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Nicotinamide mononucleotide (NMN) mediates alleviation of poly(I:C) induced inflammatory response in human primary cell cultures

ABSTRACT: NMN is the direct precursor of the nicotinamide adenine dinucleotide (NAD+) and is considered a key component to increase NAD+ levels and mitochondrial activity in cells. In this study, based on transcriptome analysis, we showed that NMN alleviates poly(I:C)-induced inflammatory response in two types of human primary cell cultures, human pulmonary microvascular endothelial cells (HPMEC) and human coronary artery endothelial cells (HCAEC). The major inflammatory mediators including IL-6 and PARP family members are grouped into co-expressed gene modules and significantly down-regulated under NMN-dosage in poly(I:C)-induced conditions in both cell types. The Bayesian network analysis of module hub genes predicted common genes including eukaryotic translation initiation factor 1B (EIF1B) and distinct genes such as platelet-derived growth factor binding molecules in HCAEC, which potentially regulate the identified inflammation modules. These results have suggested the robust regulatory mechanism of NMN to alleviate inflammatory pathways, which may open up the possibility of a new role for NMN replenishment in chronic or acute inflammation treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE233679 | GEO | 2023/07/09

REPOSITORIES: GEO

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Nicotinamide mononucleotide, a key NAD+ precursor, treats the pathophysiology of diet- and age-induced diabetes

Project description:Type 2 diabetes (T2D) has become an epidemic in our modern lifestyle, likely due to calorie-rich diets overwhelming our adaptive metabolic pathways. One such pathway is mediated by nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in mammalian NAD+ biosynthesis, and the NAD+-dependent protein deacetylase SIRT1. Here we show that NAMPT-mediated NAD+ biosynthesis is severely compromised in metabolic organs by high-fat diet (HFD). Strikingly, nicotinamide mononucleotide (NMN), a product of the NAMPT reaction and a key NAD+ intermediate, ameliorates glucose intolerance by restoring NAD+ levels in HFD-induced T2D mice. NMN also enhances hepatic insulin sensitivity and restores gene expression related to oxidative stress, inflammatory response, and circadian rhythm, partly through SIRT1 activation. Furthermore, NAD+ and NAMPT levels show significant decreases in multiple organs during aging, and NMN improves glucose intolerance and lipid profiles in age-induced T2D mice. These findings provide critical insights into a novel intervention against diet- and age-induced T2D. 4 regular chow fed mice (RC1-4) vs 4 high-fat diet fed (HFD) (HFD1a-4a) mice were analyzed on one chip (Chip-A). 4 HFD mice (HFD1b-4b) vs 4 HFD-NMN treated mice (NMN1-4) were examined on the other chip (Chip-B).

2011-12-05 | E-GEOD-31647 | biostudies-arrayexpress

Slc12a8 is a nicotinamide mononucleotide transporter that counteracts aging

Project description:NAD+ levels decline in multiple tissues over age, causing various age-associated pathophysiologies. Nicotinamide mononucleotide (NMN) is a key NAD+ intermediate that promotes NAD+biosynthesis and counteracts age-associated physiological decline. However, how NMN transport is regulated remains unknown. Here we report a novel NMN transporter encoded by the Slc12a8 gene. Slc12a8 is highly expressed and regulated by NAD+ in the small intestine. Knocking down this gene abrogates the transport of NMN in vitro and in vivo. Slc12a8 exhibits specificity to NMN and dependency on the sodium ion. Slc12a8 deficiency significantly decreases NAD+ levels in the jejunum and ileum, due to decreases in NMN uptake traced by doubly labeled isotopic NMN. Slc12a8 expression is upregulated in the aged ileum, contributing to the maintenance of NAD in aged mice. Thus, this newly identified NMN transporter plays a critical role in counteracting NAD+ decline during aging.

2019-01-01 | GSE118365 | GEO

Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice

Project description:NAD+ availability decreases with age and in certain disease conditions. Nicotinamide mononucleotide (NMN), a key NAD+ intermediate, has been shown to enhance NAD+ biosynthesis and ameliorate various pathologies in mouse disease models. In this study, we conducted a 12 month-long NMN administration to regular chow-fed wild-type C57BL/6N mice during their normal aging. Orally administered NMN was quickly utilized to synthesize NAD+ in tissues. Remarkably, NMN effectively mitigates age-associated physiological decline in mice. Without any obvious toxicity or deleterious effects, NMN suppressed age-associated body weight gain, enhanced energy metabolism, promoted physical activity, improved insulin sensitivity and plasma lipid profile, and ameliorated eye function and other pathophysiologies. Consistent with these phenotypes, NMN prevented age-associated gene expression changes in key metabolic organs and enhanced mitochondrial oxidative metabolism and mitonuclear protein imbalance in skeletal muscle. These effects of NMN highlight the preventive and therapeutic potential of NAD+ intermediates as effective anti-aging interventions in humans.

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Nicotinamide mononucleotide, a key NAD+ precursor, treats the pathophysiology of diet- and age-induced diabetes

2011-12-05 | GSE31647 | GEO

Nicotinamide mononucleotide administration triggers macrophages reprogramming and alleviates inflammation during sepsis induced by experimental peritonitis

Project description:Peritonitis and subsequent sepsis lead to high morbidity and mortality in response to uncontrolled systemic inflammation primarily mediated by macrophages. We investigated whether the administration of a natural biosynthetic precursor of NAD+, β-nicotinamide mononucleotide (β‐NMN), could prevent clinical deterioration effects of sepsis. To this purpose, C57BL6 mice were subjected to the cecal ligation and puncture (CLP) model to provoke sepsis or were injected with thioglycolate (TGC) to induce a sterile peritonitis with recruitment and differentiation of macrophages into the inflamed peritoneal cavity. β-NMN was administered for 4 days after CLP and for 3 days post TGC treatment. Administration of β‐NMN decreased bacterial load in blood and reduced clinical signs of distress and mortality during sepsis. Transcriptomic analysis of hearts and lungs 24 hours post CLP-induction, revealed that β-NMN downregulated genes controlling immuno-inflammatory response and upregulated genes involved in bioenergetic metabolism, mitochondria biogenesis, and autophagy. In the thioglycolate model, β‐NMN treatment significantly reduced phagolysosomes acidification and inflammatory mediators secretion from bacteria-stimulated peritoneal macrophages. Transcriptomic signature of these macrophages showed that β‐NMN administration limited the pro-inflammatory M1 phenotype, induced the expression of specific markers of M2 type macrophages and significantly impacted gens involved in NAD+ metabolism.

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2022-12-31 | GSE156038 | GEO

Effect of nicotinamide mononucleotide on doxorubicin-induced cardiac injury in mice

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2023-06-03 | GSE233644 | GEO

Nicotinamide Mononucleotide Requires SIRT3 to Improve Cardiac Function and Bioenergetics in a Friedreich’s Ataxia Cardiomyopathy Model

Project description:Martin et al. JCI Insigh (2017). Increasing NAD+ levels by supplementing with the precursor nicotinamide mononucleotide (NMN) improves cardiac function in multiple mouse models of disease. While NMN influences several aspects of mitochondrial metabolism, the molecular mechanisms by which increased NAD+ enhances cardiac function are poorly understood. A putative mechanism of NAD+ therapeutic action is via activation of the mitochondrial NAD+-dependent protein deacetylase sirtuin 3 (SIRT3). We assessed the therapeutic efficacy of NMN and the role of SIRT3 in the Friedreich’s Ataxia cardiomyopathy mouse model (FXNKO). At baseline, the FXNKO heart has mitochondrial protein hyperacetylation, reduced Sirt3 mRNA expression, and evidence of increased NAD+ salvage. Remarkably, NMN administered to FXNKO mice restores cardiac function to near-normal levels. To determine whether SIRT3 is required for NMN therapeutic efficacy, we generated SIRT3KO and SIRT3KO/FXNKO (dKO) knockout models. The improvement in cardiac function upon NMN treatment in the FXNKO is lost in the dKO model, demonstrating that the effects of NMN are dependent upon cardiac SIRT3. Coupled with cardio- protection, SIRT3 mediates NMN-induced improvements in both cardiac and extra-cardiac metabolic function and energy metabolism. Taken together, these results serve as important preclinical data for NMN supplementation or SIRT3 activator therapy in Friedreich’s Ataxia patients.

2017-07-21 | PXD006754 | Pride

RNA-Sequencing of Aged Mouse Oocytes with in vivo Nicotinamide Mononucleotide (NMN) Treatment

Project description:We highlighted the effects of in vivo NMN administration on aged mouse oocyte transcriptome.

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Nicotinamide mononucleotide increases muscle insulin sensitivity in women with prediabetes

Project description:Studies in rodents have shown obesity and aging impair tissue nicotinamide adenine dinucleotide (NAD+) biosynthesis, which contributes to metabolic dysfunction. The availability of nicotinamide mononucleotide (NMN) is an important rate-limiting factor in mammalian NAD+ biosynthesis. We conducted a 10-week, randomized, placebo-controlled, double-blind trial to evaluate the effect of NMN supplementation on metabolic function in 25 postmenopausal women with prediabetes who were overweight/obese. Insulin-stimulated glucose disposal, assessed by using the hyperinsulinemic-euglycemic-clamp procedure, increased by 25±7% (P<0.01) in the NMN group, which was accompanied by an increase in insulin-stimulated phosphorylation of muscle AKT (P<0.01), whereas neither outcome changed after placebo treatment. Body composition (fat mass, fat-free mass, intra-abdominal fat, intrahepatic triglyceride content) and muscle mitochondrial respiratory capacity did not change after treatment with placebo or NMN. These results demonstrate NMN improves muscle insulin sensitivity in women with prediabetes who are overweight/obese, independent of changes in body composition or mitochondrial function.

2021-05-01 | GSE157988 | GEO

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