ArticleLiterature Review

Nicotinamide riboside, a trace nutrient in foods, is a Vitamin B3 with effects on energy metabolism and neuroprotection

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Abstract

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.

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... NR is a nucleoside that incorporates a nicotinamide and a ribose (Belenky et al., 2007;Chi and Sauve, 2013) group. ...
... It is a trace nutrient known as vitamin B3 (Lanska, 2012), available in certain foods (dairy products, fish, eggs, and vegetables) (Minto et al., 2017), nutritional supplements and fortified foods (Colbourne et al., 2013). Its effects are associated with energy metabolism and neuroprotection (Chi and Sauve, 2013). When the NR enters the cells it is converted to NAD + by at least two types of metabolic pathway. ...
... When the NR enters the cells it is converted to NAD + by at least two types of metabolic pathway. The first requires the participation of the nicotinamide riboside kinases (NRKs) (Chi and Sauve, 2013) in two of its isoforms (NRK1 and NRK2) (Bieganowski and Brenner, 2004) and the second requires the action of purine nucleoside phosphorylase (PNP) and nicotinamide phosphoribosyltransferase (NAMPT) (Burgos et al., 2013) (Figure 2). ...
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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that produces a selective loss of the motor neurons of the spinal cord, brain stem and motor cortex. Oxidative stress (OS) associated with mitochondrial dysfunction and the deterioration of the electron transport chain has been shown to be a factor that contributes to neurodegeneration and plays a potential role in the pathogenesis of ALS. The regions of the central nervous system affected have high levels of reactive oxygen species (ROS) and reduced antioxidant defenses. Scientific studies propose treatment with antioxidants to combat the characteristic OS and the regeneration of nicotinamide adenine dinucleotide (NAD+) levels by the use of precursors. This review examines the possible roles of nicotinamide riboside and pterostilbene as therapeutic strategies in ALS.
... When overweight individuals are successfully coached to lose >7% of their body weight in 24-wk lifestyle interventions or given metformin, improvements in insulin sensitivity can be achieved (1,2). Nicotinamide riboside (NR), a member of the vitamin B-3 family, has antiobesogenic properties and has been shown to improve insulin sensitivity in rapidly induced rodent models of metabolic diseases (3). ...
... HbA1c, glycated hemoglobin. 2 Baseline comparisons were made with unpaired 2-sample t test. 3 Statistical test performed on log-transformed data. 4 Placebo group (n = 19). ...
... P value denotes interaction. 3 Post hoc tests showed significant difference between pretreatment and post-treatment values for the NR group (P = 0.001); all other comparisons were nonsignificant. ...
Article
Background: Animal studies suggest a positive role for nicotinamide riboside (NR) on insulin sensitivity and hepatic steatosis in models of obesity and type 2 diabetes. NR, an NAD+ precursor, is a member of the vitamin B-3 family now available as an over-the-counter supplement. Although data from preclinical trials appear consistent, potential effects and safety need to be evaluated in human clinical trials. Objective: The aim of this study was to test the safety of dietary NR supplementation over a 12-wk period and potential to improve insulin sensitivity and other metabolic parameters in obese, insulin-resistant men. Design: In an investigator-initiated randomized, placebo-controlled, double-blinded, and parallel-group designed clinical trial, forty healthy, sedentary men with a body mass index (BMI) > 30 kg/m2, age-range 40-70 y were randomly assigned to 12 wk of NR (1000 mg twice daily) or placebo. We determined the effects of NR supplementation on insulin sensitivity by a hyperinsulinemic euglycemic clamp and substrate metabolism by indirect calorimetry and labeled substrates of tritiated glucose and palmitate. Body composition and fat mass distribution were determined by whole-body dual-energy X-ray absorptiometry (DXA) and MRI scans, and measurements of intrahepatic lipid content were obtained by MR spectroscopy. Results: Insulin sensitivity, endogenous glucose production, and glucose disposal and oxidation were not improved by NR supplementation. Similarly, NR supplementation had no effect on resting energy expenditure, lipolysis, oxidation of lipids, or body composition. No serious adverse events due to NR supplementation were observed and safety blood tests were normal. Conclusion: 12 wk of NR supplementation in doses of 2000 mg/d appears safe, but does not improve insulin sensitivity and whole-body glucose metabolism in obese, insulin-resistant men. This trial was registered at clinicaltrials.gov as NCT02303483.
... Nicotinic acid (NA, also named niacin or Vitamin B3), nicotinamide (NAM), nicotinamide riboside (NR), nicotinamide mononucleotide (NMN) and tryptophan are all dietarily available precursors of NAD + (nicotinamide adenine dinucleotide) with similar biological activities (75,76,153). The universal coenzyme NAD+/NADH and its phosphorylated derivatives NADP/NADPH serve oxidoreductases, dehydrogenases, sirtuins and are central to metabolic pathways (e.g., glycolysis, TCA cycle) and cell signaling (153). ...
... Nicotinic acid (NA, also named niacin or Vitamin B3), nicotinamide (NAM), nicotinamide riboside (NR), nicotinamide mononucleotide (NMN) and tryptophan are all dietarily available precursors of NAD + (nicotinamide adenine dinucleotide) with similar biological activities (75,76,153). The universal coenzyme NAD+/NADH and its phosphorylated derivatives NADP/NADPH serve oxidoreductases, dehydrogenases, sirtuins and are central to metabolic pathways (e.g., glycolysis, TCA cycle) and cell signaling (153). Numerous pre-clinical studies have shown the CRM-like properties of these precursors upon supplementation, which can prolong life-and healthspan, promote mitochondrial function, induce autophagy and act cardioprotective and neuroprotective, among others (77,(153)(154)(155)(156)(157). ...
... The universal coenzyme NAD+/NADH and its phosphorylated derivatives NADP/NADPH serve oxidoreductases, dehydrogenases, sirtuins and are central to metabolic pathways (e.g., glycolysis, TCA cycle) and cell signaling (153). Numerous pre-clinical studies have shown the CRM-like properties of these precursors upon supplementation, which can prolong life-and healthspan, promote mitochondrial function, induce autophagy and act cardioprotective and neuroprotective, among others (77,(153)(154)(155)(156)(157). NAD + concentrations decline with age (156,158) and replenishing these levels harbors therapeutic potential in humans (157,(159)(160)(161)(162)(163)(164). ...
Article
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The human diet and dietary patterns are closely linked to the health status. High-calorie Western-style diets have increasingly come under scrutiny as their caloric load and composition contribute to the development of non-communicable diseases, such as diabetes, cancer, obesity, and cardiovascular disorders. On the other hand, calorie-reduced and health-promoting diets have shown promising results in maintaining health and reducing disease burden throughout aging. More recently, pharmacological Caloric Restriction Mimetics (CRMs) have gained interest of the public and scientific community as promising candidates that mimic some of the myriad of effects induced by caloric restriction. Importantly, many of the CRM candidates activate autophagy, prolong life- and healthspan in model organisms and ameliorate diverse disease symptoms without the need to cut calories. Among others, glycolytic inhibitors (e.g., D-allulose, D-glucosamine), hydroxycitric acid, NAD+ precursors, polyamines (e.g., spermidine), polyphenols (e.g., resveratrol, dimethoxychalcones, curcumin, EGCG, quercetin) and salicylic acid qualify as CRM candidates, which are naturally available via foods and beverages. However, it is yet unclear how these bioactive substances contribute to the benefits of healthy diets. In this review, we thus discuss dietary sources, availability and intake levels of dietary CRMs. Finally, since translational research on CRMs has entered the clinical stage, we provide a summary of their effects in clinical trials.
... NR is converted into NAD + sequentially by NR kinase 1/2 and nicotinamide mononucleotide adenylyltransferase [14,15]. Thus, administration of NR efficiently boosts intracellular NAD + levels, and protects against various chronic health issues such as aging and metabolic syndrome [16][17][18][19]. It is well known that NAD + is a co-enzyme in all living cells, which drives poly (ADPribose) polymerases (PARPs) and sirtuin (SIRT) reactions [20]. ...
... One immediate option would be NAD + supplement. Unfortunately, NAD + is easily degraded by serum hydrolases [17] and it is not readily taken up by cells because of its high polarity [44,45], which makes it difficult to be replenished directly. Alternatively, NAD + can be biosynthesized from nicotinamide and niacin through the salvage pathway and from tryptophan through the de novo pathway [46]. ...
... However, the use of niacin is limited by painful flushing [48], and nicotinamide may inhibit SIRTs [49], a family of deacetylases required for various essentially cellular functions. On the contrary, administration of NR efficiently boosts intracellular NAD + levels without negatively affecting SIRT activity, and instead, increasing SIRT activities [16][17][18][19]. Thus, NR has the potential to overcome limitations of other precursors while still providing the benefits of elevated NAD + . ...
Article
Aims: 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+), which is important in regulating oxidative stress. This study investigated whether administration of NR prevented oxidative stress and organ injury in sepsis. Methods: 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. Results: Administration of NR elevated the NAD+ levels, and elicited a reduction of oxidative stress, inflammation and caspase-3 activity in lung and heart tissues, which correlated with attenuation of pulmonary microvascular permeability and myocardial dysfunction, leading to less mortality in sepsis models. These protective effects of NR were associated with decreased levels of plasma high mobility group box-1 (HMGB1) in septic mice. Consistently, pre-treatment of macrophages with NR increased NAD+ content and reduced HMGB1 release upon LPS stimulation. NR also prevented reactive oxygen species (ROS) production and apoptosis in endothelial cells induced by a conditioned-medium collected from LPS-treated macrophages. Furthermore, inhibition of SIRT1 by EX527 offset the negative effects of NR on HMGB1 release in macrophages, and ROS and apoptosis in endothelial cells. Conclusions: Administration of NR prevents lung and heart injury, and improves the survival in sepsis, likely by inhibiting HMGB1 release and oxidative stress via the NAD+/SIRT1 signaling. Given NR has been used as a health supplement, it may be a useful agent to prevent organ injury in sepsis.
... Nutritional compounds combined with conventional weight loss interventions have been widely encouraged against obesity, especially if they simultaneously bring benefits to SMT (8). In line with this, nicotinamide riboside (NR), a dietary compound analogous to vitamin B3, has been shown in recent experiments as effective for weight loss and SMT health maintenance (9)(10)(11). We have previously shown that supplementation with NR positively modulates obesity-related parameters in both obese rats and obese rats under CR, including reduced BW gain and reduced adiposity (12), unaware of whether this process affected SMT or neuroinflammatory parameters. ...
... Additionally, evidence for its effect on muscle tissue from obese/overweight individuals follows the same dilemma. At the same time, in the CNS, NR-led neuromodulatory and neuroprotective effects have been extremely interesting (10,11). In this way, investigations in the line of neuropsychiatric disorders such as those that directly impact weight and body composition, especially bulimia and anorexia, are very promising. ...
Article
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Obesity treatments, such as calorie restriction (CR), eventually lead to muscle wasting and higher rates of neuroinflammation, whereas hypothalamic inflammatory conditions impair body weight (BW) control. Nicotinamide riboside (NR) has been proposed against obesity but with little evidence on skeletal muscle tissue (SMT) and neuroinflammation. Therefore, we aimed to investigate the effects of CR on SMT and on hypothalamic inflammatory biomarkers in obese adult male Wistar rats, and whether NR supplementation alone or in combination with CR affects these parameters. Obesity was induced in rats through a cafeteria diet for 6 weeks. After that, a group of obese rats was exposed to CR, associated or not associated with NR supplementation (400 mg/kg), for another 4 weeks. As a result, obese rats, with or without CR, presented lower relative weight of SMT when compared with eutrophic rats. Rats under CR presented lower absolute SMT weight compared with obese and eutrophic rats, in addition to presenting elevated hypothalamic levels of TNF-α. NR supplementation, in all groups, enhanced weight loss and increased relative weight of the SMT. Furthermore, in animals under CR, NR reversed increases TNF-α levels in the hypothalamus. In this study, these data, although succinct, are the first to evidence the effects of NR on SMT and neuroinflammation when associated with CR, especially in obesity conditions. Therefore, this provides preliminary support for future studies in this investigative field. Furthermore, NR emerges as a potential adjuvant for preventing muscle mass loss in the weight loss processes.
... These 2 compounds are trace nutrients and thus do not exceed the micromolar range in foods. 2 As a result, nicotinamide riboside and nicotinic acid should be taken as supplements to achieve adequate circulating levels able to boost NAD þ production across the different tissues. significantly in the liver, lung, intestine, and spleen, in addition to the kidney. 1 Indeed, a recent study identified the liver as the main site at which NAD þ is converted from tryptophan and NAD þ precursors are released into the bloodstream to reach other tissues. ...
... Mutations in these genes, however, only explain 10% to 20% of CAKUT cases. 2 Moreover, the clinical phenotype and severity of CAKUT can vary markedly among patients, both within and between families with the same underlying mutation, demonstrating the complex genotype-phenotype relationship in CAKUT. ...
... The nicotinamide (Nam) salvage pathway generates nicotinamide adenine dinucleotide (NaD + ) from the precursor Nam or the upstream NaD + vitamin precursor nicotinamide riboside (Nr) or nicotinamide mononucleotide (NmN) (see Fig. 1a), which can be found in a variety of daily foods such as milk, fruits, vegetables and meat 178,199 . as NaD + is not cell permeable, it was thought that all the dietary precursors, including nicotinic acid, Nam, Nr and tryptophan, are imported directly into the cells and made available for NaD + biosynthesis, with the exception of NmN. ...
... Restoration of NAD + levels with NAD + supplements and the overexpression of the two biosynthetic enzymes NAMPT and NMNAT1 were found to prevent axon degeneration 60,146 . Moreover, the NAD + precursors NR and NMN improve neuronal cell health, memory and cognitive function in rat and mouse models of Alzheimer disease 136,161,[175][176][177][178][179][180] , and also showed neuroprotective properties in Drosophila melanogaster models of Parkinson disease 181,182 and in mouse models of ALS 139 . Importantly, there are now several clinical trials in progress using NAD + precursors, especially NR, to treat neurological disorders 68 and to promote healthy ageing (TABLe 2). ...
Article
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Nicotinamide adenine dinucleotide (NAD⁺) is a coenzyme for redox reactions, making it central to energy metabolism. NAD⁺ is also an essential cofactor for non-redox NAD⁺-dependent enzymes, including sirtuins, CD38 and poly(ADP-ribose) polymerases. NAD⁺ can directly and indirectly influence many key cellular functions, including metabolic pathways, DNA repair, chromatin remodelling, cellular senescence and immune cell function. These cellular processes and functions are critical for maintaining tissue and metabolic homeostasis and for healthy ageing. Remarkably, ageing is accompanied by a gradual decline in tissue and cellular NAD⁺ levels in multiple model organisms, including rodents and humans. This decline in NAD⁺ levels is linked causally to numerous ageing-associated diseases, including cognitive decline, cancer, metabolic disease, sarcopenia and frailty. Many of these ageing-associated diseases can be slowed down and even reversed by restoring NAD⁺ levels. Therefore, targeting NAD⁺ metabolism has emerged as a potential therapeutic approach to ameliorate ageing-related disease, and extend the human healthspan and lifespan. However, much remains to be learnt about how NAD⁺ influences human health and ageing biology. This includes a deeper understanding of the molecular mechanisms that regulate NAD⁺ levels, how to effectively restore NAD⁺ levels during ageing, whether doing so is safe and whether NAD⁺ repletion will have beneficial effects in ageing humans.
... Nicotinamide, or vitamin B3, is a precursor of nicotinamide adenine dinucleotide (NAD+) and is involved in a multitude of intracellular and intercellular processes, which regulate some of the cell's metabolic, stress, and immune responses to physiological or pathological signals (85). Nicotinamide riboside is a form of vitamin B3 found in dairy milk, yeast, and beer (22). Nicotinamide riboside may be the only vitamin precursor that supports neuronal NAD+ synthesis (19). ...
... Nicotinamide riboside may be the only vitamin precursor that supports neuronal NAD+ synthesis (19). Nicotinamide riboside effects of raising tissue NAD concentrations in rodents may be important in recovery from brain injury (22). Sterile alpha and TIR motif-containing 1 (SARM1) protein is an essential mediator of axon degeneration (34). ...
Article
Concussions are common neurologic events that affect many athletes. Very little has been studied on the treatment of concussions with supplements and medications. The U.S. Food and Drug Administration (FDA) reminds us that no supplement has been proven to treat concussions. Many animal studies show that supplements have potential for improving the effects of a brain injury but none have been shown to be of consistent benefit in human studies. Animal studies on severe traumatic brain injury (TBI) may not therefore be applicable transfer to sports-related concussions (SRC). Of the many supplements reviewed in this article, omega-3 fatty acids (Ω-3 FA) have potential for SRC treatment but in the one human trial those taking higher dosages preinjury had more concussions. In animal studies, postinjury administration was as effective as pretreatment. N-acetyl-cysteine has demonstrated a positive short-term effect on blast injuries in soldiers if administered within 24 h, but there are no studies in SRC. Caffeine, conversely, may be detrimental if taken after SRC. Lower serum levels of vitamins D, C, or E preinjury have worse outcomes in animal studies. Preinjury correction of deficiencies may be of benefit. Current human trials for nicotinamide ribose, melatonin, and branched chain amino acids (BCAA) may soon provide more evidence for the use of these supplements to reduce the impact of SRC in athletes.
... 53 There is an urgent need to identify neuroprotective, and ideally neuro-regenerative, treatments for AD, but clinical trials have thus far failed to reliably demonstrate efficacy in a substantial number of patients. However, several lines of evidence suggest that nicotinamide or related molecules may offer therapeutic benefits for patients with AD. [54][55][56][57][58][59][60][61] For example, severe tryptophan/niacin deficiency leads to the syndrome pellagra, where patients can develop neurological deficits manifesting as dementia, and described as 'premature ageing'. 62 Symptoms are similar to AD and include psychosis, disorientation, memory loss, and confusion, which can all be combated by niacin supplementation. ...
Article
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Nicotinamide, the amide form of vitamin B3 (niacin), has long been associated with neuronal development, survival, and function in the central nervous system (CNS), being implicated in both neuronal death and neuroprotection. Here, we summarise a body of research investigating the role of nicotinamide in neuronal health within the CNS, with a focus on studies that have shown a neuroprotective effect. Nicotinamide appears to play a role in protecting neurons from traumatic injury, ischaemia, and stroke, as well as being implicated in 3 key neurodegenerative conditions: Alzheimer’s, Parkinson’s, and Huntington’s diseases. A key factor is the bioavailability of nicotinamide, with low concentrations leading to neurological deficits and dementia and high levels potentially causing neurotoxicity. Finally, nicotinamide’s potential mechanisms of action are discussed, including the general maintenance of cellular energy levels and the more specific inhibition of molecules such as the nicotinamide adenine dinucleotide-dependent deacetylase, sirtuin 1 (SIRT1).
... Moreover, CR increases concentrations of NR and NAD + and restores normal circadian gene transcription in the liver, further suggesting that NR may act as a CR mimetic 30 . Thus, NMN and NR are NAD + boosting compounds that hold promise for enhancing cardiovascular health and physiological function with aging 31,32 . ...
Article
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Nicotinamide adenine dinucleotide (NAD+) has emerged as a critical co-substrate for enzymes involved in the beneficial effects of regular calorie restriction on healthspan. As such, the use of NAD+precursors to augment NAD+bioavailability has been proposed as a strategy for improving cardiovascular and other physiological functions with aging in humans. Here we provide the evidence in a 2 × 6-week randomized, double-blind, placebo-controlled, crossover clinical trial that chronic supplementation with the NAD+precursor vitamin, nicotinamide riboside (NR), is well tolerated and effectively stimulates NAD+metabolism in healthy middle-aged and older adults. Our results also provide initial insight into the effects of chronic NR supplementation on physiological function in humans, and suggest that, in particular, future clinical trials should further assess the potential benefits of NR for reducing blood pressure and arterial stiffness in this group.
... Nicotinamide riboside, another form of niacin, improves cognitive function with the change of proliferatoractivated receptor-␥, BACE1, coactivator 1␣, and mitochondrial genes in AD mouse models. Nicotinamide (NAM) treatment suppressed poly (ADP-ribose) polymerase-1 (PRP1) over-activation in a rat model of AD [76][77][78]. Nicotinamide pre-treatment in A␤injected mice significantly reduced the gene expression of amyloid precursor protein and presenilin 1, and increased sirtuin 1 (conserved NAD+-dependent enzyme effective on AD) expression in brain tissue, while the expression of nuclear factor-B (Nf-ÄB) in brain was decreased [79]. ...
Article
An increase in the prevalence of Alzheimer's disease (AD) as a multifactorial neurodegenerative disorder is an almost obvious issue in the world. Researches on natural products for finding effective drugs to prevent the disease are in progress. There is special attention to the three types of nuts including almond, hazelnut and walnut in manuscripts of traditional Persian medicine (PM) as preventive agents against brain's atrophy and memory loss. The purpose of this study is a pharmacological review of their bioactive constituents and introducing the value of these nuts as effective supplements and natural medicinal foods in AD patients. Databases including PubMed and ScienceDirect were searched in title, abstract and keywords from year 2000 to present for AD-related researches on these tree nuts, their major phytochemicals and their mechanisms of action. As result, almond, hazelnut and walnut provide macronutrients, micronutrients, and phytochemicals which affect several pathways in AD pathogenesis such as amyloidogenesis, tau phosphorylation, oxidative stress, cholinergic pathways, and some non-target mechanisms including cholesterol lowering and anti-inflammatory properties, as well as effect on neurogenesis. These nuts are recommended in PM for their brain-protective activity and particularly reversing brain atrophy in case of hazelnut. The therapeutical statements of PM scholars mentioned in their books are based on their clinical observations with support of a long history of experiences. Beyond the molecular activities attributed to the phytochemicals, the use of these tree nuts could be more considered in scientific researches as effective nutrients for prevention or even management of AD.
... Nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) have drawn attention as alternative nicotinamide adenine dinucleotide (NAD) substrates, devoid of side effects for nicotinic acid (NicA), such as "flushing" or hepatotoxicity and side effects of nicotinamide (NA), including sirtuin inhibition. Both NAD substrates, NR and NMN were proposed to be used in sports nutrition as good dietary supplements [9,8] and display numerous beneficial effects in various settings, but their bioavailability and pathways of metabolism towards NAD differs. ...
Article
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Background nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) are effective substrates for NAD synthesis, which may act as vasoprotective agents. Here we characterize the effects of NMN and NR on endothelial inflammation and dysfunction and test the involvement of CD73 in these effects. Materials and methods The effect of NMN and NR on IL1β or TNFα –induced endothelial inflammation (ICAM-1 and vWF expression), intracellular NAD concentration and NAD-related enzyme expression (NAMPT, CD38, CD73), were studied in HAECs. The effect of NMN and NR on angiotensin II-induced impairment of endothelium-dependent vasodilation was analyzed in murine aortic rings. The involvement of CD73 in NMN and NR effects was tested using CD73 inhibitor- AOPCP, or CD73-/- mice. Results 24h-incubation with NMN and NR induced anti-inflammatory effects in HAEC stimulated by IL1β or TNFα, as evidenced by a reduction in ICAM-1 and vWF expression. Effects of exogenous NMN but not NR was abrogated in the presence of AOPCP, that efficiently inhibited extracellular endothelial conversion of NMN to NR, without a significant effect on the metabolism of NMN to NA. Surprisingly, intracellular NAD concentration increased in HAEC stimulated by IL1β or TNFα and this effect was associated with upregulation of NAMPT and CD73, whereas changes in CD38 expression were less pronounced. NMN and NR further increased NAD in IL1β-stimulated HAECs and AOPCP diminished NMN-induced increase in NAD, without an effect on NR-induced response. In ex vivo aortic rings stimulated with angiotensin II for 24 hours, NO-dependent vasorelaxation induced by Acetylcholine was impaired. NMN and NR, both prevented Ang II-induced endothelial dysfunction in the aorta. In aortic rings taken from CD73-/- mice NMN effect was lost, whereas NR effect was preserved. Conclusion NMN and NR modulate intracellular NAD content in endothelium, inhibit endothelial inflammation and improve NO-dependent function by CD73-dependent and independent pathways, respectively. Extracellular conversion of NMN to NR by CD73 localized in the luminal surface of endothelial cells represent important vasoprotective mechanisms to maintain intracellular NAD.
... Tryptophan and vitamin B3 are both dietary precursors to NAD+. Together, nicotinic acid and nicotinamide are commonly known as niacin, while nicotine riboside (NR) is a newly discovered form of vitamin B3 (161)(162)(163). NAD+ must be permanently resynthesized because of the activity of NAD+ consuming enzymes. ...
Article
The biological age of organisms differs from the chronological age and is determined by internal aging clock(s). How cells estimate time on a scale of 24 h is relatively well-studied; however, how biological time is measured by cells, tissues, organs or organisms in longer time periods (years and decades) is largely unknown. What is clear and widely agreed upon is that the link to age and age-related diseases is not chronological, as it does not depend on a fixed passage of time. Rather, this link depends on the biological age of an individual cell, tissue, organ or organism and not on time in a strictly chronological sense. Biological evolution does not invent new methods as often as improving upon already existing ones. It should be easier to evolve and remodel the existing (circadian) time clock mechanism to use it for measurement or regulation of longer time periods than to invent a new time mechanism/clock. Specifically, it will be demonstrated that the circadian clock can also be used to regulate circannual or even longer time periods. Nicotinamide phosphoribosyltransferase (NAMPT)-mediated nicotinamide adenine dinucleotide (NAD+) levels, being regulated by the circadian clock, might be the missing link between aging, cell cycle control, DNA damage repair, cellular metabolism and the aging clock, which is responsible for the biological age of an organism. The hypothesis that NAMPT/NAD+/SIRT1 might represent the time regulator that determines the organismal biological age will be presented. The biological age of tissues and organs might be regulated and synchronized through eNAMPT blood secretion. The "NAD World 2.0" concept will be upgraded with detailed insights into mechanisms that regulate NAD+-mediated aging clock ticking, the duration and amplitude of which is responsible for the aging rate of humans.
... NAD + can be synthesized from various precursors. Biosynthesis from nicotinic acid or nicotinamide (NAM)-both present in our diet as vitamin B3-is the primary source of NAD + (1)(2)(3). This pathway, also known as the salvage, is important for NAD + homeostasis. ...
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Cardiomyopathy caused by lamin A/C gene (LMNA) mutations (hereafter referred as LMNA cardiomyopathy) is an anatomic and pathologic condition associated with muscle and electrical dysfunction of the heart, often leading to heart failure-related disability. There is currently no specific therapy available for patients that target the molecular pathophysiology of LMNA cardiomyopathy. Recent studies suggested that nicotinamide adenine dinucleotide (NAD+) cellular content could be a critical determinant for heart function. Biosynthesis of NAD+ from vitamin B3 (known as salvage pathways) is the primary source of NAD+. We showed here that NAD+ salvage pathway was altered in the heart of mouse and human carrying LMNA mutation, leading to an alteration of one of NAD+ co-substrate enzymes, PARP-1. Oral administration of nicotinamide riboside, a natural NAD+ precursor and a pyridine-nucleoside form of vitamin B3, leads to a marked improvement of the NAD+ cellular content, an increase of PARylation of cardiac proteins, and an improvement of left ventricular structure and function in a model of LMNA cardiomyopathy. Collectively, our results provide mechanistic and therapeutic insights into dilated cardiomyopathy caused by LMNA mutations.
... Previous studies proposed nicotinamide riboside as a potential AD treatment since it showed beneficial effects on cognition and β-amyloid toxicity in AD mouse model [42], and in DNA repair [43]. This metabolite also showed beneficial effects on neuroprotection and energy metabolism that is directly implied in AD pathology [44]. Regarding inositol pathway, some metabolites were down-regulated in MCI-AD (inositol-1,3,4,5-tetraphosphate or 1D-myoinositol-1,3,4,6-tetrakisphosphate or D-myo-inositol-3,4,5,6-tetrakisphosphate or 1D-myo-inositol-1,4,5,6-tetrakisphosphate). ...
... Even though the metabolic pathway of NR has yet to be fully understood, recent studies imply that NR is a potent nicotinamide adenine dinucleotide (NAD + ) precursor 1−3 and an additional vitamin B3 form. 4 The discovery of nicotinamide riboside kinases (NRK 1 and 2) in humans implied that an NRK-dependent pathway should exist in humans. 5 This hypothesis was proven to be correct for mammalian cells in 2016. 1 Yang et al. showed that NR treated cells have a 270% increase in NAD + production compared to control experiments. ...
Article
For the first time, the X-ray structure of nicotinamide riboside could be determined. Five nicotinamide riboside (NR) derivatives in their native, thioamide and triacetyl protected form could be crystallized as their chloride and bromide salts. The single crystals were obtained with the help of the vapor diffusion technique. The use of the much slower layering technique for crystallization led to the decomposition of the nicotinamide ribosides yielding the corresponding nicotinamide salts. The χ torsion angles of the five nicotinamide riboside derivatives were compared with those obtained from the two nicotinamide adenine dinucleotide crystal and the three protein nicotinamide riboside cocrystal structures.
... Nicotinamide riboside (NR) is a pyridine-nucleoside form of vitamin B3 found in human diets [21]. NR is converted to nicotinamide adenine dinucleotide (NAD + ) in a two-step reaction catalyzed by NR kinases 1/2 and nicotinic acid mononucleotide adenylyl-transferase [22,23]. ...
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Doxorubicin (DOX) is widely used as a first-line chemotherapeutic drug for various malignancies. However, DOX causes severe cardiotoxicity, which limits its clinical uses. Oxidative stress is one of major contributors to DOX-induced cardiotoxicity. While autophagic flux serves as an important defense mechanism against oxidative stress in cardiomyocytes, recent studies have demonstrated that DOX induces the blockage of autophagic flux, which contributes to DOX cardiotoxicity. The present study investigated whether nicotinamide riboside (NR), a precursor of nicotinamide adenine dinucleotide (NAD)+, prevents DOX cardiotoxicity by improving autophagic flux. We report that administration of NR elevated NAD+ levels, and reduced cardiac injury and myocardial dysfunction in DOX-injected mice. These protective effects of NR were recapitulated in cultured cardiomyocytes upon DOX treatment. Mechanistically, NR prevented the blockage of autophagic flux, accumulation of autolysosomes, and oxidative stress in DOX-treated cardiomyocytes, the effects of which were associated with restoration of lysosomal acidification. Furthermore, inhibition of lysosomal acidification or SIRT1 abrogated these protective effects of NR during DOX-induced cardiotoxicity. Collectively, our study shows that NR enhances autolysosome clearance via the NAD+/SIRT1 signaling, thereby preventing DOX-triggered cardiotoxicity.
... 1-(Beta-D-ribofuranosyl)-1,4-dihydronicotinamide is the reduced form of nicotinamide riboside. Nicotinamide riboside is a precursor of neuronal nicotinamide adenine dinucleotide and a source of vitamin B3. 22 Studies have shown that nicotinamide riboside may prevent Aβ production in the brain by promoting peroxisome proliferator-activated receptor-γ coactivator-1αmediated BACE1 ubiquitination and degradation. 23 In APP/ PS1 mice, there was a decrease in 1-(beta-D-ribofuranosyl)-1,4dihydronicotinamide levels. ...
... NAD+ regeneration is particularly important during states of high glycolytic flux, oxidative stress, and inflammation, during which endogenous precursors for NAD+ can become depleted (72). Our observation that B3 vitamers were inversely related to serum IL-6 and reduced LPSinduced cytokine production when exogenously administered to splenocytes is consistent with studies displaying protection against inflammatory diseases when nicotinamide riboside supplementation is provided, such as during high-fat dietinduced obesity, Alzheimer's disease, and aging (35,73). ...
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Background: Exposure to stressful stimuli dysregulates inflammatory processes and alters the gut microbiota. Prebiotics, including long-chain fermentable fibers and milk oligosaccharides, have the potential to limit inflammation through modulation of the gut microbiota. To determine whether prebiotics attenuate stress-induced inflammation and microbiota perturbations, mice were fed either a control diet or a diet supplemented with galactooligosaccharides, polydextrose and sialyllactose (GOS+PDX+SL) or sialyllactose (SL) for 2 weeks prior to and during a 6-day exposure to a social disruption stressor. Spleens were collected for immunoreactivity assays. Colon contents were examined for stressor- and diet- induced changes in the gut microbiome and metabolome through 16S rRNA gene sequencing, shotgun metagenomic sequencing and UPLC-MS/MS. Results: Stress increased circulating IL-6 and enhanced splenocyte immunoreactivity to an ex vivo LPS challenge. Diets containing GOS+PDX+SL or SL alone attenuated these responses. Stress exposure resulted in large changes to the gut metabolome, including robust shifts in amino acids, peptides, nucleotides/nucleosides, tryptophan metabolites, and B vitamins. Multiple B vitamins were inversely associated with IL-6 and were augmented in mice fed either GOS+PDX+SL or SL diets. Stressed mice exhibited distinct microbial communities with lower abundances of Lactobacillus spp. and higher abundances of Bacteroides spp. Diet supplementation with GOS+PDX+SL, but not SL alone, orthogonally altered the microbiome and enhanced the growth of Bifidobacterium spp. Metagenome-assembled genomes (MAGs) from mice fed the GOS+PDX+SL diet unveiled genes in a Bifidobacterium MAG for de novo B vitamin synthesis. B vitamers directly attenuated the stressor-induced exacerbation of cytokine production in LPS-stimulated splenocytes. Conclusions: Overall, these data indicate that colonic metabolites, including B vitamins, are responsive to psychosocial stress. Dietary prebiotics reestablish colonic B vitamins and limit stress-induced inflammation.
... Therefore, boosting cellular NAD + level serves as a potential target for treating mitochondrial disorders and aging (114). Cells aim to secure the NAD + balance by increasing the NAD + production by synthesizing NAD + either through de novo or salvage pathways (8,25,50). However, the NAD + salvage pathway is considered the most important for maintaining the cellular NAD + level (102). ...
Article
Significance: Extranuclear sirtuins in cytosol (SIRT2) and mitochondria (SIRT3, SIRT4 and SIRT5) are key regulators of metabolic enzymes and the antioxidative defense mechanisms. They play an important role in the adjustment of metabolic pathways in alterations of the nutritional status. Recent Advances: Recent studies have shown that in addition to lysine deacetylation, sirtuins catalyze several different lysine deacylation reactions, removal of lipid modifications and ADP-ribosylation. Large-scale studies have revealed hundreds of target proteins regulated by different sirtuin modifications. Critical issues: Sensing of the metabolic state and regulation of the sirtuin function and expression is a critical component of the machinery optimizing cellular functions in the switch from fed to fasting condition. Overfeeding, obesity and metabolic diseases cause metabolic stress that dysregulates the sirtuins which may play a role in the pathogenesis and complications of metabolic diseases such as type 2 diabetes, fatty liver disease and cardiac diseases. In the current review we will discuss the significance of the extranuclear sirtuins as metabolic regulators and in protection against the reactive oxygen species, and also how these sirtuins are regulated by metabolic status and their putative role in metabolic diseases. Future directions: To efficiently utilize sirtuins as drug targets for treatment of the metabolic diseases, better understanding of the sirtuin functions, targets, regulation and cross-talk is needed. Furthermore, more studies in humans are needed to confirm the many observations mainly made in animal and cell models so far.
... Micromolar amounts of nicotinamide riboside are reported to be present in milk-derived products, and yeast-containing food products are presumed to be natural sources of nicotinamide riboside (Chi and Sauve, 2013). From the information available, the Panel considers that the contribution of nicotinamide riboside from food sources other than the NF is too small to be relevant for the safety assessment. ...
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Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Allergens (NDA) was asked to deliver an opinion on nicotinamide riboside chloride as a novel food (NF) pursuant to Regulation (EU) 2015/2283, including an evaluation of the safety of its use in food supplements as a source of niacin, and the bioavailability of nicotinamide from this source, in the context of Directive 2002/46/EC. The NF, a synthetic form of nicotinamide riboside, is proposed to be used in food supplements for the healthy adult population at levels up to 300 mg/day. The production process, composition, specifications, batch-to-batch variability and stability of the NF do not raise safety concerns. Animal and human data indicate that the NF contributes to the nicotinamide body pool. There are no concerns regarding genotoxicity. Human studies do not raise safety concerns. The proposed maximum use level corresponds to an amount of nicotinamide, which is sixfold lower than the tolerable upper intake level (UL) set for adults, excluding pregnant and lactating women. The margin of exposure (MoE) of 70 derived from repeated dose toxicity studies with rats and dogs is considered sufficient for the adult population, excluding pregnant and lactating women. Regarding these two population groups, the MoE of 76 derived from a developmental toxicity study in rats is considered insufficient in the absence of data which could justify accepting a MoE lower than 100. The Panel concludes that the NF is safe under the proposed conditions of use for the healthy adult population, excluding pregnant and lactating women, and that an intake of the NF up to 230 mg/day is safe for pregnant and lactating women. The Panel also concludes that the NF is a source from which nicotinamide, a form of niacin, is bioavailable. © 2019 European Food Safety Authority. EFSA Journal published by John Wiley and Sons Ltd on behalf of European Food Safety Authority.
... These enzymes, are involved in a host of metabolic actions throughout the body, but, they seem to decline with age [23]. Earlier studies [24][25] had established that the NAD-dependent deacetylase activity of sirtuins regulates many fundamental biology such as aging processes in response to both environment and nutritional stimuli [26][27][28]. Thus, NAD+ boosting compounds such as delonix regia hold promise for enhancing cardiovascular health and other physiological function including aging ...
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Plants contain many bioactive compounds such as nutrients (minerals and vitamins) and, which are very important for the treatment of various diseases. Delonix regia seed powder was analyzed for the vitamins and mineral contents. Using spectrophotometer combined with titration, the vitamins content of Delonix regia was analyzed. Further, Atomic absorption spectrophotometer was used to analyze the mineral contents. The plant was show to contain low amounts of vitamin B1 (0.04 ± 0.0001mg %), B 2 (0.08 ± 0.0003mg %), and B 12 (0.08 ± 0.001mg %) with high vitamin B 3 (766.66 ± 8.81mg) and B 6 (316.46 ± 6.35mg). Vitamin C (16.0 ± 0.3mg/100g) was significantly higher in the plant compare to vitamin E (0.54 ± 0.01), vitamin A (2.81 ± 0.012), vitamin B 1 , B 2 , and B 12. Delonix regia seed also contain important minerals such as Magnesium and Calcium in moderate amount (16.83 ± 8.23mg/g and 27.58 ± 0.00). Also, Chromium, Zinc, Cadmium and Iron were observed in trace amount (0.56 ± 0.0003mg/g, 0.51 ± 0.29 mg/g, 9.48 ± 0.03mg/g and 1.64 ± 0.33mg/g) respectively. In conclusion, Delonix regia seed as a phytochemical maybe necessary in the management of diseases like diabetes, Sickle cell and Aging as it may influence cellular systems with varied network, impacting on multiple targets with effects on enzymatic/or protein-protein interaction processes. Our results provide insight on the rich contents of Delonix regia extract however; further investigation on this plant is required ascertaining supplementary dosage necessary for good health in both resource poor, industrial and postindustrial environment, moving forward. Citation: Michael P Okoh and Chijoke Madu. "Phyto and Natriuretic Analysis of Delonix Regia Plant Extract for Vitamins and Mineral Contents". Nutrition and Food Toxicology 2.6 (2018): 540-548.
... It was also shown that SAM, which can supply ATP and GTP independently of PRPP [118], may alleviate some of the symptoms of patients with Arts syndrome. NR can form NADP(H) independently of PRPP by virtue of NR kinases 1 and 2 to produce NMN (nicotinamide mononucleotide), which is adenylated to NAD + [171,172]. Shortly after commencing treatment, the intervals between respiratory infections increased and recovery was improved. The patient's muscular strength, speech, ability to play and overall well-being improved markedly. ...
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Phosphoribosyl pyrophosphate synthetase (PRS EC 2.7.6.1) is a rate-limiting enzyme that irreversibly catalyzes the formation of phosphoribosyl pyrophosphate (PRPP) from ribose-5-phosphate and adenosine triphosphate (ATP). This key metabolite is required for the synthesis of purine and pyrimidine nucleotides, the two aromatic amino acids histidine and tryptophan, the cofactors nicotinamide adenine dinucleotide (NAD+) and nicotinamide adenine dinucleotide phosphate (NADP+), all of which are essential for various life processes. Despite its ubiquity and essential nature across the plant and animal kingdoms, PRPP synthetase displays species-specific characteristics regarding the number of gene copies and architecture permitting interaction with other areas of cellular metabolism. The impact of mutated PRS genes in the model eukaryote Saccharomyces cerevisiae on cell signalling and metabolism may be relevant to the human neuropathies associated with PRPS mutations. Human PRPS1 and PRPS2 gene products are implicated in drug resistance associated with recurrent acute lymphoblastic leukaemia and progression of colorectal cancer and hepatocellular carcinoma. The investigation of PRPP metabolism in accepted model organisms, e.g., yeast and zebrafish, has the potential to reveal novel drug targets for treating at least some of the diseases, often characterized by overlapping symptoms, such as Arts syndrome and respiratory infections, and uncover the significance and relevance of human PRPS in disease diagnosis, management, and treatment.
... The bulk of the research in this area has been focused on two NAD + precursor molecules, namely NMN and NR. This is unsurprising as evidence suggests that oral supplementation of NMN or NR rapidly elevates levels of NAD + in the brain and periphery, often as soon as a few minutes following their administration [406][407][408]. Importantly, the results of human and animal studies have provided robust evidence of tolerability and long-term safety as they appear to be free of the serious side-effects associated with other NAD + -elevating supplements such as nicotinamide [406,409,410]. ...
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Nitro-oxidative stress and lowered antioxidant defences play a key role in neuropsychiatric disorders such as major depression, bipolar disorder and schizophrenia. The first part of this paper details mitochondrial antioxidant mechanisms and their importance in reactive oxygen species (ROS) detoxification, including details of NO networks, the roles of H2O2 and the thioredoxin/peroxiredoxin system, and the relationship between mitochondrial respiration and NADPH production. The second part highlights and identifies the causes of the multiple pathological sequelae arising from self-amplifying increases in mitochondrial ROS production and bioenergetic failure. Particular attention is paid to NAD+ depletion as a core cause of pathology; detrimental effects of raised ROS and reactive nitrogen species on ATP and NADPH generation; detrimental effects of oxidative and nitrosative stress on the glutathione and thioredoxin systems; and the NAD+-induced signalling cascade, including the roles of SIRT1, SIRT3, PGC-1α, the FOXO family of transcription factors, Nrf1 and Nrf2. The third part discusses proposed therapeutic interventions aimed at mitigating such pathology, including the use of the NAD+ precursors nicotinamide mononucleotide and nicotinamide riboside, both of which rapidly elevate levels of NAD+ in the brain and periphery following oral administration; coenzyme Q10 which, when given with the aim of improving mitochondrial function and reducing nitro-oxidative stress in the brain, may be administered via the use of mitoquinone, which is in essence ubiquinone with an attached triphenylphosphonium cation; and N-acetylcysteine, which is associated with improved mitochondrial function in the brain and produces significant decreases in oxidative and nitrosative stress in a dose-dependent manner.
... Conversion of nicotinamide or nicotinic acid to NAD(P) is PRPPdependent [7] and patients with a dysfunctional, superactive PRPS1 have extremely low NAD(P) concentrations in erythrocytes [8]. Nicotinamide riboside (NR) can form NAD(P) independent from PRPP, using NR kinases 1 and 2 to produce nicotinamide mononucleotide which is adenylated to NAD [9,10]. NR is contained in low concentrations in milk and dairy products, and freely available as a nutrition supplement. ...
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Arts syndrome or phosphoribosyl-pyrophosphate-synthetase-1 (PRPS1) deficiency is caused by loss-of-function mutations in the PRPS1 gene (Xq22.3). PRPS1 is an initial and essential step for the synthesis of the nucleotides of purines, pyrimidines, and nicotinamide. Classically, affected males present with sensorineural hearing loss, optic atrophy, muscular hypotonia, developmental impairment, and recurrent severe respiratory infections early in life. Treatment of a 3-year old boy with S-adenosylmethionine (SAM) replenished erythrocyte purine nucleotides of adenosine and guanosine, while SAM and nicotinamide riboside co-therapy further improved his clinical phenotype as well as T-cell survival and function.
... Therefore, supplementation with exogenous NAD + to maintain the NAD + /NADH balance is an effective approach to ameliorate cellular stress. Due to the high impermeability of NAD + and its serum instability [6], administration of at least millimolar amounts is needed to achieve micromolar concentrations at the target tissue [7], thus it is not feasible to use NAD + as a therapeutic supplement. NAD + precursors, including nicotinamide mononucleotide (NMN), nicotinamide ribose (NR), nicotinic acid (NA), nicotinamide (NAM), and tryptophan (Trp), can be converted to NAD + , and may serve as useful alternatives [8,9]. ...
Article
Background Nicotinamide adenine dinucleotide (NAD⁺), a coenzyme that plays crucial roles in many cellular processes, is a potential therapeutic target for various diseases. Dihydronicotinamide riboside (NRH), a novel reduced form of nicotinamide riboside, has emerged as a potent NAD⁺ precursor. Here, we studied the protective effects and underlying mechanism of NRH on aminoglycoside-induced ototoxicity. Methods Auditory function and hair-cell (HC) morphology were examined to assess the effects of NRH on kanamycin-induced hearing loss. The pharmacokinetic parameters of NRH were measured in plasma and the cochlea using liquid chromatography tandem mass spectrometry. NAD⁺ levels in organ explant cultures were assessed to compare NRH with known NAD⁺ precursors. Immunofluorescence analysis was performed to detect reactive oxygen species (ROS) and apoptosis. We analyzed SIRT1 and 14–3–3 protein expression. EX527 and resveratrol were used to investigate the role of SIRT1 in the protective effect of NRH against kanamycin-induced ototoxicity. Results NRH alleviated kanamycin-induced HC damage and attenuated hearing loss in mice. NRH reduced gentamicin-induced vestibular HC loss. Compared with NAD and NR, NRH produced more NAD⁺ in cochlear HCs and significantly ameliorated kanamycin-induced oxidative stress and apoptosis. NRH rescued the aminoglycoside-induced decreases in SIRT1 and 14–3–3 protein expression. Moreover, EX527 antagonized the protective effect of NRH on kanamycin-induced HC loss by inhibition of SIRT1, while resveratrol alleviated HC damage caused by EX527. Conclusions NRH ameliorates aminoglycoside-induced ototoxicity by inhibiting HC apoptosis by activating SIRT1 and decreasing ROS. NRH is an effective therapeutic option for aminoglycoside-induced ototoxicity.
... On hydrolyses of the amide group of NAM with Pcn1, the NA are produced (Hong and Huh 2021;Ghugari et al. 2020), thereby suggesting that at mutant of PNC1, NAM concentration could be tremendously increase while also inhibiting sirtuin functions (Mei and Brenner 2014;Jiang et al. 2016). At this convergence point, nicotinamide mononucleotide adenylyltransferase 1 & 2 (Nma1 and Nma2) participates in the conversion of NaMN to nicotinic acid adenine dinucleotide (NaAD) by adenosine monophosphate (AMP moiety) addition (Pinson et al. 2019), which undergoes amidation by glutamine (Q)-dependent NAD synthetase (Qns1) to yield NAD molecules (Kropotov et al. 2021;Chi and Sauve 2013). Aside from Qns1 which carries out amidation of NaAD to NAD, there exist also other de novo route which uses molecular oxygen as a substrate (Bna2, Bna4 and Bna1), thus suggesting utilization of anaerobic cellular growth conditions on the salvage pathways for NAD synthesis (Croft et al. 2020). ...
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Molecular causes of aging and longevity interventions have witnessed an upsurge in the last decade. The resurgent interests in the application of small molecules as potential geroprotectors and/or pharmacogenomics point to nicotinamide adenine dinucleotide (NAD) and its precursors, nicotinamide riboside, nicotinamide mononucleotide, nicotinamide, and nicotinic acid as potentially intriguing molecules. Upon supplementation, these compounds have shown to ameliorate aging related conditions and possibly prevent death in model organisms. Besides being a molecule essential in all living cells, our understanding of the mechanism of NAD metabolism and its regulation remain incomplete owing to its omnipresent nature. Here we discuss recent advances and techniques in the study of chronological lifespan (CLS) and replicative lifespan (RLS) in the model unicellular organism Saccharomyces cerevisiae. We then follow with the mechanism and biology of NAD precursors and their roles in aging and longevity. Finally, we review potential biotechnological applications through engineering of microbial lifespan, and laid perspective on the promising candidature of alternative redox compounds for extending lifespan.
... Nicotinamide riboside (NR) is a vitamin B 3 derivative and NAD 1 precursor that has been the subject of recent studies and clinical trials as a potential treatment for human diseases that arise from mitochondrial degeneration, such as obesity and T2D (13). NR is found in our diet (13,14) and can be synthesized by the gut microbiota. In a mouse model of diet-induced obesity, male mice fed a 60% high-fat diet (HFD) supplemented with NR had a reduction in diet-induced weight gain due to increased energy expenditure and had improved obesity-related conditions (15). ...
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With obesity and type 2 diabetes (T2D) at epidemic levels, we need to understand the complex nature of these diseases to design better therapeutics. The underlying causes of both obesity and T2D are complex, but both are thought to develop, in part, based on contributions from the gut microbiota.
... Aside from our primary vascular end points, there is also strong evidence from animal studies suggesting that NR supplementation may improve cognitive function through direct neuroprotective benefits including reduced neuroinflammation, accelerated brain amyloid clearance, increased neurogenesis, and improved brain energy metabolism. [12][13][14] To test this, we are conducting a 12-week, randomized, doubleblind, placebo controlled clinical trial in older adults with amnestic MCI to determine if NR supplementation improves memory and markers of cardiovascular function and brain health including blood pressure, arterial stiffness, and cerebral blood flow. Our study is funded by a grant from the National Institute on Aging and is actively enrolling participants with a targeted completion date of spring 2023. ...
... In humans, nicotinamide is converted to Nicotinamide Adenine Dinucleotide (NAD) which plays an important role in cellular functions in the body [22,23]. Various nicotinamide derivatives have been reported with many biological activities such as antituberculosis [24,25], antifungal [26] antitumor [27][28][29] antidiabetic [30][31][32], antioxidative [33] and neuroprotective [34,35] activities. The effects of nicotinamide on AD and other neurodegenerative disorders have been investigated, and it was reported that nicotinamide can cross the blood and brain barrier [36] and thus, this may have some positive effects against neurodegenerative diseases [37][38][39][40]. ...
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In this study, a total of 18 new benzamide/ nicotinamide/ cinnamamide derivative compounds were designed and synthesized for the first time (except B1 and B5) by conventional and microwave irradiation methods. The chemical structures of the synthesized compounds were characterized by ¹H NMR, ¹³C NMR, and HRMS spectra. In vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition effects of the compounds were evaluated to find out new possible drug candidate molecule/s. According to the inhibition results, the IC50 values of the compounds synthesized were in the range of 10.66–83.03 nM towards AChE, while they were in the range of 32.74–66.68 nM towards BuChE. Tacrine was used as the reference drug and its IC50 values were 20.85 nM and 15.66 nM towards AChE and BuChE, respectively. The most active compounds B4 (IC50: 15.42 nM), N4 (IC50: 12.14 nM), and C4 (IC50: 10.67 nM) in each series towards AChE were docked at the binding site of AChE enzyme to explain the inhibitory activities of each series. On the other hand, the compounds B4, N4, and C4 showed satisfactory pharmacokinetic properties via the prediction of ADME profiles. Graphic abstract
... Nicotinamide riboside (NR), a new pyridine-nucleoside form of vitamin B3, occurs naturally at low concentrations in yeast, bacteria, and milk (Chi and Sauve, 2013). In mouse embryonic stem cells and young and aged mouse models NR supplementation increased Downloaded from https://academic.oup.com/tas/article-abstract/doi/10.1093/tas/txaa126/5872322 by guest on 16 July 2020 A c c e p t e d M a n u s c r i p t nicotinamide adenine dinucleotide (NAD+) levels (Yang et al., 2007, Zhang et al., 2016. ...
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The objective of this study was to examine the effect of nicotinamide riboside (NR) on pectoralis major muscle (PM) development and growth. Fertilized Cobb 500 broiler eggs (N = 156; average weight of 70.3 g) were ordered by weight and within each 4 egg strata eggs were randomly assigned to treatments within a 2 × 2 factorial arrangement. Factor 1 consisted of NR treatment with eggs receiving 0 or 250 mM NR. Factor 2 consisted of injection location, with treatments injected into either the yolk sac or albumen. Eggs were incubated at a temperature of 37°C and a relative humidity of 40 ± 2% for the first 18 d of incubation and humidity was increased to 60 ± 2°C for the final 3 d. On d 10 of incubation, eggs were injected in their designated location with 100 μL of 0.9% sterile saline containing the assigned NR dose. Chicks were hatched, euthanized, and morphometric measurements of the body and left PM were collected. The left PM was also analyzed for muscle fiber cross-sectional area (CSA) and density. There were no treatment × location or main effects for all body morphometric measurements (P > 0.07), except chest width of chicks from eggs injected in the yolk were wider (P = 0.01) than chicks from eggs injected in the albumen. There were only treatment × location interactions for PM weight and length (P < 0.01). When NR was injected into the albumen, PM weight did not differ (P = 0.09); however, when NR was injected into the yolk sac, PM weight increased (P < 0.01). When NR was injected into both locations, PM length increased (P < 0.01), but increased to a greater extent when NR was injected into the yolk sac. There were treatment main effects for PM width and depth (P < 0.01), with NR injected chicks having PM with greater width and depth. There were no treatment × location or main effects for PM fiber CSA (P > 0.06). There was a treatment × location interaction (P < 0.01) for fiber density. When NR was injected into the albumen, fiber density did not differ (P = 0.09); however, when NR was injected into the yolk sac, fiber density increased (P < 0.01). Injecting NR into the yolk sac of the developing embryo at d 10 of incubation increased PM development which was due to an increase in muscle density.
... In vitro and in vivo study show that ternatin (N-methylated cyclic peptide), isolated from endophytic fungi Coriolus versicolor, inhibits the accumulation of fat in an adipose tissue cell line (3T3-L1) and reduces mice fat mass (Ito et al. 2009). Nicotinamide riboside is isolated from the endophytes like Saccharomyces cerevisiae, Piriformospora sp., Epichloe sp., and Colletotrichum sp. of Bacopa monnieri and Azadirachta indica plants (Chi and Sauve 2013). Administration of nicotinamide riboside in a mice model of cardiomyopathy, that lacks transferrin receptor protein 1 (TfR1) in the heart, resulted in prevention of cardiomegaly, mitochondrial respiration poor cardiac function, and impaired mitophagy (Xu W et al. 2015). ...
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Endophytes are a potent source of bioactive compounds that mimic plant-based metabolites. The relationship of host plant and endophyte is significantly associated with alteration in fungal colonisation and the extraction of endophyte-derived bioactive compounds. Screening of fungal endophytes and their relationship with host plants is essential for the isolation of bioactive compounds. Numerous bioactive compounds with antioxidant, antimicrobial, anticancer, and immunomodulatory properties are known to be derived from fungal endophytes. Bioinformatics tools along with the latest techniques such as metabolomics, next-generation sequencing, and metagenomics multilocus sequence typing can potentially fill the gaps in fungal endophyte research. The current review article focuses on bioactive compounds derived from plant-associated fungal endophytes and their pharmacological importance. We conclude with the challenges and opportunities in the research area of fungal endophytes.
... Other genes of interest in L. brandtii include the upregulated Nmrk2, which catalyzes the conversion of nicotinamide ribose into NAD + to participate in oxidative phosphorylation (Chi and Sauve, 2013). Moreover, upregulated Treh, which encodes trehalase, may help L. brandtii convert more dietary trehalose into glucose for consumption by the body (Jiao et al., 2019;Oesterreicher et al., 2001) (Fig. 8B). ...
Article
The effects of global warming and anthropogenic disturbance force animals to migrate from lower to higher elevations to find suitable new habitats. As such migrations increase hypoxic stress on the animals, it is important to understand how plateau- and plain-dwelling animals respond to low-oxygen environments. We used comparative transcriptomics to explore the response of Neodon fuscus, Lasiopodomys brandtii, and Mus musculus skeletal muscle tissues to hypoxic conditions. Results indicate that these species have adopted different oxygen transport and energy metabolism strategies for dealing with a hypoxic environment. N. fuscus promotes oxygen transport by increasing hemoglobin synthesis and reduces the risk of thrombosis through cooperative regulation of genes, including Fga, Fgb, Alb, and Ttr; genes such as Acs16, Gpat4, and Ndufb7 are involved in regulating lipid synthesis, fatty acid β-oxidation, hemoglobin synthesis, and electron-linked transmission, thereby maintaining a normal energy supply in hypoxic conditions. In contrast, the oxygen-carrying capacity and angiogenesis of red blood cells in L. brandtii are promoted by genes in the CYP and COL families; this species maintains its bodily energy supply by enhancing the pentose phosphate pathway and mitochondrial fatty acid synthesis pathway. However, under hypoxia, M. musculus cannot effectively transport additional oxygen; thus, its cell cycle, proliferation, and migration are somewhat affected. Given its lack of hypoxic tolerance experience, M. musculus also shows significantly reduced oxidative phosphorylation levels under hypoxic conditions. Our results suggest that the glucose capacity of M. musculus skeletal muscle does not provide sufficient energy during hypoxia; thus, we hypothesize that it supplements its bodily energy by synthesizing ketone bodies. For the first time, we describe the energy metabolism pathways of N. fuscus and L. brandtii skeletal muscle tissues under hypoxic conditions. Our findings, therefore, improve our understanding of how vertebrates thrive in high altitude and plain habitats when faced with hypoxic conditions.
... In particular, NAD + intermediates, such as nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), have been extensively tested for their ability to increase NAD + levels and beneficial effects in biosynthesis as a potential target for prevention and treatment of aging and aging-associated diseases [132]. Nicotinamide riboside is a trace nutrient in foods functioning as a precursor to nicotinamide adenine dinucleotide [133]. As a NAD + booster, NR has been mostly studied for its pharmacological effects in aging-related pathologies and disorders in not only animals but humans as well. ...
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Sirtuin-3 (SIRT3) is a NAD⁺-dependent protein deacetylase that is located in mitochondria, regulating mitochondrial proteins and maintaining cellular antioxidant status. Increasing evidence demonstrates that SIRT3 plays a role in degenerative disorders including Parkinson’s disease (PD), which is a devastating nervous system disease currently with no effective treatments available. Although the etiology of PD is still largely ambiguous, substantial evidence indicates that mitochondrial dysfunction and oxidative stress play major roles in the pathogenesis of PD. The imbalance of reactive oxygen species (ROS) production and detoxification leads to oxidative stress that can accelerate the progression of PD. By causing conformational changes in the deacetylated proteins SIRT3 modulates the activities and biological functions of a variety of proteins involved in mitochondrial antioxidant defense and various mitochondrial functions. Increasingly more studies have suggested that upregulation of SIRT3 confers beneficial effect on neuroprotection in various PD models. This review discusses the mechanism by which SIRT3 regulates intracellular oxidative status and mitochondrial function with an emphasis in discussing in detail the regulation of SIRT3 on each component of the five complexes of the mitochondrial respiratory chain and mitochondrial antioxidant defense, as well as the pharmacological regulation of SIRT3 in light of therapeutic strategies for PD.
... Keywords: Melanoma, Nicotinamide, Vitamin B3, Melanoma mouse-animal model, Metabolism, Sirtuin 2, HCAR2, HCAR3, Dietary intake Background Nicotinamide (NAM) is the amide form of niacin (vitamin B3 or vitamin PP). It is a precursor of nicotinamideadenine dinucleotide NAD + [1] and is known to play an essential role in energy metabolism and to act in several tissues including skin [2], nervous system [3,4], and muscles [5]. Its metabolic pathway is related to tryptophan metabolism [6]. ...
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... In this regard, a mini-review has been published [16] based on results of NAD + precursor supplementation, which have been presented by basic researchers and clinicians in a recent meeting (3rd NO-Age Symposium, 2019). These NAD + precursors, namely nicotinic acid (NA), nicotinamide (NAM) and nicotinamide riboside (NR), belong to the group of vitamin B3 and are used for NAD + biosynthesis across species, spanning from yeast to human [1,12,[17][18][19]. They are available in the diet since they are present in traces in some daily foods (vegetables, fruits, meat and milk) and are currently the object of considerable interest in the nutraceutical field, with the aim of using them as dietary supplements with preventive pro-healthy aging properties. ...
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... Coenzyme nicotinamide adenine dinucleotide (NAD + ), which contains two covalently joined mononucleotides (nicotinamide mononucleotide or NMN, and AMP) [9], has an important role in an energy metabolism like mitochondrial electron transport, glycolysis, and citric acid cycle [10] in order to generate adenosine triphosphate (ATP) [11]. NAD + is also a rate-limiting substrate for many signalling enzymes such as sirtuin (SIRT) proteins SIRT1 and SIRT3, the poly (ADP-ribose) polymerase (PARP) proteins PARP1 and PARP2, a COOH-terminal binding protein (CtBP), cyclic ADP-ribose (ADPR) synthetases CD38 and CD157, and many other NAD + -dependent enzymes. ...
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Human nicotinamide phosphoribosyltransferase (NAMPT) replenishes the NAD pool and controls the activities of sirtuins (SIRT), mono- and poly-(ADP-ribose) polymerases (PARP) and NAD nucleosidase (CD38). The nature of the enzymatic transition-state (TS) is central to understanding the function of NAMPT. We determined the TS structure for pyrophosphorolysis of nicotinamide mononucleotide (NMN) by kinetic isotope effects (KIEs). With the natural substrates, NMN and pyrophosphate (PPi), the intrinsic KIEs of [1'-14C], [1-15N], [1'-3H] and [2'-3H] are 1.047, 1.029, 1.154 and 1.093, respectively. A unique quantum computational approach was used for TS analysis that included structural elements of the catalytic site. Without constraints (e.g. imposed torsion angles), the theoretical and experimental data are in excellent agreement. The quantum-mechanical calculations incorporated a crucial catalytic site residue (D313), two magnesium atoms and coordinated water molecules. The transition state model predicts primary 14C, primary 15N and -secondary 3H KIE close to the experimental values. The analysis reveals significant ribocation character at the TS. The attacking PPi nucleophile is weakly interacting (rC-O = 2.60 Å) and the N-ribosidic C1'-N bond is highly elongated at the TS (rC-N = 2.35 Å). Together with the crystal structure of the NMN•PPi•Mg2•enzyme complex, the reaction coordinate is defined. The enzyme holds the nucleophile and leaving group in relatively fixed positions to create a reaction coordinate with C1'-anomeric migration from nicotinamide to the PPi. The transition state is reached by a 0.85 Å migration of C1'.
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As NAD(+) is a rate-limiting cosubstrate for the sirtuin enzymes, its modulation is emerging as a valuable tool to regulate sirtuin function and, consequently, oxidative metabolism. In line with this premise, decreased activity of PARP-1 or CD38-both NAD(+) consumers-increases NAD(+) bioavailability, resulting in SIRT1 activation and protection against metabolic disease. Here we evaluated whether similar effects could be achieved by increasing the supply of nicotinamide riboside (NR), a recently described natural NAD(+) precursor with the ability to increase NAD(+) levels, Sir2-dependent gene silencing, and replicative life span in yeast. We show that NR supplementation in mammalian cells and mouse tissues increases NAD(+) levels and activates SIRT1 and SIRT3, culminating in enhanced oxidative metabolism and protection against high-fat diet-induced metabolic abnormalities. Consequently, our results indicate that the natural vitamin NR could be used as a nutritional supplement to ameliorate metabolic and age-related disorders characterized by defective mitochondrial function.
Article
SIRT1 is the closest mammalian homologue of enzymes that extend life in lower organisms. Its role in mammals is incompletely understood, but includes modulation of at least 34 distinct targets through its nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase activity. Recent experiments using small molecule activators and genetically engineered mice have provided new insight into the role of this enzyme in mammalian biology and helped to highlight some of the potentially relevant targets. The most widely employed activator is resveratrol, a small polyphenol that improves insulin sensitivity and vascular function, boosts endurance, inhibits tumor formation, and ameliorates the early mortality associated with obesity in mice. Many of these effects are consistent with modulation of SIRT1 targets, such as PGC1α and NFκB, however, resveratrol can also activate AMPK, inhibit cyclooxygenases, and influence a variety of other enzymes. A novel activator, SRT1720, as well as various methods to manipulate NAD+ metabolism, are emerging as alternative methods to increase SIRT1 activity, and in many cases recapitulate effects of resveratrol. At present, further studies are needed to more directly test the role of SIRT1 in mediating beneficial effects of resveratrol, to evaluate other strategies for SIRT1 activation, and to confirm the specific targets of SIRT1 that are relevant in vivo. These efforts are especially important in light of the fact that SIRT1 activators are entering clinical trials in humans, and “nutraceutical” formulations containing resveratrol are already widely available.
Article
NAD+ is essential for life in all organisms, both as a coenzyme for oxidoreductases and as a source of ADPribosyl groups used in various reactions, including those that retard aging in experimental systems. Nicotinic acid and nicotinamide were defined as the vitamin precursors of NAD+ in Elvehjem's classic discoveries of the 1930s. The accepted view of eukaryotic NAD+ biosynthesis, that all anabolism flows through nicotinic acid mononucleotide, was challenged experimentally and revealed that nicotinamide riboside is an unanticipated NAD+ precursor in yeast. Nicotinamide riboside kinases from yeast and humans essential for this pathway were identified and found to be highly specific for phosphorylation of nicotinamide riboside and the cancer drug tiazofurin. Nicotinamide riboside was discovered as a nutrient in milk, suggesting that nicotinamide riboside is a useful compound for elevation of NAD+ levels in humans.
Article
Although NAD(+) biosynthesis is required for Sir2 functions and replicative lifespan in yeast, alterations in NAD(+) precursors have been reported to accelerate aging but not to extend lifespan. In eukaryotes, nicotinamide riboside is a newly discovered NAD(+) precursor that is converted to nicotinamide mononucleotide by specific nicotinamide riboside kinases, Nrk1 and Nrk2. In this study, we discovered that exogenous nicotinamide riboside promotes Sir2-dependent repression of recombination, improves gene silencing, and extends lifespan without calorie restriction. The mechanism of action of nicotinamide riboside is totally dependent on increased net NAD(+) synthesis through two pathways, the Nrk1 pathway and the Urh1/Pnp1/Meu1 pathway, which is Nrk1 independent. Additionally, the two nicotinamide riboside salvage pathways contribute to NAD(+) metabolism in the absence of nicotinamide-riboside supplementation. Thus, like calorie restriction in the mouse, nicotinamide riboside elevates NAD(+) and increases Sir2 function.
Article
A major cause of cell death caused by genotoxic stress is thought to be due to the depletion of NAD(+) from the nucleus and the cytoplasm. Here we show that NAD(+) levels in mitochondria remain at physiological levels following genotoxic stress and can maintain cell viability even when nuclear and cytoplasmic pools of NAD(+) are depleted. Rodents fasted for 48 hr show increased levels of the NAD(+) biosynthetic enzyme Nampt and a concomitant increase in mitochondrial NAD(+). Increased Nampt provides protection against cell death and requires an intact mitochondrial NAD(+) salvage pathway as well as the mitochondrial NAD(+)-dependent deacetylases SIRT3 and SIRT4. We discuss the relevance of these findings to understanding how nutrition modulates physiology and to the evolution of apoptosis.
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A new two-step methodology achieves stereoselective synthesis of beta-nicotinamide riboside and a series of related amide, ester, and acid nucleosides. Compounds were prepared through a triacetylated-nicotinate ester nucleoside, via coupling of either ethylnicotinate or phenylnicotinate with 1,2,3,5-tetra-O-acetyl-beta-D-ribofuranose. Nicotinamide riboside, nicotinic acid riboside, O-ethylnicotinate riboside, O-methylnicotinate riboside, and several N-alkyl derivatives increased NAD+ concentrations from 1.2-2.7-fold in several mammalian cell lines. These findings establish bioavailability and potent effects of these nucleosides in stimulating the increase of NAD+ concentrations in mammalian cells.
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The PGC1 transcriptional coactivators are major regulators of several crucial aspects of energy metabolism. PGC1alpha controls many aspects of oxidative metabolism, including mitochondrial biogenesis and respiration through the coactivation of many nuclear receptors, and factors outside the nuclear receptor family. ERRalpha, NRF1 and NRF2 are key targets of the PGC1s in mitochondrial biogenesis. We have recently addressed the question of the role of PGC1 coactivators in the metabolism of reactive oxygen species (ROS). We now show that PGC1alpha and beta are induced when cells are given an oxidative stressor, H2O2. In fact, experiments with either genetic knockouts or RNAi for the PGC1s show that the ability of ROS to induce a ROS scavenging programme depends entirely on the PGC1s. This includes genes encoding mitochondrial proteins like SOD2, but also includes cytoplasmic proteins such as catalase and GPX1. Cells lacking PGC1alpha are hypersensitive to death from oxidative stress caused by H2O2 or paraquat. Mice deficient in PGC1alpha get excessive neurodegeneration when given kainic acid-induced seizures or MPTP, which causes Parkinsonism. These data show that the PGC1s are key modulators of mitochondrial biology and important protective molecules against ROS generation and damage. The implications of this for diabetes and neurodegenerative diseases are discussed.
PGC-1 alpha expression decreases in the Alzheimer disease brain as a function of dementia Nicotinamide riboside, a trace Vitamin B3 in fo ods Chi and Sauve 1363-1950
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Qin WP, Haroutunian V, Katsel P, et al. PGC-1 alpha expression decreases in the Alzheimer disease brain as a function of dementia. Arch Neurol 2009; 66:352–361. Nicotinamide riboside, a trace Vitamin B3 in fo ods Chi and Sauve 1363-1950 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins www.co-clinicalnutrition.com 661
Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-gamma coactivator 1alpha regulated beta-secretase 1 degradation and mitochondrial gene expression in Alzheimer's mouse models
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  • B Gong
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AND RECOMMENDED READING Gong B, Pan Y, Vempati P, et al. Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-gamma coactivator 1alpha regulated beta-secretase 1 degradation and mitochondrial gene expression in Alzheimer's mouse models. Neurobiol Aging 2013; 34: 1581-1588.