels. These findings indicated that the combination of exogenous SAM with AO inhibitors, such as HYD, has beneficial effects for improving fatty liver with NAM.
Collapse
Affiliation(s)
- Chie Yokouchi
- Department of Drug Metabolism and Pharmacokinetics, Nonclinical Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd
- Division of Pharmaceutical Cell Biology, Graduate School of Pharmaceutical Sciences, Kyushu University
| | - Yukari Nishimura
- Department of Drug Safety, Nonclinical Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd
| | - Hirohiko Goto
- Department of Drug Safety, Nonclinical Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd
| | - Makoto Sato
- Department of Drug Safety, Nonclinical Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd
| | - Yuya Hidoh
- Department of Drug Metabolism and Pharmacokinetics, Nonclinical Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd
| | - Kenji Takeuchi
- Department of Drug Metabolism and Pharmacokinetics, Nonclinical Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd
| | - Yuji Ishii
- Division of Pharmaceutical Cell Biology, Graduate School of Pharmaceutical Sciences, Kyushu University
| |
Collapse
|
|
11
|
Amer S, Zarad W, El-Gendy H, Abdel-Salam R, Hadad G, Emara S, Masujima T. Dilute-and-shoot-based direct nano-electrospray ionization tandem mass spectrometry as screening methodology for multivitamins in dietary supplement and human urine. J Adv Res 2020; 26:1-13. [PMID: 33133679 PMCID: PMC7584677 DOI: 10.1016/j.jare.2020.06.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2020] [Revised: 05/25/2020] [Accepted: 06/09/2020] [Indexed: 11/26/2022] Open
Abstract
INTRODUCTION In recent years, analytical screening methods for simultaneous detection of multivitamins have gained substantial attention to ensure quality and public confidence in dietary supplements. Even so, few analytical methods have been proposed for simultaneous analysis of multivitamin constituents due to the large divergence in chemical characteristics. OBJECTIVES In the present study, the objective was to develop a simple and rapid direct nano-electrospray ionization-tandem mass spectrometry (DI-nano-ESI-MS/MS) method for targeted detection of water soluble vitamins, fat soluble vitamins, amino acids, royal jelly, ginkgo biloba, and ginseng in a dietary supplement. The applicability of dilute-and-shoot-based DI-nano-ESI-MS/MS to analyze the same tested compounds and their related metabolites in clinical samples was also examined. METHODS Intact urine mixed with the ionization solvent was loaded (4-μL aliquot) into a nanospray (NS) capillary of 1-μm tip diameter. The NS capillary was then fitted into an off-line ion source at a distance of 5 mm from MS aperture. The sample was directly injected by applying a voltage of 1.1 kV, producing a numerous of m/z peaks for analysis in mere minutes. RESULTS The DI-nano-ESI-MS/MS method successfully identified almost all dietary supplement components, as well as a plethora of component-related metabolites in clinical samples. In addition, a new merit of the proposed method for the detection of index marker and chemical contaminants as well as subspecies identification was investigated for further quality evaluation of the dietary supplement. CONCLUSIONS The previous findings illustrated that DI-nano-ESI-MS/MS approach can emerge as a powerful, high throughput, and promising analytical tool for screening and accurate detection of various pharmaceuticals and ingredient in dietary supplements as well as biological fluids.
Collapse
Affiliation(s)
- Sara Amer
- Faculty of Pharmacy, Misr International University, Km 28 Ismailia Road, Cairo, Egypt
- Quantitative Biology Center (QBiC), RIKEN, 6-2-3 Furuedai, Suita, Osaka 565–0874, Japan
| | - Walaa Zarad
- Faculty of Pharmacy, Misr International University, Km 28 Ismailia Road, Cairo, Egypt
| | - Heba El-Gendy
- Faculty of Pharmacy, Misr International University, Km 28 Ismailia Road, Cairo, Egypt
| | - Randa Abdel-Salam
- Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Canal Suez University, Ismailia, Egypt
| | - Ghada Hadad
- Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Canal Suez University, Ismailia, Egypt
| | - Samy Emara
- Faculty of Pharmacy, Misr International University, Km 28 Ismailia Road, Cairo, Egypt
| | - Tsutomu Masujima
- Quantitative Biology Center (QBiC), RIKEN, 6-2-3 Furuedai, Suita, Osaka 565–0874, Japan
| |
Collapse
|
|
12
|
Brachem C, Langenau J, Weinhold L, Schmid M, Nöthlings U, Oluwagbemigun K. Associations of BMI and Body Fat with Urine Metabolome in Adolescents Are Sex-Specific: A Cross-Sectional Study. Metabolites 2020; 10:metabo10080330. [PMID: 32823620 PMCID: PMC7463425 DOI: 10.3390/metabo10080330] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 07/25/2020] [Accepted: 08/11/2020] [Indexed: 11/30/2022] Open
Abstract
Epidemiologic studies examining the relationship between body composition and the urine metabolome may improve our understanding of the role of metabolic dysregulation in body composition-related health conditions. Previous studies, mostly in adult populations, have focused on a single measure of body composition, body mass index (BMI), and sex-specific associations are rarely explored. We investigate sex-specific associations of two measures of body composition—BMI and body fat (BF)—with the urine metabolome in adolescents. In 369 participants (age 16–18, 49% female) of the Dortmund Nutritional and Anthropometric Longitudinally Designed (DONALD) study, we examined sex-specific associations of these two measures of body composition, BMI and BF, and 1407 (467 unknown) 24 h urine metabolites analyzed by untargeted metabolomics cross-sectionally. Missing metabolites were imputed. We related metabolites (dependent variable) to BMI and BF (independent variable) separately using linear regression. The models were additionally adjusted for covariates. We found 10 metabolites associated with both BMI and BF. We additionally found 11 metabolites associated with only BF, and nine with only BMI. None of these associations was in females. We observed a strong sexual dimorphism in the relationship between body composition and the urine metabolome.
Collapse
Affiliation(s)
- Christian Brachem
- Unit of Nutritional Epidemiology, Department of Nutrition and Food Sciences, Rheinische Friedrich-Wilhelms-University Bonn, 53115 Bonn, Germany; (J.L.); (U.N.); (K.O.)
- Correspondence: ; Tel.: +49-(0)-228-73-3989
| | - Julia Langenau
- Unit of Nutritional Epidemiology, Department of Nutrition and Food Sciences, Rheinische Friedrich-Wilhelms-University Bonn, 53115 Bonn, Germany; (J.L.); (U.N.); (K.O.)
| | - Leonie Weinhold
- Institute for Medical Biometry, Informatics and Epidemiology (IMBIE), University Hospital Bonn, 53127 Bonn, Germany; (L.W.); (M.S.)
| | - Matthias Schmid
- Institute for Medical Biometry, Informatics and Epidemiology (IMBIE), University Hospital Bonn, 53127 Bonn, Germany; (L.W.); (M.S.)
| | - Ute Nöthlings
- Unit of Nutritional Epidemiology, Department of Nutrition and Food Sciences, Rheinische Friedrich-Wilhelms-University Bonn, 53115 Bonn, Germany; (J.L.); (U.N.); (K.O.)
| | - Kolade Oluwagbemigun
- Unit of Nutritional Epidemiology, Department of Nutrition and Food Sciences, Rheinische Friedrich-Wilhelms-University Bonn, 53115 Bonn, Germany; (J.L.); (U.N.); (K.O.)
| |
Collapse
|
|
13
|
Buqué A, Bloy N, Perez-Lanzón M, Iribarren K, Humeau J, Pol JG, Levesque S, Mondragon L, Yamazaki T, Sato A, Aranda F, Durand S, Boissonnas A, Fucikova J, Senovilla L, Enot D, Hensler M, Kremer M, Stoll G, Hu Y, Massa C, Formenti SC, Seliger B, Elemento O, Spisek R, André F, Zitvogel L, Delaloge S, Kroemer G, Galluzzi L. Immunoprophylactic and immunotherapeutic control of hormone receptor-positive breast cancer. Nat Commun 2020; 11:3819. [PMID: 32732875 PMCID: PMC7393498 DOI: 10.1038/s41467-020-17644-0] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Accepted: 07/10/2020] [Indexed: 12/27/2022] Open
Abstract
Hormone receptor (HR)+ breast cancer (BC) causes most BC-related deaths, calling for improved therapeutic approaches. Despite expectations, immune checkpoint blockers (ICBs) are poorly active in patients with HR+ BC, in part reflecting the lack of preclinical models that recapitulate disease progression in immunocompetent hosts. We demonstrate that mammary tumors driven by medroxyprogesterone acetate (M) and 7,12-dimethylbenz[a]anthracene (D) recapitulate several key features of human luminal B HR+HER2- BC, including limited immune infiltration and poor sensitivity to ICBs. M/D-driven oncogenesis is accelerated by immune defects, demonstrating that M/D-driven tumors are under immunosurveillance. Safe nutritional measures including nicotinamide (NAM) supplementation efficiently delay M/D-driven oncogenesis by reactivating immunosurveillance. NAM also mediates immunotherapeutic effects against established M/D-driven and transplantable BC, largely reflecting increased type I interferon secretion by malignant cells and direct stimulation of immune effector cells. Our findings identify NAM as a potential strategy for the prevention and treatment of HR+ BC.
Collapse
MESH Headings
- 9,10-Dimethyl-1,2-benzanthracene
- Animals
- Breast Neoplasms/immunology
- Breast Neoplasms/metabolism
- Breast Neoplasms/therapy
- Carcinogenesis/drug effects
- Carcinogenesis/immunology
- Disease Progression
- Female
- Humans
- Immunotherapy/methods
- Interferon Type I/immunology
- Interferon Type I/metabolism
- Mammary Neoplasms, Experimental/chemically induced
- Mammary Neoplasms, Experimental/immunology
- Mammary Neoplasms, Experimental/prevention & control
- Medroxyprogesterone Acetate
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Mice, Knockout
- Niacinamide/administration & dosage
- Receptor, ErbB-2/immunology
- Receptor, ErbB-2/metabolism
- Survival Analysis
Collapse
Affiliation(s)
- Aitziber Buqué
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
- Equipe labellisée par la Ligue contre le cancer, Centre de Recherche des Cordeliers, INSERM U1138, Université de Paris, Sorbonne Université, Paris, France
| | - Norma Bloy
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
- Equipe labellisée par la Ligue contre le cancer, Centre de Recherche des Cordeliers, INSERM U1138, Université de Paris, Sorbonne Université, Paris, France
| | - Maria Perez-Lanzón
- Equipe labellisée par la Ligue contre le cancer, Centre de Recherche des Cordeliers, INSERM U1138, Université de Paris, Sorbonne Université, Paris, France
- Faculté de Médecine, Université de Paris Sud, Paris-Saclay, Le Kremlin-Bicêtre, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France
| | - Kristina Iribarren
- Equipe labellisée par la Ligue contre le cancer, Centre de Recherche des Cordeliers, INSERM U1138, Université de Paris, Sorbonne Université, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France
| | - Juliette Humeau
- Equipe labellisée par la Ligue contre le cancer, Centre de Recherche des Cordeliers, INSERM U1138, Université de Paris, Sorbonne Université, Paris, France
- Faculté de Médecine, Université de Paris Sud, Paris-Saclay, Le Kremlin-Bicêtre, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France
| | - Jonathan G Pol
- Equipe labellisée par la Ligue contre le cancer, Centre de Recherche des Cordeliers, INSERM U1138, Université de Paris, Sorbonne Université, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France
| | - Sarah Levesque
- Equipe labellisée par la Ligue contre le cancer, Centre de Recherche des Cordeliers, INSERM U1138, Université de Paris, Sorbonne Université, Paris, France
- Faculté de Médecine, Université de Paris Sud, Paris-Saclay, Le Kremlin-Bicêtre, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France
| | - Laura Mondragon
- Equipe labellisée par la Ligue contre le cancer, Centre de Recherche des Cordeliers, INSERM U1138, Université de Paris, Sorbonne Université, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France
| | - Takahiro Yamazaki
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
| | - Ai Sato
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
| | - Fernando Aranda
- Equipe labellisée par la Ligue contre le cancer, Centre de Recherche des Cordeliers, INSERM U1138, Université de Paris, Sorbonne Université, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France
| | - Sylvère Durand
- Equipe labellisée par la Ligue contre le cancer, Centre de Recherche des Cordeliers, INSERM U1138, Université de Paris, Sorbonne Université, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France
| | - Alexandre Boissonnas
- Sorbonne Université, Inserm, CNRS, Centre d'Immunologie et des Maladies Infectieuses CIMI, Paris, France
| | - Jitka Fucikova
- Sotio, Prague, Czech Republic
- Department of Immunology, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic
| | - Laura Senovilla
- Equipe labellisée par la Ligue contre le cancer, Centre de Recherche des Cordeliers, INSERM U1138, Université de Paris, Sorbonne Université, Paris, France
| | - David Enot
- Equipe labellisée par la Ligue contre le cancer, Centre de Recherche des Cordeliers, INSERM U1138, Université de Paris, Sorbonne Université, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France
| | | | - Margerie Kremer
- Equipe labellisée par la Ligue contre le cancer, Centre de Recherche des Cordeliers, INSERM U1138, Université de Paris, Sorbonne Université, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France
| | - Gautier Stoll
- Equipe labellisée par la Ligue contre le cancer, Centre de Recherche des Cordeliers, INSERM U1138, Université de Paris, Sorbonne Université, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France
| | - Yang Hu
- Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA
| | - Chiara Massa
- Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Silvia C Formenti
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
- Sandra and Edward Meyer Cancer Center, New York, NY, USA
| | - Barbara Seliger
- Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Olivier Elemento
- Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA
- Sandra and Edward Meyer Cancer Center, New York, NY, USA
| | - Radek Spisek
- Sotio, Prague, Czech Republic
- Department of Immunology, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic
| | | | - Laurence Zitvogel
- Faculté de Médecine, Université de Paris Sud, Paris-Saclay, Le Kremlin-Bicêtre, Paris, France
- Gustave Roussy Cancer Center, Villejuif, France
- INSERM U1015, Villejuif, France
- Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, France
| | - Suzette Delaloge
- Department of Cancer Medicine, Gustave Roussy Cancer Center, Villejuif, France
| | - Guido Kroemer
- Equipe labellisée par la Ligue contre le cancer, Centre de Recherche des Cordeliers, INSERM U1138, Université de Paris, Sorbonne Université, Paris, France.
- Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.
- Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
- Suzhou Institute for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China.
- Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden.
| | - Lorenzo Galluzzi
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA.
- Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA.
- Sandra and Edward Meyer Cancer Center, New York, NY, USA.
- Department of Dermatology, Yale School of Medicine, New Haven, CT, USA.
- Université de Paris, Paris, France.
| |
Collapse
|
|
14
|
Fang H, Li Z, Graff EC, McCafferty KJ, Judd RL. Niacin increases diet-induced hepatic steatosis in B6129 mice. Biochim Biophys Acta Mol Cell Biol Lipids 2020; 1865:158731. [PMID: 32404278 DOI: 10.1016/j.bbalip.2020.158731] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 04/24/2020] [Accepted: 04/27/2020] [Indexed: 12/18/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a very common disorder affecting between 20 and 30% of adults in the United States. However, there is no effective pharmacotherapy for treating NAFLD. Niacin, a water-soluble vitamin (B3), at pharmacological doses, decreases hepatic triglyceride (TG) content in NAFLD through inhibition of diacylglycerol acyltransferase 2, a key enzyme that catalyzes the final step in TG synthesis. Alternatively, some studies indicate that niacin induces fatty liver in high-fat diet (HFD)-fed rats. Therefore, in this study we investigated whether niacin is beneficial in treating NAFLD in two strains of mice, C57BL/6J (B6) and B6129SF2/J (B6129) mice, with 20 weeks of HFD feeding. Niacin treatment was started from week 5 until the end of the study. Niacin treatment increased normalized liver weight, hepatic TG content and NAFLD score in HFD-fed B6129 mice but had no impact on B6 mice. Metabolomics analysis revealed that in B6129 mice, 4-hydroxyphenylpyruvic acid (4-HPP), which is associated with fatty acid oxidation, did not change with HFD feeding but significantly decreased with niacin treatment. Lipidomics analysis discovered that the abundance of phosphocholine (PC), which is critical for very low-density lipoprotein (VLDL)-TG production and secretion, was decreased in HFD-fed B6129 with niacin treatment. In conclusion, niacin had no impact on diet-induced NAFLD development in B6 mice but potentiated hepatic steatosis in HFD-fed B6129 mice due to impaired fatty acid oxidation and decreased VLDL-TG production and secretion.
Collapse
Affiliation(s)
- Han Fang
- Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, United States of America
| | - Zhuoyue Li
- Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, United States of America
| | - Emily C Graff
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, United States of America
| | - Kayleen J McCafferty
- Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, United States of America
| | - Robert L Judd
- Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, United States of America.
| |
Collapse
|
|
15
|
Urinary Excretion of N1-methyl-2-pyridone-5-carboxamide and N1-methylnicotinamide in Renal Transplant Recipients and Donors. J Clin Med 2020; 9:jcm9020437. [PMID: 32041099 PMCID: PMC7074074 DOI: 10.3390/jcm9020437] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 01/28/2020] [Accepted: 02/04/2020] [Indexed: 12/12/2022] Open
Abstract
N1-methylnicotinamide (N1-MN) and N1-methyl-2-pyridone-5-carboxamide (2Py) are successive end products of NAD+ catabolism. N1-MN excretion in 24-h urine is the established biomarker of niacin nutritional status, and recently shown to be reduced in renal transplant recipients (RTR). However, it is unclear whether 2Py excretion is increased in this population, and, if so, whether a shift in excretion of N1-MN to 2Py can be attributed to kidney function. Hence, we assessed the 24-h urinary excretion of 2Py and N1-MN in RTR and kidney donors before and after kidney donation, and investigated associations of the urinary ratio of 2Py to N1-MN (2Py/N1-MN) with kidney function, and independent determinants of urinary 2Py/N1-MN in RTR. The urinary excretion of 2Py and N1-MN was measured in a cross-sectional cohort of 660 RTR and 275 healthy kidney donors with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Linear regression analyses were used to investigate associations and determinants of urinary 2Py/N1-MN. Median 2Py excretion was 178.1 (130.3–242.8) μmol/day in RTR, compared to 155.6 (119.6–217.6) μmol/day in kidney donors (p < 0.001). In kidney donors, urinary 2Py/N1-MN increased significantly after kidney donation (4.0 ± 1.4 to 5.2 ± 1.5, respectively; p < 0.001). Smoking, alcohol consumption, diabetes, high-density lipoprotein (HDL), high-sensitivity C-reactive protein (hs-CRP) and estimated glomerular filtration rate (eGFR) were identified as independent determinants of urinary 2Py/N1-MN in RTR. In conclusion, the 24-h urinary excretion of 2Py is higher in RTR than in kidney donors, and urinary 2Py/N1-MN increases after kidney donation. As our data furthermore reveal strong associations of urinary 2Py/N1-MN with kidney function, interpretation of both N1-MN and 2Py excretion may be recommended for assessment of niacin nutritional status in conditions of impaired kidney function.
Collapse
|
|
16
|
Milanowski B, Hejduk A, Bawiec MA, Jakubowska E, Urbańska A, Wiśniewska A, Garbacz G, Lulek J. Biorelevant In Vitro Release Testing and In Vivo Study of Extended-Release Niacin Hydrophilic Matrix Tablets. AAPS PharmSciTech 2020; 21:83. [PMID: 31989330 PMCID: PMC6985042 DOI: 10.1208/s12249-019-1600-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Accepted: 12/03/2019] [Indexed: 11/30/2022] Open
Abstract
Niacin (nicotinic acid, NA) is administered orally as an antihyperlipidemic agent in extended-release (ER) tablets in high doses. Due to rapid absorption and extensive metabolism (non-linear pharmacokinetics), the drug plasma levels are highly variable, which may correlate with side effects. Interestingly, this erratic drug delivery behavior of niacin ER products cannot be clarified by compendial in vitro release testing. The standard dissolution tests do not allow to mimic the selected GI tract characteristics in order to estimate the robustness of formulation under the variability of the physiological conditions. These are characterized by the pH value, impact of motility forces and composition, as well as volume of GI liquids. Our paper demonstrates a comparison of a newly developed ER HPMC niacin formulation with an originator product. The research aimed to design a robust matrix tablet of comparable biopharmaceutical behavior, safety and efficacy. The extensive in vitro investigation, including dynamic studies in flow-through cell apparatus and stress test device, forms the basis for the evaluation of nicotinic acid plasma concentrations in vivo. The occurrence of erratic, multiple NA plasma peaks after the administration of both extended-release products is a result of its local input excess over the metabolic threshold (at the level corresponding to maximum 2% of the administered dose, i.e., 20 mg of drug) due to the mechanical stresses of physiological intensity. We demonstrate how this behavior is similar for both marketed and test products. In this context, we describe how a robust ER matrix and well-designed formulation does not guarantee the test product’s bioequivalence to the comparator one out of reasons unrelated to technology and biopharmaceutical properties, but because of the active compound’s intrinsic pharmacokinetic characteristics, i.e., highly variable, extensive metabolism of nicotinic acid.
Collapse
|
|
17
|
Urinary Excretion of N1-Methylnicotinamide, as a Biomarker of Niacin Status, and Mortality in Renal Transplant Recipients. J Clin Med 2019; 8:jcm8111948. [PMID: 31726722 PMCID: PMC6912198 DOI: 10.3390/jcm8111948] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 11/08/2019] [Accepted: 11/11/2019] [Indexed: 12/15/2022] Open
Abstract
Renal transplant recipients (RTR) commonly suffer from vitamin B6 deficiency and its functional consequences add to an association with poor long-term outcome. It is unknown whether niacin status is affected in RTR and, if so, whether this affects clinical outcomes, as vitamin B6 is a cofactor in nicotinamide biosynthesis. We compared 24-h urinary excretion of N1-methylnicotinamide (N1-MN) as a biomarker of niacin status in RTR with that in healthy controls, in relation to dietary intake of tryptophan and niacin as well as vitamin B6 status, and investigated whether niacin status is associated with the risk of premature all-cause mortality in RTR. In a prospective cohort of 660 stable RTR with a median follow-up of 5.4 (4.7-6.1) years and 275 healthy kidney donors, 24-h urinary excretion of N1-MN was measured with liquid chromatography-tandem mass spectrometry LC-MS/MS. Dietary intake was assessed by food frequency questionnaires. Prospective associations of N1-MN excretion with mortality were investigated by Cox regression analyses. Median N1-MN excretion was 22.0 (15.8-31.8) μmol/day in RTR, compared to 41.1 (31.6-57.2) μmol/day in healthy kidney donors (p < 0.001). This difference was independent of dietary intake of tryptophan (1059 ± 271 and 1089 ± 308 mg/day; p = 0.19), niacin (17.9 ± 5.2 and 19.2 ± 6.2 mg/day; p < 0.001), plasma vitamin B6 (29.0 (17.5-49.5), and 42.0 (29.8-60.3) nmol/L; p < 0.001), respectively. N1-MN excretion was inversely associated with the risk of all-cause mortality in RTR (HR 0.57; 95% CI 0.45-0.71; p < 0.001), independent of potential confounders. RTR excrete less N1-MN in 24-h urine than healthy controls, and our data suggest that this difference cannot be attributed to lower dietary intake of tryptophan and niacin, nor vitamin B6 status. Importantly, lower 24-h urinary excretion of N1-MN is independently associated with a higher risk of premature all-cause mortality in RTR.
Collapse
|
|
18
|
Braidy N, Berg J, Clement J, Khorshidi F, Poljak A, Jayasena T, Grant R, Sachdev P. Role of Nicotinamide Adenine Dinucleotide and Related Precursors as Therapeutic Targets for Age-Related Degenerative Diseases: Rationale, Biochemistry, Pharmacokinetics, and Outcomes. Antioxid Redox Signal 2019; 30:251-294. [PMID: 29634344 PMCID: PMC6277084 DOI: 10.1089/ars.2017.7269] [Citation(s) in RCA: 165] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Revised: 02/22/2018] [Accepted: 02/22/2018] [Indexed: 12/20/2022]
Abstract
Significance: Nicotinamide adenine dinucleotide (NAD+) is an essential pyridine nucleotide that serves as an essential cofactor and substrate for a number of critical cellular processes involved in oxidative phosphorylation and ATP production, DNA repair, epigenetically modulated gene expression, intracellular calcium signaling, and immunological functions. NAD+ depletion may occur in response to either excessive DNA damage due to free radical or ultraviolet attack, resulting in significant poly(ADP-ribose) polymerase (PARP) activation and a high turnover and subsequent depletion of NAD+, and/or chronic immune activation and inflammatory cytokine production resulting in accelerated CD38 activity and decline in NAD+ levels. Recent studies have shown that enhancing NAD+ levels can profoundly reduce oxidative cell damage in catabolic tissue, including the brain. Therefore, promotion of intracellular NAD+ anabolism represents a promising therapeutic strategy for age-associated degenerative diseases in general, and is essential to the effective realization of multiple benefits of healthy sirtuin activity. The kynurenine pathway represents the de novo NAD+ synthesis pathway in mammalian cells. NAD+ can also be produced by the NAD+ salvage pathway. Recent Advances: In this review, we describe and discuss recent insights regarding the efficacy and benefits of the NAD+ precursors, nicotinamide (NAM), nicotinic acid (NA), nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN), in attenuating NAD+ decline in degenerative disease states and physiological aging. Critical Issues: Results obtained in recent years have shown that NAD+ precursors can play important protective roles in several diseases. However, in some cases, these precursors may vary in their ability to enhance NAD+ synthesis via their location in the NAD+ anabolic pathway. Increased synthesis of NAD+ promotes protective cell responses, further demonstrating that NAD+ is a regulatory molecule associated with several biochemical pathways. Future Directions: In the next few years, the refinement of personalized therapy for the use of NAD+ precursors and improved detection methodologies allowing the administration of specific NAD+ precursors in the context of patients' NAD+ levels will lead to a better understanding of the therapeutic role of NAD+ precursors in human diseases.
Collapse
Affiliation(s)
- Nady Braidy
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia
| | - Jade Berg
- Australasian Research Institute, Sydney Adventist Hospital, Sydney, Australia
| | | | - Fatemeh Khorshidi
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia
| | - Anne Poljak
- Mark Wainwright Analytical Centre, University of New South Wales, Sydney, Australia
- School of Medical Sciences, University of New South Wales, Sydney, Australia
| | - Tharusha Jayasena
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia
| | - Ross Grant
- Australasian Research Institute, Sydney Adventist Hospital, Sydney, Australia
- School of Medical Sciences, University of New South Wales, Sydney, Australia
- Sydney Medical School, University of Sydney, Sydney, Australia
| | - Perminder Sachdev
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia
- Neuropsychiatric Institute, Euroa Centre, Prince of Wales Hospital, Sydney, Australia
| |
Collapse
|
|
19
|
Midttun Ø, Ulvik A, Nygård O, Ueland PM. Performance of plasma trigonelline as a marker of coffee consumption in an epidemiologic setting. Am J Clin Nutr 2018; 107:941-947. [PMID: 29771289 DOI: 10.1093/ajcn/nqy059] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Accepted: 03/07/2018] [Indexed: 11/14/2022] Open
Abstract
Background Coffee is a widely consumed beverage, and studies suggest that drinking coffee has beneficial health effects. The phytohormone trigonelline is present in large amounts in coffee beans, and circulating concentrations of trigonelline have been shown to be positively related to dietary intake of coffee and to increase significantly after the consumption of a bolus dose of coffee. Objective We cross-sectionally investigated the utility of plasma trigonelline as a marker of coffee consumption in an epidemiologic setting. We secondarily investigated if coffee intake is related to plasma concentrations of vitamin B-3 (niacin) forms. Design In a Norwegian cohort of 3503 participants, we combined questionnaire data on the number of cups of coffee consumed per day with plasma trigonelline to evaluate trigonelline as a marker of coffee intake. The suitability of plasma trigonelline to discriminate those not consuming from those consuming coffee was investigated by receiver operating characteristic (ROC) analysis. Plasma collected at 2 time points 1 y apart was used to determine the within-person reproducibility of trigonelline. Results We found that plasma trigonelline concentrations increased strongly with increasing amounts of coffee consumed. ROC analysis showed that trigonelline had an area under the curve of 0.92 (95% CI: 0.90, 0.94) for distinguishing coffee abstainers from coffee drinkers. Plasma trigonelline had a good within-person reproducibility (0.66; 95% CI: 0.64, 0.68) for samples collected 1 y apart. The amount of coffee consumed was not associated with plasma concentrations of the niacin vitamers nicotinamide and N1-methylnicotinamide. Conclusions Plasma trigonelline performs well as a marker of coffee intake. Data used in this study were derived from the clinical trial registered at www.clinicaltrials.gov as NCT00354081.
Collapse
Affiliation(s)
| | | | - Ottar Nygård
- Department of Heart Disease.,Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Per M Ueland
- Laboratory of Clinical Biochemistry, Haukeland University Hospital, Bergen, Norway.,Department of Clinical Science, University of Bergen, Bergen, Norway
| |
Collapse
|
|
20
|
Kremer JI, Gömpel K, Bakuradze T, Eisenbrand G, Richling E. Urinary Excretion of Niacin Metabolites in Humans After Coffee Consumption. Mol Nutr Food Res 2018; 62:e1700735. [PMID: 29468817 PMCID: PMC5900739 DOI: 10.1002/mnfr.201700735] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Revised: 02/01/2018] [Indexed: 11/25/2022]
Abstract
SCOPE Coffee is a major natural source of niacin in the human diet, as it is formed during coffee roasting from the alkaloid trigonelline. The intention of our study was to monitor the urinary excretion of niacin metabolites after coffee consumption under controlled diet. METHODS AND RESULTS We performed a 4-day human intervention study on the excretion of major niacin metabolites in the urine of volunteers after ingestion of 500 mL regular coffee containing 34.8 μmol nicotinic acid (NA) and 0.58 μmol nicotinamide (NAM). In addition to NA and NAM, the metabolites N1 -methylnicotinamide (NMNAM), N1 -methyl-2-pyridone-5-carboxamide (2-Py), and nicotinuric acid (NUA) were identified and quantified in the collected urine samples by stable isotope dilution analysis (SIVA) using HPLC-ESI-MS/MS. Rapid urinary excretion was observed for the main metabolites (NA, NAM, NMNAM, and 2-Py), with tmax values within the first hour after ingestion. NUA appeared in traces even more rapidly. In sum, 972 nmol h-1 of NA, NAM, NMNAM, and 2-Py were excreted within 12 h after coffee consumption, corresponding to 6% of the ingested NA and NAM. CONCLUSION The results indicate regular coffee consumption to be a source of niacin in human diet.
Collapse
Affiliation(s)
- Jonathan Isaak Kremer
- Department of ChemistryDivision of Food Chemistry and ToxicologyMolecular NutritionTechnische Universität KaiserslauternKaiserslauternGermany
| | - Katharina Gömpel
- Department of ChemistryDivision of Food Chemistry and ToxicologyMolecular NutritionTechnische Universität KaiserslauternKaiserslauternGermany
| | - Tamara Bakuradze
- Department of ChemistryDivision of Food Chemistry and ToxicologyMolecular NutritionTechnische Universität KaiserslauternKaiserslauternGermany
| | - Gerhard Eisenbrand
- Department of ChemistryDivision of Food Chemistry and ToxicologyMolecular NutritionTechnische Universität KaiserslauternKaiserslauternGermany
| | - Elke Richling
- Department of ChemistryDivision of Food Chemistry and ToxicologyMolecular NutritionTechnische Universität KaiserslauternKaiserslauternGermany
| |
Collapse
|
|
21
|
Müller F, Sharma A, König J, Fromm MF. Biomarkers for In Vivo Assessment of Transporter Function. Pharmacol Rev 2018; 70:246-277. [PMID: 29487084 DOI: 10.1124/pr.116.013326] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Drug-drug interactions are a major concern not only during clinical practice, but also in drug development. Due to limitations of in vitro-in vivo predictions of transporter-mediated drug-drug interactions, multiple clinical Phase I drug-drug interaction studies may become necessary for a new molecular entity to assess potential drug interaction liabilities. This is a resource-intensive process and exposes study participants, who frequently are healthy volunteers without benefit from study treatment, to the potential risks of a new drug in development. Therefore, there is currently a major interest in new approaches for better prediction of transporter-mediated drug-drug interactions. In particular, researchers in the field attempt to identify endogenous compounds as biomarkers for transporter function, such as hexadecanedioate, tetradecanedioate, coproporphyrins I and III, or glycochenodeoxycholate sulfate for hepatic uptake via organic anion transporting polypeptide 1B or N1-methylnicotinamide for multidrug and toxin extrusion protein-mediated renal secretion. We summarize in this review the currently proposed biomarkers and potential limitations of the substances identified to date. Moreover, we suggest criteria based on current experiences, which may be used to assess the suitability of a biomarker for transporter function. Finally, further alternatives and supplemental approaches to classic drug-drug interaction studies are discussed.
Collapse
Affiliation(s)
- Fabian Müller
- Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany (F.M., J.K., M.F.F.); and Department of Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach a.d. Riß, Germany (F.M., A.S.)
| | - Ashish Sharma
- Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany (F.M., J.K., M.F.F.); and Department of Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach a.d. Riß, Germany (F.M., A.S.)
| | - Jörg König
- Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany (F.M., J.K., M.F.F.); and Department of Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach a.d. Riß, Germany (F.M., A.S.)
| | - Martin F Fromm
- Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany (F.M., J.K., M.F.F.); and Department of Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach a.d. Riß, Germany (F.M., A.S.)
| |
Collapse
|
|
22
|
Turck D, Bresson JL, Burlingame B, Dean T, Fairweather-Tait S, Heinonen M, Hirsch-Ernst KI, Mangelsdorf I, McArdle HJ, Naska A, Neuhäuser-Berthold M, Nowicka G, Pentieva K, Sanz Y, Siani A, Sjödin A, Stern M, Tomé D, Vinceti M, Willatts P, Engel KH, Marchelli R, Pöting A, Poulsen M, Schlatter JR, Gelbmann W, Ververis E, van Loveren H. Safety of 1-methylnicotinamide chloride (1-MNA) as a novel food pursuant to Regulation (EC) No 258/97. EFSA J 2017; 15:e05001. [PMID: 32625296 PMCID: PMC7010160 DOI: 10.2903/j.efsa.2017.5001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
Following a request from the European Commission, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) was asked to deliver an opinion on 1-methylnicotinamide chloride (1-MNA) as a novel food (NF) ingredient submitted pursuant to Regulation (EC) No 258/97 of the European Parliament and of the Council, taking into account the comments and objections of a scientific nature raised by Member States. 1-MNA is a substance present naturally in the human body as a normal downstream product of niacin metabolism. The Panel considers that the information provided on the composition, the specification and the batch-to-batch variability of the NF is sufficient. The applicant intends to use 1-MNA in food supplements and proposes a maximum intake of 58 mg/day. 1-MNA is not genotoxic. In a subchronic rat study, epithelium degeneration of the non-glandular stomach was observed at all dose levels with increasing frequency. The Panel notes that the human stomach does not have non-glandular epithelium and considers this finding is toxicologically not relevant for humans. At doses of 500 and 1,000 mg/kg body weight (bw), changes of the urine pH, that did not reverse in the recovery period, were reported. As adversity of this finding cannot be ruled out, the Panel selected 250 mg/kg bw in this rat study as the reference point. The Margin of Exposure to humans weighing 70 kg and consuming 58 mg would be about 300. The Panel notes the upper level for nicotinamide, i.e. 900 mg/day for adults. Taking into account that 1-MNA is a main metabolite from nicotinamide, the Panel considers that it is unlikely that an intake of 58 mg 1-MNA from food supplements would result in adverse health outcomes in humans. The Panel concludes that the NF, 1-MNA, is safe under the proposed uses and use levels.
Collapse
|
|
23
|
Abstract
Two cardiovascular outcome trials established niacin 3 g daily prevents hard cardiac events. However, as detailed in part I of this series, an extended-release (ER) alternative at only 2 g nightly demonstrated no comparable benefits in two outcome trials, implying the alternative is not equivalent to the established cardioprotective regimen. Since statins leave a significant treatment gap, this presents a major opportunity for developers. Importantly, the established regimen is cardioprotective, so the pathway is likely beneficial. Moreover, though effective, the established cardioprotective regimen is cumbersome, limiting clinical use. At the same time, the ER alternative has been thoroughly discredited as a viable substitute for the established cardioprotective regimen. Therefore, by exploiting the pathway and skillfully avoiding the problems with the established cardioprotective regimen and the ER alternative, developers could validate cardioprotective variations facing little meaningful competition from their predecessors. Thus, shrewd developers could effectively tap into a gold mine at the grave of the ER alternative. The GPR109A receptor was discovered a decade ago, leading to a large body of evidence commending the niacin pathway to a lower cardiovascular risk beyond statins. While mediating niacin's most prominent adverse effects, GPR109A also seems to mediate anti-lipolytic, anti-inflammatory, and anti-atherogenic effects of niacin. Several developers are investing heavily in novel strategies to exploit niacin's therapeutic pathways. These include selective GPR109A receptor agonists, niacin prodrugs, and a niacin metabolite, with encouraging early phase human data. In part II of this review, we summarize the accumulated results of these early phase studies of emerging niacin mimetics.
Collapse
|
|
24
|
Pang DKT, Nong Z, Sutherland BG, Sawyez CG, Robson DL, Toma J, Pickering JG, Borradaile NM. Niacin promotes revascularization and recovery of limb function in diet-induced obese mice with peripheral ischemia. Pharmacol Res Perspect 2016; 4:e00233. [PMID: 27433343 PMCID: PMC4876143 DOI: 10.1002/prp2.233] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Revised: 03/07/2016] [Accepted: 03/11/2016] [Indexed: 12/20/2022] Open
Abstract
Niacin can reduce vascular disease risk in individuals with metabolic syndrome, but in light of recent large randomized controlled trials outcomes, its biological actions and clinical utility remain controversial. Niacin can improve endothelial function, vascular inflammation, and vascular regeneration, independent of correcting dyslipidemia, in various lean rodent models of vascular injury. Here, we tested whether niacin could directly improve endothelial cell angiogenic function during combined exposure to excess fatty acids and hypoxia, and whether intervention with niacin during continued feeding of western diet could improve revascularization and functional recovery in obese, hyperlipidemic mice with peripheral ischemia. Treatment with niacin (10 μmol/L) increased human microvascular endothelial cell angiogenic function during exposure to high fatty acids and hypoxia (2% oxygen), as determined by tube formation on Matrigel. To assess revascularization in vivo, we used western diet-induced obese mice with unilateral hind limb femoral artery ligation and excision. Treatment for 14 days postinjury with once daily i.p. injections of a low dose of niacin (50 mg/kg) improved recovery of hind limb use, in association with enhanced revascularization and decreased inflammation of the tibialis anterior muscle. These effects were concomitant with decreased plasma triglycerides, but not increased plasma apoAI. Thus, niacin improves endothelial tube formation under lipotoxic and hypoxic conditions, and moreover, promotes revascularization and functional hind limb recovery following ischemic injury in diet-induced obese mice with hyperlipidemia. These data may have implications for niacin therapy in the treatment of peripheral ischemic vascular disease associated with metabolic syndrome.
Collapse
Affiliation(s)
- Dominic K T Pang
- Department of Physiology and Pharmacology Schulich School of Medicine and Dentistry Western University London Ontario Canada N6A 5C1
| | - Zengxuan Nong
- Robarts Research Institute Western University London Ontario Canada N6A 5C1
| | - Brian G Sutherland
- Robarts Research Institute Western University London Ontario Canada N6A 5C1
| | - Cynthia G Sawyez
- Department of Physiology and Pharmacology Schulich School of Medicine and Dentistry Western University London Ontario Canada N6A 5C1; Robarts Research Institute Western University London Ontario Canada N6A 5C1; Department of Medicine Schulich School of Medicine and Dentistry Western University London Ontario Canada N6A 5C1
| | - Debra L Robson
- Department of Physiology and Pharmacology Schulich School of Medicine and Dentistry Western University London Ontario Canada N6A 5C1
| | - Jelena Toma
- Department of Physiology and Pharmacology Schulich School of Medicine and Dentistry Western University London Ontario Canada N6A 5C1
| | - J Geoffrey Pickering
- Robarts Research Institute Western University London Ontario Canada N6A 5C1; Department of Medicine Schulich School of Medicine and Dentistry Western University London Ontario Canada N6A 5C1; Department of Biochemistry Schulich School of Medicine and Dentistry Western University London Ontario Canada N6A 5C1; Department of Medical Biophysics Schulich School of Medicine and Dentistry Western University London Ontario Canada N6A 5C1; London Health Sciences Centre London Ontario Canada N6A 5C1
| | - Nica M Borradaile
- Department of Physiology and Pharmacology Schulich School of Medicine and Dentistry Western University London Ontario Canada N6A 5C1
| |
Collapse
|
|
25
|
Ganji SH, Kashyap ML, Kamanna VS. Niacin inhibits fat accumulation, oxidative stress, and inflammatory cytokine IL-8 in cultured hepatocytes: Impact on non-alcoholic fatty liver disease. Metabolism 2015; 64:982-90. [PMID: 26024755 DOI: 10.1016/j.metabol.2015.05.002] [Citation(s) in RCA: 91] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Revised: 04/06/2015] [Accepted: 05/04/2015] [Indexed: 12/21/2022]
Abstract
OBJECTIVE Non-alcoholic fatty liver disease (NAFLD) is a common disorder characterized by excessive hepatic fat accumulation, production of reactive oxygen species (ROS), inflammation and potentially resulting in non-alcoholic steatohepatitis (NASH), cirrhosis and end-stage liver disease. Recently, we have shown that niacin significantly prevented hepatic steatosis and regressed pre-existing steatosis in high-fat fed rat model of NAFLD. To gain further insight into the cellular mechanisms, this study investigated the effect of niacin on human hepatocyte fat accumulation, ROS production, and inflammatory mediator IL-8 secretion. MATERIALS AND METHODS Human hepatoblastoma cell line HepG2 or human primary hepatocytes were first stimulated with palmitic acid followed by treatment with niacin or control for 24 h. RESULTS The data indicated that niacin (at 0.25 and 0.5 mmol/L doses) significantly inhibited palmitic acid-induced fat accumulation in human hepatocytes by 45-62%. This effect was associated with inhibition of diacylglycerol acyltransferase 2 (DGAT2) mRNA expression without affecting the mRNA expression of fatty acid synthase (FAS) and carnitine palmitoyltransferase 1 (CPT1). Niacin attenuated hepatocyte ROS production and it also inhibited NADPH oxidase activity. Niacin reduced palmitic acid-induced IL-8 levels. CONCLUSIONS These findings suggest that niacin, through inhibiting hepatocyte DGAT2 and NADPH oxidase activity, attenuates hepatic fat accumulation and ROS production respectively. Decreased ROS production, at least in part, may have contributed to the inhibition of pro-inflammatory IL-8 levels. These mechanistic studies may be useful for the clinical development of niacin and niacin-related compounds for the treatment of NAFLD/NASH and its complications.
Collapse
Affiliation(s)
- Shobha H Ganji
- Department of Veterans Affairs Healthcare System, Long Beach, CA; University of California, Irvine, CA
| | - Moti L Kashyap
- Department of Veterans Affairs Healthcare System, Long Beach, CA; University of California, Irvine, CA
| | - Vaijinath S Kamanna
- Department of Veterans Affairs Healthcare System, Long Beach, CA; University of California, Irvine, CA.
| |
Collapse
|
|
26
|
Zhou SS, Li D, Chen NN, Zhou Y. Vitamin paradox in obesity: Deficiency or excess? World J Diabetes 2015; 6:1158-1167. [PMID: 26322161 PMCID: PMC4549666 DOI: 10.4239/wjd.v6.i10.1158] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2015] [Revised: 07/19/2015] [Accepted: 08/03/2015] [Indexed: 02/05/2023] Open
Abstract
Since synthetic vitamins were used to fortify food and as supplements in the late 1930s, vitamin intake has significantly increased. This has been accompanied by an increased prevalence of obesity, a condition associated with diabetes, hypertension, cardiovascular disease, asthma and cancer. Paradoxically, obesity is often associated with low levels of fasting serum vitamins, such as folate and vitamin D. Recent studies on folic acid fortification have revealed another paradoxical phenomenon: obesity exhibits low fasting serum but high erythrocyte folate concentrations, with high levels of serum folate oxidation products. High erythrocyte folate status is known to reflect long-term excess folic acid intake, while increased folate oxidation products suggest an increased folate degradation because obesity shows an increased activity of cytochrome P450 2E1, a monooxygenase enzyme that can use folic acid as a substrate. There is also evidence that obesity increases niacin degradation, manifested by increased activity/expression of niacin-degrading enzymes and high levels of niacin metabolites. Moreover, obesity most commonly occurs in those with a low excretory reserve capacity (e.g., due to low birth weight/preterm birth) and/or a low sweat gland activity (black race and physical inactivity). These lines of evidence raise the possibility that low fasting serum vitamin status in obesity may be a compensatory response to chronic excess vitamin intake, rather than vitamin deficiency, and that obesity could be one of the manifestations of chronic vitamin poisoning. In this article, we discuss vitamin paradox in obesity from the perspective of vitamin homeostasis.
Collapse
|
|
27
|
Hughes-Large JM, Pang DKT, Robson DL, Chan P, Toma J, Borradaile NM. Niacin receptor activation improves human microvascular endothelial cell angiogenic function during lipotoxicity. Atherosclerosis 2014; 237:696-704. [PMID: 25463108 DOI: 10.1016/j.atherosclerosis.2014.10.090] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2014] [Revised: 10/09/2014] [Accepted: 10/21/2014] [Indexed: 12/30/2022]
Abstract
OBJECTIVE Niacin (nicotinic acid) as a monotherapy can reduce vascular disease risk, but its mechanism of action remains controversial, and may not be dependent on systemic lipid modifying effects. Niacin has recently been shown to improve endothelial function and vascular regeneration, independent of correcting dyslipidemia, in rodent models of vascular injury and metabolic disease. As a potential biosynthetic precursor for NAD(+), niacin could elicit these vascular benefits through NAD(+)-dependent, sirtuin (SIRT) mediated responses. Alternatively, niacin may act through its receptor, GPR109A, to promote endothelial function, though endothelial cells are not known to express this receptor. We hypothesized that niacin directly improves endothelial cell function during exposure to lipotoxic conditions and sought to determine the potential mechanism(s) involved. METHODS AND RESULTS Angiogenic function in excess palmitate was assessed by tube formation following treatment of human microvascular endothelial cells (HMVEC) with either a relatively low concentration of niacin (10 μM), or nicotinamide mononucleotide (NMN) (1 μM), a direct NAD(+) precursor. Although both niacin and NMN improved HMVEC tube formation during palmitate overload, only NMN increased cellular NAD(+) and SIRT1 activity. We further observed that HMVEC express GRP109A. Activation of this receptor with either acifran or MK-1903 recapitulated niacin-induced improvements in HMVEC tube formation, while GPR109A siRNA diminished the effect of niacin. CONCLUSION Niacin, at a low concentration, improves HMVEC angiogenic function under lipotoxic conditions, likely independent of NAD(+) biosynthesis and SIRT1 activation, but rather through niacin receptor activation.
Collapse
Affiliation(s)
- Jennifer M Hughes-Large
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, Canada
| | - Dominic K T Pang
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, Canada
| | - Debra L Robson
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, Canada
| | - Pak Chan
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, Canada
| | - Jelena Toma
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, Canada
| | - Nica M Borradaile
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, Canada.
| |
Collapse
|
|
28
|
Ganji SH, Kamanna VS, Kashyap ML. Niacin decreases leukocyte myeloperoxidase: mechanistic role of redox agents and Src/p38MAP kinase. Atherosclerosis 2014; 235:554-61. [PMID: 24956528 DOI: 10.1016/j.atherosclerosis.2014.05.948] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2014] [Revised: 05/15/2014] [Accepted: 05/24/2014] [Indexed: 11/27/2022]
Abstract
OBJECTIVES Leukocyte myeloperoxidase (MPO) is a major player in the pathogenesis of various chronic diseases including atherosclerosis. This study proposes the novel concept that niacin, through reactive oxygen species (ROS)-mediated signaling, decreases neutrophil MPO release and its activity, protects apolipoprotein-AI (apo-AI) modification and improves HDL function. METHODS Human blood leukocytes and leukocytic cell line HL-60 cells were treated with niacin, and stimulated with phorbol myristate acetate (PMA). Cellular and released MPO activity in the medium was measured by assessing chlorination of MPO-specific substrate. MPO protein release in the medium and apo-AI degradation was measured by Western blot analysis. Monocyte adhesion to human aortic primary endothelial cells was measured to assess biological function of HDL/apo-AI. RESULTS PMA significantly increased leukocyte MPO activity in both intracellular extract and medium. Niacin (0.25-0.5 mM) decreased PMA-induced MPO activity (cellular and released in the media). Niacin also decreased MPO protein mass in the medium without affecting its mRNA expression. Increased NADPH oxidase and ROS production by PMA were also significantly inhibited by niacin. Studies with specific inhibitors suggest that ROS-dependent Src and p38MAP kinase mediate decreased MPO activity by niacin. Niacin blocked apo-AI degradation, and apo-AI from niacin treated cells decreased monocyte adhesion to aortic endothelial cells. CONCLUSIONS These findings identify niacin as a potent inhibitor of leukocyte MPO release and MPO-mediated formation of dysfunctional HDL. Niacin and niacin-related chemical entities may form important therapeutic agents for MPO-mediated inflammatory diseases.
Collapse
Affiliation(s)
- Shobha H Ganji
- Atherosclerosis Research Center, Department of Veterans Affairs Healthcare System, Long Beach, CA, USA; The University of California, Irvine, CA, USA
| | - Vaijinath S Kamanna
- Atherosclerosis Research Center, Department of Veterans Affairs Healthcare System, Long Beach, CA, USA; The University of California, Irvine, CA, USA.
| | - Moti L Kashyap
- Atherosclerosis Research Center, Department of Veterans Affairs Healthcare System, Long Beach, CA, USA; The University of California, Irvine, CA, USA.
| |
Collapse
|
|
29
|
Gender differences in pharmacokinetics of a combination tablet of niacin extended-release/simvastatin in healthy Chinese volunteers. Eur J Drug Metab Pharmacokinet 2013; 39:321-6. [PMID: 24346851 DOI: 10.1007/s13318-013-0169-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2013] [Accepted: 12/07/2013] [Indexed: 10/25/2022]
Abstract
The gender differences in pharmacokinetics of a combination tablet of niacin extended-release/simvastatin were evaluated in healthy Chinese volunteers. Thirty-six healthy male and female volunteers were enrolled in the study receiving a single oral dose of niacin extended-release/simvastatin 1,000/20 mg. The results indicated that the systemic exposure of simvastatin hydroxy acid and the total urine excretion of niacin were significantly higher for females compared with those for males, and the T max of niacin in plasma was significantly shorter for males than that for females. There were no significant differences in the systemic exposure of simvastatin, niacin, and NUA in plasma between males and females.
Collapse
|
|
30
|
Li D, Luo N, Ma Q, Li SZ, Shi Q, Cao Y, Zhou SS. Excessive nicotinic acid increases methyl consumption and hydrogen peroxide generation in rats. PHARMACEUTICAL BIOLOGY 2013; 51:8-12. [PMID: 22971213 DOI: 10.3109/13880209.2012.697175] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
CONTEXT Recent ecological evidence has showed a lag-correlation between the prevalence of diabetes and consumption of niacin (nicotinamide and nicotinic acid) in the US. Nicotinamide has been demonstrated to induce insulin resistance due to excess reactive oxygen species and methyl depletion, whereas the effect of nicotinic acid is poorly understood. OBJECTIVE To examine the mechanism of the effect of nicotinic acid on glucose metabolism. MATERIALS AND METHODS Rats were injected with different cumulative doses of nicotinic acid (0.5, 2, 4 g/kg) and nicotinamide (2 g/kg). A glucose tolerance test was given 2 h after the final injection. The role of methyl consumption and reactive oxygen species generation were evaluated by measuring N(1)-methylnicotinamide and hydrogen peroxide. RESULTS Cumulative doses of nicotinic acid produced a dose-dependent increase in the plasma levels of N(1)-methylnicotinamide and hydrogen peroxide, which was associated with a decrease in liver and skeletal muscle glycogen levels. At the same dosage (2 g/kg), in comparison with nicotinamide, nicotinic acid was weaker in raising plasma N(1)-methylnicotinamide levels (0.7 ± 0.11 µg/mL vs. 4.69 ± 0.24 µg/mL, P < 0.001), but stronger in increasing plasma hydrogen peroxide levels (1.88 ± 0.07 µmol/L vs. 1.55 ± 0.05 µmol/L, P < 0.001). Moreover, nicotinamide, unlike nicotinic acid, did not reduce liver glycogen levels. DISCUSSION AND CONCLUSION This study suggested that excessive nicotinic acid, like nicotinamide, might induce methyl consumption, oxidative stress and insulin resistance. Long-term consumption high niacin may increase the risk of type 2 diabetes.
Collapse
Affiliation(s)
- Da Li
- Department of Physiology, Institute of Basic Medical Sciences, China Medical University, Shenyang, China
| | | | | | | | | | | | | |
Collapse
|
|
31
|
Yadav R, France M, Younis N, Hama S, Ammori BJ, Kwok S, Soran H. Extended-release niacin with laropiprant: a review on efficacy, clinical effectiveness and safety. Expert Opin Pharmacother 2012; 13:1345-62. [DOI: 10.1517/14656566.2012.690395] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
|
|
32
|
Zhang LH, Kamanna VS, Ganji SH, Xiong XM, Kashyap ML. Niacin increases HDL biogenesis by enhancing DR4-dependent transcription of ABCA1 and lipidation of apolipoprotein A-I in HepG2 cells. J Lipid Res 2012; 53:941-950. [PMID: 22389325 DOI: 10.1194/jlr.m020917] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The lipidation of apoA-I in liver greatly influences HDL biogenesis and plasma HDL levels by stabilizing the secreted apoA-I. Niacin is the most effective lipid-regulating agent clinically available to raise HDL. This study was undertaken to identify regulatory mechanisms of niacin action in hepatic lipidation of apoA-I, a critical event involved in HDL biogenesis. In cultured human hepatocytes (HepG2), niacin increased: association of apoA-I with phospholipids and cholesterol by 46% and 23% respectively, formation of lipid-poor single apoA-I molecule-containing particles up to ~2.4-fold, and pre β 1 and α migrating HDL particles. Niacin dose-dependently stimulated the cell efflux of phospholipid and cholesterol and increased transcription of ABCA1 gene and ABCA1 protein. Mutated DR4, a binding site for nuclear factor liver X receptor alpha (LXR α ) in the ABCA1 promoter, abolished niacin stimulatory effect. Further, knocking down LXR α or ABCA1 by RNA interference eliminated niacin-stimulated apoA-I lipidation. Niacin treatment did not change apoA-I gene expression. The present data indicate that niacin increases apoA-I lipidation by enhancing lipid efflux through a DR4-dependent transcription of ABCA1 gene in HepG2 cells. A stimulatory role of niacin in early hepatic formation of HDL particles suggests a new mechanism that contributes to niacin action to increase the stability of newly synthesized circulating HDL.
Collapse
Affiliation(s)
- Lin-Hua Zhang
- Atherosclerosis Research Center, Veterans Affairs Healthcare System, Long Beach, CA; and the Department of Medicine, University of California, Irvine, CA; Department of Medicine, University of California, Irvine, CA.
| | - Vaijinath S Kamanna
- Atherosclerosis Research Center, Veterans Affairs Healthcare System, Long Beach, CA; and the Department of Medicine, University of California, Irvine, CA; Department of Medicine, University of California, Irvine, CA
| | - Shobha H Ganji
- Atherosclerosis Research Center, Veterans Affairs Healthcare System, Long Beach, CA; and the Department of Medicine, University of California, Irvine, CA; Department of Medicine, University of California, Irvine, CA
| | - Xi-Ming Xiong
- Atherosclerosis Research Center, Veterans Affairs Healthcare System, Long Beach, CA; and the Department of Medicine, University of California, Irvine, CA; Department of Medicine, University of California, Irvine, CA
| | - Moti L Kashyap
- Atherosclerosis Research Center, Veterans Affairs Healthcare System, Long Beach, CA; and the Department of Medicine, University of California, Irvine, CA; Department of Medicine, University of California, Irvine, CA.
| |
Collapse
|
|
33
|
Abstract
PURPOSE OF REVIEW A lipid triad involving an atherogenic dyslipidemia characterized by moderate/high LDL-C, low HDL-C, and elevated triglyceride (TG) occurs in numerous clinical settings associated with high cardiovascular risk. This article focuses on optimizing treatment of atherogenic dyslipidemias involving this lipid triad, emphasizing niacin-based or fibrate-based therapies. RECENT FINDINGS Niacin-based therapies comprehensively improve the atherogenic lipid profile, lead to atherosclerosis regression, and exert benefits across a spectrum of cardiovascular endpoints in studies based on limited patient numbers. Fibrates impact TG, HDL-C, and LDL-C according to lipid phenotype and underlying metabolic abnormality. In a recent meta-analysis, fibrates significantly reduced major cardiovascular events (-10%) and coronary events (-13%) across a wide range of lipid phenotypes, but had no impact on stroke, sudden death, or mortality. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial in type 2 diabetic patients similarly showed no significant effect of fenofibrate + simvastatin (vs. simvastatin) on nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death; a subgroup (17%) with marked atherogenic dyslipidemia trended toward benefit. Both niacin and fibrates attenuate vascular inflammation but the potential clinical relevance is indeterminate. SUMMARY Optimal cardiovascular risk reduction in patients exhibiting the lipid triad requires integrated pharmacotherapy to normalize LDL-C, HDL-C, TGs, and potentially lipoprotein(a). Ongoing studies may provide definitive evidence of the impact of niacin plus statins on cardiovascular outcomes.
Collapse
|
|
34
|
Zhou SS, Zhou YM, Li D, Lun YZ. Dietary methyl-consuming compounds and metabolic syndrome. Hypertens Res 2011; 34:1239-45. [PMID: 21814217 DOI: 10.1038/hr.2011.133] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The metabolic syndrome, a major risk factor for type 2 diabetes and cardiovascular disease, is a cluster of metabolic abnormalities including obesity, insulin resistance, hypertension and dyslipidemia. Although systemic oxidative stress and aberrant methylation status are known to have important roles in the development of metabolic syndrome, how they occur remains unclear. The metabolism of methyl-consuming compounds generates reactive oxygen species and consumes labile methyl groups; therefore, a chronic increase in the levels of methyl-consuming compounds in the body can induce not only oxidative stress and subsequent tissue injury, but also methyl-group pool depletion and subsequent aberrant methylation status. In the past few decades, the intake amount of methyl-consuming compounds has substantially increased primarily due to pollution, food additives, niacin fortification and high meat consumption. Thus, increased methyl consumers might have a causal role in the development and prevalence of metabolic syndrome and its related diseases. Moreover, factors that decrease the elimination/metabolism of methyl-consuming compounds and other xenobiotics (for example, sweat gland inactivity and decreased liver function) or increase the generation of endogenous methyl-consuming compounds (for example, mental stress-induced increase in catecholamine release) may accelerate the progression of metabolic syndrome. Based on current nutrition knowledge and the available evidence from epidemiological, ecological, clinical and laboratory studies on metabolic syndrome and its related diseases, this review outlines the relationship between methyl supply-consumption imbalance and metabolic syndrome, and proposes a novel mechanism for the pathogenesis and prevalence of metabolic syndrome and its related diseases.
Collapse
Affiliation(s)
- Shi-Sheng Zhou
- Department of Physiology, Medical College, Dalian University, Dalian, China.
| | | | | | | |
Collapse
|
|
35
|
Inamadugu JK, Damaramadugu R, Mullangi R, Ponneri V. Simultaneous determination of niacin and its metabolites--nicotinamide, nicotinuric acid and N-methyl-2-pyridone-5-carboxamide--in human plasma by LC-MS/MS and its application to a human pharmacokinetic study. Biomed Chromatogr 2011; 24:1059-74. [PMID: 20853461 DOI: 10.1002/bmc.1406] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
An LC-MS/MS method for the simultaneous quantitation of niacin (NA) and its metabolites, i.e. nicotinamide (NAM), nicotinuric acid (NUA) and N-methyl-2-pyridone-5-carboxamide (2-Pyr), in human plasma (1 mL) was developed and validated using nevirapine as an internal standard (IS). Extraction of the NA and its metabolites along with the IS from human plasma was accomplished using a simple liquid-liquid extraction. The chromatographic separation of NA, NAM, NUA, 2-Pyr and IS was achieved on a Hypersil-BDS column (150 x 4.6 mm, 5 microm) column using a mobile phase consisting of 0.1% formic acid : acetonitrile (20:80 v/v) at a flow rate of 1 mL/min. The total run time of analysis was 2 min and elution of NA, NAM, NUA, 2-Pyr and IS occurred at 1.37, 1.46, 1.40, 1.06 and 1.27 min, respectively. A detailed validation of the method was performed as per the FDA guidelines and the standard curves were found to be linear in the range of 100-20000 ng/mL for NA; 10-1600 ng/mL for NUA and NAM and 50-5000 ng/mL for 2-Pyr with mean correlation coefficient of ≥ 0.99 for each analyte. The method was sensitive, specific, precise, accurate and suitable for bioequivalence and pharmacokinetic studies. The developed assay method was successfully applied to a pharmacokinetic study in humans.
Collapse
Affiliation(s)
- Jaswanth Kumar Inamadugu
- Analytical and Environmental Chemistry Division, Department of Chemistry, Sri Venkateswara University, Tirupati-517 502, India
| | | | | | | |
Collapse
|
|
36
|
Mullangi R, Srinivas NR. Niacin and its metabolites: role of LC-MS/MS bioanalytical methods and update on clinical pharmacology. An overview. Biomed Chromatogr 2010; 25:218-37. [PMID: 21204112 DOI: 10.1002/bmc.1522] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2010] [Accepted: 08/11/2010] [Indexed: 01/08/2023]
Abstract
Niacin (nicotinic acid), although an old drug, has seen a sudden surge in popularity for treatment of lipid disorders and other associated clinical conditions for the prevention of cardiovascular risk. Also, there has been considerable interest in clarifying the role of metabolic pathways of niacin in explaining the tolerability/adverse affect profile of the agent. Hence, it has become very important to quantify/monitor the levels of niacin and its metabolites in various clinical studies. This review describes the recent trends in the bioanalysis of niacin and its metabolites, where HPLC and LC-MS/MS assays have been successfully employed to measure the drug levels in various biological matrices arising from preclinical and clinical studies. In addition, this review encompass various considerations such as internal standard selection, extraction schemes, matrix effect, selectivity evaluation and optimization of mass spectral conditions to enable the development of sound bioanalytical methods for niacin alone or niacin along with its metabolites. Recent updates pertaining to the clinical pharmacology of niacin and ongoing debate for the clarification of adverse effects are also provided. Overall LC-MS/MS methods have proven to be choice of bioanalytical method for the quantification of niacin alone or with its metabolites in both preclinical and clinical studies.
Collapse
Affiliation(s)
- Ramesh Mullangi
- Drug Metabolism and Pharmacokinetics, Jubilant Biosys Ltd, Industrial Suburb, Yeshwanthpur, Bangalore-560 022, India.
| | | |
Collapse
|
|
37
|
Montecucco F, Quercioli A, Dallegri F, Viviani GL, Mach F. New evidence for nicotinic acid treatment to reduce atherosclerosis. Expert Rev Cardiovasc Ther 2010; 8:1457-1467. [PMID: 20936932 DOI: 10.1586/erc.10.116] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Nicotinic acid (at a daily dose of grams) has been shown to induce potent anti-atherosclerotic effects in human and animal models. Evidence from clinical studies performed in the 1950s has shown that nicotinic acid treatment remarkably improves the plasma lipid profile. Large clinical studies showed that nicotinic acid improves clinical cardiovascular outcomes. Given the protective effects of niacin, basic research studies were designed to explore additional anti-atherosclerotic pathways, such as those involved in cardiovascular inflammation. After the discovery of the nicotinic acid receptor GPR109A on adipocytes and immune cells, novel direct immunomodulatory properties of nicotinic acid have been identified. Importantly, the regulation of the release of inflammatory mediators from adipose tissue was observed, independent of lipid level amelioration. Less is known about the possible direct anti-inflammatory activities of nicotinic acid in other cells (such as hepatocytes, endothelial and vascular cells) previously indicated as key players in atherogenesis. Thus, further studies are needed to clarify this promising topic. Emerging evidence from clinical and basic research studies indicates that novel direct anti-atherosclerotic properties might mediate nicotinic acid-induced cardiovascular protection. Despite some limitations in its clinical use (mainly due to the incidence of adverse events, such as cutaneous flushing and hepatotoxicity), nicotinic acid should be considered as a very potent therapeutic approach to reduce atherosclerosis. Promising research developments are warranted in the near future.
Collapse
Affiliation(s)
- Fabrizio Montecucco
- Cardiology Division, Department of Medicine, Geneva University Hospital, Foundation for Medical Research, 64 Avenue Roseraie, Geneva, Switzerland.
| | | | | | | | | |
Collapse
|
|
38
|
Zheng X, Polli JE. Synthesis and in vitro evaluation of potential sustained release prodrugs via targeting ASBT. Int J Pharm 2010; 396:111-8. [PMID: 20600720 PMCID: PMC2912288 DOI: 10.1016/j.ijpharm.2010.06.039] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2010] [Revised: 06/03/2010] [Accepted: 06/18/2010] [Indexed: 11/23/2022]
Abstract
The objective was to synthesize prodrugs of niacin and ketoprofen that target the human apical sodium-dependent bile acid transporter (ASBT) and potentially allow for prolonged drug release. Each drug was conjugated to the naturally occurring bile acid chenodeoxycholic acid (CDCA) using lysine as a linker. Their inhibitory binding and transport properties were evaluated in stably transfected ASBT-MDCK monolayers, and the kinetic parameters K(i), K(t), normJ(max), and P(p) were characterized. Enzymatic stability of the conjugates was evaluated in Caco-2 and liver homogenate. Both conjugates were potent inhibitors of ASBT. For the niacin prodrug, substrate kinetic parameter K(t) was 8.22microM and normJ(max) was 0.0917. In 4h, 69.4% and 26.9% of niacin was released from 1microM and 5microM of the conjugate in Caco-2 homogenate, respectively. For the ketoprofen prodrug, K(t) was 50.8microM and normJ(max) was 1.58. In 4h, 5.94% and 3.73% of ketoprofen was released from 1microM and 5microM of the conjugate in Caco-2 homogenate, and 24.5% and 12.2% of ketoprofen was released in liver homogenate, respectively. In vitro results showed that these bile acid conjugates are potential prolonged release prodrugs with binding affinity for ASBT.
Collapse
Affiliation(s)
- Xiaowan Zheng
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland, 21201
| | - James E. Polli
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland, 21201
| |
Collapse
|
|
39
|
Pharmacokinetics of laropiprant and glucuronide metabolite in patients with severe renal insufficiency. Am J Ther 2010; 16:379-84. [PMID: 19433974 DOI: 10.1097/mjt.0b013e318197c59d] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Flushing symptoms limit the use of niacin as an effective treatment for dyslipidemia; laropiprant, a prostaglandin D2 receptor subtype 1 antagonist, reduces niacin-induced flushing and is being developed in combination with niacin. The aims of this study were to both determine the effect of renal insufficiency on plasma pharmacokinetics of laropiprant and to assess safety and tolerability in patients with severe renal insufficiency. This open-label study compared the pharmacokinetics of a single laropiprant 40-mg dose in 8 nondialyzed, severe renal insufficiency patients (RIs) with healthy matched subjects (HSs) (24-hour creatinine clearance <30 mL/min/1.73 m(2) and >80 mL/min/1.73 m(2) for RIs and HSs, respectively). In RIs, laropiprant was well tolerated and the area under the concentration time curve (AUC(0-infinity)) was modestly higher (ratio of geometric least-squares means [GMR] for RIs to HSs was 1.58; 90% confidence interval [CI], 1.06-2.35); neither the maximum laropiprant plasma concentration (C(max)) nor the time to C(max) (T(max)) was significantly affected. The apparent terminal half-life (t(1/2)) was 26.0 and 14.8 hours for RIs and HSs, respectively (P = 0.007). Similarly, for the inactive laropiprant glucuronide metabolite, the GMR for AUC(0-infinity) was 2.17 (90% CI, 1.44-3.27), and the apparent t(1/2) values were 25.3 to 14.5 hours (P = 0.037) in RIs and HSs, respectively. Renal insufficiency had no clinically significant effect on laropiprant pharmacokinetics. Because niacin and its metabolites are excreted through the kidneys, the combination of niacin with laropiprant should be used with caution in patients with renal impairment.
Collapse
|
|
40
|
Chapman MJ, Redfern JS, McGovern ME, Giral P. Niacin and fibrates in atherogenic dyslipidemia: pharmacotherapy to reduce cardiovascular risk. Pharmacol Ther 2010; 126:314-45. [PMID: 20153365 DOI: 10.1016/j.pharmthera.2010.01.008] [Citation(s) in RCA: 155] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2010] [Accepted: 01/15/2010] [Indexed: 12/16/2022]
Abstract
Although statin therapy represents a cornerstone of cardiovascular disease (CVD) prevention, a major residual CVD risk (60-70% of total relative risk) remains, attributable to both modifiable and non-modifiable risk factors. Among the former, low levels of HDL-C together with elevated triglyceride (TG)-rich lipoproteins and their remnants represent major therapeutic targets. The current pandemic of obesity, metabolic syndrome, and type 2 diabetes is intimately associated with an atherogenic dyslipidemic phenotype featuring low HDL-C combined with elevated TG-rich lipoproteins and small dense LDL. In this context, there is renewed interest in pharmacotherapeutic strategies involving niacin and fibrates in monotherapy and in association with statins. This comprehensive, critical review of available data in dyslipidemic subjects indicates that niacin is more efficacious in raising HDL-C than fibrates, whereas niacin and fibrates reduce TG-rich lipoproteins and LDL comparably. Niacin is distinguished by its unique capacity to effectively lower Lp(a) levels. Several studies have demonstrated anti-atherosclerotic action for both niacin and fibrates. In contrast with statin therapy, the clinical benefit of fibrates appears limited to reduction of nonfatal myocardial infarction, whereas niacin (frequently associated with statins and/or other agents) exerts benefit across a wider range of cardiovascular endpoints in studies involving limited patient numbers. Clearly the future treatment of atherogenic dyslipidemias involving the lipid triad, as exemplified by the occurrence of the mixed dyslipidemic phenotype in metabolic syndrome, type 2 diabetes, renal, and auto-immune diseases, requires integrated pharmacotherapy targeted not only to proatherogenic particles, notably VLDL, IDL, LDL, and Lp(a), but also to atheroprotective HDL.
Collapse
Affiliation(s)
- M John Chapman
- Dyslipidemia, Inflammation and Atherosclerosis Research Unit, UMR-S939, National Institute for Health and Medical Research (INSERM), Hôpital de la Pitié-Salpetriere, Paris, France.
| | | | | | | |
Collapse
|
|
41
|
Sood A, Arora R. Mechanisms of Flushing Due to Niacin and Abolition of These Effects. J Clin Hypertens (Greenwich) 2009; 11:685-9. [DOI: 10.1111/j.1559-4572.2008.00050.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
|
|
42
|
Berns JS. Editorials: Niacin and Related Compounds for Treating Hyperphosphatemia in Dialysis Patients. Semin Dial 2008; 21:203-5. [DOI: 10.1111/j.1525-139x.2008.00426.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
|