Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD+ Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures

Yasir S Elhassan, Katarina Kluckova, Rachel S Fletcher, Mark S Schmidt, Antje Garten, Craig L Doig, David M Cartwright, Lucy Oakey, Claire V Burley, Ned Jenkinson, Martin Wilson, Samuel J E Lucas, Ildem Akerman, Alex Seabright, Yu-Chiang Lai, Daniel A Tennant, Peter Nightingale, Gareth A Wallis, Konstantinos N Manolopoulos, Charles Brenner, Andrew Philp, Gareth G Lavery, Yasir S Elhassan, Katarina Kluckova, Rachel S Fletcher, Mark S Schmidt, Antje Garten, Craig L Doig, David M Cartwright, Lucy Oakey, Claire V Burley, Ned Jenkinson, Martin Wilson, Samuel J E Lucas, Ildem Akerman, Alex Seabright, Yu-Chiang Lai, Daniel A Tennant, Peter Nightingale, Gareth A Wallis, Konstantinos N Manolopoulos, Charles Brenner, Andrew Philp, Gareth G Lavery

Abstract

Nicotinamide adenine dinucleotide (NAD+) is modulated by conditions of metabolic stress and has been reported to decline with aging in preclinical models, but human data are sparse. Nicotinamide riboside (NR) supplementation ameliorates metabolic dysfunction in rodents. We aimed to establish whether oral NR supplementation in aged participants can increase the skeletal muscle NAD+ metabolome and if it can alter muscle mitochondrial bioenergetics. We supplemented 12 aged men with 1 g NR per day for 21 days in a placebo-controlled, randomized, double-blind, crossover trial. Targeted metabolomics showed that NR elevated the muscle NAD+ metabolome, evident by increased nicotinic acid adenine dinucleotide and nicotinamide clearance products. Muscle RNA sequencing revealed NR-mediated downregulation of energy metabolism and mitochondria pathways, without altering mitochondrial bioenergetics. NR also depressed levels of circulating inflammatory cytokines. Our data establish that oral NR is available to aged human muscle and identify anti-inflammatory effects of NR.

Keywords: aging; cell adhesion; inflammation; metabolism; nicotinamide adenine dinucleotide.

Conflict of interest statement

C.B. is the inventor of patents licensed by ChromaDex, owns stock in ChromaDex, and serves as an adviser to ChromaDex and Cytokinetics. The remaining authors declare no competing interests.

Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
NR Augments the Human Skeletal Muscle NAD+ Metabolome Schematic representation of nicotinamide riboside (NR) metabolism within the nicotinamide adenine dinucleotide (NAD+) metabolome, accompanied by observed levels of metabolites measured using LC-MS/MS in skeletal muscle, whole blood, and urine at baseline and after each of the NR and placebo periods. NAD+ metabolomics data at the end of the washout period are shown in Table S3. Skeletal muscle data were normalized to the weight of the muscle pellet used for extraction. Urine data were normalized to urinary creatinine. Other metabolites are shown in Figure S2. Data are obtained from 12 participants at each phase and presented as mean ± SEM. Significance was set at p < 0.05 using paired t tests and represents the differences between NR and the placebo and between NR and baseline. The absence of significance symbols indicates a lack of statistical significance. BLQ, below limit of quantification; NMN, nicotinamide mononucleotide; NAAD, nicotinic acid adenine dinucleotide; NAM, nicotinamide; NAMOx, nicotinamide N-oxide; MeNAM, N-methyl nicotinamide; Me-2-py, N1-Methyl-2-pyridone-5- carboxamide.
Figure 2
Figure 2
NR Supplementation Induces a Transcriptional Signature in Human Skeletal Muscle (A) Differential gene expression analysis on baseline and NR-treated muscle samples (n = 12 at each phase). Volcano plot of differential gene expression between baseline and NR treated human muscle samples. Fold change (Log2, x axis) of gene expression is plotted against p value for differential gene expression (–Log10, y axis). Colored dots represent Ensembl genes that are either upregulated (in orange) or downregulated (in blue) upon NR supplementation at a p value GAPDH was used as housekeeping gene. Error bars represent SEM (n = 12). (H) As in (G), but for NAD+ pathway-related genes. (I) Quantification of phosphoglycerate kinase 1 (PGK1), phosphoglucomutase 1 (PGM1), and pyruvate kinase M1 (PKM1) proteins using immunoblotting assay. Tubulin was used as a loading control. Data are obtained from 12 participants at each phase and wherever relevant are presented as mean ± SEM. Significance was set at p 

Figure 3

Human Skeletal Muscle Mitochondrial Bioenergetics…

Figure 3

Human Skeletal Muscle Mitochondrial Bioenergetics Remain Unaltered with NR Supplementation (A) Mitochondrial respiration…

Figure 3
Human Skeletal Muscle Mitochondrial Bioenergetics Remain Unaltered with NR Supplementation (A) Mitochondrial respiration of permeabilized muscle fibers upon the addition of complex I and complex II substrates at baseline and after 3 weeks of supplementation of NR and the placebo. MG, malate and glutamate; D, ADP; S, succinate; c, cytochrome C; F, FCCP; Rot, rotenone. Data are normalized to muscle fiber weight. (B) Mitochondrial respiration as per (A), but with the prior addition of the fatty acid conjugate octanoyl-carnitine to malate (MOct). (C) Citrate synthase (CS) activity in human skeletal muscle at baseline and after NR and the placebo. (D) Relative PCR expression of mitochondrial DNA (mtDNA) to nuclear DNA (nDNA) at baseline and after NR and the placebo, expressed as arbitrary units. (E) Western blot showing the expression of selected mitochondrial proteins in skeletal muscle lysates compared to β-actin as housekeeping protein. (F) Western blot showing the expression of acetylation proteins in skeletal muscle lysates compared to β-actin as housekeeping protein. Data are obtained from 12 participants at each phase and wherever relevant are presented as mean ± SEM. Significance was set at p 

Figure 4

Forearm Muscle Blood Flow and…

Figure 4

Forearm Muscle Blood Flow and Substrate Utilization Are Unaffected by NR Supplementation (A)…

Figure 4
Forearm Muscle Blood Flow and Substrate Utilization Are Unaffected by NR Supplementation (A) Muscle blood flow using venous occlusive plethysmography at baseline and after the NR and placebo phases. The green dotted line represents when 75 g of oral glucose load was taken. (B and C) Muscle O2 consumption (B) and CO2 production (C) at baseline and after NR and the placebo. The green dotted line represents when 75 g of oral glucose load was taken. (D and E) Muscle glucose uptake (D) and lactate release (E) at baseline and after NR and the placebo. The green dotted line represents when 75 g of oral glucose load was taken. Data are obtained from 12 participants at each phase and presented as mean ± SEM. Significance was set at p 

Figure 5

Systemic Readouts of Metabolism Are…

Figure 5

Systemic Readouts of Metabolism Are Unaltered with NR Supplementation (A) HOMA-IR at baseline…

Figure 5
Systemic Readouts of Metabolism Are Unaltered with NR Supplementation (A) HOMA-IR at baseline and after NR and the placebo. (B) Fasting non-esterified fatty acid (NEFA) level at baseline and after NR and the placebo. (C) Plasma glucose response in a glucose tolerance test at baseline and after NR and the placebo. The green dotted line represents when 75 g of oral glucose load was taken. (D) Plasma NEFA response in a glucose tolerance test at baseline and after NR and the placebo. The green dotted line represents when 75 g of oral glucose load was taken. (E) Respiratory exchange ratio (RER) at baseline and after NR and the placebo. The green dotted line indicates when 75 g of oral glucose was taken. Data are obtained from 12 participants at each phase and presented as mean ± SEM. Significance was set at p 

Figure 6

NR Supplementation Suppresses the Circulating…

Figure 6

NR Supplementation Suppresses the Circulating Levels of Inflammatory Cytokines (A–J) Levels of serum…

Figure 6
NR Supplementation Suppresses the Circulating Levels of Inflammatory Cytokines (A–J) Levels of serum inflammatory cytokines at baseline and after each of the NR and placebo phases, including (A) interleukin 6 (IL-6), (B) interleukin 5 (IL-5), (C) interleukin 2 (IL-2), (D) tumor necrosis factor alpha (TNF-α), (E) interleukin 12 (IL-12), (F) interleukin 8 (IL-8), (G) interferon-gamma (IFN-g), (H) monocyte chemoattractant protein-1 (MCP-1), (I) macrophage inflammatory protein-1 beta (MIP-1B), and (J) high-sensitivity C-reactive protein (hsCRP). Data are obtained from 12 participants at each phase and presented as mean ± SEM. Significance was set at p 
All figures (7)
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References
    1. Airhart S.E., Shireman L.M., Risler L.J., Anderson G.D., Nagana Gowda G.A., Raftery D., Tian R., Shen D.D., O’Brien K.D. An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers. PLoS ONE. 2017;12:e0186459. - PMC - PubMed
    1. Amici S.A., Young N.A., Narvaez-Miranda J., Jablonski K.A., Arcos J., Rosas L., Papenfuss T.L., Torrelles J.B., Jarjour W.N., Guerau-de-Arellano M. CD38 Is Robustly Induced in Human Macrophages and Monocytes in Inflammatory Conditions. Front. Immunol. 2018;9:1593. - PMC - PubMed
    1. Bergstrom J. Percutaneous needle biopsy of skeletal muscle in physiological and clinical research. Scand. J. Clin. Lab. Invest. 1975;35:609–616. - PubMed
    1. Bickerton A.S.T., Roberts R., Fielding B.A., Hodson L., Blaak E.E., Wagenmakers A.J., Gilbert M., Karpe F., Frayn K.N. Preferential uptake of dietary Fatty acids in adipose tissue and muscle in the postprandial period. Diabetes. 2007;56:168–176. - PubMed
    1. Bieganowski P., Brenner C. Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss-Handler independent route to NAD+ in fungi and humans. Cell. 2004;117:495–502. - PubMed
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Figure 3
Figure 3
Human Skeletal Muscle Mitochondrial Bioenergetics Remain Unaltered with NR Supplementation (A) Mitochondrial respiration of permeabilized muscle fibers upon the addition of complex I and complex II substrates at baseline and after 3 weeks of supplementation of NR and the placebo. MG, malate and glutamate; D, ADP; S, succinate; c, cytochrome C; F, FCCP; Rot, rotenone. Data are normalized to muscle fiber weight. (B) Mitochondrial respiration as per (A), but with the prior addition of the fatty acid conjugate octanoyl-carnitine to malate (MOct). (C) Citrate synthase (CS) activity in human skeletal muscle at baseline and after NR and the placebo. (D) Relative PCR expression of mitochondrial DNA (mtDNA) to nuclear DNA (nDNA) at baseline and after NR and the placebo, expressed as arbitrary units. (E) Western blot showing the expression of selected mitochondrial proteins in skeletal muscle lysates compared to β-actin as housekeeping protein. (F) Western blot showing the expression of acetylation proteins in skeletal muscle lysates compared to β-actin as housekeeping protein. Data are obtained from 12 participants at each phase and wherever relevant are presented as mean ± SEM. Significance was set at p 

Figure 4

Forearm Muscle Blood Flow and…

Figure 4

Forearm Muscle Blood Flow and Substrate Utilization Are Unaffected by NR Supplementation (A)…

Figure 4
Forearm Muscle Blood Flow and Substrate Utilization Are Unaffected by NR Supplementation (A) Muscle blood flow using venous occlusive plethysmography at baseline and after the NR and placebo phases. The green dotted line represents when 75 g of oral glucose load was taken. (B and C) Muscle O2 consumption (B) and CO2 production (C) at baseline and after NR and the placebo. The green dotted line represents when 75 g of oral glucose load was taken. (D and E) Muscle glucose uptake (D) and lactate release (E) at baseline and after NR and the placebo. The green dotted line represents when 75 g of oral glucose load was taken. Data are obtained from 12 participants at each phase and presented as mean ± SEM. Significance was set at p 

Figure 5

Systemic Readouts of Metabolism Are…

Figure 5

Systemic Readouts of Metabolism Are Unaltered with NR Supplementation (A) HOMA-IR at baseline…

Figure 5
Systemic Readouts of Metabolism Are Unaltered with NR Supplementation (A) HOMA-IR at baseline and after NR and the placebo. (B) Fasting non-esterified fatty acid (NEFA) level at baseline and after NR and the placebo. (C) Plasma glucose response in a glucose tolerance test at baseline and after NR and the placebo. The green dotted line represents when 75 g of oral glucose load was taken. (D) Plasma NEFA response in a glucose tolerance test at baseline and after NR and the placebo. The green dotted line represents when 75 g of oral glucose load was taken. (E) Respiratory exchange ratio (RER) at baseline and after NR and the placebo. The green dotted line indicates when 75 g of oral glucose was taken. Data are obtained from 12 participants at each phase and presented as mean ± SEM. Significance was set at p 

Figure 6

NR Supplementation Suppresses the Circulating…

Figure 6

NR Supplementation Suppresses the Circulating Levels of Inflammatory Cytokines (A–J) Levels of serum…

Figure 6
NR Supplementation Suppresses the Circulating Levels of Inflammatory Cytokines (A–J) Levels of serum inflammatory cytokines at baseline and after each of the NR and placebo phases, including (A) interleukin 6 (IL-6), (B) interleukin 5 (IL-5), (C) interleukin 2 (IL-2), (D) tumor necrosis factor alpha (TNF-α), (E) interleukin 12 (IL-12), (F) interleukin 8 (IL-8), (G) interferon-gamma (IFN-g), (H) monocyte chemoattractant protein-1 (MCP-1), (I) macrophage inflammatory protein-1 beta (MIP-1B), and (J) high-sensitivity C-reactive protein (hsCRP). Data are obtained from 12 participants at each phase and presented as mean ± SEM. Significance was set at p 
All figures (7)
Similar articles
Cited by
References
    1. Airhart S.E., Shireman L.M., Risler L.J., Anderson G.D., Nagana Gowda G.A., Raftery D., Tian R., Shen D.D., O’Brien K.D. An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers. PLoS ONE. 2017;12:e0186459. - PMC - PubMed
    1. Amici S.A., Young N.A., Narvaez-Miranda J., Jablonski K.A., Arcos J., Rosas L., Papenfuss T.L., Torrelles J.B., Jarjour W.N., Guerau-de-Arellano M. CD38 Is Robustly Induced in Human Macrophages and Monocytes in Inflammatory Conditions. Front. Immunol. 2018;9:1593. - PMC - PubMed
    1. Bergstrom J. Percutaneous needle biopsy of skeletal muscle in physiological and clinical research. Scand. J. Clin. Lab. Invest. 1975;35:609–616. - PubMed
    1. Bickerton A.S.T., Roberts R., Fielding B.A., Hodson L., Blaak E.E., Wagenmakers A.J., Gilbert M., Karpe F., Frayn K.N. Preferential uptake of dietary Fatty acids in adipose tissue and muscle in the postprandial period. Diabetes. 2007;56:168–176. - PubMed
    1. Bieganowski P., Brenner C. Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss-Handler independent route to NAD+ in fungi and humans. Cell. 2004;117:495–502. - PubMed
Show all 71 references
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Figure 4
Figure 4
Forearm Muscle Blood Flow and Substrate Utilization Are Unaffected by NR Supplementation (A) Muscle blood flow using venous occlusive plethysmography at baseline and after the NR and placebo phases. The green dotted line represents when 75 g of oral glucose load was taken. (B and C) Muscle O2 consumption (B) and CO2 production (C) at baseline and after NR and the placebo. The green dotted line represents when 75 g of oral glucose load was taken. (D and E) Muscle glucose uptake (D) and lactate release (E) at baseline and after NR and the placebo. The green dotted line represents when 75 g of oral glucose load was taken. Data are obtained from 12 participants at each phase and presented as mean ± SEM. Significance was set at p 

Figure 5

Systemic Readouts of Metabolism Are…

Figure 5

Systemic Readouts of Metabolism Are Unaltered with NR Supplementation (A) HOMA-IR at baseline…

Figure 5
Systemic Readouts of Metabolism Are Unaltered with NR Supplementation (A) HOMA-IR at baseline and after NR and the placebo. (B) Fasting non-esterified fatty acid (NEFA) level at baseline and after NR and the placebo. (C) Plasma glucose response in a glucose tolerance test at baseline and after NR and the placebo. The green dotted line represents when 75 g of oral glucose load was taken. (D) Plasma NEFA response in a glucose tolerance test at baseline and after NR and the placebo. The green dotted line represents when 75 g of oral glucose load was taken. (E) Respiratory exchange ratio (RER) at baseline and after NR and the placebo. The green dotted line indicates when 75 g of oral glucose was taken. Data are obtained from 12 participants at each phase and presented as mean ± SEM. Significance was set at p 

Figure 6

NR Supplementation Suppresses the Circulating…

Figure 6

NR Supplementation Suppresses the Circulating Levels of Inflammatory Cytokines (A–J) Levels of serum…

Figure 6
NR Supplementation Suppresses the Circulating Levels of Inflammatory Cytokines (A–J) Levels of serum inflammatory cytokines at baseline and after each of the NR and placebo phases, including (A) interleukin 6 (IL-6), (B) interleukin 5 (IL-5), (C) interleukin 2 (IL-2), (D) tumor necrosis factor alpha (TNF-α), (E) interleukin 12 (IL-12), (F) interleukin 8 (IL-8), (G) interferon-gamma (IFN-g), (H) monocyte chemoattractant protein-1 (MCP-1), (I) macrophage inflammatory protein-1 beta (MIP-1B), and (J) high-sensitivity C-reactive protein (hsCRP). Data are obtained from 12 participants at each phase and presented as mean ± SEM. Significance was set at p 
All figures (7)
Similar articles
Cited by
References
    1. Airhart S.E., Shireman L.M., Risler L.J., Anderson G.D., Nagana Gowda G.A., Raftery D., Tian R., Shen D.D., O’Brien K.D. An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers. PLoS ONE. 2017;12:e0186459. - PMC - PubMed
    1. Amici S.A., Young N.A., Narvaez-Miranda J., Jablonski K.A., Arcos J., Rosas L., Papenfuss T.L., Torrelles J.B., Jarjour W.N., Guerau-de-Arellano M. CD38 Is Robustly Induced in Human Macrophages and Monocytes in Inflammatory Conditions. Front. Immunol. 2018;9:1593. - PMC - PubMed
    1. Bergstrom J. Percutaneous needle biopsy of skeletal muscle in physiological and clinical research. Scand. J. Clin. Lab. Invest. 1975;35:609–616. - PubMed
    1. Bickerton A.S.T., Roberts R., Fielding B.A., Hodson L., Blaak E.E., Wagenmakers A.J., Gilbert M., Karpe F., Frayn K.N. Preferential uptake of dietary Fatty acids in adipose tissue and muscle in the postprandial period. Diabetes. 2007;56:168–176. - PubMed
    1. Bieganowski P., Brenner C. Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss-Handler independent route to NAD+ in fungi and humans. Cell. 2004;117:495–502. - PubMed
Show all 71 references
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Cite
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Format: AMA APA MLA NLM

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Figure 5
Figure 5
Systemic Readouts of Metabolism Are Unaltered with NR Supplementation (A) HOMA-IR at baseline and after NR and the placebo. (B) Fasting non-esterified fatty acid (NEFA) level at baseline and after NR and the placebo. (C) Plasma glucose response in a glucose tolerance test at baseline and after NR and the placebo. The green dotted line represents when 75 g of oral glucose load was taken. (D) Plasma NEFA response in a glucose tolerance test at baseline and after NR and the placebo. The green dotted line represents when 75 g of oral glucose load was taken. (E) Respiratory exchange ratio (RER) at baseline and after NR and the placebo. The green dotted line indicates when 75 g of oral glucose was taken. Data are obtained from 12 participants at each phase and presented as mean ± SEM. Significance was set at p 

Figure 6

NR Supplementation Suppresses the Circulating…

Figure 6

NR Supplementation Suppresses the Circulating Levels of Inflammatory Cytokines (A–J) Levels of serum…

Figure 6
NR Supplementation Suppresses the Circulating Levels of Inflammatory Cytokines (A–J) Levels of serum inflammatory cytokines at baseline and after each of the NR and placebo phases, including (A) interleukin 6 (IL-6), (B) interleukin 5 (IL-5), (C) interleukin 2 (IL-2), (D) tumor necrosis factor alpha (TNF-α), (E) interleukin 12 (IL-12), (F) interleukin 8 (IL-8), (G) interferon-gamma (IFN-g), (H) monocyte chemoattractant protein-1 (MCP-1), (I) macrophage inflammatory protein-1 beta (MIP-1B), and (J) high-sensitivity C-reactive protein (hsCRP). Data are obtained from 12 participants at each phase and presented as mean ± SEM. Significance was set at p 
All figures (7)
Similar articles
Cited by
References
    1. Airhart S.E., Shireman L.M., Risler L.J., Anderson G.D., Nagana Gowda G.A., Raftery D., Tian R., Shen D.D., O’Brien K.D. An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers. PLoS ONE. 2017;12:e0186459. - PMC - PubMed
    1. Amici S.A., Young N.A., Narvaez-Miranda J., Jablonski K.A., Arcos J., Rosas L., Papenfuss T.L., Torrelles J.B., Jarjour W.N., Guerau-de-Arellano M. CD38 Is Robustly Induced in Human Macrophages and Monocytes in Inflammatory Conditions. Front. Immunol. 2018;9:1593. - PMC - PubMed
    1. Bergstrom J. Percutaneous needle biopsy of skeletal muscle in physiological and clinical research. Scand. J. Clin. Lab. Invest. 1975;35:609–616. - PubMed
    1. Bickerton A.S.T., Roberts R., Fielding B.A., Hodson L., Blaak E.E., Wagenmakers A.J., Gilbert M., Karpe F., Frayn K.N. Preferential uptake of dietary Fatty acids in adipose tissue and muscle in the postprandial period. Diabetes. 2007;56:168–176. - PubMed
    1. Bieganowski P., Brenner C. Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss-Handler independent route to NAD+ in fungi and humans. Cell. 2004;117:495–502. - PubMed
Show all 71 references
Publication types
MeSH terms
[x]
Cite
Copy Download .nbib
Format: AMA APA MLA NLM
Figure 6
Figure 6
NR Supplementation Suppresses the Circulating Levels of Inflammatory Cytokines (A–J) Levels of serum inflammatory cytokines at baseline and after each of the NR and placebo phases, including (A) interleukin 6 (IL-6), (B) interleukin 5 (IL-5), (C) interleukin 2 (IL-2), (D) tumor necrosis factor alpha (TNF-α), (E) interleukin 12 (IL-12), (F) interleukin 8 (IL-8), (G) interferon-gamma (IFN-g), (H) monocyte chemoattractant protein-1 (MCP-1), (I) macrophage inflammatory protein-1 beta (MIP-1B), and (J) high-sensitivity C-reactive protein (hsCRP). Data are obtained from 12 participants at each phase and presented as mean ± SEM. Significance was set at p 
All figures (7)

References

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    1. Amici S.A., Young N.A., Narvaez-Miranda J., Jablonski K.A., Arcos J., Rosas L., Papenfuss T.L., Torrelles J.B., Jarjour W.N., Guerau-de-Arellano M. CD38 Is Robustly Induced in Human Macrophages and Monocytes in Inflammatory Conditions. Front. Immunol. 2018;9:1593.
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