nicotinamide-beta-riboside and Inflammation

Nicotinamide adenine dinucleotide (NAD+) is an essential pyridine nucleotide that is present in all living cells. NAD+ acts as an important cofactor and substrate for a multitude of biological processes including energy production, DNA repair, gene expression, calcium-dependent secondary messenger signalling and immunoregulatory roles. The de novo synthesis of NAD+ is primarily dependent on the kynurenine pathway (KP), although NAD+ can also be recycled from nicotinic acid (NA), nicotinamide (NAM) and nicotinamide riboside (NR). NAD+ levels have been reported to decline during ageing and age-related diseases. Recent studies have shown that raising intracellular NAD+ levels represents a promising therapeutic strategy for age-associated degenerative diseases in general and to extend lifespan in small animal models. A systematic review of the literature available on Medline, Embase and Pubmed was undertaken to evaluate the potential health and/or longevity benefits due to increasing NAD+ levels. A total of 1545 articles were identified and 147 articles (113 preclinical and 34 clinical) met criteria for inclusion. Most studies indicated that the NAD+ precursors NAM, NR, nicotinamide mononucleotide (NMN), and to a lesser extent NAD+ and NADH had a favourable outcome on several age-related disorders associated with the accumulation of chronic oxidative stress, inflammation and impaired mitochondrial function. While these compounds presented with a limited acute toxicity profile, evidence is still quite limited and long-term human clinical trials are still nascent in the current literature. Potential risks in raising NAD+ levels in various clinical disorders using NAD+ precursors include the accumulation of putative toxic metabolites, tumorigenesis and promotion of cellular senescence. Therefore, NAD+ metabolism represents a promising target and further studies are needed to recapitulate the preclinical benefits in human clinical trials.

Topics: Aging; Animals; Humans; Inflammation; Mice; NAD; Neurodegenerative Diseases; Niacinamide; Nicotinamide Mononucleotide; Oxidative Stress; Pyridinium Compounds; Rats; Risk Assessment

The prevalence of NAFLD is increasing globally and on a path to becoming the most frequent cause of chronic liver disease. Strategies for the prevention and treatment of NAFLD are urgently needed.. A 6-month prospective, randomized, double-blind, placebo-controlled clinical trial was conducted to assess the efficacy of daily NRPT (commercially known as Basis, a combination of nicotinamide riboside and pterostilbene) supplementation in 111 adults with NAFLD. The study consisted of three arms: placebo, recommended daily dose of NRPT (NRPT 1×), and a double dose of NRPT (NRPT 2×). NRPT appeared safe and well tolerated. At the end of the study, no significant change was seen in the primary endpoint of hepatic fat fraction with respect to placebo. However, among prespecified secondary outcomes, a time-dependent decrease in the circulating levels of the liver enzymes alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) was observed in the NRPT 1× group, and this decrease was significant with respect to placebo. Furthermore, a significant decrease in the circulating levels of the toxic lipid ceramide 14:0 was also observed in the NRPT 1× group versus placebo, and this decrease was associated with a decrease in ALT in individuals of this group. A dose-dependent effect was not observed with respect to ALT, GGT, or ceramide 14:0 in the NRPT 2× group.. This study demonstrates that NRPT at the recommended dose is safe and may hold promise in lowering markers of hepatic inflammation in patients with NAFLD.

Topics: Adult; Alanine Transaminase; Double-Blind Method; gamma-Glutamyltransferase; Humans; Inflammation; Non-alcoholic Fatty Liver Disease; Prospective Studies

BACKGROUNDWhile mitochondria play an important role in innate immunity, the relationship between mitochondrial dysfunction and inflammation in heart failure (HF) is poorly understood. In this study we aimed to investigate the mechanistic link between mitochondrial dysfunction and inflammatory activation in peripheral blood mononuclear cells (PBMCs), and the potential antiinflammatory effect of boosting the NAD level.METHODSWe compared the PBMC mitochondrial respiration of 19 hospitalized patients with stage D HF with that of 19 healthy participants. We then created an in vitro model of sterile inflammation by treating healthy PBMCs with mitochondrial damage-associated molecular patterns (MitoDAMPs) isolated from human heart tissue. Last, we enrolled patients with stage D HF and sampled their blood before and after taking 5 to 9 days of oral nicotinamide riboside (NR), a NAD precursor.RESULTSWe demonstrated that HF is associated with both reduced respiratory capacity and elevated proinflammatory cytokine gene expressions. In our in vitro model, MitoDAMP-treated PBMCs secreted IL-6 that impaired mitochondrial respiration by reducing complex I activity. Last, oral NR administration enhanced PBMC respiration and reduced proinflammatory cytokine gene expression in 4 subjects with HF.CONCLUSIONThese findings suggest that systemic inflammation in patients with HF is causally linked to mitochondrial function of the PBMCs. Increasing NAD levels may have the potential to improve mitochondrial respiration and attenuate proinflammatory activation of PBMCs in HF.TRIAL REGISTRATIONClinicalTrials.gov NCT03727646.FUNDINGThis study was funded by the NIH, the University of Washington, and the American Heart Association.

Topics: Female; Heart Failure; Humans; Inflammation; Leukocytes, Mononuclear; Male; Mitochondria, Heart; Models, Cardiovascular; NAD; Niacinamide; Oxygen Consumption; Pyridinium Compounds

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Ethanol; Inflammation; Macrophages; Mice; Niacinamide; Oxidative Stress; Pyridinium Compounds; RAW 264.7 Cells; Sirtuin 1

Neuroinflammation is initiated by activation of the brain's innate immune system in response to an inflammatory challenge. Insufficient control of neuroinflammation leads to enhanced or prolonged pathology in various neurological conditions including multiple sclerosis and Alzheimer's disease. Nicotinamide adenine dinucleotide (NAD

Topics: ADP-ribosyl Cyclase 1; Animals; Apigenin; Astrocytes; Chemokines; Cytokines; Gene Deletion; Hippocampus; Inflammation; Injections, Intraventricular; Lipopolysaccharides; Macrophage Activation; Male; Membrane Glycoproteins; Mice; Mice, Inbred ICR; Mice, Knockout; Microglia; NAD; Nerve Degeneration; NF-kappa B; Niacinamide; Pyridinium Compounds

Topoisomerase 1 (TOP1) relieves torsional stress in DNA during transcription and facilitates the expression of long (>100 kb) genes, many of which are important for neuronal functions. To evaluate how loss of Top1 affected neurons in vivo, we conditionally deleted (cKO) Top1 in postmitotic excitatory neurons in the mouse cerebral cortex and hippocampus. Top1 cKO neurons develop properly, but then show biased transcriptional downregulation of long genes, signs of DNA damage, neuroinflammation, increased poly(ADP-ribose) polymerase-1 (PARP1) activity, single-cell somatic mutations, and ultimately degeneration. Supplementation of nicotinamide adenine dinucleotide (NAD

Topics: Animals; Apoptosis; Cerebral Cortex; DNA Damage; DNA Topoisomerases, Type I; Genomic Instability; Hippocampus; Inflammation; Mice; Mice, Knockout; Mortality, Premature; Motor Activity; Mutation; NAD; Neurodegenerative Diseases; Neurons; Niacinamide; Poly (ADP-Ribose) Polymerase-1; Pyridinium Compounds

Chronic alcohol abuse is common and a leading cause of alcoholic liver disease (ALD). However, a safe and effective therapy for ALD is still elusive. In this study, we evaluated the utility of adult zebrafish as an in vivo model for rapid assessment of drug efficacy in ethanol-induced acute hepatic injury. We exposed adult zebrafish to 0.5 % ethanol for 24, 48, and 72 hours and measured serum alanine aminotransferase (ALT) activities. This treatment resulted in a significant increase in ALT levels at 48 and 72 h of ethanol treatment, compared to untreated control groups. Accompanying this, significant increases in mRNA expression of genes associated with inflammation was observed in the liver during ethanol exposure. To evaluate the effectiveness of drug testing using our zebrafish model for ethanol-induced acute hepatic injury, we investigated the protective function of nicotinamide riboside, a substrate for NAD

Topics: Alanine Transaminase; Alcoholism; Animals; Disease Models, Animal; Ethanol; Gene Expression Regulation; Inflammation; Liver Diseases, Alcoholic; Niacinamide; Pyridinium Compounds; Riboflavin; Time Factors; Zebrafish

Topics: Adipose Tissue, White; Animals; Blood Glucose; Diet, High-Fat; Dose-Response Relationship, Drug; Energy Metabolism; Glucose Intolerance; Glucose Tolerance Test; Inflammation; Male; Mice; Niacinamide; Obesity; PPAR gamma; Pyridinium Compounds

NAD is an obligate co-factor for the catabolism of metabolic fuels in all cell types. However, the availability of NAD in several tissues can become limited during genotoxic stress and the course of natural aging. The point at which NAD restriction imposes functional limitations on tissue physiology remains unknown. We examined this question in murine skeletal muscle by specifically depleting Nampt, an essential enzyme in the NAD salvage pathway. Knockout mice exhibited a dramatic 85% decline in intramuscular NAD content, accompanied by fiber degeneration and progressive loss of both muscle strength and treadmill endurance. Administration of the NAD precursor nicotinamide riboside rapidly ameliorated functional deficits and restored muscle mass despite having only a modest effect on the intramuscular NAD pool. Additionally, lifelong overexpression of Nampt preserved muscle NAD levels and exercise capacity in aged mice, supporting a critical role for tissue-autonomous NAD homeostasis in maintaining muscle mass and function.

Topics: Administration, Oral; Aging; Animals; Biological Availability; Energy Metabolism; Glucose; Homeostasis; Inflammation; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Muscle Strength; Muscle, Skeletal; NAD; Necrosis; Niacinamide; Nicotinamide Phosphoribosyltransferase; Organ Size; Physical Conditioning, Animal; Pyridinium Compounds; Transcription, Genetic

Low-grade chronic inflammation (metaflammation) is a major contributing factor for the onset and development of metabolic diseases, such as type 2 diabetes, obesity, and cardiovascular disease. Nicotinamide riboside (NR), which is present in milk and beer, is a functional vitamin B3 having advantageous effects on metabolic regulation. However, the anti-inflammatory capacity of NR is unknown. This study evaluated whether NR modulates hepatic nucleotide binding and oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome. Male, 8-week-old KK/HlJ mice were allocated to the control or NR group. NR (100 mg/kg/day) or vehicle (phosphate-buffered saline) was administrated by an osmotic pump for 7 days. Glucose control, lipid profiles, NLRP3 inflammasome, and inflammation markers were analyzed, and structural and histological analyses were conducted. NR treatment did not affect body weight gain, food intake, and liver function. Glucose control based on the oral glucose tolerance test and levels of serum insulin and adiponectin was improved by NR treatment. Among tested lipid profiles, NR lowered the total cholesterol concentration in the liver. Histological and structural analysis by hematoxylin and eosin staining and transmission electron microscopy, respectively, showed that NR rescued the disrupted cellular integrity of the mitochondria and nucleus in the livers of obese and diabetic KK mice. In addition, NR treatment significantly improved hepatic proinflammatory markers, including tumor necrosis factor-alpha, interleukin (IL)-6, and IL-1. These ameliorations were accompanied by significant shifts of NLRP3 inflammasome components (NLRP3, ASC, and caspase1). These results demonstrate that NR attenuates hepatic metaflammation by modulating the NLRP3 inflammasome.

Topics: Adiponectin; Animals; Anti-Inflammatory Agents; Apoptosis Regulatory Proteins; Blood Glucose; CARD Signaling Adaptor Proteins; Carrier Proteins; Caspase 1; Cholesterol; Diabetes Mellitus, Type 2; Disease Models, Animal; Inflammasomes; Inflammation; Insulin; Interleukin-1beta; Liver; Male; Mice; Niacinamide; NLR Family, Pyrin Domain-Containing 3 Protein; Obesity; Pyridinium Compounds; Tumor Necrosis Factor-alpha; Vitamin B Complex