ArticleLiterature Review

NAD+ and Vitamin B3: From Metabolism to Therapies

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Abstract

The role of NAD(+) metabolism in health and disease is of increased interest as the use of niacin (nicotinic acid) has emerged as a major therapy for treatment of hyperlipidemias and with the recognition that nicotinamide can protect tissues and NAD(+) metabolism in a variety of disease states, including ischemia/reperfusion. In addition, a growing body of evidence supports the view that NAD(+) metabolism regulates important biological effects, including lifespan. NAD(+) exerts potent effects through the poly(ADP-ribose) polymerases, mono-ADP-ribosyltransferases, and the recently characterized sirtuin enzymes. These enzymes catalyze protein modifications, such as ADP-ribosylation and deacetylation, leading to changes in protein function. These enzymes regulate apoptosis, DNA repair, stress resistance, metabolism, and endocrine signaling, suggesting that these enzymes and/or NAD(+) metabolism could be targeted for therapeutic benefit. This review considers current knowledge of NAD(+) metabolism in humans and microbes, including new insights into mechanisms that regulate NAD(+) biosynthetic pathways, current use of nicotinamide and nicotinic acid as pharmacological agents, and opportunities for drug design that are directed at modulation of NAD(+) biosynthesis for treatment of human disorders and infections.

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... Niacin is the generic name for both free forms of vitamin B 3 and sometimes also including their riboside derivatives. The biosynthesis of nicotinic acid occurs in the liver from the essential amino acid tryptophan [2,3]. Both nicotinic acid and nicotinamide, through different pathways in mammals, are incorporated into the essential redox coenzyme, nicotinamide adenine dinucleotide (NAD + /NADH) which is predominantly present in the oxidized form (NAD + ) and is involved in the catabolism of carbohydrates, fats and proteins and the generation of cell's energy currency ATP [2,3]. ...
... The biosynthesis of nicotinic acid occurs in the liver from the essential amino acid tryptophan [2,3]. Both nicotinic acid and nicotinamide, through different pathways in mammals, are incorporated into the essential redox coenzyme, nicotinamide adenine dinucleotide (NAD + /NADH) which is predominantly present in the oxidized form (NAD + ) and is involved in the catabolism of carbohydrates, fats and proteins and the generation of cell's energy currency ATP [2,3]. NAD + /NADH is also required in DNA damage repair and cellular signalling processes. ...
... NAD + /NADH is also required in DNA damage repair and cellular signalling processes. The phosphorylated form of NAD + /NADH (NADP + /NADPH) is mainly present in the reduced form (NADPH) and is involved in anabolic processes such as fatty acid and steroid biosynthesis [2,3]. Hence, vitamin B 3 (or tryptophan) mild deficiency causes metabolic disorders and severe deficiency in humans has been linked to diseases such as pellagra [4]. ...
Article
Vitamin B3 (nicotinic acid, nicotinamide) is an essential water-soluble vitamin and cellular energy metabolism depends on the vitamin B3-derived cofactors. Inaccessible covalently-linked nicotinic acid in food such as maize can cause vitamin B3 deficiency in animals since maize is also deficient in tryptophan, the precursor of nicotinic acid. A sensitive and reproducible GC-FID-based method for the quantification of the sum of the three forms of vitamin B3 from animal liver was developed. Free nicotinic acid, free nicotinamide and nicotinamide moiety of NAD⁺/NADP⁺(and their riboside precursors) were simultaneously derivatized as methyl nicotinate. Reaction time and temperature and the extraction procedure for methyl nicotinate were optimized. Starting from wild boar liver, removal of proteins, solvent exchange, derivatization, and chloroform extraction resulted in sufficient enrichment and baseline separation of methyl nicotinate. The within-laboratory reproducibility of the full procedure was determined with RSD < 10%. On-column limit of detection and lower limit of quantification for methyl nicotinate were both sub-picomole. The accuracy of the method was determined from the recoveries of the pre-extraction spiked-in vitamin B3 standards. The overall recovery for the full procedure was 16% but very consistent (RSD = 7%), enabling determination of apparent vitamin B3concentrations for relative quantitative comparison.
... To sum up, the sufficient sources of supply and convenient use both contribute to the usage of ARPE-19 cells in this study. Nicotinamide (NAM) as the water-soluble amide form of vitamin B3 [19] not only exerts the therapeutic effects in fibrotic disorders including fibrosis and renal interstitial fibrosis [20][21] , but also plays a role in attenuating oxidative stress by protecting cells against reactive oxygen species (ROS) [22][23][24] . Moreover, many studies have reported that oxidative stress is a trigger that can promote fibrosis in numerous organs [25][26][27] . ...
... A significant feature of NAM is antioxidation, which due to NAM is a part of the coenzyme NAM adenine dinucleotide (NADH/NAD + ) [19,24] . NAM can resist the attack from ROS and then reduce the level of oxidative stress [22][23] . ...
... The quantity of NAM synthesized by endogenous tryptophan is insufficient to satisfy the requirements of physiological functions. Therefore, diet or specific supplements, such as meats and nuts, are critical to provide additional NAM [19,34,38] . Our study also revealed the beneficial effects of NAM in preventing the tendency of EMT in ARPE-19 cells by down regulating the expressions of fibronectin, α-SMA, and vimentin, as well as up regulating ZO-1 expression at mRNA or protein levels, and further increasing the internal TAC of ARPE-19 cells. ...
Article
Aim: To investigate the effects of nicotinamide (NAM) on bevacizumab (BEV)-induced epithelial-mesenchymal transition (EMT) of human retinal pigment epithelial cells (ARPE-19) and the underling mechanisms. Methods: ARPE-19 cells were treated with BEV for 24, 48, and 72h, and the variation degrees of EMT-related markers (fibronectin, α-SMA, vimentin, and ZO-1) were assessed by Western blotting to select the optimal treatment time point which exhibited the most obvious changes of EMT-related markers for the subsequent experiments. Furthermore, NAM was added to the medium, the mRNA and protein levels of the EMT-related markers were then measured. The accumulation of reactive oxygen species (ROS) and H2O2 and the total antioxidant capacity (TAC) of the cells were also measured to evaluate the level of oxidative stress. Results: After being treated with BEV for 72h, the protein expression levels of EMT-related markers in ARPE-19 cells showed significant changes. Meanwhile the levels of ROS and H2O2 were obviously increased, and the TAC of ARPE-19 cells was decreased. Totally 72h was chosen to be the optimal treatment time point in subsequent experiments. Furthermore, NAM inhibited BEV-induced EMT by downregulating fibronectin, α-SMA, and vimentin and upregulating ZO-1, decreased the accumulation of ROS and H2O2, and enhanced TAC in BEV-treated ARPE-19 cells. Conclusion: This study demonstrates that NAM suppressed BEV-induced EMT in ARPE-19 cells by attenuating oxidative stress. Hence, NAM may be a potential therapeutic agent for alleviating neovascular fibrosis of the ocular fundus after anti-vascular endothelial growth factor therapy.
... However, tryptophan is considered an inefficient source of NAD+, as it requires 8 enzymatic reactions and, thus, has lower therapeutic value than other precursors, including NAM, NR, and NMN [39]. Therefore, these last molecules can be considered much more physiologically preferred NAD+ precursors than tryptophan [40]. Although the potential function of the kynurenine pathway of tryptophan metabolism to produce NAD+ has received little attention, emerging evidence suggests potential interplay between this pathway and cardiovascular disease [37,41]. ...
... In addition to these enzymes, others may also influence the tissue abundance of NAD+ ( Figure 1). Specifically, nicotinamide N-methyltransferase (NNMT) catalyzes the Nmethylation reaction of NAM and other analogous molecules using S-adenosyl methionine (SAM) as a donor of methyl groups [45] and produces me-NAM and S-adenosyl homocysteine (SAH) [39,40]. Recent reports suggest that NNMT may also act as a determinant of tissue NAD+ pools in vivo [43]. ...
Article
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Cardiovascular diseases are the leading cause of death worldwide. Aging and/or metabolic stress directly impact the cardiovascular system. Over the last few years, the contributions of altered nicotinamide adenine dinucleotide (NAD+) metabolism to aging and other pathological conditions closely related to cardiovascular diseases have been intensively investigated. NAD+ bioavailability decreases with age and cardiometabolic conditions in several mammalian tissues. Compelling data suggest that declining tissue NAD+ is commonly related to mitochondrial dysfunction and might be considered as a therapeutic target. Thus, NAD+ replenishment by either genetic or natural dietary NAD+-increasing strategies has been recently demonstrated to be effective for improving the pathophysiology of cardiac and vascular health in different experimental models as well as human health to a lesser extent. Here, we review and discuss recent experimental evidence illustrating that increasing NAD+ bioavailability, particularly by the use of natural NAD+ precursors, may offer hope for new therapeutic strategies to prevent and treat cardiovascular diseases.
... Evidence from animal studies also reported the protective role of adequate gestational niacin consumption against the development of congenital anomalies in utero [10,11] and showed NAD to reduce the severity of hypoxic-ischemic brain injury in newborn animals [11]. In pharmacological literature, niacin is increasingly implicated in the optimal fetal development during intrauterine growth due to its role in the production of the NAD+ molecule, which is crucial for DNA repair and organ development in utero [12][13][14]. ...
... The protective effects of adequate niacin intake during pregnancy are biologically plausible, as it is central to production of NAD+ as described in the Preiss-Handler pathway, where nicotinic acid is converted to a mononucleotide form via phosphoribosylation, then to a dinucleotide form, which is then converted to NAD+ [39]. NAD+, in turn, plays an essential role in participating in numerous metabolic pathways, including fatty acid synthesis, the energyproducing catabolic reaction of oxidative phosphorylation, and oxidation-reduction reactions as a hydride acceptor or donor [12,13]. NAD+ may be implicated in several enzymemediated reactions, including Poly (ADP-ribose) polymerase (PARP) and cADPribose synthases-pathways that assist in DNA repair and gene expression respectively [40][41][42][43]. ...
Article
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Purpose The significance of niacin in embryonic development has clinical implications in the counseling of pregnant women and may be used to inform nutrition recommendations. This study, therefore, aims to review the associations between maternal periconceptional niacin intake and congenital anomalies. Methods A systematic search of Ovid MEDLINE, ClinicalTrials.gov, AMED, CENTRAL, Emcare, EMBASE, Maternity & Infant Care and Google Scholar was conducted between inception and 30 September 2020. Medical subject heading terms included “nicotinic acids” and related metabolites, “congenital anomalies” and specific types of congenital anomalies. Included studies reported the association between maternal niacin intake and congenital anomalies in their offspring and reported the measure of association. Studies involved solely the women with co-morbidities, animal, in vitro and qualitative studies were excluded. The risk of bias of included studies was assessed using the Newcastle–Ottawa Scale (NOS). A random effects-restricted maximum likelihood model was used to obtain summary estimates, and multivariable meta-regression model was used to adjust study-level covariates. Results Of 21,908 retrieved citations, 14 case–control studies including 35,743 women met the inclusion criteria. Ten studies were conducted in the U.S, three in Netherlands and one in South Africa. The meta-analysis showed that expectant mothers with an insufficient niacin intake were significantly more likely to have babies with congenital abnormalities (odds ratio 1.13, 95% confidence interval 1.02–1.24) compared to mothers with adequate niacin intake. A similar association between niacin deficiency and congenital anomalies was observed (OR 1.15, 95% CI 1.03–1.26) when sensitivity analysis was conducted by quality of the included studies. Meta-regression showed neither statistically significant impact of study size (p = 0.859) nor time of niacin assessment (p = 0.127). The overall quality of evidence used is high—thirteen studies achieved a rating of six or seven stars out of a possible nine based on the NOS. Conclusion Inadequate maternal niacin intake is associated with an increased risk of congenital anomalies in the offspring. These findings may have implications in dietary counseling and use of niacin supplementation during pregnancy.
... NAD + is reduced to NADH during catabolic processes and can also be phosphorylated to NADP + via NAD + kinases. NAD + and NADP + are two important coenzymes involved in cellular metabolism and several signaling pathways such as DNA repair, mitochondria biogenesis, gene expression, cell cycle, cellular stress response, and cellular communication [2,[46][47][48][49][50]. More than 400 proteins are associated with NAD + and NADH in various biological reactions [51]. ...
... NAD + is produced from niacin by the Preiss-Handler pathway named after the co-discoverers Jack Preiss and Philip Handler [48] ( Fig. 1). The first step in converting niacin to its mononucleotide form, nicotinic acid mononucleotide (NaMN), is a reaction catalyzed by nicotinic acid phosphoribosyltransferase (NaPRT). ...
Article
More than a century after discovering NAD+, information is still evolving on the role of this molecule in health and diseases. The biological functions of NAD⁺ and NAD⁺ precursors encompass pathways in cellular energetics, inflammation, metabolism, and cell survival. Several metabolic and neurological diseases exhibit reduced tissue NAD⁺ levels. Significantly reduced levels of NAD⁺ are also associated with aging, and enhancing NAD⁺ levels improved healthspan and lifespan in animal models. Recent studies suggest a causal link between senescence, age-associated reduction in tissue NAD⁺ and enzymatic degradation of NAD⁺. Furthermore, the discovery of transporters and receptors involved in NAD⁺ precursor (nicotinic acid, or niacin, nicotinamide, and nicotinamide riboside) metabolism allowed for a better understanding of their role in cellular homeostasis including signaling functions that are independent of their functions in redox reactions. We also review studies that demonstrate that the functional effect of niacin is partially due to the activation of its cell surface receptor, GPR109a. Based on the recent progress in understanding the mechanism and function of NAD⁺ and NAD⁺ precursors in cell metabolism, new strategies are evolving to exploit these molecules' pharmacological potential in the maintenance of metabolic balance.
... Biological Function B1 (thiamine) cofactor for enzymes in glucose metabolism, amino acid catabolism, nucleotide synthesis, and fatty acid synthesis [11] B2 (riboflavin) precursor for flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) for cellular respiration [12] B3 (nicotinamide) precursor for nicotinamide adenine dinucleotide (NAD) utilized in biosynthetic pathways, energy metabolism, and protection from reactive oxygen species [13] B5 (pantothenic acid) precursor for coenzyme A (coA), an acyl-carrier required for the activity of many enzymes [14] B6 (pyridoxine) cofactor for over 150 enzymes involved mainly in amino acid synthesis and degradation [15] B7 (biotin) plays an essential role in carboxylation reactions [16] and also has many applications in laboratory research B9 (folate) substrate for nucleotide synthesis and methyl-donors in the one-carbon metabolism pathway [12] B12 (cobalamin) cofactor for enzymes in one-carbon metabolism and the propionate catabolic pathway [12] ...
Article
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Vitamins B9 (folate) and B12 are essential water-soluble vitamins that play a crucial role in the maintenance of one-carbon metabolism: a set of interconnected biochemical pathways driven by folate and methionine to generate methyl groups for use in DNA synthesis, amino acid homeostasis, antioxidant generation, and epigenetic regulation. Dietary deficiencies in B9 and B12, or genetic polymorphisms that influence the activity of enzymes involved in the folate or methionine cycles, are known to cause developmental defects, impair cognitive function, or block normal blood production. Nutritional deficiencies have historically been treated with dietary supplementation or high-dose parenteral administration that can reverse symptoms in the majority of cases. Elevated levels of these vitamins have more recently been shown to correlate with immune dysfunction, cancer, and increased mortality. Therapies that specifically target one-carbon metabolism are therefore currently being explored for the treatment of immune disorders and cancer. In this review, we will highlight recent studies aimed at elucidating the role of folate, B12, and methionine in one-carbon metabolism during normal cellular processes and in the context of disease progression.
... Nicotinamide (NAM), a vitamin B family member, exists in various kinds of food and serves as an economically efficient vitamin supplement (Sauve, 2008;Song et al., 2019). Physiologically, NAM is a major precursor for NAD + biosynthesis, which acts as a key coenzyme in redox and a substrate for enzymes like poly(ADP-ribose) polymerase family proteins (PARPs) and the sirtuin family proteins in non-redox reaction (Hwang and Song, 2017;Song et al., 2019;Navas and Carnero, 2021). ...
Article
Cisplatin is a commonly used anti-cancer drug, but it induces nephrotoxicity. As a water-soluble vitamin B family member, nicotinamide (NAM) was recently demonstrated to have beneficial effects for renal injury, but its underlying mechanism remains largely unclear. Here, we suggest that NAM may exert protective effects against cisplatin-induced acute kidney injury (AKI) mainly via suppressing the poly ADP-ribose polymerase 1 (PARP1)/p53 pathway. In our experiment, NAM protected against cisplatin-induced apoptosis both in cultured renal proximal tubular cells and AKI in mice. Mechanistically, NAM suppressed the expression and activation of p53, a known mediator of cisplatin-induced AKI. Upstream of p53, NAM attenuated the induction of γ-H2AX, a hallmark of DNA damage response. Interestingly, PARP1 was activated in cisplatin AKI and this activation was inhibited by NAM. Pharmacological inhibition of PARP1 with PJ34 significantly ameliorated p53 activation and cisplatin-induced cell death in RPTCs and AKI in mice. Thus, NAM may protect against cisplatin-induced AKI by suppressing the PARP1/p53 pathway.
... NAM ( Figure 1) can be obtained from the diet or through nicotinic acid synthesis [27]. NAM plays an important role in maintaining normal cell function; it was previously shown to effectively prevent cell damage [28]. ...
Article
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Vitamin B (nicotinamide (NAM)), one of the most important nutritional components for humans, exerts anti-inflammatory activity. This study was aimed at investigating the effect of NAM on the gut microbiota and short-chain fatty acids (SCFAs) in mice with chronic colitis. Colitis was induced in C57BL/6 male mice by administration of 1.5% dextran sulfate sodium (DSS), and the mice were intraperitoneally injected with normal saline (NS) or NAM. NAM treatment ameliorated weight loss and changes in colon length, disease activity index (DAI) score, and histologic scores. Moreover, enzyme-linked immunosorbent assay (ELISA) analysis of LPL cells revealed that the level of interleukin- (IL-) 6, IL-12p70, IL-1β, tumor necrosis factor- (TNF-) α, interferon- (IFN-) γ, IL-21, and IL-17A was increased, while IL-10 was reduced, in the chronic colitis group compared to the control group, but the levels of all these factors were restored after NAM treatment. Then, 16S rRNA sequencing of the large intestinal content was performed, and analysis of alpha diversity and beta diversity showed that the richness of the gut microbiota was decreased in the DSS group compared to the control group and restored after NAM treatment. In addition, NAM modulated specific bacteria, including Odoribacter, Flexispira, and Bifidobacterium, in the NAM+chronic colitis group. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) analysis indicated that NAM treatment restored disruptions in the functions of the gut microbiota (replication and repair, cell motility) in mice with DSS-induced colitis. Furthermore, NAM also restored the reduction in valeric acid in mice with DSS-induced chronic colitis. Our results suggest that NAM treatment could alleviate DSS-induced chronic colitis in mice by inhibiting inflammation and regulating the composition and function of gut microbiota.
... In this study, the intake of HC diets down-regulated hepatic SIRT1 protein and mRNA levels compared with the control group. According to a previous study, the intake of HC diets could inhibit the activities of pyruvate dehydrogenase complex, thereby decreasing NAD + contents (Sauve, 2007). This might inevitably reduce SIRT1 protein and mRNA levels. ...
Article
A 12-week nutritional research was conducted to evaluate the influences of benfotiamine on the growth performance, oxidative stress, inflammation and apoptosis in Megalobrama amblycephala (45.25 ± 0.34 g) fed high-carbohydrate (HC) diets. Six diets were prepared, containing the control diet (30% carbohydrate, C), the HC diet (43% carbohydrate) and the HC diet supplemented with four benfotiamine levels (0.7125 (HCB1), 1.425 (HCB2), 2.85 (HCB3) and 5.7 (HCB4) mg/kg). HC diet remarkably decreased DGC, GRMBW, liver T-AOC, SOD and CAT activities, SIRT1 protein expression as well as the mRNA levels of SIRT1, Nrf2, CAT, Mn-SOD and IL10 in liver compared with the C group, but the opposite trend was found in plasma activities of AST and ALT, and contents of IL1β and IL6, liver contents of MDA and mRNA levels of Keap1, NF-κB, TNF α, IL1β, IL6, Bax, caspase 3, caspase 9 and P53. As for benfotiamine supplementation, HCB2 diet remarkably increased DGC, GRMBW, liver T-AOC, SOD and CAT activities, SIRT1 protein expression as well as liver mRNA levels of SIRT1, Nrf2, CAT, Mn-SOD, IL10 and Bcl2, while the opposite was true for plasma AST and ALT activities, and IL1β and IL6 contents, liver MDA contents as well as mRNA levels of Keap1, NF-κB, TNF α, IL1β, IL6, Bax, caspase 3, caspase 9 and P53. In summary, benfotiamine (1.425 mg/kg) promoted the growth, and alleviated the oxidative stress, inflammation and apoptosis of M. amblycephala fed HC diets through the SIRT1-mediated signaling pathway.
... NAD cofactor contains a vital role in cellular metabolism such as electron transfer, redox reactions, and removing protein acetyl groups [66,67]. The enzyme that utilizes the NAD cofactor is essential in pharmacological research and targeted as potential disease therapies [68]. Therefore, we intended to find the role of NAD cofactor with GALE proteins in understanding the shift in the binding configurations using MDS. ...
Article
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Epimerase-deficiency galactosemia (EDG) is caused by mutations in the UDP-galactose 4'-epimerase enzyme, encoded by gene GALE. Catalyzing the last reaction in the Leloir pathway, UDP-galactose-4-epimerase catalyzes the interconversion of UDP-galactose and UDP-glucose. This study aimed to use in-depth computational strategies to prioritize the pathogenic missense mutations in GALE protein and investigate the systemic behavior, conformational spaces, atomic motions, and cross-correlation matrix of the GALE protein. We searched four databases (dbSNP, ClinVar, UniProt, and HGMD) and major biological literature databases (PubMed, Science Direct, and Google Scholar), for missense mutations that are associated with EDG patients, our search yielded 190 missense mutations. We applied a systematic computational prediction pipeline, including pathogenicity, stability, biochemical, conservational, protein residue contacts, and structural analysis, to predict the pathogenicity of these mutations. We found three mutations (p.K161N, p.R239W, and p.G302D) with a severe phenotype in patients with EDG that correlated with our computational prediction analysis; thus, they were selected for further structural and simulation analyses to compute the flexibility and stability of the mutant GALE proteins. The three mutants were subjected to molecular dynamics simulation (MDS) with native protein for 200 ns using GROMACS. The MDS demonstrated that these mutations affected the beta-sheets and helical region that are responsible for the catalytic activity; subsequently, affects the stability and flexibility of the mutant proteins along with a decrease and more deviations in compactness when compared to that of a native. Also, three mutations created major variations in the combined atomic motions of the catalytic and C-terminal regions. The network analysis of the residues in the native and three mutant protein structures showed disturbed residue contacts occurred owing to the missense mutations. Our findings help to understand the structural behavior of a protein owing to mutation and are intended to serve as a platform for prioritizing mutations, which could be potential targets for drug discovery and development of targeted therapeutics.
... Nicotinamide has important functions in mammalian metabolism and is a metabolic precursor to oxidized nicotinamide adenine dinucleotide (NAD + )/reduced nicotinamide adenine dinucleotide (NADH) [23][24][25]. With further development, we envision using our technique to observe the conversion of nicotinamide to NAD + /NADH, 010305-4 which could allow NMR measurement of the redox status in cells. ...
Article
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Optically probed nitrogen-vacancy (NV)) quantum defects in diamond can detect nuclear magnetic resonance (NMR) signals with high-spectral resolution from micron-scale sample volumes of about 10 pl. However, a key challenge for NV-NMR spectroscopy is detecting samples at millimolar concentrations. Here we demonstrate an increase in NV-NMR proton concentration sensitivity by hyperpolarizing sample proton spins to about 0.5% through signal amplification by reversible exchange (SABRE), enabling micron-scale NMR spectroscopy of small-molecule sample concentrations as low as 1 mM in picoliter volumes. The SABRE-enhanced NV-NMR technique may enable detection and chemical analysis of low-concentration molecules and their dynamics in complex micron-scale systems such as single cells.
... In this study, the intake of HC diets down-regulated hepatic SIRT1 protein and mRNA levels compared with the control group. According to previous study, the intake of HC diets can inhibit the activity of pyruvate dehydrogenase complex, thereby resulting in a decrease of NAD + content [51]. This might inevitably reduces SIRT1 protein and mRNA levels. ...
Preprint
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Background: The impairment of immunity induced by high-carbohydrate diet is closely associated with the development of glucose metabolic disorders. In the study of diabetes, benfotiamine can prevent β-cell dysfunction by inhibiting inflammation, thereby improving insulin resistance. However, information regarding the effects of this substance on aquatic animals is extremely scarce. Methods: A 12-week nutritional research was conducted to evaluate the influences of benfotiamine on the growth performance, oxidative stress, inflammation and apoptosis in Megalobrama amblycephala (45.25 ± 0.34 g) fed high-carbohydrate (HC) diets. Six experimental diets were formulated, containing a control diet (30% carbohydrate, C), a HC diet (43% carbohydrate), and the HC diet supplemented with four graded benfotiamine levels (0.7125 (HCB1), 1.425 (HCB2), 2.85 (HCB3), and 5.7 (HCB4) mg/kg). Results: HC diet intake remarkably decreased daily growth coefficient (DGC), growth rate per metabolic body weight (GRMBW), feed intake (FI), liver antioxidant enzymes activities, sirtuin-1 (SIRT1) protein expression as well as liver mRNA levels of SIRT1, nuclear factor erythroid 2-related factor 2 (Nrf2), catalase (CAT), manganese superoxide dismutase (Mn-SOD), interleukin10 (IL10) than those of the control group, but the opposite was true for plasma activities of alanine transaminase (AST) and aspartate aminotransferase (ALT), and contents of interleukin 1β (IL1β) and interleukin 6 (IL6), liver contents of malondialdehyde (MDA), and mRNA levels of kelch-like ECH associating protein 1 (Keap1), nuclear factor kappa B (NF-κB), tumour necrosis factor α (TNF α), IL1β, IL6, Bax, Caspase 3, Caspase 9 and P53. As with benfotiamine supplementation, HCB2 diet remarkably increased DGC, GRMBW, liver antioxidant enzymes activities, SIRT1 protein expression as well as liver mRNA levels of SIRT1, Nrf2, CAT, Mn-SOD, IL10 and Bcl2, while the opposite was true for plasma activities of AST and ALT, and contents of IL1β and IL6, liver MDA contents as well as mRNA levels of Keap1, NF-κB, TNF α, IL1β, IL6, Bax, Caspase 3, Caspase 9 and P53. Conclusion: Benfotiamine at 1.425 mg/kg can improve the growth performance and alleviate the oxidative stress, inflammation and apoptosis of M. amblycephala fed HC diets through the activation of the SIRT1 pathway.
... (a) (b) (c) Figure 14: Sequential back-to-back inversions of stereochemistry at C-1 of NAD+ yields retention of stereochemistry during mono-ADP ribosylation (MARylation) and poly-ADP ribosylation (MARylation) of proteins during inflammatory states. (a) potential electrophilic sites within NAD+ for non-enzymatic reversible cleavage and recycling during energy metabolism and redox homeostasis by the B3 metabolome (Sauve 2008;Makarov 2018;Chini 2020;Tan 2021). Under the ascorbolysis hypothesis, such electrophilic sites are postulated to undergo reversible, stereospecific SN2 reactions with the L-AA free radical. ...
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Adverse events of myocarditis, pericarditis, and thrombosis, temporally associated with mRNA vaccination(s) and/or mRNA vaccine boosters, have been reported during post-marketing safety surveillance in the U.S. CDC VAERS database and 2021 CDC guidance to physicians. An interim report unexpectedly revealed inflammatory biomarker elevations in vaccine recipients. During review of considerable published research on the Sanarelli-Shwartzman phenomenon (SSP) and the use of nucleic acids as vaccine adjuvants, a novel, hypothesis is proposed. Even today, after being studied for over a century, the pathophysiology of the SSP is not fully understood. Motivated by a paper from 1950, titled "General Adaptation Syndrome" by Hans Selye, and recent published research by Korean investigators, a novel, non-conventional hypothesis was generated. Gluten and lectin sensitivity are cited as examples of sensitizing events of the SSP, for which we propose ensemble hydrophobic chiroptical catalysis may have therapeutic benefit. Under the ensemble HCC hypothesis, we propose that inflammatory stress and scurvy promote loss of chirality control, anomeric fidelity, phenotypic stability, and immune function, both humoral and cell-mediated, with the dialyzable transfer factor, L-ascorbic acid, and spin water playing central roles. It is proposed that therapeutic synergy of L-ascorbic acid, bioflavonoids, and corticosteroids in countering the SARS-CoV-2 pathogen arises from memory of chirality which originated during their biosynthesis. It is proposed that ensemble HCC is powered by radiant and or zero-point energy (quantum vacuum fluctuations) which may support a paradigm shift to supramolecular biology. The distinction between supramolecular biology and supramolecular xenobiology is highlighted.
... In neurons, NMNAT2 plays a pivotal role in axon development and survival [29][30][31] and its depletion can trigger Wallerian degeneration [32,33]. While the role of NAD + in balancing cellular homeostasis is evolutionally conserved [34], only three pathways that lead to NAD + synthesis have been described (in mammalian cells, the core focus of this review) [35]. De novo NAD + synthesis initiates with the amino acid tryptophan (TRP) which is enzymatically degraded into kynurenine, which after a series of reactions leads to NAD + [36]. ...
Article
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Glaucoma and age-related macular degeneration are leading causes of irreversible blindness worldwide with significant health and societal burdens. To date, no clinical cures are available and treatments target only the manageable symptoms and risk factors (but do not remediate the underlying pathology of the disease). Both diseases are neurodegenerative in their pathology of the retina and as such many of the events that trigger cell dysfunction, degeneration, and eventual loss are due to mitochondrial dysfunction, inflammation, and oxidative stress. Here, we critically review how a decreased bioavailability of nicotinamide adenine dinucleotide (NAD; a crucial metabolite in healthy and disease states) may underpin many of these aberrant mechanisms. We propose how exogenous sources of NAD may become a therapeutic standard for the treatment of these conditions.
... NAM originates from the diet or can be produced by the activity of a variety of NAD hydrolase enzymes, including sirtuins, PARPs, and CD38, which are strictly coupled with the salvage pathway and influence inflammation, cell growth, and bioenergetics [5]. These enzymes degrade NAD and generate NAM as a by-product [6,7]. ...
Article
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Dysregulated cross-talk between immune cells and epithelial compartments is responsible for the onset and amplification of pathogenic auto-inflammatory circuits occurring in psoriasis. NAMPT-mediated NAD salvage pathway has been recently described as an immunometabolic route having inflammatory function in several disorders, including arthritis and inflammatory bowel diseases. To date, the role of NAD salvage pathway has not been explored in the skin of patients affected by psoriasis. Here, we show that NAD content is enhanced in lesional skin of psoriatic patients and is associated to high NAMPT transcriptional levels. The latter are drastically reduced in psoriatic skin following treatment with the anti-IL-17A biologics secukinumab. We provide evidence that NAMPT-mediated NAD+ metabolism fuels the immune responses executed by resident skin cells in psoriatic skin. In particular, intracellular NAMPT, strongly induced by Th1/Th17-cytokines, acts on keratinocytes by inducing hyper-proliferation and impairing their terminal differentiation. Furthermore, NAMPT-mediated NAD+ boosting synergizes with psoriasis-related cytokines in the upregulation of inflammatory chemokines important for neutrophil and Th1/Th17 cell recruitment. In addition, extracellular NAMPT, abundantly released by keratinocytes and dermal fibroblasts, acts in a paracrine manner on endothelial cells by inducing their proliferation and migration, as well as the expression of ICAM-1 membrane molecule and chemokines important for leukocyte recruitment into inflamed skin. In conclusion, our results showed that NAMPT-mediated NAD salvage pathway contributes to psoriasis pathogenic processes by amplifying epithelial auto-inflammatory responses in psoriasis.
... There is growing evidence from pharmacological studies that nicotinamide administration can result in alterations in nitric oxide production which reduces the DNA damage response, and improves mitochondrial activity [61,62]. NAD+ exerts potent preventive effects through the poly (ADP-ribose) polymerases, mono-ADPribosyltransferases, and sirtuin enzymes. ...
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The ageing-associated decline of biological functions represents an important contributor to the increase in morbidity and mortality of human beings. Of these biological functions deterioration; there is a significant decline in the heart function, impairments in the lungs gas exchange, and impairments in the immune function. Many alterations in the body humeral and cellular immune response were observed with ageing process: The circulating pro-inflammatory cytokines are increased, the naive lymphocytes are decreased, the numbers of the antigen-presenting cells areelevated and the overall response is impaired. In addition, ageing is associated with a progressive restriction in the telomere length. Telomeres are located at chromosomes ends and play an essential role in preserving chromosome stability. Also, telomere length is very important to the immune system, because of the high sensitivity of the immune cells to the shortening of telomeres. Telomeres shortening adversely affect the immune cells’ function and developments. These adverse changes increased the susceptibility for severe infection, risk of hospitalization, and even death. Elderly COVID-19 patients are at a real risk of complications due to impaired immune function, cytokine storm and defective respiratory function. Administration of anti-ageing immunomodulation factors like Nicotinamide Adenine Dinucleotide NAD+ can minimize these changes through its potent immunomodulation and longevity effects. NAD+ has a direct inhibitory effect on PARP-1 and can prevent pro-inflammatory cytokines over-activation. Increasing the NAD+ level will also result in stabilizing telomeres and this has a positive impact on immune cells function.
... Sufficient tissue NAD + concentrations are known to be important for human health, as depletion of NAD + leads to the nutritional deficiency known as pellagra, which killed more than 100,000 people in the United States in the early part of the 20th century 2,3 . Kornberg 4,5 and Preiss and Handler [6][7][8] showed that NAD + could be made from enzymatic steps originating from mononucleotides synthesized from nicotinamide and nicotinic acid (Extended Data Fig. 1) 9,10 . Tryptophan catabolism through the kynurenine pathway to quinolinate and downstream to nicotinate mononucleotide (NaMN) 11,12 provides a human de novo pathway for NAD + biosynthesis 11,12 . ...
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Dihydronicotinamide riboside (NRH) has been suggested to act as a precursor for the synthesis of NAD⁺, but the biochemical pathway converting it has been unknown. Here, we show that NRH can be converted into NAD⁺ via a salvage pathway in which adenosine kinase (ADK, also known as AK) acts as an NRH kinase. Using isotope-labelling approaches, we demonstrate that NRH is fully incorporated into NAD⁺, with NMNH acting as an intermediate. We further show that AK is enriched in fractions from cell lysates with NRH kinase activity, and that AK can convert NRH into NAD⁺. In cultured cells and mouse liver, pharmacological or genetic inhibition of AK blocks formation of reduced nicotinamide mononucleotide (NMNH) and inhibits NRH-stimulated NAD⁺ biosynthesis. Finally, we confirm the presence of endogenous NRH in the liver with metabolomics. Our findings establish NRH as a natural precursor of NAD⁺ and reveal a new route for NAD⁺ biosynthesis via an NRH salvage pathway involving AK.
... However, such information in fish is still barely understood. In the present study, hepatic transcriptions of SIRT1, PGC-1α and FOXO1 as well as SIRT1 protein expressions were all TA B L E 7 Hepatic protein and transcriptional levels of SIRT1 in blunt snout bream fed different diets for 12 weeks (Sauve, 2007). This inevitably led to a decrease expression of SIRT1. ...
Article
A 12-week feeding trial was conducted to evaluate the effects of nicotinamide on the growth performance, glucose and lipid metabolism of blunt snout bream fed high-carbohydrate diets. Fish were randomly fed four diets including two dietary carbohydrate levels (300 and 430 g/kg, deriving from corn starch) and two nicotinamide levels (0 and 31.0 mg/kg). Microcrystalline cellulose was incorporated to compensate for the carbohydrate levels required. High-carbohydrate levels significantly (P < 0.05) increased the hepatosomatic index, intraperitoneal fat percentage, the contents of whole-body lipid and tissues (including liver, muscle and adipose tissue) glycogen and lipid, plasma levels of glucose, glycated serum protein, advanced glycation end products, triglyceride, pyruvate and lactic acid, as well as the hepatic transcriptions of peroxisome proliferator-activated receptor γ (PPARγ), PPARα, glucose transporter 2 (GLUT2), glucokinase (GK), pyruvate kinase (PK), glycogen synthase (GS), glucose-6-phosphate dehydrogenase, sterol regulatory element-binding protein-1, fatty acid synthase (FAS), carnitine palmitoyl transferase I (CPTI), acetyl-CoA carboxylase α, whereas the opposite was found for hepatic nicotinamide adenine dinucleotide (NAD+), nicotinamide adenine dinucleotide phosphate (NADH) and hepatic sirtuin-1 (SIRT1) protein level and the transcriptions of SIRT1, forkhead transcription factor 1(FOXO1), phosphoenolpyruvate carboxykinase, glucose-6-phosphatase (G6pase) and acyl-CoA oxidase (P < 0.05). Additionally, nicotinamide supplementation significantly (P < 0.05) increased whole-body lipid and tissues glycogen contents, hepatic NAD+ content and the NAD+/NADH ratio, hepatic SIRT1 protein level and the transcriptions of SIRT1 co-activators (PPARγ coativator-1α, FOXO1 PPARα), GLUT2, GK, PK, G6pase, GS and CPTI, while the opposite was found for the remaining indicators. Furthermore, a significant (P < 0.05) interaction between dietary carbohydrate levels and nicotinamide were also observed in most parameters aforementioned. Overall, nicotinamide benefits the glucose and lipid metabolism of Megalobrama amblycephala fed high-carbohydrate diets by mediating the transcriptions of SIRT1 and glucose and lipid metabolism-related genes as well as stimulating glucose transportation, glycolysis, glycogenesis, fatty acid oxidation, while depressing both lipogenesis and gluconeogenesis.
... First, Nam is the most abundant NAD precursor in the bloodstream (39), and can be easily introduced by diet (vitamin B3). Second, Nam is a by-product of all NADmetabolizing enzymes activity, increasing its availability (77). Third, the rate limiting enzyme NAMPT (EC 2.4.2.12) is expressed in all mammalian tissues (78), as detailed below. ...
Article
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Nicotinamide phosphoribosyltransferase (NAMPT) and nicotinate phosphoribosyltransferase (NAPRT) are two intracellular enzymes that catalyze the first step in the biosynthesis of NAD from nicotinamide and nicotinic acid, respectively. By fine tuning intracellular NAD levels, they are involved in the regulation/reprogramming of cellular metabolism and in the control of the activity of NAD-dependent enzymes, including sirtuins, PARPs, and NADases. However, during evolution they both acquired novel functions as extracellular endogenous mediators of inflammation. It is well-known that cellular stress and/or damage induce release in the extracellular milieu of endogenous molecules, called alarmins or damage-associated molecular patterns (DAMPs), which modulate immune functions through binding pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), and activate inflammatory responses. Increasing evidence suggests that extracellular (e)NAMPT and eNAPRT are novel soluble factors with cytokine/adipokine/DAMP-like actions. Elevated eNAMPT were reported in several metabolic and inflammatory disorders, including obesity, diabetes, and cancer, while eNAPRT is emerging as a biomarker of sepsis and septic shock. This review will discuss available data concerning the dual role of this unique family of enzymes.
... Nicotinic acid (NA or niacin) and its amide derivative, nicotinamide (NAM or niacinamide), serve as precursors for the biosynthesis of the coenzyme nicotinamide adenine dinucleotide (NAD + ), which participates in various metabolic reactions (e.g., glycolysis, citric acid cycle, and electron transport chain) that maintain the redox state of cells [1]. Additionally, NA is known to raise high density lipoprotein (HDL) levels in humans, while providing improvements against other cardiovascular risk factors by lowering very low-density lipoprotein and low-density lipoprotein in patients with dyslipidemia [2][3][4]. ...
Article
Nicotinic acid (NA) and nicotinamide (NAM) are biosynthetic precursors of nicotinamide adenine dinucleotide (NAD+) - a physiologically important coenzyme that maintains the redox state of cells. Mechanisms driving their entry into cells are not well understood. Here we evaluated the hepatic uptake mechanism(s) of NA and NAM using transporter-transfected cell systems and primary human hepatocytes. NA showed robust organic anion transporter (OAT)2-mediated transport with an uptake ratio (i.e., ratio of accumulation in transfect cells to wild-type cells) of 9.7±0.3, and a Michaelis-Menten constant (Km) of 13.5±3.3 µM. However, no transport was apparent via other major hepatic uptake and renal secretory transporters, including OAT1/3/4, organic anion transporting polypeptide (OATP)1B1/1B3/2B1, sodium-taurocholate co-transporting polypeptide, organ cation transporter 1/2/3. OAT2-specific transport of NA was inhibited by ketoprofen and indomethacin (known OAT2 inhibitors) in a concentration-dependent manner. Similarly, NA uptake into primary human hepatocytes showed pH- and concentration-dependence and was subject to inhibition by specific OAT2 inhibitors. Unlike NA, NAM was not transported by the hepatic and renal solute carriers upon assessment in transfected cells, although its uptake into human hepatocytes was significantly inhibited by excess unlabelled NAM and a pan-SLC inhibitor (rifamycin SV 1 mM). In conclusion, these studies demonstrate, for the first time, a specific transport mechanism for NA uptake in the human liver and suggest that OAT2 (SLC22A7) has a critical role in its physiological and pharmacological functions.
... İnsan organizmasında bulunan bir çok enzim niasin koenzimleri olan NAD ve NADP'ye ihtiyaç duymaktadır (104). Bu enzimler apoptoz, DNA onarımı, stres direnci, metabolizma ve endokrin sinyalleri düzenleyerek terapötik etki göstermektedir (105). Yapılan randomize kontrollü çalışmada Niasinin triptofanın kynurenine yıkımını sağladığı triptofan oksidasyonunu kontrol ettiği ve CD4 + yardımcı T hücresi aktivasyonunu arttırarak dolaylı olarak immün aktivasyonu iyileştirdiği saptanmıştır (106). ...
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THE ROLE OF NUTRİTİON İN SUPPORTİNG THE IMMUNE SYSTEM İN COMBATİNG CORONAVİRUS DİSEASE (COVID-19) Gazi Sağlık Bilimleri Dergisi 2020: Özel Sayı: 18-45 Nilüfer ACAR TEK, Tevfik KOÇAK ABSTRACT The novel coronavirus disease “COVID-19” is a serious public health problem threatening human life in the world. Considering that there is still no specific treatment for SARS-CoV-2 in prevention or alleviating disease severity, it is important to keep the immune system active and strong. There is a very complex and strong relationship between nutrition and immunity. Epidemiological and experimental studies point to the importance of dietary interventions in the nutrition, immune system and infection triangle. In this process, complying with a nutrition plan that provides adequate intake of macro and micronutrient requirements will be effective in maintaining health along with other mandatory measures. In addition, nutritional interventions made in accordance with the course of the disease, as part of the treatment, will have an impact on the potential for increasing healing and survival. In this article, the effects of nutrition on the support of the immune system in COVID-19 are examined in detail on the basis of nutrients. Keywords: SARS-CoV-2, COVID-19, Immune System, Immunonutrition, Macro and Micronutrients KORONAVİRÜSLE (COVİD-19) MÜCADELEDE BESLENMENİN BAĞIŞIKLIK SİSTEMİNİN DESTEKLENMESİNDE ROLÜ ÖZET Yeni koronavius hastalığı “COVID-19” dünyada birçok insanın hayatını tehdit eden ciddi bir halk sağlığı sorunu olmuştur. Bu yeni virüsten korunmada veya hastalık şiddetini hafifletmede, SARS-CoV-2 için halen spesifik bir tedavinin olmadığı da dikkate alındığında, bağışıklık sistemin aktif ve güçlü tutulması önemlidir. Beslenme ve bağışıklık arasında oldukça karmaşık ve güçlü ilişki bulunmaktadır. Epidemiyolojik ve deneysel çalışmalar beslenme, bağışıklık sistemi ve enfeksiyon üçgeninde diyet müdahalelerinin önemine işaret etmektedir. Bu süreçte makro ve mikro besin öğesi gereksinimlerini karşılayacak şekilde yeterli alımını sağlayan bir beslenme planına uyulması, diğer zorunlu tedbirler ile birlikte hastalıktan korunmada etkili olacaktır. Ayrıca hastalığın seyrine uygun olarak yapılan beslenme müdahaleleri tedavinin bir parçası olarak, iyileşme ve sağ kalım oranının artmasında potansiyel etki sağlayacaktır. Bu makalede COVİD-19’da beslenmenin bağışıklık sistemin desteklenmesi üzerindeki etkileri ayrıntılı olarak besin ögesi bazında irdelenmiştir.
... NAD + levels in mitochondria are important for maintaining metabolic functions and cell survival in oxidative metabolic tissues, including the skeletal muscle, heart, and liver. In metabolic tissues that dominantly use oxidative phosphorylation to generate ATP, NAD + levels in mitochondria should be maintained at a higher level than that in the cytoplasm [13,[72][73][74]. Malate dehydrogenase (MDH) and aspartate aminotransferase (AST) form the malate-aspartate shuttle (MAS), which plays a vital role in the exchange of cytosolic NADH for mitochondrial NAD + , which is an irreversible step in the exchange of mitochondrial aspartate and cytosolic glutamate and a proton by the aspartate-glutamate carrier (AGC) [75][76][77] (Figure 2). ...
Article
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Mitochondria play vital roles, including ATP generation, regulation of cellular metabolism, and cell survival. Mitochondria contain the majority of cellular nicotinamide adenine dinucleotide (NAD+), which an essential cofactor that regulates metabolic function. A decrease in both mitochondria biogenesis and NAD+ is a characteristic of metabolic diseases, and peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) orchestrates mitochondrial biogenesis and is involved in mitochondrial NAD+ pool. Here we discuss how PGC-1α is involved in the NAD+ synthesis pathway and metabolism, as well as the strategy for increasing the NAD+ pool in the metabolic disease state.
... The role of nicotinamide adenine dinucleotide (NAD + ) metabolism in health and disease is of increased interest because nicotinamide can protect tissues, and NAD + metabolism has been implicated in a variety of disease states in addition to extending the lifespan (Belenky et al., 2007;Sauve, 2008). As a result, enzymes including poly (ADP-ribose) polymerases (PARP), mono-ADP-ribosyltransferases, and sirtuin and/or NAD + metabolism could be targeted for the therapeutic benefit of patients with cachexia and sarcopenia because the NAD + precursor, NR, has been implicated in improving myopathy and muscle atrophy (Bogan and Brenner, 2008). ...
Article
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Nicotinamide riboside (NR), vitamin B3, is a substrate for nicotinamide adenine dinucleotide (NAD+)–consuming enzymes and is a coenzyme for hydride-transfer enzymes, including adenosine diphosphate (ADP)–ribose transferases, poly (ADP-ribose) polymerases, cADP-ribose synthases, and sirtuins, which play a central role in the aging process, neurodegenerative processes, and myopathy. Since cancer cachexia is a disease condition presenting with weight loss, skeletal muscle atrophy, and loss of adipose tissue in patients with advanced cancer, we hypothesized that NR intake could ameliorate sarcopenia. In this study, we investigated whether preemptive administration of NR ameliorated C26 adenocarcinoma–induced cancer cachexia and explored anti-cachexic mechanisms focused on the changes in muscle atrophy, cachexic inflammation, and catabolic catastrophe. Dietary intake of the NR-containing pellet diet significantly attenuated cancer cachexia in a mouse model. Starting with significant inhibition of cachexic factors, tumor necrosis factor alpha, and interleukin-6, NR significantly inhibited muscle-specific ubiquitin-proteasome ligases, such as atrogin-1, muscle RING-finger protein-1 (MuRF-1), mitofusin-2, and peroxisome proliferator–activated receptor gamma coactivator-1-alpha (PCG-1α). Significant inhibition of epididymal fat lipolysis was noted with significant inhibition of adipose triglyceride lipase (ATGL) gene. Furthermore, NR administration significantly increased the levels of crucial enzymes involved in the biosynthesis of NAD+ and nicotinamide phosphoribosyl transferase and significantly inhibited the NAD+-sensitive deacetylase sirtuin 1 (SIRT1). Preemptive intake of NR in patients vulnerable to cachexia can be a preemptive option to ameliorate cancer cachexia.
... Therefore, the methylation of NA is not only relevant to the abundance of free NAD + but is also relevant to the activity of these NAD + -consuming enzymes, because as a metabolite of these NAD +consuming reactions, NA naturally has inhibitive effects on these enzymes. NAD + is the key coenzyme for glycolysis and the tricarboxylic acid cycle and for the conversion of carbohydrates to lipids [12]. Sirtuins are a family of NAD + -dependent deacylases that have been shown to regulate a myriad of biological functions, ranging from cell growth to lifespan extension, including oxidative stress, DNA damage, glycolysis, gluconeogenesis, and lipogenesis [13][14][15][16]. ...
Article
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Type 2 diabetes (T2D) is thought to be a complication of metabolic syndrome caused by disorders of energy utilization and storage and characterized by insulin resistance or deficiency of insulin secretion. Though the mechanism linking obesity to the development of T2D is complex and unintelligible, it is known that abnormal lipid metabolism and adipose tissue accumulation possibly play important roles in this process. Recently, nicotinamide N-methyltransferase (NNMT) has been emerging as a new mechanism-of-action target in treating obesity and associated T2D. Evidence has shown that NNMT is associated with obesity and T2D. NNMT inhibition or NNMT knockdown significantly increases energy expenditure, reduces body weight and white adipose mass, improves insulin sensitivity, and normalizes glucose tolerance and fasting blood glucose levels. Additionally, trials of oligonucleotide therapeutics and experiments with some small-molecule NNMT inhibitors in vitro and in preclinical animal models have validated NNMT as a promising therapeutic target to prevent or treat obesity and associated T2D. However, the exact mechanisms underlying these phenomena are not yet fully understood and clinical trials targeting NNMT have not been reported until now. Therefore, more researches are necessary to reveal the acting mechanism of NNMT in obesity and T2D and to develop therapeutics targeting NNMT.
... Considering the known roles of NAM [19,20,[25][26][27][28][29][30], the effects of NAM were mimicked by treating the in vitro cultured lenses with several specific activators/ inhibitors, including inhibitors of SIRT1 (Sirtnol), TGFβ (SB431542), casein kinase 1A (CKi) and NAD+ (NAD). Only the regenerated lens treated with CKi appeared relatively transparent (Fig. 5). ...
Article
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Background Mammalian lens regeneration holds great potential as a cataract therapy. However, the mechanism of mammalian lens regeneration is unclear, and the methods for optimization remain in question. Methods We developed an in vitro lens regeneration model using mouse capsular bag culture and improved the transparency of the regenerated lens using nicotinamide (NAM). We used D4476 and SSTC3 as a casein kinase 1A inhibitor and agonist, respectively. The expression of lens-specific markers was examined by real-time PCR, immunostaining, and western blotting. The structure of the in vitro regenerated lens was investigated using 3,3′-dihexyloxacarbocyanine iodide (DiOC6) and methylene blue staining, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and transmission electron microscopy. Results The in vitro lens regeneration model was developed to mimic the process of in vivo mammalian lens regeneration in a mouse capsular bag culture. In the early stage, the remanent lens epithelial cells proliferated across the posterior capsule and differentiated into lens fiber cells (LFCs). The regenerated lenses appeared opaque after 28 days; however, NAM treatment effectively maintained the transparency of the regenerated lens. We demonstrated that NAM maintained lens epithelial cell survival, promoted the differentiation and regular cellular arrangement of LFCs, and reduced lens-related cell apoptosis. Mechanistically, NAM enhanced the differentiation and transparency of regenerative lenses partly by inhibiting casein kinase 1A activity. Conclusion This study provides a new in vitro model for regeneration study and demonstrates the potential of NAM in in vitro mammalian lens regeneration.
... Prema podacima iz literature dvonedeljni tretman miševa sa visokim dozama nikotinske kiseline i nikotiamida (500 i 1000 mg kg -1 ) ima uticaj na nivo NAD-a u raznim tkivima pa je nađena je povišena koncetracija NAD-a za 40 do 60% u krvi i u jetri (Jackson i sar, 1995). To ukazuje na sposobnost niacina da stimuliše sintezu NAD-a u jetri i krvi i da se nikotiamid može konvertovati u alternativnoj formi i time povećati bioraspoložlivost nikotiamida i/ili tretman nikotiamidom može izazivati ćelijsku adaptaciju koja dalje vodi do bolje biosinteze NAD-a (Sauve, 2008). Hara i sar. ...
Conference Paper
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Vitamin niacin is of great importance for energy metabolism. Physiological niacin is incorporated into the coenzyme nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). The aim of this study was to determine the concentration of NAD and NADP in the blood of cows during the application of niacin in the peripartum period. The value of these vitamins depends on the peripartum week, regardless of the constant exogenous source of niacin.
... Vitamin B3, also known as niacin, plays a role in energy metabolism, redox reactions, and reduce oxidative stress [76,77]. Dietary vitamin B3 is primarily in the form of nicotinic acid and nicotinamide; however some foods may contain small amounts of nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP) [78]. ...
Article
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Vitamins have many established roles in human health. However, the role of habitual dietary intake of vitamins in glucose homeostasis in individuals after acute pancreatitis (AP) is yet to be elucidated. The aim was to investigate the associations between habitual intake of fat- and water-soluble vitamins/vitamers and markers of glucose metabolism (fasting plasma glucose (FPG), homeostasis model assessment insulin resistance (HOMA-IR) index, and homeostasis model assessment β-cell function (HOMA-β)) in individuals after AP. A total of 106 participants after AP were included in this cross-sectional study and were grouped based on glycaemic status: new-onset prediabetes/diabetes after AP (NODAP), pre-existing prediabetes/type 2 diabetes (T2DM), and normoglycaemia after AP (NAP). Habitual intake of seven fat-soluble vitamins/vitamers and seven water-soluble vitamins were determined by the EPIC-Norfolk food frequency questionnaire. Multiple linear regression analyses were conducted using five statistical models built to adjust for covariates (age, sex, daily energy intake, visceral/subcutaneous fat volume ratio, smoking status, daily alcohol intake, aetiology of AP, number of AP episodes, cholecystectomy, and use of antidiabetic medications). In the NODAP group, three fat-soluble vitamins/vitamers (α-carotene, β-carotene, and total carotene) were significantly associated with HOMA-β. One water-soluble vitamin (vitamin B3) was also significantly associated with HOMA-β in the NODAP group. None of the studied vitamins were significantly associated with FPG or HOMA-IR in the NODAP group. Prospective longitudinal studies and randomised controlled trials are now warranted to investigate if the observed associations between vitamin/vitamer intake and NODAP are causal and to unveil the specific mechanisms underlying their involvement with NODAP.
... Accumulated ATP can stimulate purinergic P2 receptors (P2XRs and P2YRs) or be further degraded to Adenosine by the sequential action of CD39 and CD73 ectonucleotidases. In situations of great metabolic stress, in this case, the magnitude of hypoxia produced in SARS-CoV-2 infection in a cellular medium depleted of NAD/NADH+ [58,[92][93][94], requiring tissue lysis to guarantee amino acids for gluconeogenesis, Adenosine is produced in large quantities. It may reflect metabolic exhaustion in the face of cell damage. ...
Article
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SARS-CoV-2 causes placental changes that can lead to embryonic/foetal death. However, the pregnant woman who in other diseases is considered (e.g., H1N1) a risk group for the development of severe forms of the disease, in COVID-19 rarely evolves with severity, except when childbirth occurs, and the woman loses the bond with the placenta. The answer for the pregnant woman is in the immunosuppression promoted by the placenta, in the metabolism of tryptophan and phenylalanine (Try) and functions of Furins and cathepsins. This article discusses at crucial points the main pathophysiological mechanisms that can explain the events observed during pregnancy and the peri-and postpartum phenomena. It also shows the vital role of the placenta in this period of gestation, which is one of the most significant evolutionary adaptations that humans have in the face of SARS-CoV-2 infection. The studies for the elaboration of this article could also bring to light theories about the formation of the syncytial lung in COVID-19, about the physiology of the Faget's Sign and justify new therapeutic approaches that should be carried out seeking a better outcome for patients in this case aimed at pregnant and postpartum women. This article names the main clinical manifestations of COVID-19 as the thrombometabolic and immune tolerant syndrome induced by SARS-CoV-2 infection (TMITSy-CoV-2). Finally, this article aims to bring to light a host-parasite interaction that, if well understood, can help in the management of the pregnant woman and the first postpartum moments, because even without specific medications, we can perform better clinical management, resulting in a good outcome for the pregnant woman and the foetus. Reading the Appendix is essential as it complements the general pathophysiology of COVID-19.
... NAD + is an electron carrier and a co-substrate for NAD + -dependent enzymes such as poly(ADP-ribose) polymerases (Bouchard et al. 2003;Sauve 2008). The byproduct of these enzymatic reactions, nicotinamide (NAM), must be salvaged to maintain a readily available NAD + pool. ...
Article
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Nicotinamide recycling is critical to the development and function of Caenorhabditis elegans. Excess nicotinamide in a pnc-1 nicotinamidase mutant causes the necrosis of uv1 and OLQ cells and a highly penetrant egg laying defect. An EGF receptor (let-23) gain-of-function mutation suppresses the Egl phenotype in pnc-1 animals. However, gain-of-function mutations in either of the known downstream mediators, let-60/ Ras or itr-1, are not sufficient. Phosphatidylcholine synthesis is neither required nor sufficient, in contrast to its role in the let-23gf rescue of uv1 necrosis. The mechanism behind the let-23gf suppression of the pnc-1 Egl phenotype is unknown.
... Thus NAD + homeostasis is crucial for axon maintenance as well as overall neuronal health (Gerdts et al., 2015). NAD + is generated from Nam in two steps: the rate-limiting conversion of Nam to NMN by NAMPT, followed by synthesis of NAD + from NMN by NMNAT2 and its paralogs (Sauve, 2008). NMN and NAD + compete to bind an allosteric pocket that modulates SARM1 autoinhibition, rendering SARM1 a metabolic sensor that responds to an elevated NMN/NAD + ratio Jiang et al., 2020;Sporny et al., 2020). ...
Article
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SARM1 is an inducible TIR-domain NAD+ hydrolase that mediates pathological axon degeneration. SARM1 is activated by an increased ratio of NMN to NAD+, which competes for binding to an allosteric activating site. When NMN binds, the TIR domain is released from autoinhibition, activating its NAD+ hydrolase activity. The discovery of this allosteric activating site led us to hypothesize that other NAD+-related metabolites might activate SARM1. Here, we show the nicotinamide analog 3-acetylpyridine (3-AP), first identified as a neurotoxin in the 1940s, is converted to 3-APMN, which activates SARM1 and induces SARM1-dependent NAD+ depletion, axon degeneration, and neuronal death. In mice, systemic treatment with 3-AP causes rapid SARM1-dependent death, while local application to the peripheral nerve induces SARM1-dependent axon degeneration. We identify 2-aminopyridine as another SARM1-dependent neurotoxin. These findings identify SARM1 as a candidate mediator of environmental neurotoxicity and suggest that SARM1 agonists could be developed into selective agents for neurolytic therapy.
... El conocer los mecanismos mediante los cuales los seres vivos obtienen NAD es particularmente importante para comprender la relación entre su metabolismo y las alteraciones que conducen a enfermedades (Berger, et al., 2004). Las perturbaciones en la regulación de la síntesis del NAD derivan en deficiencias fatales para el organismo (Dolle, et al., 2013;Mao, et al., 2016;Padiadpu, et al., 2016;Sauve, 2008). Además, las particularidades de las rutas bioquímicas que involucran el NAD en organismos patógenos pueden considerarse como posibles blancos terapéuticos contra enfermedades infecciosas. ...
Article
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La nicotinamida/nicotinato mononucleótido adenililtransferasa (NMNAT, EC 2.7.7.1/18) desempeñauna función central en la síntesis del dinucleótido de adenina y nicotinamida (NAD) debido a queen esta enzima confluyen las rutas de síntesis de novo y de reciclaje. El NAD es una moléculatrascendental en el metabolismo de todos los seres vivos, principalmente en el metabolismo redox. Eneste estudio se presenta una nueva estrategia metodológica para la evaluación de posibles inhibidoresde la NMNAT de Leishmania braziliensis (LbNMNAT). El método suprime la actividad inhibitoriacruzada con la enzima acoplada al ensayo de detección, la alcohol dehidrogenasa (ADH, EC 1.1.1.1).Experimentalmente se introdujo un paso intermedio de extracción en fase sólida de los inhibidoresantes de la ejecución del sistema enzimático de detección. La implementación del paso de extracciónposibilitó la evaluación específica de la enzima de interés, la LbNMNAT, sin afectar la enzimaacoplada ADH. El nuevo método permitió estudiar el efecto inhibitorio de la galotanina, productonatural de especies del género Rhus (Rhus chinensis), en la actividad de la LbNMNAT.
... The tumor microenvironment has the potential to provide critical metabolites to promote tumor cell growth and immune modulation 1 as well as support cellular metabolism via metabolic coupling 2 or metabolic plasticity 3,4 . A key energy metabolite in the tumor microenvironment is the hydride exchanger nicotinamide adenine dinucleotide (NAD + /NADH) which plays an important role in redox reactions for a number of energy-related and regulatory processes [5][6][7][8] . Mammalian cells, in order to sustain intracellular NAD + homeostasis, can preferentially utilize a de novo synthesis pathway from L-tryptophan (Trp) or the Preiss-Handler pathway from nicotinic acid (NA), or employ the more effective salvage pathway 9 , which initiates from nicotinamide (NAM), or the nicotinamide riboside (NR) kinase pathway. ...
Article
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Changes in nicotinamide adenine dinucleotide (NAD+) levels that compromise mitochondrial function trigger release of DNA damaging reactive oxygen species. NAD+ levels also affect DNA repair capacity as NAD+ is a substrate for PARP-enzymes (mono/poly-ADP-ribosylation) and sirtuins (deacetylation). The ecto-5′-nucleotidase CD73, an ectoenzyme highly expressed in cancer, is suggested to regulate intracellular NAD+ levels by processing NAD+ and its bio-precursor, nicotinamide mononucleotide (NMN), from tumor microenvironments, thereby enhancing tumor DNA repair capacity and chemotherapy resistance. We therefore investigated whether expression of CD73 impacts intracellular NAD+ content and NAD+-dependent DNA repair capacity. Reduced intracellular NAD+ levels suppressed recruitment of the DNA repair protein XRCC1 to sites of genomic DNA damage and impacted the amount of accumulated DNA damage. Further, decreased NAD+ reduced the capacity to repair DNA damage induced by DNA alkylating agents. Overall, reversal of these outcomes through NAD+ or NMN supplementation was independent of CD73. In opposition to its proposed role in extracellular NAD+ bioprocessing, we found that recombinant human CD73 only poorly processes NMN but not NAD+. A positive correlation between CD73 expression and intracellular NAD+ content could not be made as CD73 knockout human cells were efficient in generating intracellular NAD+ when supplemented with NAD+ or NMN.
... Niacin, or nicotinic acid (a vitamer of vitamin B3), is absorbed by the body when dissolved in water and taken orally. It is converted to the major vitamer niacinamide in the body, along with other minor vitamers such as nicotinamide N-oxide and nicotinuric acid [12]. Niacin and nicotinamide are crucial for all living cells. ...
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Water-soluble B vitamins participate in numerous crucial metabolic reactions and are critical for maintaining our health. Vitamin B deficiencies cause many different types of diseases, such as dementia, anaemia, cardiovascular disease, neural tube defects, Crohn’s disease, celiac disease, and HIV. Vitamin B3 deficiency is linked to pellagra and cancer, while niacin (or nicotinic acid) lowers low-density lipoprotein (LDL) and triglycerides in the blood and increases high-density lipoprotein (HDL). A highly sensitive and robust liquid chromatography–tandem mass spectroscopy (LC/MS-MS) method was developed to detect and quantify a vitamin B3 vitamer (nicotinamide) and vitamin B6 vitamers (pyridoxial 5′-phosphate (PLP), pyridoxal hydrochloride (PL), pyridoxamine dihydrochloride (PM), pridoxamine-5′-phosphate (PMP), and pyridoxine hydrochloride (PN)) in human hair samples of the UAE population. Forty students’ volunteers took part in the study and donated their hair samples. The analytes were extracted and then separated using a reversed-phase Poroshell EC-C18 column, eluted using two mobile phases, and quantified using LC/MS-MS system. The method was validated in human hair using parameters such as linearity, intra- and inter-day accuracy, and precision and recovery. The method was then used to detect vitamin B3 and B6 vitamers in the human hair samples. Of all the vitamin B3 and B6 vitamers tested, only nicotinamide was detected and quantified in human hair. Of the 40 samples analysed, 12 were in the range 100–200 pg/mg, 15 in the range 200–500 pg/mg, 9 in the range of 500–4000 pg/mg. The LC/MS-MS method is effective, sensitive, and robust for the detection of vitamin B3 and its vitamer nicotinamide in human hair samples. This developed hair test can be used in clinical examination to complement blood and urine tests for the long-term deficiency, detection, and quantification of nicotinamide.
... Thus NAD + homeostasis is crucial for axon maintenance as well as overall neuronal health (Gerdts et al., 2015). NAD + is generated from Nam in two steps: the rate-limiting conversion of Nam to NMN by NAMPT, followed by synthesis of NAD + from NMN by NMNAT2 and its paralogs (Sauve, 2008). NMN and NAD + compete to bind an allosteric pocket that modulates SARM1 autoinhibition, rendering SARM1 a metabolic sensor that responds to an elevated NMN/NAD + ratio Jiang et al., 2020;Sporny et al., 2020). ...
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SARM1 is an inducible TIR-domain NAD ⁺ hydrolase that mediates pathological axon degeneration. SARM1 is activated by an increased ratio of NMN to NAD ⁺ , which competes for binding to an allosteric activating site. When NMN binds, the TIR domain is released from autoinhibition, activating its NAD ⁺ hydrolase activity. The discovery of this allosteric activating site led us to hypothesize that other NAD ⁺ -related metabolites might also activate SARM1. Here we show that the nicotinamide analogue 3-acetylpyridine (3-AP), first identified as a neurotoxin in the 1940s, is converted to 3-APMN which activates SARM1 and induces SARM1-dependent NAD ⁺ depletion, axon degeneration and neuronal death. Systemic treatment with 3-AP causes rapid SARM1-dependent death, while local application to peripheral nerve induces SARM1-dependent axon degeneration. We also identify a related pyridine derivative, 2-aminopyridine, as another SARM1-dependent neurotoxin. These findings identify SARM1 as a candidate mediator of environmental neurotoxicity, and furthermore, suggest that SARM1 agonists could be developed into selective agents for neurolytic therapy.
... В связи с этим очень интересны данные о вмешательстве предшественника NAD + -никотинамида в такие клеточные процессы, как синтез поли-(ADP-рибозо)полимеразы (PARP), функционирование митохондриальных мембран, транскрипционных факторов, каспаз и т. д. (Li et al., 2006). Обнаружено также, что состояние здоровья человека зависит от метаболизма NAD + , проявляющего свои эффекты через PARP, моно-ADP-рибозилтрансферазы и сиртуины (Sauve, 2008). Последние (сиртуины Sir1-7) принадлежат к недавно открытому семейству ферментов, модифицирующих белки и влияющих на рост и дифференциацию клеток, апоптоз, репарацию ДНК, устойчивость к стрессу и другие жизненно важные функции, обеспечивающие анти-старение (Michan, Sinclair, 2007;Ghosh, 2008). ...
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Background Nicotinamide (vitamin B3) is a metabolite of tryptophan and dietary precursor of enzymes involved in many regulatory processes, which may influence fetal immune development. Objective We examined whether maternal plasma concentrations of nicotinamide, tryptophan or nine related tryptophan metabolites during pregnancy were associated with risk of development of infant eczema, wheeze, rhinitis or allergic sensitization. Methods In the Growing Up in Singapore Towards Healthy Outcomes (GUSTO) study, we analysed the associations between maternal plasma levels of nicotinamide, tryptophan and tryptophan metabolites at 26-28 weeks gestation and allergic outcomes collected through interviewer-administered questionnaires at multiple timepoints and skin prick testing to egg, milk, peanut and mites at age 18 months. Multivariate analysis was undertaken adjusting for all metabolites measured, and separately adjusting for relevant demographic and environmental exposures. Analyses were also adjusted for multiple comparisons using the false discovery method. Results Tryptophan metabolites were evaluated in 976/1247 (78%) women enrolled in GUSTO. In multivariate analysis including all metabolites, maternal plasma 3-hydrokynurenine was associated with increased allergic sensitization at 18 months (AdjRR 2.6, 95% CI 1.3-5.2 for highest quartile) but the association with nicotinamide was not significant (AdjRR 1.8, 95% CI 0.9-3.6). In analysis adjusting for other exposures, both 3-hydrokynurenine and nicotinamide were associated with increased allergic sensitization (AdjRR 2.0, 95% CI 1.1-3.6 for both metabolites). High maternal plasma nicotinamide was associated with increased infant eczema diagnosis by 6 and 12 months, which was not significant when adjusting for all metabolites measured, but was significant when adjusting for relevant environmental and demographic exposures. Other metabolites measured were not associated with allergic sensitisation or eczema, and maternal tryptophan metabolites were not associated with offspring rhinitis and wheeze. Conclusions and Clinical Relevance Maternal tryptophan metabolism during pregnancy may influence the development of allergic sensitization and eczema in infants.
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Chapter
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Cancer chemotherapy agents cause short-term leukopenia during treatment and the development of secondary leukemias after recovery from the original disease. We reported that niacin deficiency in rats increases the severity of nitrosourea-induced leukopenia and the subsequent development of cancers. This study was designed to test the effects of supplementing an already high quality diet with pharmacologic levels of niacin. For a period of 4 wk, nontumor-bearing weanling Long-Evans rats were pair-fed AIN-93M diets that were niacin adequate (30 mg/kg diet) or pharmacologically supplemented (4 g/kg diet) with nicotinic acid (NA) or nicotinamide (Nam). One week after the initiation of niacin feeding protocols, ethylnitrosourea (ENU) treatment began (12 doses, 30 mg/kg by gavage, every other day). ENU treatment caused leukopenia, which was not prevented by niacin supplementation. At the end of ENU treatment, all rats were switched to a niacin-adequate diet and monitored. Within 36 wk after the start of treatment, all of the ENU-treated rats either lost 5% of peak body weight or had palpable tumors > 1 cm in diameter, and were necropsied. Supplementation with NA or Nam at 4.0 g/kg diet (combined analysis) increased the latency of the ENU-induced morbidity curve, relative to niacin-adequate controls. Morbidity could be attributed in almost all cases to some form of neoplasm, with leukemias the predominant form. In short-term studies, supplementation with either NA or Nam caused dramatic increases in bone marrow NAD(+) (1- to 1.5-fold), basal poly(ADP-ribose) (3- to 5-fold) and ENU-induced poly(ADP-ribose) levels (1.5-fold). These data show that supplementation of a niacin-adequate, high quality diet with pharmacologic levels of nicotinic acid or nicotinamide increases NAD(+) and poly(ADP-ribose) levels in bone marrow and may be protective against DNA damage.
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Cancer chemotherapy agents cause damage in the bone marrow, resulting in leukopenia during treatment and secondary cancers after recovery from the original disease. We created an experimental model of alkylation-based chemotherapy using ethylnitrosourea (ENU) to investigate the effect of niacin status on cancer induction. For 4 wk, nontumor-bearing weanling Long-Evans rats were fed niacin-deficient (ND) diets or were pair-fed (PF) identical quantities of a niacin-adequate diet. One week after the initiation of niacin feeding protocols, ENU treatment began (12 doses, 30 mg/kg by gavage, every other day). At the end of dietary modulation and ENU treatment, all rats were fed a high quality control diet and monitored for weight loss (>5%) and palpable tumors (>1cm), at which point they were necropsied for the presence of disease. The morbidity curves were significantly different; ND rats reached 20% morbidity 10 wk earlier than PF rats. In the first 20 wk after ENU treatment, ND rats developed 17 malignancies, including 11 leukemias, whereas PF rats developed 3 malignancies with 2 leukemias. In the end, there was a 47% greater average number of malignancies in ND vs. PF rats, despite a more rapid onset of morbidity. In short-term studies, niacin deficiency caused an 80% decrease in bone marrow NAD(+). Basal poly(ADP-ribose) levels were dramatically reduced by niacin deficiency. A single dose of ENU increased poly(ADP-ribose) levels fivefold in PF rats, whereas levels in ND rats remained 90% lower. Niacin deficiency did not alter the initial accumulation of DNA damage, indicating that drug metabolism is not an underlying factor in the diet-induced changes. These data show that niacin deficiency alters poly(ADP-ribose) metabolism in the bone marrow and increases the risk of nitrosourea-induced leukemias.
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Novel drug targets are required in order to design new defenses against antibiotic-resistant pathogens. Comparative genomics provides new opportunities for finding optimal targets among previously unexplored cellular functions, based on an understanding of related biological processes in bacterial pathogens and their hosts. We describe an integrated approach to identification and prioritization of broad-spectrum drug targets. Our strategy is based on genetic footprinting in Escherichia coli followed by metabolic context analysis of essential gene orthologs in various species. Genes required for viability of E. coli in rich medium were identified on a whole-genome scale using the genetic footprinting technique. Potential target pathways were deduced from these data and compared with a panel of representative bacterial pathogens by using metabolic reconstructions from genomic data. Conserved and indispensable functions revealed by this analysis potentially represent broad-spectrum antibacterial targets. Further target prioritization involves comparison of the corresponding pathways and individual functions between pathogens and the human host. The most promising targets are validated by direct knockouts in model pathogens. The efficacy of this approach is illustrated using examples from metabolism of adenylate cofactors NAD(P), coenzyme A, and flavin adenine dinucleotide. Several drug targets within these pathways, including three distantly related adenylyltransferases (orthologs of the E. coli genes nadD, coaD, and ribF), are discussed in detail.
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The murine homologue of the previously identified human "pre-B-cell colony-enhancing factor" (PBEF) gene coding for a putative cytokine has been identified by screening a subtractive library enriched in genes expressed in activated T lymphocytes. Unlike most cytokine genes known to date, the PBEF gene is ubiquitously expressed in lymphoid and non-lymphoid tissues and displays significant homology with genes from primitive metazoans (marine sponges) and prokaryotic organisms. Recently, a bacterial protein encoded by nadV, a gene from the prokaryote Haemophilus ducreyi displaying significant homology with PBEF, has been identified as a nicotinamide phosphoribosyltranferase (NAmPRTase), an enzyme involved in nicotinamide adenine dinucleotide (NAD) biosynthesis. Using a panel of antibodies to murine PBEF, we demonstrate in this work that, similarly to its microbial counterpart, the murine protein is a NAmPRTase, catalyzing the condensation of nicotinamide with 5-phosphoribosyl-1-pyrophosphate to yield nicotinamide mononucleotide, an intermediate in the biosynthesis of NAD. The role of PBEF as a NAmPRTase was further confirmed by showing that the mouse gene was able to confer the ability to grow in the absence of NAD to a NAmPRTase-defective bacterial strain. The present findings are in keeping with the ubiquitous nature of this protein, and indicate that NAD biosynthesis may play an important role in lymphocyte activation.
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Poly(ADP-ribose) polymerase-1 (PARP-1) is a member of the PARP enzyme family consisting of PARP-1 and several recently identified novel poly( ADP-ribosylating) enzymes. PARP-1 is an abundant nuclear protein functioning as a DNA nick-sensor enzyme. Upon binding to DNA breaks, activated PARP cleaves NAD(+) into nicotinamide and ADP-ribose and polymerizes the latter onto nuclear acceptor proteins including histones, transcription factors, and PARP itself. Poly(ADP-ribosylation) contributes to DNA repair and to the maintenance of genomic stability. On the other hand, oxidative stress-induced overactivation of PARP consumes NAD(+) and consequently ATP, culminating in cell dysfunction or necrosis. This cellular suicide mechanism has been implicated in the pathomechanism of stroke, myocardial ischemia, diabetes, diabetes-associated cardiovascular dysfunction, shock, traumatic central nervous system injury, arthritis, colitis, allergic encephalomyelitis, and various other forms of inflammation. PARP has also been shown to associate with and regulate the function of several transcription factors. Of special interest is the enhancement by PARP of nuclear factor kappaB-mediated transcription, which plays a central role in the expression of inflammatory cytokines, chemokines, adhesion molecules, and inflammatory mediators. Herein we review the double-edged sword roles of PARP in DNA damage signaling and cell death and summarize the underlying mechanisms of the anti-inflammatory effects of PARP inhibitors. Moreover, we discuss the potential use of PARP inhibitors as anticancer agents, radiosensitizers, and antiviral agents.
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Background Results of studies in animals and human beings suggest that type 1 diabetes is preventable. Nicotinamide prevents autoimmune diabetes in animal models, possibly through inhibition of the DNA repair enzyme poly-ADP-ribose polymerase and prevention of β-cell NAD depletion. We aimed to assess whether high dose nicotinamide prevents or delays clinical onset of diabetes in people with a first-degree family history of type 1 diabetes. Methods We did a randomised double-blind placebo-controlled trial of nicotinamide in 552 relatives with confirmed islet cell antibody (ICA) levels of 20 Juvenile Diabetes Federation (JDF) units or more, and a non-diabetic oral glucose tolerance test. Participants were recruited from 18 European countries, Canada, and the USA, and were randomly allocated oral modified release nicotinamide (1·2 g/m2) or placebo for 5 years. Random allocation was done with a pseudorandom number generator and we used size balanced blocks of four and stratified by age and national group. Primary outcome was development of diabetes, as defined by WHO criteria. Analysis was done on an intention-to-treat basis. Findings There was no difference in the development of diabetes between the treatment groups. Of 159 participants who developed diabetes in the course of the trial, 82 were taking nicotinamide and 77 were on placebo. The unadjusted hazard ratio for development of diabetes was 1·07 (95% CI 0·78–1·45; p=0·69), and the hazard ratio adjusted for age-at-entry, baseline glucose tolerance, and number of islet autoantibodies detected was 1·01 (0·73–1·38; p=0·97). Of 168 (30·4%) participants who withdrew from the trial, 83 were on placebo. The number of serious adverse events did not differ between treatment groups. Nicotinamide treatment did not affect growth in children or first-phase insulin secretion. Interpretation Large-scale controlled trials of interventions designed to prevent the onset of type 1 diabetes are feasible, but nicotinamide was ineffective at the dose we used.
Article
Previous studies have demonstrated two different biosynthetic pathways to quinolinate, the universal de novo precursor to the pyridine ring of NAD. In prokaryotes, quinolinate is formed from aspartate and dihydroxyacetone phosphate; in eukaryotes, it is formed from tryptophan. It has been generally believed that the tryptophan to quinolinic acid biosynthetic pathway is unique to eukaryotes; however, this paper describes the use of comparative genome analysis to identify likely candidates for all five genes involved in the tryptophan to quinolinic acid pathway in several bacteria. Representative examples of each of these genes were overexpressed, and the predicted functions are confirmed in each case using unambiguous biochemical assays.
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It is generally accepted that the increased concentrations of apolipoprotein (apo) B containing very low-density lipoproteins (VLDL) and low-density lipoproteins (LDL), and decreased levels of apo AI containing high-density lipoproteins (HDL) are correlated to atherosclerotic cardiovascular disease. Current evidence indicates that the post-translational apo-B degradative processes regulate the hepatic assembly and secretion of VLDL and the subsequent generation of LDL particles. The availability of triglycerides (TG) for the addition to apo B during intracellular processing appears to play a central role in targeting apo B for either intracellular degradation or assembly and secretion as VLDL particles. Based on the availability of TG, the liver secretes either dense TG-poor VLDL2 or large TG-rich VLDL1 particles, and these particles serve as precursors for the formation of more buoyant or small, dense LDL particles by lipid transfer protein- and hepatic lipase-mediated processes. HDLs are a heterogenous class of lipoproteins, and apo AI (the major protein of HDL) participates in reverse cholesterol transport, a process by which excess cholesterol is eliminated. Recent studies indicate that HDL particles containing only apo A-I (LPA-I) are more effective in reverse cholesterol transport and more anti-atherogenic than HDL particles containing both apo A-I and apo A-II (LPA-I+A-II).
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Hepatocytes isolated from fed or starved rats were rapidly lysed using the recently described technique of turbulent flow (M. E. Tischler, P. Hecht, and J. R. Williamson, 1977, Arch. Biochem. Biophys., 181, 278–292). Pyridine nucleotide and metabolite contents were measured in the particulate fraction of both whole and disrupted cells after centrifugation through silicone oil. Lactate/pyruvate, β-hydroxybutyrate/acetoacetate, isocitrate/α-ketoglutarate, and malate/pyruvate ratios were determined for calculation of the free and ratios in the cytosol and mitochondria. Lactate/pyruvate ratios measured in the extracellular and cytosolic compartments were in good agreement. Ratios of β-hydroxybutyrate/acetoacetate measured in the extracellular, cytosolic, and mitochondrial compartments also agreed well. Addition of ammonia to fed or starved rat liver cells incubated with lactate, pyruvate, β-hydroxybutyrate, and acetoacetate caused an oxidation of both the NAD and NADP redox states in the mitochondria and cytosol, although the NADP system was oxidized to a greater extent. Calculation of the free NADH and NAD concentrations in the cytosol provided values of about 1 and 400 to 500 μm, respectively, under control conditions. The concentrations of free NADH and NAD in the mitochondria were considerably higher, being 300 to 400 μm and 4 to 6 mm, respectively. The free andm bound NAD systems in both the cytosol and mitochondria were more oxidized in the presence of ammonia. NAD and NADP redox potential differences across the mitochondrial membrane (ΔEh) were not significantly affected by ammonia addition and were generally similar in cells from both fed and starved rats: −52 and −56 mV for the NAD system and −19 to −29 mV for the NADP system. For the NAD system the cytosolic potential was −260 mV in the absence of ammonia and −250 mV in its presence, the mitochondrial values being −315 and −303 mV, respectively. The average cytosolic NADP potential, on the other hand, was −400 mV in the absence and −384 mV in the presence of ammonia. The mitochondrial fractions yielded NADP potentials of −420 mV in the absence of ammonia with both fed and starved rats. Ammonia decreased the mitochondrial NADP potential to −404 mV in fed rats and to −415 mV in starved rats. The calculated free and ratios as well as metabolite concentrations were used to evaluate the mass action ratios of both cytosolic and mitochondrial enzymes. Cytosolic alanine aminotransferase remained near equilibrium in the absence and presence of ammonia, while cytosolic and mitochondrial aspartate aminotransferase reactions deviated up to fivefold. The glutamate dehydrogenase reaction was in near equilibrium with the NAD system, but deviated by three to four orders of magnitude from equilibrium with the NADP system in the direction favoring glutamate synthesis rather than deaminatión. Cytosolic malate dehydrogenase deviated from equilibrium by about one order of magnitude, while mitochondrial malate dehydrogenase and citrate synthase deviated by two to six orders of magnitude. These data emphasize the importance of regulation of the citric acid cycle at the citrate synthase step.
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1. The concentrations of the oxidized and reduced substrates of the lactate-, beta-hydroxybutyrate- and glutamate-dehydrogenase systems were measured in rat livers freeze-clamped as soon as possible after death. The substrates of these dehydrogenases are likely to be in equilibrium with free NAD(+) and NADH, and the ratio of the free dinucleotides can be calculated from the measured concentrations of the substrates and the equilibrium constants (Holzer, Schultz & Lynen, 1956; Bücher & Klingenberg, 1958). The lactate-dehydrogenase system reflects the [NAD(+)]/[NADH] ratio in the cytoplasm, the beta-hydroxybutyrate dehydrogenase that in the mitochondrial cristae and the glutamate dehydrogenase that in the mitochondrial matrix. 2. The equilibrium constants of lactate dehydrogenase (EC 1.1.1.27), beta-hydroxybutyrate dehydrogenase (EC 1.1.1.30) and malate dehydrogenase (EC 1.1.1.37) were redetermined for near-physiological conditions (38 degrees ; I0.25). 3. The mean [NAD(+)]/[NADH] ratio of rat-liver cytoplasm was calculated as 725 (pH7.0) in well-fed rats, 528 in starved rats and 208 in alloxan-diabetic rats. 4. The [NAD(+)]/[NADH] ratio for the mitochondrial matrix and cristae gave virtually identical values in the same metabolic state. This indicates that beta-hydroxybutyrate dehydrogenase and glutamate dehydrogenase share a common pool of dinucleotide. 5. The mean [NAD(+)]/[NADH] ratio within the liver mitochondria of well-fed rats was about 8. It fell to about 5 in starvation and rose to about 10 in alloxan-diabetes. 6. The [NAD(+)]/[NADH] ratios of cytoplasm and mitochondria are thus greatly different and do not necessarily move in parallel when the metabolic state of the liver changes. 7. The ratios found for the free dinucleotides differ greatly from those recorded for the total dinucleotides because much more NADH than NAD(+) is protein-bound. 8. The bearing of these findings on various problems, including the following, is discussed: the number of NAD(+)-NADH pools in liver cells; the applicability of the method to tissues other than liver; the transhydrogenase activity of glutamate dehydrogenase; the physiological significance of the difference of the redox states of mitochondria and cytoplasm; aspects of the regulation of the redox state of cell compartments; the steady-state concentration of mitochondrial oxaloacetate; the relations between the redox state of cell compartments and ketosis.
Article
Previous work in our laboratory has shown that dietary megadoses of nicotinamide, used in the prevention of diabetes, cause increases in hepatic poly(ADP-ribose). Poly(ADP-ribose) is synthesized from NAD+ by a nuclear enzyme, poly(ADP-ribose)polymerase, which is activated by DNA strand breaks. The nicotinamide-induced increase in poly(ADP-ribose) could result from an increase in substrate, NAD+, or the induction of strand breaks in DNA. Strand breaks may result from the depletion of single carbon groups, through the excretion of methylated derivatives of nicotinamide. To differentiate between these mechanisms, a 3 x 3 factorial experiment was conducted in which rats were fed diets containing various supplements of choline bitartrate (0, 2, 20 g/kg diet) and nicotinamide (0, 1, 2 g/kg diet). At the conclusion of treatments, blood NAD+ and liver lipid, NAD+ and poly(ADP-ribose) levels were determined. Choline deficiency caused the characteristic accumulation of fat in the liver at all levels of nicotinamide. In choline deficient rats, nicotinamide supplements further increased liver lipid concentration. Blood and liver NAD+ concentrations were increased by nicotinamide supplementation, irrespective of choline status. In contrast, liver poly(ADP-ribose) levels were increased by nicotinamide supplementation only in choline deficient rats. These results show that nicotinamide-induced increases in poly(ADP-ribose) levels appear to be dependent on decreased methyl donor status and suggest that adequate choline status is important for preventing some deleterious effects of nicotinamide treatment.
Article
Poly(ADP-ribose) is a homopolymer of ADP-ribose units synthesized from NAD+ on nuclear acceptor proteins and is known to be involved in DNA repair. It is not known whether large oral doses of the clinically utilized NAD precursors nicotinic acid or nicotinamide affect poly(ADP-ribose) metabolism or the cellular response to DNA damage. In our first study, using Fischer-344 rats, 2 wk of dietary nicotinic acid supplementation (500 and 1000 mg/kg diet) caused elevated levels of NAD+ in the blood, liver, heart and kidney, while nicotinamide caused elevated levels only in the blood and liver, compared with controls fed a diet containing 30 mg/kg nicotinic acid. Both nicotinic acid and nicotinamide, at 1000 mg/kg diet, caused elevations in liver NAD+, by 44 and 43%, respectively. Only nicotinamide, however, elevated liver poly(ADP-ribose) (63% higher than control group). Following treatment with the hepatocarcinogen diethylnitrosamine, higher levels of hepatic NAD+ were observed in rats fed both nicotinic acid and nicotinamide at 1000 mg/kg diet, but only nicotinic acid supplementation caused a greater accumulation of hepatic poly(ADP-ribose) (61% higher than control group). Neither of the dietary treatments significantly affected the proportion of the liver occupied by placental glutathione-S-transferase positive foci. These results show that poly(ADP-ribose) synthesis is not directly responsive to hepatic NAD+ levels during niacin supplementation, and that the mechanisms of action of nicotinic acid and nicotinamide are different. The observed changes in poly(ADP-ribose) metabolism do not appear to cause any change in susceptibility to chemically induced carcinogenesis in this organ.
Article
Nutritionists, including those involved in famine relief, have learned in the last 25 years that certain deficiency diseases arise from the high protein foods used to rehabilitate starving populations. Other, sometimes inappropriate relief foods starving populations. Other, sometimes inappropriate relief foods include unprocessed or inappropriate grains and unfortified dry skimmed milk. Yet, relief workers do not always receive the most appropriate food for distribution to certain populations. Millions of dollars are appropriated to protect relief supplies for starving people in Somalia, but money is not spent to develop and evaluate simple foods that might save the lives of starving people. There are several items relief agencies and governments should consider when deciding on the most appropriate foods to prevent starvation in famine situations. During kwashiorkor, intestinal mucous produce grossly defective cells, resulting in considerable lactose malabsorption. Thus, using milk to rehabilitate people, especially children, poses a considerable hazard. High carbohydrate diets to rehabilitate starving people can cause gross edema and fatal congestive heart failure. Generally, clinically apparent vitamin or mineral deficiencies do not occur during famines, because the amount of vitamins or minerals needed to small to maintain a very shrunken body. Yet, when the body demand increases as a result of a rehabilitation diet poor in vitamins and minerals but high in protein or calories, clinical deficiency symptoms emerge, e.g., pellagra in Mozambique. Common food combinations used in relief situations consists of corn, soy, and milk fortified with vitamins and minerals (Bal'ahar mixture, India). Both mixtures require the addition of vegetable oils to make it easier for infants and small children to digest the mixtures.
Article
Folate is an essential cofactor in the generation of endogenous methionine, and there is evidence that folate deficiency exacerbates the effects of a diet low in choline and methionine, including alterations in poly(ADP-ribose) polymerase (PARP) activity, an enzyme associated with DNA replication and repair. Because PARP requires NAD as its substrate, we postulated that a deficiency of both folate and niacin would enhance the development of liver cancer in rats fed a diet deficient in methionine and choline. In two experiments, rats were fed choline- and folate-deficient, low methionine diets containing either 12 or 8% casein (12% MCFD, 8% MCFD) or 6% casein and 6% gelatin with niacin (MCFD) or without niacin (MCFND) and were compared with folate-supplemented controls. Liver NAD concentrations were lower in all methyl-deficient rats after 2-17 mo. At 17 mo, NAD concentrations in other tissues of rats fed these diets were also lower than in controls. Compared with control values, liver PARP activity was enhanced in rats fed the 12% MCFD diet but was lower in MCFND-fed rats following a further reduction in liver NAD concentration. These changes in PARP activity associated with lower NAD concentrations may slow DNA repair and enhance DNA damage. Only rats fed the MCFD and MCFND diets developed hepatocarcinomas after 12-17 mo. In Experiment 2, hepatocarcinomas were found in 100% of rats fed the MCFD and MCFND diets. These preliminary results indicate that folic acid deficiency enhances tumor development. Because tumors developed in 100% of the MCFD-fed rats and because tissue concentrations of NAD in these animals were also low, further studies are needed to clearly define the role of niacin in methyl-deficient rats.
Article
The opening of the mitochondrial permeability transition pore (PTP) has been suggested to play a key role in various forms of cell death, but direct evidence in intact tissues is still lacking. We found that in the rat heart, 92% of NAD+glycohydrolase activity is associated with mitochondria. This activity was not modified by the addition of Triton X-100, although it was abolished by mild treatment with the protease Nagarse, a condition that did not affect the energy-linked properties of mitochondria. The addition of Ca2+ to isolated rat heart mitochondria resulted in a profound decrease in their NAD+ content, which followed mitochondrial swelling. Cyclosporin A(CsA), a PTP inhibitor, completely prevented NAD+ depletion but had no effect on the glycohydrolase activity. Thus, in isolated mitochondria PTP opening makes NAD+ available for its enzymatic hydrolysis. Perfused rat hearts subjected to global ischemia for 30 min displayed a 30% decrease in tissue NAD+ content, which was not modified by extending the duration of ischemia. Reperfusion resulted in a more severe reduction of both total and mitochondrial contents of NAD+, which could be measured in the coronary effluent together with lactate dehydrogenase. The addition of 0.2 μm CsA or of its analogue MeVal-4-Cs (which does not inhibit calcineurin) maintained higher NAD+ contents, especially in mitochondria, and significantly protected the heart from reperfusion damage, as shown by the reduction in lactate dehydrogenase release. Thus, upon reperfusion after prolonged ischemia, PTP opening in the heart can be documented as a CsA-sensitive release of NAD+, which is then partly degraded by glycohydrolase and partly released when sarcolemmal integrity is compromised. These results demonstrate that PTP opening is a causative event in reperfusion damage of the heart.
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Because of the original observation by Altschul et al., that nicotinic acid (niacin), not nicotinamide, in pharmacologic doses lowered human serum cholesterol levels, an avalanche of reports have been published over the past 45 years on the plasma lipid-regulating properties of this drug and its beneficial cardiovascular effects. A myriad of studies that have examined efficacy, safety, adverse effects, and pharmacologic properties of niacin rendered convincing evidence that niacin, used alone or combined with other agents, has favorable effects on serum lipoprotein regulation and on containment of atherothrombotic cardiovascular diseases. However, because of the unusual side effect profile of niacin and the availability of various formulations of this drug, niacin must be used prudently and with careful instruction and monitoring of patients. This review summarizes the pertinent and recent literature on niacin that impacts its therapeutic use. We also discuss some controversial issues and personal clinical experience and opinions on this topic.