nicotinamide-beta-riboside and Disease-Models--Animal

Alterations in cellular nicotinamide adenine dinucleotide (NAD

Topics: Animals; Disease Models, Animal; Mice; NAD; Niacinamide; Pyridinium Compounds

Despite the progress in the development of new anticancer strategies, cancer is rapidly spreading around the world and remains one of the most common diseases. For more than 40 years, doxorubicin has been widely used in the treatment of solid and hematological tumors. At the same time, the problem of its cardiotoxicity remains unresolved, despite the high efficiency of this drug. Symptomatic therapy is used as a treatment for side-effects of doxorubicin or pathological conditions that have already appeared in their background. To date, there are no treatment methods for doxorubicin cardiomyopathy as such. A drug such as nicotinamide riboside can play an important role in solving this problem. Nicotinamide riboside is a pyridine nucleoside similar to vitamin B3 that acts as a precursor to NAD

Topics: Animals; Antibiotics, Antineoplastic; Biomarkers; Cardiomyopathies; Cardiotonic Agents; Cardiotoxicity; Disease Management; Disease Models, Animal; Disease Susceptibility; Doxorubicin; Humans; Metabolic Networks and Pathways; NAD; Niacinamide; Oxidative Stress; Pyridinium Compounds; Signal Transduction; Sirtuins

The present review aims to address the clinical benefits of using nicotinamide riboside, a precursor to the essential pyridine nucleotide, nicotinamide adenine dinucleotide (NAD+) as a therapeutic agent to attenuate age-related cognitive decline.. Oral supplementation with nicotinamide riboside can inhibit the accumulation of pathological hallmarks of Alzheimer's disease and improve learning and memory in various murine models for dementia. Nicotinamide riboside can also reduce DNA damage, neuroinflammation, apoptosis, and improved hippocampal synaptic plasticity in diabetic mice, and another Alzheimer's disease mouse model. The cognitive benefits of nicotinamide riboside in Alzheimer's disease models may be modulated in part by upregulation of proliferator-activated-γ coactivator 1α-mediated β-secretase 1(BACE-1) ubiquitination and degradation, preventing Aβ production in the brain. Nicotinamide riboside also maintained blood-brain barrier integrity and maintained the gut microbiota in a mouse model for cerebral small vessel disease and alcohol-induced depression, respectively. Oral nicotinamide riboside has been shown to be bioavailable and well tolerated in humans with limited adverse effects compared to other NAD+ precursors.. Oral nicotinamide riboside may represent a promising stratagem to improve cognitive decline during 'normal' ageing, Alzheimer's disease and other diseases. Results from recent clinical trials are needed to enumerate the preclinical benefits in humans.

Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Brain; Cognitive Aging; Cognitive Dysfunction; Dietary Supplements; Disease Models, Animal; Humans; Mice; Niacinamide; Pyridinium Compounds

This review focuses upon the biology and metabolism of a trace component in foods called nicotinamide riboside. Nicotinamide riboside is a precursor of nicotinamide adenine dinucleotide (NAD), and is a source of Vitamin B3. Evidence indicates that nicotinamide riboside has unique properties as a Vitamin B3. We review knowledge of the metabolism of this substance, as well as recent work suggesting novel health benefits that might be associated with nicotinamide riboside taken in larger quantities than is found naturally in foods.. Recent work investigating the effects of nicotinamide riboside in yeast and mammals established that it is metabolized by at least two types of metabolic pathways. The first of these is degradative and produces nicotinamide. The second pathway involves kinases called nicotinamide riboside kinases (Nrk1 and Nrk2, in humans). The likely involvement of the kinase pathway is implicated in the unique effects of nicotinamide riboside in raising tissue NAD concentrations in rodents and for potent effects in eliciting insulin sensitivity, mitochondrial biogenesis, and enhancement of sirtuin functions. Additional studies with nicotinamide riboside in models of Alzheimer's disease indicate bioavailability to brain and protective effects, likely by stimulation of brain NAD synthesis.. Initial studies have clarified the potential for a lesser-known Vitamin B3 called nicotinamide riboside that is available in selected foods, and possibly available to humans by supplements. It has properties that are insulin sensitizing, enhancing to exercise, resisting to negative effects of high-fat diet, and neuroprotecting.

Topics: Alzheimer Disease; Animals; Brain; Disease Models, Animal; Energy Metabolism; Humans; Insulin Resistance; Intracellular Signaling Peptides and Proteins; Mitochondrial Turnover; Muscle, Skeletal; NAD; Neuroprotective Agents; Niacinamide; Phosphotransferases (Alcohol Group Acceptor); Pyridinium Compounds

Nicotinamide adenine dinucleotide (NAD+) is involved in regulating oxidative stress. Although NAD+ is associated with various health issues, its role in the intestinal microcirculation in necrotizing enterocolitis (NEC) remains to be confirmed. In the current study, we explored whether nicotinamide riboside (NR), a natural NAD + precursor, ameliorates the severity of NEC through endothelial nitric oxide synthase(eNOS) signaling.. A mouse experimental NEC model was induced by formula gavage and hypoxia in full-term mouse pups. Intestinal endothelial cells (MIMECs) were isolated and subjected to stress using tumor necrosis factor (TNF)-α. NR was administered to assess the intestinal microcirculation and lipid peroxidation levels and to explore the involved signaling pathways.. NAD + levels were reduced after induction of NEC stress, which was associated with intestinal injury. NR administration promoted NAD + levels, attenuated oxidative stress and relieved the symptoms of experimental NEC, which were relevant to increased intestinal microcirculatory perfusion through the sirtuin (SIRT) 1 pathway in experimental NEC mice. However, this improvement was not found in eNOS-knockout mice. Consistently, MIMECs exposed to TNFα showed decreased SIRT1 activity associated with increased eNOS acetylation, which could bring about endothelial dysfunction due to limited nitric oxide production. NR administration increased the NAD + content and repressed the production of reactive oxygen species (ROS) in MIMECs under TNFα stress. NR also promoted SIRT1 activity and accordingly suppressed the eNOS acetylation levels under TNFα stress.. The current data indicate that NR administration improves the survival of experimental NEC mice via SIRT1-associated eNOS acetylation/deacetylation modulation, which is implicated in endothelial dysfunction. Although NR is commonly found in the human diet, it may also be a promising strategy for NEC treatment because of its pathogenic association with NEC.

Topics: Animals; Disease Models, Animal; Endothelial Cells; Enterocolitis, Necrotizing; Mice; Microcirculation; NAD; Niacinamide; Nitric Oxide Synthase Type III; Pyridinium Compounds; Sirtuin 1; Tumor Necrosis Factor-alpha

Nicotinamide adenine dinucleotide (NAD+) is a ubiquitous coenzyme involved in electron transport and a co-substrate for sirtuin function. NAD+ deficiency has been demonstrated in the context of acute kidney injury (AKI).. We studied the expression of key NAD+ biosynthesis enzymes in kidney biopsies from human allograft patients and patients with chronic kidney disease (CKD) at different stages. We used ischaemia-reperfusion injury (IRI) and cisplatin injection to model AKI, urinary tract obstruction [unilateral ureteral obstruction (UUO)] and tubulointerstitial fibrosis induced by proteinuria to investigate CKD in mice. We assessed the effect of nicotinamide riboside (NR) supplementation on AKI and CKD in animal models.. RNA sequencing analysis of human kidney allograft biopsies during the reperfusion phase showed that the NAD+de novo synthesis is impaired in the immediate post-transplantation period, whereas the salvage pathway is stimulated. This decrease in de novo NAD+ synthesis was confirmed in two mouse models of IRI where NR supplementation prevented plasma urea and creatinine elevation and tubular injury. In human biopsies from CKD patients, the NAD+de novo synthesis pathway was impaired according to CKD stage, with better preservation of the salvage pathway. Similar alterations in gene expression were observed in mice with UUO or chronic proteinuric glomerular disease. NR supplementation did not prevent CKD progression, in contrast to its efficacy in AKI.. Impairment of NAD+ synthesis is a hallmark of AKI and CKD. NR supplementation is beneficial in ischaemic AKI but not in CKD models.

Topics: Acute Kidney Injury; Animals; Antineoplastic Agents; Cisplatin; Disease Models, Animal; Disease Progression; Humans; Male; Mice; Mice, Inbred C57BL; Niacinamide; Pyridinium Compounds; Renal Insufficiency, Chronic; Reperfusion Injury

Senescence phenotypes and mitochondrial dysfunction are implicated in aging and in premature aging diseases, including ataxia telangiectasia (A-T). Loss of mitochondrial function can drive age-related decline in the brain, but little is known about whether improving mitochondrial homeostasis alleviates senescence phenotypes. We demonstrate here that mitochondrial dysfunction and cellular senescence with a senescence-associated secretory phenotype (SASP) occur in A-T patient fibroblasts, and in ATM-deficient cells and mice. Senescence is mediated by stimulator of interferon genes (STING) and involves ectopic cytoplasmic DNA. We further show that boosting intracellular NAD

Topics: Animals; Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; Case-Control Studies; Cell Line, Tumor; Dietary Supplements; Disease Models, Animal; Female; Fibroblasts; Humans; Male; Membrane Proteins; Mice; Mice, Knockout; Mitochondria; Mitophagy; NAD; Neurons; Niacinamide; Pyridinium Compounds; Rats; Rats, Sprague-Dawley; Senescence-Associated Secretory Phenotype; Signal Transduction; Transfection; Treatment Outcome

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Topics: Acetylation; Acyl-CoA Dehydrogenase; Animals; Disease Models, Animal; Down-Regulation; Fatty Acids; Heart Failure, Diastolic; Humans; Ketone Oxidoreductases; Male; Mice; Mice, Inbred C57BL; Mitochondria, Heart; Mitochondrial Myopathies; NAD; Niacinamide; Oxidation-Reduction; Oxygen Consumption; Pyridinium Compounds; Sirtuin 3

Supplementation with precursors of NAD has been shown to prevent and reverse insulin resistance, mitochondrial dysfunction, and liver damage in mouse models of diet-induced obesity. We asked whether the beneficial effects of supplementation with the NAD precursor nicotinamide riboside (NR) are dependent on mouse strain. We compared the effects of NR supplementation on whole-body energy metabolism and mitochondrial function in mildly obese C57BL/6N and C57BL/6J mice, two commonly used strains to investigate metabolism. Male C57BL/6N and C57BL/6J mice were fed a high-fat diet (HFD) or standard chow with or without NR supplementation for 8 weeks. Body and organ weights, glucose tolerance, and metabolic parameters as well as mitochondrial O2 flux in liver and muscle fibers were assessed. We found that NR supplementation had no influence on body or organ weight, glucose metabolism or hepatic lipid accumulation, energy expenditure, or metabolic flexibility but increased mitochondrial respiration in soleus muscle in both mouse strains. Strain-dependent differences were detected for body and fat depot weight, fasting blood glucose, hepatic lipid accumulation, and energy expenditure. We conclude that, in mild obesity, NR supplementation does not alter metabolic phenotype in two commonly used laboratory mouse strains.

Topics: Animals; Cell Respiration; Diet, High-Fat; Disease Models, Animal; Drug Evaluation; Energy Metabolism; Glucose Intolerance; Lipid Metabolism; Liver; Male; Mice, Inbred C57BL; Muscle, Skeletal; Niacinamide; Obesity; Pyridinium Compounds

The gut microbiota play an important role in many central nervous system diseases through the gut microbiota-brain axis. Recent studies suggest that nicotinamide riboside (NR) has neuroprotective properties. However, it is unknown whether NR can prevent or protect against alcohol-induced depression. Furthermore, it is unclear whether its therapeutic action involves changes in the composition of the gut microbiome. Here, we investigated the effects of NR in the mouse model of alcohol-induced depression. Treatment with NR improved the alcohol-induced depressive behaviour in mice. In addition, NR decreased the number of activated microglia in the hippocampus, and it reduced the levels of pro-inflammatory (IL-1β, IL-6, and TNF-α) and anti-inflammatory (IL-10 and TGF-β) cytokines in the brain of mice with alcohol-induced depression. Furthermore, NR significantly upregulated BDNF and diminished the inhibition of the AKT/GSK3β/β-catenin signalling pathway in the hippocampus of these mice. 16S rRNA sequencing revealed that, compared with control and NR-treated mice, the gut microbiome richness and composition were significantly altered in the depressed mice. Spearman's correlation analysis showed that differential gut bacterial genera correlated with the levels of inflammation-related cytokines and BDNF in the brain. After faecal microbiota transplantation, cognitive behaviours, microglial activity, levels of cytokines and BDNF, and activation state of the AKT/GSK3β/β-catenin signalling pathway (which is downstream of the BDNF receptor, TrkB) in recipient mice were similar to those in donor mice. Collectively, our findings show that NR dietary supplementation protects against alcohol-induced depression-like behaviours, possibly by altering the composition of the gut microbiota.

Topics: Animals; Brain-Derived Neurotrophic Factor; Cytokines; Depression; Disease Models, Animal; Ethanol; Gastrointestinal Microbiome; Hippocampus; Male; Mice; Mice, Inbred C57BL; Microglia; Niacinamide; Pyridinium Compounds; RNA, Ribosomal, 16S

Gulf War Illness (GWI) affects 30% of veterans from the 1991 Gulf War (GW), who suffer from symptoms that reflect ongoing mitochondria dysfunction. Brain mitochondria bioenergetics dysfunction in GWI animal models corresponds with astroglia activation and neuroinflammation. In a pilot study of GW veterans (n = 43), we observed that blood nicotinamide adenine dinucleotide (NAD) and sirtuin 1 (Sirt1) protein levels were decreased in the blood of veterans with GWI compared to healthy GW veterans. Since nicotinamide riboside (NR)-mediated targeting of Sirt1 is shown to improve mitochondria function, we tested whether NR can restore brain bioenergetics and reduce neuroinflammation in a GWI mouse model. We administered a mouse diet supplemented with NR at 100μg/kg daily for 2-months to GWI and control mice (n = 27). During treatment, mice were assessed for fatigue-type behavior using the Forced Swim Test (FST), followed by euthanasia for biochemistry and immunohistochemistry analyses. Fatigue-type behavior was elevated in GWI mice compared to control mice and lower in GWI mice treated with NR compared to untreated GWI mice. Levels of plasma NAD and brain Sirt1 were low in untreated GWI mice, while GWI mice treated with NR had higher levels, similar to those of control mice. Deacetylation of the nuclear-factor κB (NFκB) p65 subunit and peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) was an increase in the brains of NR-treated GWI mice. This corresponded with a decrease in pro-inflammatory cytokines and lipid peroxidation and an increase in markers of mitochondrial bioenergetics in the brains of GWI mice. These findings suggest that targeting NR mediated Sirt1 activation restores brain bioenergetics and reduces inflammation in GWI mice. Further evaluation of NR in GWI is warranted to determine its potential efficacy in treating GWI.

Topics: Aged; Animals; Anti-Inflammatory Agents; Astrocytes; Behavior, Animal; Brain; Case-Control Studies; Disease Models, Animal; Energy Metabolism; Fatigue; Female; Gulf War; Humans; Male; Mice, Inbred C57BL; Middle Aged; Mitochondria; NAD; Niacinamide; Organelle Biogenesis; Oxidative Stress; Persian Gulf Syndrome; Pilot Projects; Pyridinium Compounds; Sirtuin 1; Veterans Health

Oxytocin (OT) is a critical molecule for social recognition and memory that mediates social and emotional behaviours. In addition, OT acts as an anxiolytic factor and is released during stress. Based on the activity of CD38 as an enzyme that produces the calcium-mobilizing second messenger cyclic ADP-ribose (cADPR), CD157, a sister protein of CD38, has been considered a candidate mediator for the production and release of OT and its social engagement and anti-anxiety functions. However, the limited expression of CD157 in the adult mouse brain undermined confidence that CD157 is an authentic and/or actionable molecular participant in OT-dependent social behaviour. Here, we show that CD157 knockout mice have low levels of circulating OT in cerebrospinal fluid, which can be corrected by the oral administration of nicotinamide riboside, a recently discovered vitamin precursor of nicotinamide adenine dinucleotide (NAD). NAD is the substrate for the CD157- and CD38-dependent production of cADPR. Nicotinamide riboside corrects social deficits and fearful and anxiety-like behaviours in CD157 knockout males. These results suggest that elevating NAD levels with nicotinamide riboside may allow animals with cADPR- and OT-forming deficits to overcome these deficits and function more normally.

Topics: ADP-ribosyl Cyclase; Animals; Antigens, CD; Anxiety; Autism Spectrum Disorder; Dietary Supplements; Disease Models, Animal; Female; GPI-Linked Proteins; Male; Mice; Mice, Mutant Strains; Niacinamide; Oxytocin; Pyridinium Compounds; Social Behavior

Maintaining levels of nicotinamide adenine dinucleotide (NAD+), a coenzyme critical for cellular energetics and biosynthetic pathways, may be therapeutic in retinal disease because retinal NAD+ levels decline during retinal damage and degeneration. The purpose of this study was to investigate whether systemic treatment with nicotinamide riboside (NR), a NAD+ precursor that is orally deliverable and well-tolerated by humans, is protective in a mouse model of light-induced retinal degeneration.. Mice were injected intraperitoneally with vehicle or NR the day before and the morning of exposure to degeneration-inducing levels of light. Retinal function was assessed by electroretinography and in vivo retinal morphology and inflammation was assessed by optical coherence tomography. Post mortem retina sections were assessed for morphology, TUNEL, and inflammatory markers Iba1 and GFAP. Retinal NAD+ levels were enzymatically assayed.. Exposure to degeneration-inducing levels of light suppressed retinal NAD+ levels. Mice undergoing light-induced retinal degeneration exhibited significantly suppressed retinal function, severely disrupted photoreceptor cell layers, and increased apoptosis and inflammation in the outer retina. Treatment with NR increased levels of NAD+ in retina and prevented these deleterious outcomes.. This study is the first to report the protective effects of NR treatment in a mouse model of retinal degeneration. The positive outcomes, coupled with human tolerance to NR dosing, suggest that maintaining retinal NAD+ via systemic NR treatment should be further explored for clinical relevance.

Topics: Animals; Disease Models, Animal; Electroretinography; Fluorescent Antibody Technique; Injections, Intraperitoneal; Light; Male; Mice; Mice, Inbred BALB C; NAD; Niacinamide; Photoreceptor Cells, Vertebrate; Pyridinium Compounds; Retina; Retinal Degeneration; Tomography, Optical Coherence

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

Older individuals suffer from low NADH levels. We have previously shown that nicotinamide riboside [NR; a NAD(P)(H) precursor] administration impaired exercise performance in young rats. It has been suggested that supplementation of redox agents exerts ergogenic effect only in deficient individuals. We hypothesized that old individuals would more likely benefit from NR supplementation. We investigated the effect of acute NR supplementation on redox homeostasis and physical performance in young and old individuals.. Twelve young and twelve old men received NR or placebo in a double-blind cross-over design. Before and 2 h after NR or placebo supplementation, blood and urine samples were collected, while physical performance (VO. At rest, old individuals exhibited lower erythrocyte NAD(P)H levels, higher urine F. NR supplementation increased NAD(P)H levels, decreased oxidative stress, and improved physical performance only in old subjects, substantiating that redox supplementation may be beneficial only in individuals with antioxidant deficiencies.

Topics: Adult; Age Factors; Aged; Animals; Cross-Over Studies; Dietary Supplements; Disease Models, Animal; Double-Blind Method; Homeostasis; Humans; Male; Niacinamide; Oxidation-Reduction; Oxidative Stress; Physical Endurance; Pyridinium Compounds; Young Adult

Supplementation with the NAD

Topics: Animals; Blood Glucose; Diet, High-Fat; Disease Models, Animal; DNA Damage; Gene Knockout Techniques; Genetic Predisposition to Disease; Glucose Intolerance; Hepatocytes; Insulin Resistance; Lipid Metabolism; Liver; Liver Diseases; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Knockout; NAD; Niacinamide; Phosphotransferases (Alcohol Group Acceptor); Protective Agents; Pyridinium Compounds

Nicotinamide adenine dinucleotide (NAD) supplementation to repair the disabled mitochondria is a promising strategy for the treatment of Alzheimer's disease (AD) and other dementia. Nicotinamide ribose (NR) is a safe NAD precursor with high oral bioavailability, and has beneficial effects on aging. Here, we applied NR supplied food (2.5 g/kg food) to APP/PS1 transgenic AD model mice and aged mice for 3 months. Cognitive function, locomotor activity and anxiety level were assessed by standard behavioral tests. The change of body weight, the activation of microglia and astrocytes, the accumulation of Aβ and the level of serum nicotinamide phosphoribosyltransferase (NAMPT) were determined for the evaluation of pathological processes. We found that NR supplementation improved the short-term spatial memory of aged mice, and the contextual fear memory of AD mice. Moreover, NR supplementation inhibited the activation of astrocytes and the elevation of serum NAMPT of aged mice. For AD model mice, NR supplementation inhibited the accumulation of Aβ and the migration of astrocyte to Aβ. In addition, NR supplementation inhibit the body weight gain of aged and APP/PS1 mice. Thus, NR has selective benefits for both AD and aged mice, and the oral uptake of NR can be used to prevent the progression of dementia.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Astrocytes; Brain; Cognition; Cognitive Dysfunction; Disease Models, Animal; Memory; Mice; Microglia; Motor Activity; Niacinamide; Nicotinamide Phosphoribosyltransferase; Pyridinium Compounds

Liver fibrosis is part of the non-alcoholic fatty liver disease (NAFLD) spectrum, which currently has no approved pharmacological treatment. In this study, we investigated whether supplementation of nicotinamide riboside (NR), a nicotinamide adenine dinucleotide (NAD+) precursor, can reduce the development of liver fibrosis in a diet-induced mouse model of liver fibrosis.. Male C57BL/6 J mice were fed a low-fat control (LF), a high-fat/high-sucrose/high-cholesterol control (HF) or a HF diet supplemented with NR at 400 mg/kg/day (HF-NR) for 20 weeks. Features of liver fibrosis were assessed by histological and biochemical analyses. Whole-body energy metabolism was also assessed using indirect calorimetry. Primary mouse and human hepatic stellate cells were used to determine the anti-fibrogenic effects of NR in vitro.. NR supplementation significantly reduced body weight of mice only 7 weeks after mice were on the supplementation, but did not attenuate serum alanine aminotransferase levels, liver steatosis, or liver inflammation. However, NR markedly reduced collagen accumulation in the liver. RNA-Seq analysis suggested that the expression of genes involved in NAD+ metabolism is altered in activated hepatic stellate cells (HSCs) compared to quiescent HSCs. NR inhibited the activation of HSCs in primary mouse and human HSCs. Indirect calorimetry showed that NR increased energy expenditure, likely by upregulation of β-oxidation in skeletal muscle and brown adipose tissue.. NR attenuated HSC activation, leading to reduced liver fibrosis in a diet-induced mouse model of liver fibrosis. The data suggest that NR may be developed as a potential preventative for human liver fibrosis.

Topics: Animals; Body Weight; Collagen; Diet, High-Fat; Dietary Supplements; Disease Models, Animal; Energy Metabolism; Hepatic Stellate Cells; Humans; Liver; Mice; Mice, Inbred C57BL; Muscle, Skeletal; NAD; Niacinamide; Non-alcoholic Fatty Liver Disease; Pyridinium Compounds

Topics: Animals; Antioxidants; Autophagy; Cardiotoxicity; Cells, Cultured; Cytoprotection; Disease Models, Animal; Doxorubicin; Heart Diseases; Hydrogen-Ion Concentration; Lysosomes; Male; Mice, Inbred C57BL; Mice, Transgenic; Myocytes, Cardiac; NAD; Niacinamide; Oxidative Stress; Pyridinium Compounds; Sirtuin 1

Myocardial metabolic impairment is a major feature in chronic heart failure. As the major coenzyme in fuel oxidation and oxidative phosphorylation and a substrate for enzymes signaling energy stress and oxidative stress response, nicotinamide adenine dinucleotide (NAD. To explore possible alterations of NAD. We observed a 30% loss in levels of NAD. The data show that nicotinamide riboside, the most energy-efficient among NAD precursors, could be useful for treatment of heart failure, notably in the context of DCM, a disease with few therapeutic options.

Topics: Acrylamides; AMP-Activated Protein Kinases; Animals; Cardiomyopathy, Dilated; Citric Acid; Cytokines; Dietary Supplements; Disease Models, Animal; Gene Expression Profiling; Heart Failure; Metabolome; Mice; Mice, Transgenic; Myocytes, Cardiac; NAD; Niacinamide; Nicotinamide Phosphoribosyltransferase; Phosphotransferases (Alcohol Group Acceptor); Piperidines; PPAR alpha; Pyridinium Compounds; Rats; Serum Response Factor

Sepsis-caused multiple organ failure remains the major cause of morbidity and mortality in intensive care units. Nicotinamide riboside (NR) is a precursor of nicotinamide adenine dinucleotide (NAD. Mouse sepsis models were induced by injection of lipopolysaccharides (LPS) or feces-injection-in-peritoneum. NR was given before sepsis onset. Cultured macrophages and endothelial cells were incubated with various agents.. Administration of NR elevated the NAD

Topics: Animals; Apoptosis; Disease Models, Animal; HMGB1 Protein; Lipopolysaccharides; Macrophages; Male; Mice; Mice, Inbred C57BL; Multiple Organ Failure; Niacinamide; Oxidative Stress; Pyridinium Compounds; Sepsis

While mitochondrial dysfunction is emerging as key in Parkinson's disease (PD), a central question remains whether mitochondria are actual disease drivers and whether boosting mitochondrial biogenesis and function ameliorates pathology. We address these questions using patient-derived induced pluripotent stem cells and Drosophila models of GBA-related PD (GBA-PD), the most common PD genetic risk. Patient neurons display stress responses, mitochondrial demise, and changes in NAD+ metabolism. NAD+ precursors have been proposed to ameliorate age-related metabolic decline and disease. We report that increasing NAD+ via the NAD+ precursor nicotinamide riboside (NR) significantly ameliorates mitochondrial function in patient neurons. Human neurons require nicotinamide phosphoribosyltransferase (NAMPT) to maintain the NAD+ pool and utilize NRK1 to synthesize NAD+ from NAD+ precursors. Remarkably, NR prevents the age-related dopaminergic neuronal loss and motor decline in fly models of GBA-PD. Our findings suggest NR as a viable clinical avenue for neuroprotection in PD and other neurodegenerative diseases.

Topics: Animals; Autophagy; Disease Models, Animal; Dopaminergic Neurons; Drosophila melanogaster; Endoplasmic Reticulum Stress; Glucosylceramidase; Humans; Induced Pluripotent Stem Cells; Mitochondria; Mitochondrial Dynamics; Motor Activity; NAD; Neurons; Niacinamide; Parkinson Disease; Pyridinium Compounds; Unfolded Protein Response

Sirtuin 3 (Sirt3) is a key regulator of energy metabolism and oxidative stress. To investigate the role of Sirt3 in contrast-induced acute kidney injury (CIAKI), we established the model both in vivo and in vitro to explore the potential mechanisms.. In vivo, we established CIAKI models in wild-type (WT) and Sirt3-knockout (Sirt3-KO) mice. Blood urea nitrogen (BUN) and serum creatinine (Scr) were detected by enzyme-linked immunosorbent assay, Glomerular Filtration Rate (GFR) and creatinine clearance were also investigated. We detected the production of reactive oxygen species (ROS) via 2'7'-dichlorodihydro-fluorescein diacetate. The expressions of Sirt3, oxidative stress and apoptosis related markers (MnSOD, Catalase, Acetyl-MnSOD K68, Nox4, Bax, Bcl-2 and Caspase3) were measured and analyzed. In addition, we observed the effect of nicotinamide riboside (NR) on CIAKI in WT and Sirt3-KO mice. In vitro, Sirt3 was knocked out by siRNA transfection method in HK-2 cells. Sirt3, ROS, oxidative stress and apoptosis markers in HK-2 cells were also measured.. Our data demonstrated that the levels of Scr and BUN in Sirt3-KO mice were increased while the levels of the GFR and creatinine clearance were decreased in CIAKI mice. In Sirt3-KO or siRNA groups, the activities of MnSOD and Catalase were markedly down-regulated. Also, the expression of Caspase3 were markedly increased and the ratio of Bcl-2/Bax was decreased, while the ROS level was increased in Sirt3 deficiency groups. NR ameliorated CIAKI in WT mice but not in Sirt3-KO mice.. Our results suggest that Sirt3 deficiency aggravates contrast-induced acute kidney injury. Sirt3 is critical in NR-mediated renoprotection in CIAKI.

Topics: Acute Kidney Injury; Animals; Apoptosis; Cell Line; Contrast Media; Cytoprotection; Disease Models, Animal; Humans; Kidney; Male; Mice, Knockout; Niacinamide; Oxidative Stress; Pyridinium Compounds; Reactive Oxygen Species; Sirtuin 3; Triiodobenzoic Acids

Acute mesenteric ischaemia is a syndrome caused by inadequate blood flow through the mesenteric vessels, resulting in ischaemia and eventual gangrene of the bowel wall. Although relatively rare, it is a potentially life-threatening condition. The maintenance of haemodynamic stability, along with adequate oxygen saturation, and the correction of any electrolyte imbalance, are of the utmost importance. However, nicotinamide adenine dinucleotide (NAD) biosynthesis modulation by precursor introduction can also be a powerful tool for preventing injury. Nicotinamide riboside is a pyridine-nucleoside form of vitamin B3 that functions as a precursor to NAD

Topics: Animals; Disease Models, Animal; Drug Evaluation, Preclinical; Endothelium, Vascular; Intestine, Small; Laser-Doppler Flowmetry; Male; Mesenteric Arteries; Mesenteric Ischemia; Microcirculation; Niacinamide; Pyridinium Compounds; Rats, Wistar; Reperfusion Injury

Injury to sensory afferents may contribute to the peripheral neuropathies that develop after administration of chemotherapeutic agents. Manipulations that increase levels of nicotinamide adenine dinucleotide (NAD) can protect against neuronal injury. This study examined whether nicotinamide riboside (NR), a third form of vitamin B3 and precursor of NAD, diminishes tactile hypersensitivity and place escape-avoidance behaviors in a rodent model of paclitaxel-induced peripheral neuropathy. Female Sprague-Dawley rats received 3 intravenous injections of 6.6 mg/kg paclitaxel over 5 days. Daily oral administration of 200 mg/kg NR beginning 7 days before paclitaxel treatment and continuing for another 24 days prevented the development of tactile hypersensitivity and blunted place escape-avoidance behaviors. These effects were sustained after a 2-week washout period. This dose of NR increased blood levels of NAD by 50%, did not interfere with the myelosuppressive effects of paclitaxel, and did not produce adverse locomotor effects. Treatment with 200 mg/kg NR for 3 weeks after paclitaxel reversed the well-established tactile hypersensitivity in a subset of rats and blunted escape-avoidance behaviors. Pretreatment with 100 mg/kg oral acetyl-L-carnitine (ALCAR) did not prevent paclitaxel-induced tactile hypersensitivity or blunt escape-avoidance behaviors. ALCAR by itself produced tactile hypersensitivity. These findings suggest that agents that increase NAD, a critical cofactor for mitochondrial oxidative phosphorylation systems and cellular redox systems involved with fuel utilization and energy metabolism, represent a novel therapeutic approach for relief of chemotherapy-induced peripheral neuropathies. Because NR is a vitamin B3 precursor of NAD and a nutritional supplement, clinical tests of this hypothesis may be accelerated.

Topics: Animals; Antineoplastic Agents, Phytogenic; Disease Models, Animal; Eosinophils; Escape Reaction; Female; Hyperalgesia; Leukocyte Count; Locomotion; NAD; Neutrophils; Niacinamide; Nociception; Paclitaxel; Pain Measurement; Peripheral Nervous System Diseases; Pyridinium Compounds; Rats; Rats, Sprague-Dawley; Statistics, Nonparametric; Time Factors

Alzheimer's disease is a common and devastating disease characterized by aggregation of the amyloid-β peptide. However, we know relatively little about the underlying molecular mechanisms or how to treat patients with Alzheimer's disease. Here we provide bioinformatic and experimental evidence of a conserved mitochondrial stress response signature present in diseases involving amyloid-β proteotoxicity in human, mouse and Caenorhabditis elegans that involves the mitochondrial unfolded protein response and mitophagy pathways. Using a worm model of amyloid-β proteotoxicity, GMC101, we recapitulated mitochondrial features and confirmed that the induction of this mitochondrial stress response was essential for the maintenance of mitochondrial proteostasis and health. Notably, increasing mitochondrial proteostasis by pharmacologically and genetically targeting mitochondrial translation and mitophagy increases the fitness and lifespan of GMC101 worms and reduces amyloid aggregation in cells, worms and in transgenic mouse models of Alzheimer's disease. Our data support the relevance of enhancing mitochondrial proteostasis to delay amyloid-β proteotoxic diseases, such as Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Caenorhabditis elegans; Disease Models, Animal; Homeostasis; Humans; Male; Memory; Mice; Mice, Transgenic; Mitochondria; Mitophagy; NAD; Niacinamide; Oxidative Phosphorylation; Protein Aggregation, Pathological; Protein Biosynthesis; Proteostasis; Pyridinium Compounds; Unfolded Protein Response

The regenerative capacity of the liver is essential for recovery from surgical resection or injuries induced by trauma or toxins. During liver regeneration, the concentration of nicotinamide adenine dinucleotide (NAD) falls, at least in part due to metabolic competition for precursors. To test whether NAD availability restricts the rate of liver regeneration, we supplied nicotinamide riboside (NR), an NAD precursor, in the drinking water of mice subjected to partial hepatectomy. NR increased DNA synthesis, mitotic index, and mass restoration in the regenerating livers. Intriguingly, NR also ameliorated the steatosis that normally accompanies liver regeneration. To distinguish the role of hepatocyte NAD levels from any systemic effects of NR, we generated mice overexpressing nicotinamide phosphoribosyltransferase, a rate-limiting enzyme for NAD synthesis, specifically in the liver. Nicotinamide phosphoribosyltransferase overexpressing mice were mildly hyperglycemic at baseline and, similar to mice treated with NR, exhibited enhanced liver regeneration and reduced steatosis following partial hepatectomy. Conversely, mice lacking nicotinamide phosphoribosyltransferase in hepatocytes exhibited impaired regenerative capacity that was completely rescued by administering NR.. NAD availability is limiting during liver regeneration, and supplementation with precursors such as NR may be therapeutic in settings of acute liver injury. (Hepatology 2017;65:616-630).

Topics: Animals; Disease Models, Animal; Fluorescent Antibody Technique; Hepatectomy; Immunoblotting; Immunohistochemistry; Liver; Liver Regeneration; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; NAD; Niacinamide; Pyridinium Compounds; Random Allocation; Sensitivity and Specificity

With no approved pharmacological treatment, nonalcoholic fatty liver disease (NAFLD) is now the most common cause of chronic liver disease in Western countries and its worldwide prevalence continues to increase along with the growing obesity epidemic. Here, we show that a high-fat high-sucrose (HFHS) diet, eliciting chronic hepatosteatosis resembling human fatty liver, lowers hepatic nicotinamide adenine dinucleotide (NAD(+) ) levels driving reductions in hepatic mitochondrial content, function, and adenosine triphosphate (ATP) levels, in conjunction with robust increases in hepatic weight, lipid content, and peroxidation in C57BL/6J mice. To assess the effect of NAD(+) repletion on the development of steatosis in mice, nicotinamide riboside, a precursor of NAD(+) biosynthesis, was added to the HFHS diet, either as a preventive strategy or as a therapeutic intervention. We demonstrate that NR prevents and reverts NAFLD by inducing a sirtuin (SIRT)1- and SIRT3-dependent mitochondrial unfolded protein response, triggering an adaptive mitohormetic pathway to increase hepatic β-oxidation and mitochondrial complex content and activity. The cell-autonomous beneficial component of NR treatment was revealed in liver-specific Sirt1 knockout mice (Sirt1(hep-/-) ), whereas apolipoprotein E-deficient mice (Apoe(-/-) ) challenged with a high-fat high-cholesterol diet affirmed the use of NR in other independent models of NAFLD.. Our data warrant the future evaluation of NAD(+) boosting strategies to manage the development or progression of NAFLD.

Topics: Analysis of Variance; Animals; Area Under Curve; Biopsy, Needle; Diet, High-Fat; Disease Models, Animal; Fatty Liver; Immunohistochemistry; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Mitochondria; NAD; Niacinamide; Pyridinium Compounds; Random Allocation; Sensitivity and Specificity; Treatment Outcome; Unfolded Protein Response

Adult stem cells (SCs) are essential for tissue maintenance and regeneration yet are susceptible to senescence during aging. We demonstrate the importance of the amount of the oxidized form of cellular nicotinamide adenine dinucleotide (NAD(+)) and its effect on mitochondrial activity as a pivotal switch to modulate muscle SC (MuSC) senescence. Treatment with the NAD(+) precursor nicotinamide riboside (NR) induced the mitochondrial unfolded protein response and synthesis of prohibitin proteins, and this rejuvenated MuSCs in aged mice. NR also prevented MuSC senescence in the mdx (C57BL/10ScSn-Dmd(mdx)/J) mouse model of muscular dystrophy. We furthermore demonstrate that NR delays senescence of neural SCs and melanocyte SCs and increases mouse life span. Strategies that conserve cellular NAD(+) may reprogram dysfunctional SCs and improve life span in mammals.

Topics: Animals; Cellular Reprogramming; Cellular Senescence; Disease Models, Animal; Longevity; Melanocytes; Mice; Mice, Inbred C57BL; Mice, Inbred mdx; Mitochondria; Muscular Dystrophies; Myoblasts, Skeletal; NAD; Neural Stem Cells; Niacinamide; Oxidative Stress; Prohibitins; Pyridinium Compounds; Repressor Proteins; Unfolded Protein Response

Topics: Animals; Disease Models, Animal; Hearing Loss; Humans; Mice; Mice, Knockout; NAD; Neurodegenerative Diseases; Niacinamide; Pyridinium Compounds; Sirtuin 3

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

Mitochondrial disorders are highly heterogeneous conditions characterized by defects of the mitochondrial respiratory chain. Pharmacological activation of mitochondrial biogenesis has been proposed as an effective means to correct the biochemical defects and ameliorate the clinical phenotype in these severely disabling, often fatal, disorders. Pathways related to mitochondrial biogenesis are targets of Sirtuin1, a NAD(+)-dependent protein deacetylase. As NAD(+) boosts the activity of Sirtuin1 and other sirtuins, intracellular levels of NAD(+) play a key role in the homeostatic control of mitochondrial function by the metabolic status of the cell. We show here that supplementation with nicotinamide riboside, a natural NAD(+) precursor, or reduction of NAD(+) consumption by inhibiting the poly(ADP-ribose) polymerases, leads to marked improvement of the respiratory chain defect and exercise intolerance of the Sco2 knockout/knockin mouse, a mitochondrial disease model characterized by impaired cytochrome c oxidase biogenesis. This strategy is potentially translatable into therapy of mitochondrial disorders in humans.

Topics: Animals; Dietary Supplements; Disease Models, Animal; Electron Transport Complex IV; Energy Metabolism; Enzyme Activation; Gene Expression; Mice; Mice, Knockout; Mitochondria; Mitochondrial Diseases; Molecular Chaperones; NAD; Niacinamide; Oxidative Phosphorylation; Phenanthrenes; Phenotype; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Pyridinium Compounds; Sirtuin 1

Nicotinamide adenine dinucleotide (NAD)(+), a coenzyme involved in redox activities in the mitochondrial electron transport chain, has been identified as a key regulator of the lifespan-extending effects, and the activation of NAD(+) expression has been linked with a decrease in beta-amyloid (Aβ) toxicity in Alzheimer's disease (AD). Nicotinamide riboside (NR) is a NAD(+) precursor, it promotes peroxisome proliferator-activated receptor-γ coactivator 1 (PGC)-1α expression in the brain. Evidence has shown that PGC-1α is a crucial regulator of Aβ generation because it affects β-secretase (BACE1) degradation. In this study we tested the hypothesis that NR treatment in an AD mouse model could attenuate Aβ toxicity through the activation of PGC-1α-mediated BACE1 degradation. Using the Tg2576 AD mouse model, using in vivo behavioral analyses, biochemistry assays, small hairpin RNA (shRNA) gene silencing and electrophysiological recording, we found (1) dietary treatment of Tg2576 mice with 250 mg/kg/day of NR for 3 months significantly attenuates cognitive deterioration in Tg2576 mice and coincides with an increase in the steady-state levels of NAD(+) in the cerebral cortex; (2) application of NR to hippocampal slices (10 μM) for 4 hours abolishes the deficits in long-term potentiation recorded in the CA1 region of Tg2576 mice; (3) NR treatment promotes PGC-1α expression in the brain coinciding with enhanced degradation of BACE1 and the reduction of Aβ production in Tg2576 mice. Further in vitro studies confirmed that BACE1 protein content is decreased by NR treatment in primary neuronal cultures derived from Tg2576 embryos, in which BACE1 degradation was prevented by PGC-1α-shRNA gene silencing; and (4) NR treatment and PGC-1α overexpression enhance BACE1 ubiquitination and proteasomal degradation. Our studies suggest that dietary treatment with NR might benefit AD cognitive function and synaptic plasticity, in part by promoting PGC-1α-mediated BACE1 ubiquitination and degradation, thus preventing Aβ production in the brain.

Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Cells, Cultured; Cognition Disorders; Disease Models, Animal; Gene Expression Regulation; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria; Niacinamide; Organ Culture Techniques; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Pyridinium Compounds; Transcription Factors; Up-Regulation