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N1-methylnicotinamide (MNAM), a product of methylation of nicotinamide through nicotinamide N-methyltransferase, displays antidiabetic effects in male rodents. This study aimed to evaluate the ameliorative potential of MNAM on glucose metabolism in a gestational diabetes mellitus (GDM) model. C57BL/6N mice were fed with a high-fat diet (HFD) for 6 weeks before pregnancy and throughout gestation to establish the GDM model. Pregnant mice were treated with 0.3% or 1% MNAM during gestation. MNAM supplementation in CHOW diet and HFD both impaired glucose tolerance at gestational day 14.5 without changes in insulin tolerance. However, MNAM supplementation reduced hepatic lipid accumulation as well as mass and inflammation in visceral adipose tissue. MNAM treatment decreased GLUT4 mRNA and protein expression in skeletal muscle, where NAD+ salvage synthesis and antioxidant defenses were dampened. The NAD+/sirtuin system was enhanced in liver, which subsequently boosted hepatic gluconeogenesis. GLUT1 protein was diminished in placenta by MNAM. In addition, weight of placenta, fetus weight, and litter size were not affected by MNAM treatment. The decreased GLUT4 in skeletal muscle, boosted hepatic gluconeogenesis and dampened GLUT1 in placenta jointly contribute to the impairment of glucose tolerance tests by MNAM. Our data provide evidence for the careful usage of MNAM in treatment of GDM. [ABSTRACT FROM AUTHOR]

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Age-related hearing loss (ARHL) is the most common form of hearing loss and the predominant neurodegenerative disease associated with aging. Sirtuin 1 (SIRT1) is associated with the most complex physiological processes, including metabolism, cancer onset, and aging. SIRT1 protein levels are enhanced by the conversion of nicotinamide to N1-methylnicotinamide (MNAM), independent of its mRNA levels. Moreover, MNAM has implications in increased longevity achieved through its mitohormetic effects. Nicotinamide N-methyltransferase (Nnmt) is an enzyme involved in MNAM metabolism, and its level increases under caloric restriction (CR) conditions. The CR condition has implications in delaying ARHL onset. In this study, we aimed to determine the relationship between diet, hearing function, SIRT1 and SIRT3 expression levels in the inner ear, and cochlear morphology. Mice fed with a high-fat diet (HFD), HFD + 1% MNAM, and low-fat diet (LFD) were monitored for age-related auditory-evoked brainstem responses, and changes in cochlear histology, metabolism, and protein and mRNA expressions were analyzed. Our results revealed that the HFD- and aging-mediated downregulated expression of SIRT1 and SIRT3 promoted hearing loss that was obfuscated by MNAM supplementation-induced upregulated expression of cochlear SIRT1 and SIRT3. Thus, our results suggest that MNAM can be used as a therapeutic agent for preventing ARHL.

Age-related hearing loss (ARHL) is the most common form of hearing loss and the predominant neurodegenerative disease associated with aging. Sirtuin 1 (SIRT1) is associated with the most complex physiological processes, including metabolism, cancer onset, and aging. SIRT1 protein levels are enhanced by the conversion of nicotinamide to N1-methylnicotinamide (MNAM), independent of its mRNA levels. Moreover, MNAM has implications in increased longevity achieved through its mitohormetic effects. Nicotinamide N-methyltransferase (Nnmt) is an enzyme involved in MNAM metabolism, and its level increases under caloric restriction (CR) conditions. The CR condition has implications in delaying ARHL onset. In this study, we aimed to determine the relationship between diet, hearing function, SIRT1 and SIRT3 expression levels in the inner ear, and cochlear morphology. Mice fed with a high-fat diet (HFD), HFD + 1% MNAM, and low-fat diet (LFD) were monitored for age-related auditory-evoked brainstem responses, and changes in cochlear histology, metabolism, and protein and mRNA expressions were analyzed. Our results revealed that the HFD- and aging-mediated downregulated expression of SIRT1 and SIRT3 promoted hearing loss that was obfuscated by MNAM supplementation-induced upregulated expression of cochlear SIRT1 and SIRT3. Thus, our results suggest that MNAM can be used as a therapeutic agent for preventing ARHL. [ABSTRACT FROM AUTHOR]

Background: The current study evaluated the level of serum N1-methylnicotinamide (me-NAM) in cervical cancer patients and further explored whether serum me-NAM was related to the prognosis of cervical cancer. Methods: Fifty-eight cases of cervical intraepithelial neoplasia patients, 78 cases of cervical cancer patients, and 52 healthy women were included in the present study. Serum me-NAM concentrations were determined by liquid chromatography with tandem mass spectrometry. Receiver operating characteristic (ROC) curve was used to assess me-NAM as a biomarker and Kaplan-Meier analysis was carried out to evaluate the survival rate. Results: Our data showed that the level of serum me-NAM in cervical cancer patients was significantly higher than that in the cervical intraepithelial neoplasia group and the healthy control group. Furthermore, the level of me-NAM in cervical cancer tissues of stage I, II, III, and IV was higher than that of those without lymph node metastasis. The area under the receiver operating characteristic curve (ROC) for me-NAM was higher than that of squamous cell carcinoma antigen (SCC Ag) and carbohydrate antigen 125 (CA125) when comparing cervical cancer from CIN or healthy control. The combination of me-NAM and SCC Ag or CA125 could improve the diagnostic efficiency better than SCC Ag or CA125 alone. Compared with me-NAM low expression group, the survival rate and time of me-NAM high expression group were lower and shorter. Conclusions: Altogether, elevated serum me-NAM levels contribute to the progression of cervical cancer and may be used as a marker for the prognosis of patients with cervical cancer. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease, which has been rapidly increasing in the world in recent years, is roughly classified into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis. This study was based on our previous reports that stated that the combination treatment of N1-methylnicotinamide (MNA) and hydralazine (HYD) improves fatty liver in NAFL model rats. This finding was attributed to the MNA metabolism inhibition by HYD, which is a strong inhibitor of aldehyde oxidase (AO); this results in an increase in hepatic MNA and improved fatty liver. We hypothesized that orally administered nicotinamide (NAM), which is the precursor of MNA and is a form of niacin, would be efficiently metabolized by nicotinamide N-methyltransferase in the presence of exogenous S-adenosylmethionine (SAM) in NAFL rats. To address this issue, NAFL model rats were orally administered with NAM, SAM, and/or HYD. As a result, liver triglyceride (TG) and lipid droplet levels were barely altered by the administration of NAM, SAM, NAM+SAM, or NAM+HYD. By contrast, the triple combination of NAM+SAM+HYD significantly reduced hepatic TG and lipid droplet levels and significantly increased hepatic MNA levels. These findings indicated that the combination of exogenous SAM with AO inhibitors, such as HYD, has beneficial effects for improving fatty liver with NAM. [ABSTRACT FROM AUTHOR]

abstract Nonalcoholic fatty liver disease (NAFLD) has increased worldwide in recent years. NAFLD is classified into two types, nonalcoholic fatty liver (NAFL), with few complications, and nonalcoholic steatohepatitis (NASH), which leads to liver cirrhosis or cancer. This study was based on previous reports that N 1-methylnicotinamide (MNA) can stabilise sirtuin 1 protein, leading to decreased lipid levels in the liver. We hypothesised that fatty liver improvement by MNA would be further enhanced by suppressing its rapid metabolism by aldehyde oxidase in the liver. To test this, hydralazine (HYD), a potent aldehyde oxidase inhibitor, was administered orally to NAFL model rats. Liver triglyceride (TG) levels in the model were nearly unchanged by administration of MNA alone. In contrast, TG levels were marked decreased in NAFL rats treated with a combination of MNA and HYD. In addition, TG levels were decreased even in NAFL rats treated with only HYD. These findings supported our hypothesis that maintaining MNA concentrations in the liver, by suppressing MNA metabolism, would at least partially ameliorate fatty liver. Highlights • A slight positive correlation between human liver MNA and NNMT protein level. • Increase of liver MNA concentrations in rat alleviate fatty liver. • Inhibition of liver MNA metabolism would lead to fatty liver amelioration. • Hydralazine might be suitable for the combined treatment of hypertension and NAFLD. [ABSTRACT FROM AUTHOR]

Atherosclerosis is identified as the formation of atherosclerotic plaques, which could initiate the formation of a blood clot in which its growth to coronary artery can lead to a heart attack. N‐methyltransferase (NNMT) is an enzyme that converts the NAM (nicotinamide) to its methylated form, N1‐methylnicotinamide (MNAM). Higher levels of MNAM have been reported in cases with coronary artery disease (CAD). Further, MNAM increases endothelial prostacyclin (PGI2) and nitric oxide (NO) and thereby causes vasorelaxation. The vasoprotective, anti‐inflammatory and anti‐thrombotic roles of MNAM have been well documented; however, the exact underlying mechanisms remain to be clarified. Due to potential role of MNAM in the formation of lipid droplets (LDs), it might exert its function in coordination with lipids, and their targets. In this study, we summarized the roles of MNAM in cardiovascular system and highlighted its possible mode of actions. [ABSTRACT FROM AUTHOR]

BackgroundWe previously reported that serum N1‐methylnicotinamide (me‐Nam), an indicator of nicotinamide N‐methyltransferase activity, is associated with obesity and diabetes mellitus in Chinese patients. However, whether nicotinamide N‐methyltransferase plays a role in human coronary artery disease (CAD) remains to be elucidated. We aim to investigate the associations of serum me‐Nam with CAD in Chinese patients. Methods and ResultsSerum me‐NAM was measured by liquid chromatography‐mass spectrometry in patients with (n=230) or without (n=103) CAD as defined by coronary angiography. The severity of CAD was expressed by number of diseased coronary arteries. Serum me‐Nam was higher (7.65 ng/mL versus 4.95 ng/mL, P

Background/Aims: Tryptophan is the precursor of serotonin and niacin (vitamin B3). The latter is critical for normal cellular metabolism. Tryptophan and niacin can be deficient in patients with serotonin-producing neuroendocrine tumors (NETs). Niacin deficiency may lead to severe symptoms including pellagra. In patients with serotonin-producing NET, data on niacin status are scarce and niacin supplementation hardly receives attention. We aimed to assess the niacin status before and after supplementation in these patients. Methods: We identified serotonin-producing NET patients who had received oral niacin supplementation (mean dose 144 mg daily) for tryptophan deficiency and/or pellagra-associated symptoms. Presupplementation plasma tryptophan levels and niacin status based on the urinary niacin metabolite N1-methylnicotinamide (N1-MN) before (n = 42) and after the start of the supplementation (in 34 paired samples) were assessed. Reference values for urinary N1-MN levels were established in 133 healthy individuals. Results: The mean presupplementation plasma tryptophan level was 31.8 ± 9.7 µmol/l (reference value 40.0-70.0). Presupplementation urinary N1-MN levels were lower in patients (median 17.9 µmol/24 h, range 2.6-70.3) compared to healthy controls (median 43.7 µmol/24 h, range 9.5-169.3, p < 0.0001) and below normal in 45% of the patients. Niacin supplementation increased urinary N1-MN levels to high normal levels (median 55.5 µmol/24 h, range 7.4-489.0) in 86% of the niacin-deficient patients. Conclusion: In serotonin-producing NET patients, niacin deficiency is prevalent. Therefore, urinary N1-MN deserves to be included in their standard biochemical evaluation. Niacin supplementation normalizes the niacin status in most niacin-deficient serotonin-producing NET patients. A prospective study is warranted. [ABSTRACT FROM AUTHOR]

The article examines whether N¹1-methylnicotinamide (MNA+) might induce vasorelation in human blood vessels through the improvement of nitric oxide (NO) bioavailability and a reduction of oxidative stress mediated by endothelial NO synthase (eNOS) function. MNA+ was previously thought to be a biologically inactive product of nicotinamide metabolism. The article also indicates that targeting eNOS with MNA+ might be therapeutically relevant to functional disorders of the endothelium.

Macroautophagy is a "cell cleansing" process that rids cells of protein aggregates and damaged organelles that may contribute to disease pathogenesis and the dysfunctions associated with aging. Measures which boost longevity and health span in rodents typically up-regulate macroautophagy, and it has often been suggested that safe strategies which can promote this process in humans may contribute to healthful aging. The kinase ULK1 serves as a trigger for autophagy initiation, and the transcription factors TFEB, FOXO1, ATF4 and CHOP promote expression of a number of proteins which mediate macroautophagy. Nutraceutical or dietary measures which stimulate AMPK, SIRT1, eIF5A, and that diminish the activities of AKT and mTORC1, can be expected to boost the activities of these pro-autophagic factors. The activity of AMPK can be stimulated with the phytochemical berberine. SIRT1 activation may be achieved with a range of agents, including ferulic acid, melatonin, urolithin A, N1-methylnicotinamide, nicotinamide riboside, and glucosamine; correction of ubiquinone deficiency may also be useful in this regard, as may dietary strategies such as time-restricted feeding or intermittent fasting. In the context of an age-related decrease in cellular polyamine levels, provision of exogenous spermidine can boost the hypusination reaction required for the appropriate post-translational modification of eIF5A. Low-protein plant-based diets could be expected to increase ATF4 and CHOP expression, while diminishing IGF-I-mediated activation of AKT and mTORC1. Hence, practical strategies for protecting health by up-regulating macroautophagy may be feasible. [ABSTRACT FROM AUTHOR]

More than 500 enzymes need niacin coenzymes. Therefore, elucidation of the control mechanisms of coenzyme metabolism is fundamentally important. Objective: NAD+ is involved in ATP production. Because energy expenditure is generally higher during the day than at night, we investigated whether the metabolism of nicotinamide changes at various times of day and whether stress affects nicotinamide metabolism. Design: Twelve women were housed in the same facility and followed the same schedule for activities of daily living for 12 d. Urinary outputs were collected during 5 specific periods to investigate diurnal variations in nicotinamide metabolism. The effects of cold exposure (physical stress), having to perform arithmetic calculations (mental stress), and dark exposure (emotional stress) on nicotinamide metabolism were investigated. Results: A diurnal variation in the nicotinamide metabolites N1-methylnicotinamide, N1-methyl-2-pyridone-5-carboxamide, and N1-methyl-4-pyridone-3-carboxamide was observed. Of the stresses studied, cold exposure significantly increased the urinary excretory outputs of the nicotinamide metabolites. Conclusions: Diurnal variations in nicotinamide metabolism were found in these women. The biosynthesis of nicotinamide from tryptophan seemed to be increased by cold exposure. [ABSTRACT FROM AUTHOR]

Five healthy males, age 25-32 y, were fed in sequence a diet of ordinary foods (10 d, PI), a low-methionine diet (285 mg/d, 14 d, PII), and an adequate-methionine diet (725 mg/d, 7 d, PIII). Diets contained 9 g nitrogen (N) per day with soy protein and synthetic L-amino acids as the N sources in PII and PIII. In PII, subjects were in negative N balance whereas, in PIII, four subjects were in positive N balance. On the last day of each period, fasting subjects ingested a dose of nicotinamide (NAM, 102 µmol/kg body wt). Plasma and urine samples were analyzed for methylated derivatives of NAM by high-performance liquid chromatography (HPLC) methods. Mean values of methylated metabolites in urine from the three diet periods (for four subjects in N balance during PIII) were not different (59.8, 56.7, and 59.9 µmol/(kg body wt X 24 h) for PI, PII, and PIII, respectively). Plasma values of these metabolites also were similar. Results suggest that during a 2-wk period of negative N balance due to a low-methionine intake hepatic methylation processes are not impaired. These processes appear to have a higher metabolic priority than maintenance of the net protein synthesis rate. [ABSTRACT FROM AUTHOR]

Insulin resistance is one of important factors causing type 2 diabetes; therefore, regulating insulin sensitivity is considered a beneficial therapeutic approach against type 2 diabetes. The present study aimed to determine the effects of N1-methylnicotinamide (MNAM) on insulin resistance (IR) in skeletal muscle from a mouse model of type 2 diabetes mellitus (T2DM), and to investigate the regulatory mechanisms of the sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) signaling pathway. C57BL/6 mice were fed a normal diet with or without 1% MNAM and ob/ob mice were also fed a normal diet with or without 0.3 or 1% MNAM. Blood glucose, insulin levels, insulin resistance (IR), sensitivity indices and triglyceride (TG) content were detected using ELISAs. The expression of gluconeogenesis-related, insulin signaling-related and SIRT1/PGC-1α pathway-related proteins was analyzed using reverse transcription-quantitative PCR (RT-qPCR) and western blotting. In vitro, C2C12 cells were used to establish an IR muscle cell model by 0.75 mM palmitic acid (PA) treatment (PA group). The IR cell model was subsequently supplemented with 1 mM MNAM (PM group) or 1 mM MNAM + 30 µM SIRT1 inhibitor, EX527 (PME group). After treatment the glucose levels and insulin signaling-related proteins were detected by ELISAs and western blotting, respectively. Furthermore, the expression levels of SIRT1/PGC-1α signaling pathway-related mRNA and proteins under MNAM treatment were detected by RT-qPCR and western blotting. MNAM reduced body weight gain in T2DM mice, decreased fasting blood glucose and fasting insulin levels, and inhibited IR. MNAM also regulated insulin signal transduction and promoted glucose utilization in skeletal muscle, and reduced lipid deposition. Thus, MNAM improved IR in the skeletal muscle of T2DM mice. Following application of a SIRT1 inhibitor, the effects of MNAM on the increased glucose utilization in insulin-resistant myocytes and the insulin signaling pathway were suppressed. The mechanism of action was associated with activation of the SIRT1/PGC-1α signaling pathway, which promoted the activation of the insulin receptor substrate IRS1/PI3K/AKT pathway. [ABSTRACT FROM AUTHOR]

The article presents findings of a research conducted on urinary excretory ratio of nicotinamide catabolites which was associated with the conversion ratio of tryptophan to nicotinamide in growing rats fed a viacin-free 20 percent casein diet. Under the research, nicotinamide and its catabolites were measured. It concludes that there is the possibility that the conversion ratio can be deduced from the excretory ratio.

It is unclear whether niacin nutritional status is a target for improvement of long-term outcome after renal transplantation. The 24-h urinary excretion of N 1 -methylnicotinamide ( N 1 -MN), as a biomarker of niacin status, has previously been shown to be negatively associated with premature mortality in kidney transplant recipients (KTR). However, recent evidence implies higher enzymatic conversion of N 1 -MN to N 1 -methyl-2-pyridone-5-carboxamide (2Py) in KTR, therefore the need exists for interpretation of both N 1 -MN and 2Py excretion for niacin status assessment. We assessed niacin status by means of the 24-h urinary excretion of the sum of N 1 -MN and 2Py ( N 1 -MN + 2Py), and its associations with risk of premature mortality in KTR. N 1 -MN + 2Py excretion was measured in a longitudinal cohort of 660 KTR with LS-MS/MS. Prospective associations of N 1 -MN + 2Py excretion were investigated with Cox regression analyses. Median N 1 -MN + 2Py excretion was 198.3 (155.9-269.4) µmol/day. During follow-up of 5.4 (4.7-6.1) years, 143 KTR died, of whom 40 due to an infectious disease. N 1 -MN + 2Py excretion was negatively associated with risk of all-cause mortality (HR 0.61; 95% CI 0.47-0.79; p < 0.001), and infectious mortality specifically (HR 0.47; 95% CI 0.29-0.75; p = 0.002), independent of potential confounders. Secondary analyses showed effect modification of hs-CRP on the negative prospective association of N 1 -MN + 2Py excretion, and sensitivity analyses showed negative and independent associations of N 1 -MN and 2Py excretion with risk of all-cause mortality separately. These findings add further evidence to niacin status as a target for nutritional strategies for improvement of long-term outcome in KTR.

Background: N 1 -methylnicotinamide (1-NMN) has been proposed as a potential clinical biomarker to assess drug-drug interactions involving organic cation transporters (OCT2) and multidrug and toxin extrusion protein transporters., Results: A hydrophilic interaction liquid chromatography-MS/MS assay, to quantify 1-NMN, in human plasma and urine is reported., Materials & Methods: A hydrophilic interaction chromatography (HILIC)-tandem mass spectrometry (MS/MS) assay to quantify 1-NMN in human plasma and urine is reported. The basal 1-NMN levels in plasma and urine were 4-120 and 2000-15,000 ng/ml, respectively., Conclusion: 1-NMN plasma AUCs increased two- to fourfold versus placebo following the administration of a clinical candidate that in vitro experiments indicated was an OCT2 inhibitor. The described hydrophilic interaction liquid chromatography-MS/MS assay can be used to assess a clinical compound candidate for the inhibition of OCT2 and multidrug and toxin extrusion protein transporter in first-in-human studies.