Subacute toxicity study of nicotinamide mononucleotide via oral administration
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE157594 | GEO | 2020/09/08
REPOSITORIES: GEO
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Project description:Nicotinamide mononucleotide (NMN), a key precursory metabolite of NAD+, has been shown to elevate the cellular level of NAD+ and ameliorate various age-related diseases. Despite these progresses, systemic evaluation pertaining to the subacute toxicity of NMN remains to be determined. Here, we examine the subacute toxicity of NMN in mice and beagle dogs. Mice were gavaged with a saturated concentration of NMN solution at the maximum intragastric dose once or twice per day for 7 days. Dogs were gavaged twice per day for 14 days. In mice, NMN administrated once per day for 7 days is well tolerated with minimal deleterious effects. Upon higher dosage, we observe slightly increased level of alamine aminotransferase, while other biomarkers remain unchanged. Consistently, administration of NMN in beagle dogs only results in mild increases in creatinine and uric acid. Together, our study highlights the safety of NMN, providing a possible safe dose range for oral administration of NMN.
| S-EPMC7770224 | biostudies-literature
Project description:Subacute toxicity study of nicotinamide mononucleotide via oral administration
| PRJNA662085 | ENA
Project description:In this study we investigated whether nicotinamide mononucleotide (NMN) could protect against Doxorubicin-induced cardiotoxicity and physical dysfunction in vivo. To assess the short- and long-term toxicity, two Doxo regimens were tested, acute and chronic. In the acute study, C57BL6/J (B6) mice were injected intraperitoneally (i.p.) once with Doxo (20 mg/kg) and NMN (180 mg/kg/day, i.p.) was administered daily for five days before and after the Doxo injection. In the chronic study, B6 mice received a cumulative dose of 20 mg/kg Doxo administered in fractionated doses for five days. NMN (500 mg/kg/day) was supplied in the mice’s drinking water beginning five days before the first injection of Doxo and continuing for 60 days after.
2023-01-11 | GSE221003 | GEO
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.
2016-12-01 | GSE85718 | GEO
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.
2022-06-08 | GSE199156 | GEO
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
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
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
Project description:Advanced maternal age, defined as 35 years or older, is associated with a decline in both ovarian reserve and oocyte quality, which leads to the female infertility, pregnancy loss, fetal anomalies, stillbirth, and obstetric complications. At present, the effective approaches to counteract the maternal age-related decay of oocyte quality are still not fully determined. Here, we report that in vivo supplementation of nicotinamide mononucleotide (NMN) efficaciously ameliorates the quality of oocytes from naturally aged mice by recovering nicotinamide adenine dinucleotide (NAD + ) levels in oocytes. NMN supplementation increases the number of antral follicles, ovulated oocytes and matured oocytes from aged mice. Specifically, NMN supplementation maintains the normal spindle/chromosome structure and dynamics of cortical granule component ovastacin to ensure the meiotic competency and fertilization ability of aged oocytes. Moreover, single cell transcriptome analysis shows that the beneficial effect of NMN on the aged oocytes is mediated by the restoration of the mitochondrial function, thereby reducing the accumulated ROS to suppress the occurrence of apoptosis. To sum up, our data reveal that supplementation of NMN is a feasible approach to prevent oocyte quality from advanced maternal age-related deterioration, contributing to improve the reproductive outcome of aged women and the assisted reproductive technology.
2023-07-01 | GSE153920 | GEO
Project description:Doxorubicin (DOX) is the cornerstone of chemotherapy regimens for many malignancies, but its clinical usage is limited by severe cardiotoxicity. Accumulating evidence suggest that nicotinamide adenine dinucleotide (NAD+) depletion contributes to DOX-induced cardiotoxicity, making NAD+ boosting an appealing strategy. Nicotinamide mononucleotide (NMN) is an NAD+ precursor that shows promising therapeutic effects in various diseases. To understand the impact of NMN on gene expression in myocardial tissue of DOX-exposed mice, a RNA-seq assay was carried out.
2023-06-03 | GSE233644 | GEO