Correlational assessment of the effects of JM-20 in a rat model of parkinsonism.

We previously demonstrated that JM-20, a molecule with neuroactive functions, protects rats against rotenone and 6-hydroxydopamine (6-OHDA) neurotoxicity. In addition, we demonstrated that JM-20 inhibits the aggregation and cytotoxicity of alpha-synuclein in vitro. In this study, we performed correlation studies between morphological and molecular variables, as well as the motor behavior of parkinsonian rats (6-OHDA and rotenone lesion) treated with JM-20 at different doses (oral with gavage). Our results showed that higher asymmetry evaluated in the cylinder test correlated with greater redox alterations, death of dopaminergic neurons and increased astrogliosis. In the rotenone model, our results showed that a lower number of vertical rearing was correlated with greater redox alterations and increased mitochondrial dysfunction. In both models (6-OHDA and rotenone), parkinsonian animals treated with the highest doses of JM-20 (20 and 40 mg/kg) showed reduced behavioral impairments (lower asymmetry value and higher amount of vertical rearing). Also, a reduced loss of mesencephalic dopaminergic neurons, a smaller number of astrocyte cells in this region, less redox alterations and less mitochondrial dysfunction was observed. In total, our results demonstrate a correlation between behavioral and biochemical variables evaluated in the preclinical models of parkinsonism induced by 6-OHDA and rotenone.

Exploring fermentative metabolic response to varying exogenous supplies of redox cofactor precursors in selected wine yeast species.

The use of non-Saccharomyces yeasts in winemaking is gaining traction due to their specific phenotypes of technological interest, including their unique profile of central carbon metabolites and volatile compounds. However, the lack of knowledge about their physiology hinders their industrial exploitation. The intracellular redox status, involving NAD/NADH and NADP/NADPH cofactors, is a key driver of yeast activity during fermentation, notably directing the formation of metabolites that contribute to the wine bouquet. The biosynthesis of these cofactors can be modulated by the availability of their precursors, nicotinic acid and tryptophan, and their ratio by that of thiamine. In this study, a multifactorial experiment was designed to assess the effects of these three nutrients and their interactions on the metabolic response of various wine yeast species. The data indicated that limiting concentrations of nicotinic acid led to a species-dependent decrease in intracellular NAD(H) concentrations, resulting in variations of fermentation performance and production of metabolic sinks. Thiamine limitation did not directly affect redox cofactor concentrations or balance, but influenced redox management and subsequently the production of metabolites. Overall, this study identified nicotinic acid and thiamine as key factors to consider for species-specific modulation of the metabolic footprint of wine yeasts.

Association of niacin intake and metabolic dysfunction-associated steatotic liver disease: findings from National Health and Nutrition Examination Survey.

AIM: This study aims to explore the relationship between niacin intake and the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) within a large, multi-ethnic cohort. METHODS: A total of 2946 participants from the National Health and Nutrition Examination Survey (NHANES) were carefully selected based on strict inclusion and exclusion criteria. Participants meeting the eligibility criteria underwent two dietary recall interviews, and niacin intake was calculated using the USDA's Food and Nutrient Database for Dietary Studies (FNDDS). Liver steatosis was diagnosed using a Controlled Attenuation Parameter (CAP) of 248 dB/m, and MASLD diagnosis was based on metabolic indicators. Weighted multivariate logistic regression was utilized to analyze the correlation between niacin intake and MASLD prevalence, with potential nonlinear relationships explored through restricted cubic spline (RCS) regression. RESULTS: Analysis of baseline data revealed that MASLD patients had lower niacin intake levels and poorer metabolic biomarker profiles. Both RCS analysis and multivariate logistic regression indicated a U-shaped association between niacin intake and MASLD prevalence. Specifically, there was a non-linear dose-response relationship, with the odds of MASLD gradually decreasing with increasing niacin intake until reaching a threshold of 23.6 mg, beyond which the odds of MASLD began to increase. CONCLUSION: This study confirms a U-shaped nonlinear relationship between niacin intake and MASLD prevalence within the diverse American population.

Nicotinate-Modified Lanthanide-Substituted Selenotungstate and Its Catalase-like Activity for the Detection of H2O2 and Ascorbic Acid.

A rigid nicotinate-modified lanthanide-substituted selenotungstate [H2N(CH3)2]6Na3H[La4SeW8(H2O)16(nica)2O28][SeW9O33]2·32H2O (1, Hnica = nicotinic acid) was synthesized and consists of two trivacant Keggin [B-α-SeW9O33]8- fragments and one unusual [SeW4O18]8- fragment bridged by a heterometallic [La4W4(H2O)16(nica)2O28]18- cluster. In the heterometallic cluster, two carboxyl O atoms in two nicotinate ligands directly coordinate with two W atoms in a stable C-O-W-O-W-O six-membered ring fashion. According to its catalase-like activity, 1 was utilized to catalyze the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) by H2O2 to produce blue oxidized TMB (ox-TMB), which can be used to establish a colorimetric sensing method for the detection of ascorbic acid. This work not only provides a promising platform for detecting H2O2 and ascorbic acid but also expands the application potential of polyoxometalate-based materials in biological and clinical analyses.

Candida tropicalis-derived vitamin B3 exerts protective effects against intestinal inflammation by promoting IL-17A/IL-22-dependent epithelial barrier function.

Candida tropicalis-a prevalent gut commensal fungus in healthy individuals - contributes to intestinal health and disease. However, how commensal C. tropicalis influences intestinal homeostasis and barrier function is poorly understood. Here, we demonstrated that the reference strain of C. tropicalis (MYA-3404) ameliorated intestinal inflammation in murine models of chemically induced colitis and bacterial infection. Intestinal colonization of C. tropicalis robustly upregulated the expression of IL-17A and IL-22 to increase barrier function and promote proliferation of intestinal epithelial cells in the mouse colon. Metabolomics analysis of fecal samples from mice colonized with C. tropicalis revealed alterations in vitamin B3 metabolism, promoting conversion of nicotinamide to nicotinic acid. Although nicotinamide worsened colitis, treatment with nicotinic acid alleviated disease symptoms and enhanced epithelial proliferation and Th17 cell differentiation. Oral gavage of C. tropicalis mitigated nicotinamide-induced intestinal dysfunction in experimental colitis. Blockade of nicotinic acid production with nicotinamidase inhibitors lowered the protective effects against colitis in mice treated with C. tropicalis. Notably, a clinical C. tropicalis strain isolated from patients with candidemia lacked the protective effects against murine colitis observed with the reference strain. Together, our results highlight a novel role for C. tropicalis in resolving intestinal inflammation through the modulation of vitamin B3 metabolism.

• Protection against colitis conferred by intestinal colonization of Candida tropicalis depends on metabolic activity and strain• C. tropicalis MYA-3404 supplementation promotes intestinal epithelial barrier function through IL-17A and IL-22 expressed by Th17 cells, γδ T cells, and ILC3• MYA-3404 strain uses its enzymatic activity to modulate vitamin B3 metabolism for protective benefits.

Niacin intake and mortality (total and cardiovascular disease) in patients with cardiovascular disease: Insights from NHANES 2003-2018.

BACKGROUND: Cardiovascular disease (CVD) poses a significant challenge to global public health. Dietary intervention therapy offers high cost-effectiveness for treating CVD. Currently, there is limited research on the dietary niacin intake and survival of CVD patients. This study aims to examine the association of dietary niacin intake with long-term survival in people with CVD. METHODS: A nationally representative sample of 4,377 diabetes subjects was drawn from the NHANES (National Health and Nutrition Examination Survey) data collected between 2003 and 2018. Dietary niacin intake in this study represents either the average of the two recalls or the value from one recall (if only one recall was available for a participant). Weighted Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% CIs to examine the associations between dietary niacin intake and the risk of all-cause and CVD mortality. RESULTS: After adjustment for multiple covariates, HRs and 95% CIs in model 3 indicated that participants in the highest quartile (Quartile 4) of dietary niacin intake were at lower risk for all-cause mortality (HR = 0.74, 95% CI: 0.60-0.90, P for trend = 0.010) and CVD mortality (HR = 0.67, 95% CI:0.51-0.89, P for trend = 0.020). CONCLUSION: Higher dietary niacin intake may be associated with a reduced risk of all-cause and cardiovascular disease mortality among CVD patients. Additionally, significant interactions were found between dietary niacin intake and BMI as well as vitamin B12 subgroups.

Structural and Functional Characterization of a Novel Class A Flavin Monooxygenase from Bacillus niacini.

A gene cluster responsible for the degradation of nicotinic acid (NA) in Bacillus niacini has recently been identified, and the structures and functions of the resulting enzymes are currently being evaluated to establish pathway intermediates. One of the genes within this cluster encodes a flavin monooxygenase (BnFMO) that is hypothesized to catalyze a hydroxylation reaction. Kinetic analyses of the recombinantly purified BnFMO suggest that this enzyme catalyzes the hydroxylation of 2,6-dihydroxynicotinic acid (2,6-DHNA) or 2,6-dihydroxypyridine (2,6-DHP), which is formed spontaneously by the decarboxylation of 2,6-DHNA. To understand the details of this hydroxylation reaction, we determined the structure of BnFMO using a multimodel approach combining protein X-ray crystallography and cryo-electron microscopy (cryo-EM). A liganded BnFMO cryo-EM structure was obtained in the presence of 2,6-DHP, allowing us to make predictions about potential catalytic residues. The structural data demonstrate that BnFMO is trimeric, which is unusual for Class A flavin monooxygenases. In both the electron density and coulomb potential maps, a region at the trimeric interface was observed that was consistent with and modeled as lipid molecules. High-resolution mass spectral analysis suggests that there is a mixture of phosphatidylethanolamine and phosphatidylglycerol lipids present. Together, these data provide insights into the molecular details of the central hydroxylation reaction unique to the aerobic degradation of NA in Bacillus niacini.

L-shaped association between dietary niacin intake and chronic kidney disease among adults in the USA: a cross-sectional study.

BACKGROUND: Chronic kidney disease (CKD), which has become a global public health issue, is associated with mitochondrial dysfunction. Niacin is a necessary coenzyme for mitochondrial energy metabolism. However, the association between dietary niacin intake and CKD remains uncertain. This study aimed to investigate the association between dietary niacin intake and CKD in American adults. METHODS: This is a cross-sectional study. 25,608 individuals aged ≥20 years from the National Health and Nutrition Examination Survey from 2007 to 2018 were involved.Dietary niacin intake was estimated based on 24-hour dietary recalls conducted by trained personnel. CKD was determined by an estimated glomerular filtration rate (eGFR) (<60 ml/min/1.73 m2) or a urinary albumin-to-creatinine ratio (ACR) (≥30mg/g). The association between dietary niacin intake and CKD was investigated using multivariable logistic regression analysis. RESULTS: Of 25,608 participants, 17.14% (4388/25,608) had CKD. Compared to individuals with lower niacin intake (quartile [Q]1, ≤15.30 mg/day), those with higher niacin intake in Q2 (15.31-22.07 mg/day), Q3 (22.08-31.09 mg/day), and Q4 (≥31.10 mg/day) exhibited adjusted odds ratios for CKD of 0.89 (95% confidence interval [CI]:0.81-0.99, p = 0.024), 0.83 (95% CI:0.75-0 .92, p < 0 .001), and 0.83 (95% CI:0.75-0.93, p = 0.001) respectively. The relationship between dietary niacin intake and CKD among U.S. adults follows an L-shaped pattern, with an inflection point at approximately 28.04 mg/day. CONCLUSIONS: These results suggest an L-shaped association between dietary niacin intake and CKD. Individuals with low dietary niacin intake levels should be alert to the risk of CKD.

3D structure of acetolactate synthase explains why the Asp-376-Glu point mutation does not give the same resistance level to different imidazolinone herbicides.

Resistance to ALS-inhibiting herbicides has dramatically increased worldwide due to the persisting evolution of target site mutations that reduce the affinity between the herbicide and the target. We evaluated the effect of the well-known ALS Asp-376-Glu target site mutation on different imidazolinone herbicides, including imazamox and imazethapyr. Greenhouse dose response experiments indicate that the Amaranthus retroflexus biotype carrying Asp-376-Glu was fully controlled by applying the field recommended dose of imazamox, whereas it displayed high level of resistance to imazethapyr. Likewise, Sorghum halepense, carrying Asp-376-Glu showed resistance to field recommended doses of imazethapyr but not of imazamox. Biochemical inhibition and kinetic characterization of the Asp-376-Glu mutant enzyme heterologously expressed using different plant sequence backbones, indicate that the Asp-376-Glu shows high level of insensitivity to imazethapyr but not to imazamox, corroborating the greenhouse results. Docking simulations revealed that imazamox can still inhibit the Asp-376-Glu mutant enzyme through a chalcogen interaction between the oxygen of the ligand and the sulfur atom of the ALS Met200, while imazethapyr does not create such interaction. These results explain the different sensitivity of the Asp-376-Glu mutation towards imidazolinone herbicides, thus providing novel information that can be exploited for defining stewardship guidelines to manage fields infested by weeds harboring the Asp-376-Glu mutation.

NAD+ and Niacin Supplementation as Possible Treatments for Glaucoma and Age-Related Macular Degeneration: A Narrative Review.

Glaucoma and age-related macular degeneration (AMD) are progressive retinal diseases characterized by increased oxidative stress, inflammation, and mitochondrial dysfunction. This review investigates the potential therapeutic benefits of NAD+ and niacin supplementation in managing glaucoma and AMD. A literature search was conducted encompassing keywords such as "niacin", "NAD", "glaucoma", "AMD", and "therapeutics". NAD+ depletion is associated with increased oxidative stress and mitochondrial dysfunction in glaucoma and AMD. Niacin, a precursor to NAD+, has shown promise in replenishing NAD+ levels, improving choroidal blood flow, and reducing oxidative damage. Animal studies in glaucoma models indicate that nicotinamide (NAM) supplementation preserves RGC density and function. Large-scale population-based studies indicate an inverse correlation between niacin intake and glaucoma prevalence, suggesting a preventative role. Randomized controlled trials assessing niacin supplementation showed significant improvements in visual field sensitivity and inner retinal function, with a dose-dependent relationship. In AMD, nicotinamide supplementation may improve rod cell function and protect against oxidative stress-induced damage. Cross-sectional studies reveal that individuals with AMD have a lower dietary intake of niacin. Further studies suggest niacin's role in improving choroidal blood flow and dilating retinal arterioles, potentially mitigating ischemic damage and oxidative stress in AMD. Beyond current management strategies, NAD+ and niacin supplementation may offer novel therapeutic avenues for glaucoma and AMD. Further research is warranted to elucidate their efficacy and safety in clinical settings.

Niacin produces an inconsistent treatment response in the EAE model of multiple sclerosis.

Niacin was found in the lysolecithin model of multiple sclerosis (MS) to promote the phagocytic clearance of debris and enhance remyelination. Lysolecithin lesions have prominent microglia/macrophages but lack lymphocytes that populate plaques of MS or its experimental autoimmune encephalomyelitis (EAE) model. Thus, the current study assessed the efficacy of niacin in EAE. We found that niacin inconsistently affects EAE clinical score, and largely does not ameliorate neuropathology. In culture, niacin enhances phagocytosis by macrophages, but does not reduce T cell proliferation. We suggest that studies of niacin for potential remyelination in MS should include a therapeutic that targets adaptive immunity.

Association between dietary niacin intake and Helicobacter pylori seropositivity in US adults: A cross-sectional study.

OBJECTIVES: This study delves into the association between dietary niacin intake and Helicobacter pylori seropositivity, a topic gaining prominence in academic discourse. However, the precise role of Niacin in the development and progression of Helicobacter pylori seropositivity remains inadequately understood. Thus, this research aims to investigate the connections between H. pylori seropositivity and dietary niacin intake using a nationally representative sample of adults. METHODS: A cross-sectional analysis encompassed 4,000 participants from the National Health and Nutrition Examination Survey (NHANES) conducted in the United States between 1999 and 2000, all aged 20 years or older. The study employed the generalized additive model (GAM) and multivariate logistic regression to explore the potential relationship between niacin intake and Helicobacter pylori seropositivity. Subgroup analyses were performed based on gender, age, diabetes, hypertension, and hyperlipemia. RESULTS: Analyzing cross-sectional data from NHANES 1999-2000 involving individuals aged 20 years and above revealed that out of 4,000 participants, 1,842 tested positive for H. pylori via serology. Multivariate analyses unveiled a significant inverse correlation between niacin intake and H. pylori seropositivity. Adjusted odds ratios (ORs) for dietary niacin intake in quartiles Q2 (13.31-19.26 mg/d), Q3 (19.27-27.42 mg/d), and Q4 (>27.42 mg/d) compared to Q1 (<13.31 mg/d) were 0.83 (95% CI: 0.69-1.01), 0.74 (95% CI: 0.61-0.90), and 0.66 (95% CI: 0.54-0.81), respectively. Moreover, a nonlinear L-shaped relationship (P = 0.022) emerged between niacin intake and H. pylori seropositivity, indicating minimal risk of H. pylori infection at approximately 44.69 mg of niacin per day in the diet. CONCLUSION: This study suggests a potential link between increased dietary niacin intake and reduced prevalence of Helicobacter pylori seropositivity. This correlation is bolstered by plausible mechanisms involving immunomodulatory function, mitochondrial dysfunction, and cellular oxidative stress.

Association between dietary niacin intake and benign prostatic hyperplasia: a population-based results from NHANES 2003-2008.

PURPOSE: Benign prostatic hyperplasia (BPH) commonly impacts the quality of life in older men. However, there is lack of research on relationship between dietary niacin intake and the risk of BPH. The purpose of this study was to investigate the relationship between dietary niacin intake and the risk of BPH. METHODS: Data from the NHANES spanning 2003 to 2008 were utilized. BPH was determined using a self-report questionnaire, while dietary niacin intake was calculated based on the mean of two distinct diet interviews. Multivariate logistic regressions were performed to explore the association, supplemented with restricted cubic splines and subgroup analysis. RESULTS: A total of 700 males were enrolled, of which 653 men had BPH. After adjusting for all covariates, a high dietary intake of niacin was associated with an increased risk of BPH (OR: 1.04; 95%CI: 1.01-1.07). Furthermore, when the lowest dietary niacin intake is used as the reference, the highest tertile is associated with an increased risk of BPH (OR: 2.34, 95% CI: 1.24-4,42). Restricted cubic splines demonstrated a positive correlation between dietary niacin intake and BPH risk. CONCLUSIONS: The study results demonstrated a positive association between dietary niacin intake and the risk of BPH in elderly men in the US. These findings underscore the importance of systematic assessment before supplementing micronutrients in elderly men.

A Supramolecular Biosensor for Rapid and High-Throughput Quantification of a Disease-Associated Niacin Metabolite.

Metabolic abnormalities play a pivotal role in various pathological conditions, necessitating the quantification of specific metabolites for diagnosis. While mass spectrometry remains the primary method for metabolite measurement, its limited throughput underscores the need for biosensors capable of rapid detection. Previously, we reported that pillar[6]arene with 12 carboxylate groups (P6AC) forms host-guest complexes with 1-methylnicotinamide (1-MNA), which is produced in vivo by nicotinamide N-methyltransferase (NNMT). P6AC acts as a biosensor by measuring the fluorescence quenching caused by photoinduced electron transfer upon 1-MNA binding. However, the low sensitivity of P6AC makes it impractical for detecting 1-MNA in unpurified biological samples. In this study, we found that P6A with 12 sulfonate groups (P6AS) is a specific and potent supramolecular host for 1-MNA interactions even in biological samples. The 1-MNA binding affinity of P6AS in water was found to be (5.68 ± 1.02) × 106 M-1, which is approximately 700-fold higher than that of P6AC. Moreover, the 1-MNA detection limit of P6AS was determined to be 2.84 × 10-7 M, which is substantially lower than that of P6AC. Direct addition of P6AS to culture medium was sufficient to quantify 1-MNA produced by cancer cells. Furthermore, this sensor was able to specifically detect 1-MNA even in unpurified human urine. P6AS therefore enables rapid and high-throughput quantification of 1-MNA, and further improvement of our strategy will contribute to the establishment of high-throughput screening of NNMT inhibitors, diagnosis of liver diseases, and imaging of human cancer cells in vivo.

Urine Metabolites Changes in Acute Myocardial Infarction Rats via Metabolomic Analysis.

OBJECTIVES: To screen biomarkers for forensic identification of acute myocardial infarction (AMI) by non-targeted metabolomic studies on changes of urine metabolites in rats with AMI. METHODS: The rat models of the sham surgery group, AMI group and hyperlipidemia + acute myocardial infarction (HAMI) group were established. Ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) was used to analyze the changes of urine metabolic spectrometry in AMI rats. Principal component analysis, partial least squares-discriminant analysis, and orthogonal partial least squares-discriminant analysis were used to screen differential metabolites. The MetaboAnalyst database was used to analyze the metabolic pathway enrichment and access the predictive ability of differential metabolites. RESULTS: A total of 40 and 61 differential metabolites associated with AMI and HAMI were screened, respectively. Among them, 22 metabolites were common in both rat models. These small metabolites were mainly concentrated in the niacin and nicotinamide metabolic pathways. Within the 95% confidence interval, the area under the curve (AUC) values of receiver operator characteristic curve for N8-acetylspermidine, 3-methylhistamine, and thymine were greater than 0.95. CONCLUSIONS: N8-acetylspermidine, 3-methylhistamine, and thymine can be used as potential biomarkers for AMI diagnosis, and abnormal metabolism in niacin and nicotinamide may be the main causes of AMI. This study can provide reference for the mechanism and causes of AMI identification.

Evaluation of NAD+ precursors for improved metabolism and productivity of antibody-producing CHO cell.

In the previous study, the culture medium was treated with nicotinamide adenine dinucleotide (NAD+) under the hypothesis that NAD+ regeneration is a major factor causing excessive lactate accumulation in Chinese hamster ovary (CHO) cells. The NAD+ treatment improved metabolism by not only reducing the Warburg effect but also enhancing oxidative phosphorylation, leading to enhanced antibody production. Building on this, four NAD+ precursors - nicotinamide mononucleotide (NMN), nicotinic acid (NA), nicotinamide riboside (NR), and nicotinamide (NAM) - were tested to elevate intracellular NAD+ levels more economically. First, the ability of CHO cells to utilize both the salvage and Preiss-Handler pathways for NAD+ biosynthesis was verified, and then the effect of NAD+ precursors on CHO cell cultures was evaluated. These precursors increased intracellular NAD+ levels by up to 70.6% compared to the non-treated group. Culture analysis confirmed that all the precursors induced metabolic changes and that NMN, NA, and NR improved productivity akin to NAD+ treatment, with comparable integral viable cell density. Despite the positive effects such as the increase in the specific productivity and changes in cellular glucose metabolism, none of the precursors surpassed direct NAD+ treatment in antibody titer, presumably due to the reduction in nucleoside availability, as evidenced by the decrease in ATP levels in the NAD+ precursor-treated groups. These results underscore the complexity of cellular metabolism as well as the necessity for further investigation to optimize NAD+ precursor treatment strategies, potentially with the supplementation of nucleoside precursors. Our findings suggest a feasible approach for improving CHO cell culture performances by using NAD+ precursors as medium and feed components for the biopharmaceutical production.

Dietary niacin Intake and its association with all-cause and cardiovascular mortality rates in individuals with metabolic syndrome.

BACKGROUND: Individuals with metabolic syndrome face elevated cardiovascular and mortality risks, and there is ongoing debate regarding the cardiovascular effects of niacin and its impact on the prognosis of metabolic syndrome. EXPOSURE: Levels of dietary niacin intake based on 24-hour dietary recall. METHODS: Kaplan-Meier survival curves were used to compare survival status among quartiles of dietary niacin intake. Weighted Cox proportional hazards models and restricted cubic splines were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of all-cause and CVD mortality associated with the exposure. RESULTS: This cohort study included 8,744 participants, and during a median follow-up period of 106 months, 1,552 (17.7%) deaths were recorded, with 511 attributed to cardiovascular disease. Kaplan-Meier curves comparing quartiles of dietary niacin intake showed significant differences in both all-cause and cardiovascular mortality rates (log-rank p < 0.001). In the fully adjusted model, the highest quartile of dietary niacin intake was associated with HRs of 0.68 (95% CI: 0.54, 0.87, P = 0.002) for all-cause mortality and 0.63 (95% CI: 0.39, 0.78, P < 0.001) for cardiovascular mortality. CONCLUSION: The results of this cohort study suggest that higher dietary niacin intake is associated with reduced cardiovascular and all-cause mortality risks in the metabolic syndrome population. Furthermore, there appears to be a dose-response relationship between dietary niacin intake and the risks of all-cause and cardiovascular mortality.

Niacin supplementation in a child with novel MTTN variant m.5670A>G causing early onset mitochondrial myopathy and NAD+ deficiency.

Myopathy is a common manifestation in mitochondrial disorders, but the pathomechanisms are still insufficiently studied in children. Here, we report a severe, progressive mitochondrial myopathy in a four-year-old child, who died at eight years. He developed progressive loss of muscle strength with nocturnal hypoventilation and dilated cardiomyopathy. Skeletal muscle showed ragged red fibers and severe combined respiratory chain deficiency. Mitochondrial DNA sequencing revealed a novel m.5670A>G mutation in mitochondrial tRNAAsn (MTTN) with 88 % heteroplasmy in muscle. The proband also had systemic NAD+ deficiency but rescuing this with the NAD+ precursor niacin did not stop disease progression. Targeted metabolomics revealed an overall shift of metabolism towards controls after niacin supplementation, with normalized tryptophan metabolites and lipid-metabolic markers, but most amino acids did not respond to niacin therapy. To conclude, we report a new MTTN mutation, secondary NAD+ deficiency in childhood-onset mitochondrial myopathy with metabolic but meager clinical response to niacin supplementation.

Preventing loss of sirt1 lowers mitochondrial oxidative stress and preserves C2C12 myotube diameter in an in vitro model of cancer cachexia.

Cancer cachexia is a multifactorial syndrome associated with advanced cancer that contributes to mortality. Cachexia is characterized by loss of body weight and muscle atrophy. Increased skeletal muscle mitochondrial reactive oxygen species (ROS) is a contributing factor to loss of muscle mass in cachectic patients. Mice inoculated with Lewis lung carcinoma (LLC) cells lose weight, muscle mass, and have lower muscle sirtuin-1 (sirt1) expression. Nicotinic acid (NA) is a precursor to nicotinamide dinucleotide (NAD+) which is exhausted in cachectic muscle and is a direct activator of sirt1. Mice lost body and muscle weight and exhibited reduced skeletal muscle sirt1 expression after inoculation with LLC cells. C2C12 myotubes treated with LLC-conditioned media (LCM) had lower myotube diameter. We treated C2C12 myotubes with LCM for 24 h with or without NA for 24 h. C2C12 myotubes treated with NA maintained myotube diameter, sirt1 expression, and had lower mitochondrial superoxide. We then used a sirt1-specific small molecule activator SRT1720 to increase sirt1 activity. C2C12 myotubes treated with SRT1720 maintained myotube diameter, prevented loss of sirt1 expression, and attenuated mitochondrial superoxide production. Our data provides evidence that NA may be beneficial in combating cancer cachexia by maintaining sirt1 expression and decreasing mitochondrial superoxide production.