Search Results (359)

Sarcopenia, the progressive loss of muscle mass, strength, and regenerative capacity with age, is driven by interconnected processes such as oxidative stress, chronic inflammation, mitochondrial dysfunction, and reduced activity of muscle stem cells. As the population ages, nutritional strategies that target these mechanisms are becoming increasingly important. This review focuses on nicotinamide (vitamin B3) and pyridoxine (vitamin B6), two essential micronutrients found in functional foods, which play complementary roles in redox regulation, immune balance, and muscle repair. Nicotinamide supports nicotinamide adenine dinucleotide (NAD⁺) metabolism, boosts mitochondrial function, and activates sirtuin pathways involved in autophagy and stem cell maintenance. Pyridoxine, via its active form pyridoxal 5′-phosphate (PLP), is key to amino acid metabolism, antioxidant defense, and the regulation of inflammatory cytokines. We summarize how these vitamins influence major molecular pathways such as Sirtuin1 (SIRT1), protein kinase B (AKT)/mechanistic target of rapamycin (mTOR), Nuclear factor-κB (NF-κB), and Nrf2, contributing to improved myogenic differentiation and protection of the aging muscle environment. We also highlight emerging preclinical and clinical data, including studies suggesting possible synergy between B3 and B6. Finally, we discuss how biomarkers such as PLP, nicotinamide mononucleotide (NMN), and C-reactive protein (CRP) may support the development of personalized nutrition strategies using these vitamins. Safe, accessible, and mechanistically grounded, nicotinamide and pyridoxine offer promising tools for sarcopenia prevention and healthy aging. Full article

Precision nutrition is an emerging approach that tailors dietary recommendations based on an individual’s unique genetic, metabolic, microbiome, and lifestyle factors. β-hydroxybutyrate (β-HB) is a key ketone body produced during fat metabolism, especially in states of fasting, low-carbohydrate intake, or prolonged exercise. Therefore, monitoring β-HB levels provides valuable insights into an individual’s metabolic state, making it an essential biomarker for precision and personalized nutrition. A smartphone-connected electrochemical biosensor for single-use, rapid, low-cost, accurate, and selective detection of β-HB in whole blood and saliva at the Point-of-Care (POC) is reported. A graphite screen-printed carbon electrode modified with potassium ferricyanide (Fe(III)GSPE) was used as an electrode platform for the deposition of β-hydroxybutyrate dehydrogenase (HBDH), nicotinamide adenine dinucleotide oxidized form (NAD⁺), and chitosan nanoparticles (ChitNPs). An outer poly(vinyl) chloride (PVC) diffusion-limiting membrane was used to protect the modified electrode. The biosensor showed a linear range in the clinically relevant range, between 0.4 and 8 mM, with a detection limit (LOD) of 0.1 mM. The biosensor was tested on human blood and saliva samples, and the results were compared to those obtained with a commercial ketone meter, showing excellent agreement. Full article

Sterile alpha and Toll/interleukin receptor motif-containing protein 1 (SARM1) is a nicotinamide adenine dinucleotide (NAD⁺) hydrolase involved in axonal degeneration and neuronal cell death. SARM1 plays a pivotal role in triggering the neurodegenerative processes that underlie peripheral neuropathies, traumatic brain injury, and neurodegenerative diseases. Importantly, SARM1 knockdown or knockout prevents the degeneration; as a result, SARM1 has been attracting attention as a potent therapeutic target. In recent years, the development of several SARM1 inhibitors derived from synthetic chemical compounds has been reported; however, no dietary ingredients with SARM1 inhibitory activity have been identified. Therefore, we here focused on dietary ingredients and found that carnosol, an antioxidant contained in rosemary, inhibits the NAD⁺-cleavage activity of SARM1. Purified carnosol inhibited the enzymatic activity of SARM1 and suppressed neurite degeneration and cell death induced by the anti-cancer medicine vincristine (VCR). Carnosol also inhibited VCR-induced hyperalgesia symptoms, suppressed the loss of intra-epidermal nerve fibers in vivo, and reduced the blood fluid level of phosphorylated neurofilament-H caused by an axonal degeneration event. These results indicate that carnosol has a neuroprotective effect via SARM1 inhibition in addition to its previously known antioxidant effect via NF-E2-related factor 2 and thus suppresses neurotoxin-induced peripheral neuropathy. Full article

CD38, a nicotinamide adenine dinucleotide (NAD⁺) glycohydrolase, increases in old murine macrophages after infection compared to young controls. We aimed to determine whether the increase in CD38 in old murine macrophages after infection is directly associated with enhanced inflammation induced by the oral pathogens Aggregatibacter actinomycetemcomitans (Aa) or Porphyromonas gingivalis (Pg) when compared to young controls. Additionally, we determined the effects of a specific CD38 inhibitor (78c) on CD38, NAD⁺, interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α expressions, and anti-oxidative responses in old murine macrophages induced by oral pathogens. Old and young murine macrophages were either uninfected or infected with the oral pathogens Aa or Pg for 1 to 24 h. Protein levels of CD38 and protein kinases, including nuclear factor kappa-B (NF-κB), phosphoinositide 3-kinase (PI3K), and mitogen-activated protein kinases (MAPKs), NAD⁺, and inflammatory cytokine (IL-1β, IL-6, TNF-α) levels were evaluated. Additionally, old murine macrophages were treated with a vehicle or a CD38 inhibitor (78c) and cells were either uninfected or infected with Aa or Pg. CD38, NAD⁺, cytokine (IL-1β, IL-6, TNF-α) levels, reactive oxygen species (ROS), NAPDH oxidase 1 (Nox1), and anti-oxidative enzymes, including superoxide dismutase1 (Sod1), glutathione peroxidase 4 (Gpx4), Peroxiredoxin 1 (Prdx1), thioredoxin reductase 1 (Txnrd1), and catalase (Cat), were evaluated. The results showed that old murine macrophages significantly enhanced CD38 and reduced NAD⁺ levels 24 h after Aa or Pg infection compared to young controls. This enhanced CD38 in old murine macrophages was not directly correlated with the activation of protein kinases (NF-κB, PI3K, and MAPKs), nor the (IL-1β, IL-6, TNF-α) levels in macrophages. The inhibition of CD38 by 78c reduced CD38, enhanced NAD⁺ levels, attenuated IL-1β, IL-6 and TNF-α pro-inflammatory cytokine levels, reduced ROS and Nox1 expressions, and enhanced expressions of Sod1, Gpx4, Prdx1, Txnrd1, and Cat in old murine macrophages infected with Aa or Pg. These results suggest that the inhibition of CD38 by 78c is a promising therapeutic strategy to treat aging-associated periodontitis. Full article

The protein associated with the silencing information regulator 2-associated enzyme1 (SIRT1) is a highly conserved nicotinamide adenine dinucleotide (NAD⁺)-dependent deacetylase and a key member of the sirtuin family. SIRT1 plays an essential role in various cellular physiological processes, primarily localized in the nucleus but also active in the cytoplasm and mitochondria. Recent studies have demonstrated its capacity to delay aging in multiple organs and tissues, although its underlying mechanisms remain incompletely understood. Additionally, SIRT1 exerts a significant influence on metabolic regulation and genetic processes. As the primary source of cellular energy, mitochondria are central to numerous biological functions. Mitochondrial dysfunction has been implicated in the onset and progression of various diseases and is increasingly recognized for its role in aging-related processes. This article investigates the interaction between SIRT1 and mitochondria in regulating reproductive system aging and elucidates their potential mechanisms of action, providing insights for clinical research into reproductive system aging. Full article

Heart failure represents the terminal stage in the development of many cardiovascular diseases, and its pathological mechanisms are closely related to disturbances in energy metabolism and mitochondrial dysfunction in cardiomyocytes. In recent years, nicotinamide adenine dinucleotide (NAD⁺), a core coenzyme involved in cellular energy metabolism and redox homeostasis, has been shown to potentially ameliorate heart failure through the regulation of mitochondrial function. This review systematically investigates four core mechanisms of mitochondrial dysfunction in heart failure: imbalance of mitochondrial dynamics, excessive accumulation of reactive oxygen species (ROS) leading to oxidative stress injury, dysfunction of mitochondrial autophagy, and disturbance of Ca²⁺ homeostasis. These abnormalities collectively exacerbate the progression of heart failure by disrupting ATP production and inducing apoptosis and myocardial fibrosis. NAD⁺ has been shown to regulate mitochondrial biosynthesis and antioxidant defences through the activation of the deacetylase family (e.g., silent information regulator 2 homolog 1 (SIRT1) and SIRT3) and to increase mitochondrial autophagy to remove damaged mitochondria, thus restoring energy metabolism and redox balance in cardiomyocytes. In addition, the inhibition of NAD⁺-degrading enzymes (e.g., poly ADP-ribose polymerase (PARP), cluster of differentiation 38 (CD38), and selective androgen receptor modulators (SARMs)) increases the tissue intracellular NAD⁺ content, and supplementation with NAD⁺ precursors (e.g., β-nicotinamide mononucleotide (NMN), nicotinamide riboside, etc.) also significantly elevates myocardial NAD⁺ levels to ameliorate heart failure. This study provides a theoretical basis for understanding the central role of NAD⁺ in mitochondrial homeostasis and for the development of targeted therapies for heart failure. Full article

We report the synthesis of highly enantiopure perdeuterated poly-L-lactic acid and poly-D-lactic acid polymers with well-defined molecular weight by polymerization of perdeuterated lactides. Enantiopure D- and L-lactic acid-d₄ monomers were synthesized from sodium pyruvate-d₃ using D- and L-lactate dehydrogenase enzymes (D-LDH and L-LDH) as biocatalysts. The reduced form of the co-enzyme nicotinamide adenine dinucleotide-d₁ (NADH-d₁) was generated in situ from the oxidized form nicotinamide adenine dinucleotide (NAD⁺) by formate dehydrogenase (FDH)-catalyzed oxidation of sodium formate-d₁ to carbon dioxide with concerted reduction of NAD⁺ to NADH-d₁. For the conversion of the perdeuterated lactic acid monomers to the corresponding lactide dimers, we developed a process for generating these compounds in the high purity needed for the final anionic ring-opening polymerization step. This method enabled the generation of a range of perdeuterated polylactic acid polymers that are highly suitable for the characterization of polymer structure and dynamics using neutron scattering, infrared and nuclear magnetic resonance spectroscopy methods that are sensitive to deuterium. Furthermore, these deuterium-labeled polymers are well-suited to the study of the biodegradation of PLA-based plastics. Full article

Mechanical stress is known to be a pivotal risk factor in the development of OA. However, the involvement of repetitive compressive loading in mitochondrial dysfunction in chondrocytes remains unclear. The aim of this study was to investigate whether physiologic levels of repetitive mechanical force affect the regulation of energy metabolism and activities of mitochondrial function regulators, sirtuin 1 and nicotinamide adenine dinucleotide (NAD) in chondrocytes, and to clarify any correlation with chondrocyte catabolic activity. Repetitive physiological mechanical stress was applied in a 3D chondrocyte-collagen scaffold construct, and the 3D cultured tissues were collected at different time points by collagenase treatment to collect cellular proteins. Changes in chondrocyte activity (cell proliferation, MMP-13 production), energy metabolism regulator levels (sirtuin 1), mitochondrial function (ATP production, NAD level), and the expression level of the osteogenic and hypertrophic chondrogenic transcription factor, runt-related transcription factor 2 (Runx2), were measured. Treatment with repetitive compressive loading resulted in no significant change in the cell viability of chondrocytes. In the repetitive mechanical loading group, there were statistically significant increases in MMP-13 production and expression of both sirtuin 1 and Runx2 in chondrocytes relative to the non-loading control group. Furthermore, ATP production and NAD activity in mitochondria decreased in the repetitive mechanical loading group. Our present study reveals that in chondrocytes, repetitive compressive loading accelerated sirtuin activation, which requires and consumes NAD within mitochondria, leading to a decrease of NAD and ultimately in reduced mitochondrial ATP production. Additionally, since sirtuin 1 is known to positively regulate Runx2 activity in chondrocytes, the activation of sirtuin 1 by repetitive load stimulation may induce an increase in the expression of Runx2, which promotes the expression of MMP-13, and subsequently enhances MMP-13 production. Our findings indicate that repetitive compression loading-mediated mitochondrial dysfunction plays a pivotal role in the progression of OA, primarily by driving the downregulation of ATP production and promoting the expression of the matrix-degrading enzyme MMP-13. Full article

This study investigated the effects of two nanofertilizers (NFs): copper nanoparticles (NPs) synthesised using cotton (CuC) and chitosan (CuCh) as well as two biofertilizers (BFs), nopal extract (NE) and commercial Biojal^® worm humus (WH), on the growth of black bean seedlings. The treatments consisted of applying 50 mg L⁻¹ of CuC, 50 mg L⁻¹ of CuCh, 50 mg L⁻¹ of NE, 100 mg L⁻¹ of WH, their respective combinations, and an absolute control that consisted of distilled water. The CuC, CuCh, WH, and WH + CuC leaf applications resulted in an increase in plant height by 34.4%, 19.5%, 25.7%, and 20.3%, respectively. Furthermore, the CuC and WH applications led to an increase in the number of leaves by 53.2% and 36.9%, respectively. However, the addition of NE + CuC resulted in a 37.4% decrease in dry weight. A total of 44 metabolites were identified, including 7 sugars, 17 amino acids, 12 organic acids, 4 nucleosides, 1 alcohol, and 3 miscellaneous metabolites. The NE + CuC and WH treatments resulted in a notably higher concentration of various metabolites, including amino acids, organic acids, and sugars. Conversely, the CuCh treatment led to an increased concentration of nucleosides, amino acids, trigonelline, and nicotinamide adenine dinucleotide (NAD⁺). Full article

Background/Objectives: Supplementation with nicotinamide mononucleotide (NMN), a key nicotinamide adenine dinucleotide (NAD⁺) intermediate, exerts anti-aging, anti-obesity, and anti-diabetic effects in animal experiments. However, previous studies have evaluated NMN supplementation using oral administration in drinking water or by intraperitoneal administration. No studies have reported whether NMN exerts beneficial effects when incorporated into the diet. The diet is a multicomponent mixture of many nutrients that may interact with each other, thus weakening the effects of NMN. In the present study, we evaluated whether dietary NMN intake protects obese diabetic db/db mice from obesity-related metabolic disorders, such as dyslipidemia, hepatic steatosis, hyperglycemia, and hyperinsulinemia. Methods: Five-week-old male db/db mice were randomly assigned to two groups and fed for four weeks either a control diet containing 7% corn oil and 0.1% cholesterol (CON group, n = 6) or a diet supplemented with 0.5% NMN (NMN group, n = 5). Results: After 4 weeks of feeding, dietary NMN intake alleviated obesity, hypertriglyceridemia, and hepatic triglyceride accumulation in db/db mice. Respiratory gas analysis indicated that dietary NMN intake significantly enhanced energy expenditure by suppressing carbohydrate oxidation and increasing fat oxidation after 3 weeks of feeding. Additionally, the suppression of the increase in plasma triglyceride (TG) levels by dietary NMN intake was attributable to a reduction in hepatic TG levels through the suppression of fatty acid synthesis and the enhancement of fatty acid β-oxidation in the liver. Furthermore, the improvement in hepatic fatty acid metabolism induced by dietary NMN intake was partially responsible for the significant increase in plasma adiponectin and soluble T-cadherin levels. Conclusions: This is the first report to show that dietary NMN intake but not oral administration in drinking water or intraperitoneal administration alleviates body fat mass and hypertriglyceridemia by enhancing energy expenditure, with preferential promotion of fat oxidation, the enhancement of hepatic lipolysis, and the suppression of hepatic lipogenesis in db/db mice. Full article

Subclinical chronic kidney disease (sCKD) predisposes one to acute kidney injury (AKI) and chronic kidney disease (CKD). Reduced kidney functional reserve (KFR) detects sCKD in preclinical studies and predicts AKI after cardiac surgery. We evaluated renal protection in a rat model of kidney injury where ischaemia–reperfusion injury (IRI) was induced after sCKD. Dual treatment boosting nicotinamide adenine dinucleotide (NAD) by nicotinamide riboside (NR) combined with the mitochondria-targeted antioxidant SkQR1 protected the KFR and reduced structural kidney damage, including markers of vascular integrity and the relative blood volume (rBV). The dual treatment upregulated Sirt1 and Nrf2, increased the nuclear localisation of the mitochondrial biogenesis regulator PGC-1α and the mitochondrial protein marker COX4, and upregulated the antioxidant gene NOQ1. These observations suggest mitochondrial protection and modulation of the cellular redox state provided long-term structural and functional protection against kidney injury superimposed on background sCKD. Full article

Recently published data indicate that elevated circulating concentrations of N1-methyl-2-pyridone-5-carboxamide (2PY, also described as Met2PY) and N1-methyl-4-pyridone-5-carboxamide (4PY, also described as Met4PY), terminal catabolites of nicotinamide adenine dinucleotide (NAD⁺), are associated with cardiovascular disease (CVD) risk in humans. Previously, we and the others have shown that patients with advanced stages of chronic kidney disease (CKD) exhibit several-fold higher circulating 2PY and 4PY concentrations compared to healthy subjects or patients in the early stages of the disease. It is also well documented that patients with advanced CKD stages exhibit markedly elevated CVD risk, which is the main cause of premature death (in these patients). Therefore, we hypothesize that high concentrations of circulating 2PY and 4PY are important factors that may contribute to cardiovascular events and, ultimately, premature death in CKD patients. However, further, accurately controlled clinical research is needed to provide definitive answers concerning the role of 2PY and 4PY in CVD risk in CKD patients. Moreover, we are dealing with some issues related to the use of NAD⁺ precursors (NAD⁺ boosters) as drugs (also in CKD patients) and/or supplements. Due to the increase in circulating 2PY and 4PY levels during treatment with NAD⁺ boosters, these precursors should be used with caution, especially in patients with increased CVD risk. Full article

Background: Sepsis-induced acute lung injury (SALI) is a critical clinical challenge with high mortality. Metabolic dysregulation drives SALI pathogenesis, disrupting lung function and energy metabolism. Despite proven benefits, metabolic restoration is underused in sepsis. This study explores chiglitazar’s role in balancing metabolism to protect against SALI. Methods: The protective effects of chiglitazar in CLP rats were demonstrated by the survival curve, histological analysis, and immunohistochemical analysis in the lung tissue. Metabolomic and lipidomic analyses of lung tissue samples using gas chromatography–mass spectrometry (GC-MS) and liquid chromatography–mass spectrometry (LC-MS) were performed to evaluate metabolic shifts induced by CLP surgery and chiglitazar pretreatment. The mRNA and protein levels of the underlying targets directing nicotinamide adenine dinucleotide (NAD+) and triglyceride synthesis were analyzed by qPCR and Western blotting. To validate the mechanism by which chiglitazar protected against SALI, the SIRT1 inhibitor EX-527 was applied to human normal lung epithelial (BEAS-2B) cells and another batch of rats to observe its reverse effect against chiglitazar’s action. Results: Chiglitazar pretreatment significantly restored NAD+ and improved dysregulated lipid metabolism by enhancing the synthesis of triglycerides (TGs) and suppressing accumulated fatty acids (FAs). The metabolic modulation mediated by chiglitazar was associated with the upregulations of the SIRT1/PGC-1α/PPARα/GPAT3 axis. Co-treatment with EX-527 in LPS-stimulated BEAS-2B cells and CLP rats inhibited the effects of chiglitazar on the aforementioned signaling pathways and worsened the protective effects of chiglitazar on lung injury, respectively. Conclusions: Chiglitazar alleviates SALI by restoring NAD+ and TG synthesis, highlighting the balancing of metabolism as a promising therapeutic strategy in the management of SALI. Full article

Exercise is one of the main challenges to the body’s homeostasis since it needs an immediate, substantial rise in ATP re-synthesis, which leads to the prevention of response capacity and performance of players. Therefore, it is vital to monitor sweat metabolites in soccer players during vigorous exercise to comprehend their functional variations. This flagged the requirement metabonomic approaches for the determination of the distinct metabolic pathways and signature metabolites that are involved in soccer players pre- and post-exercise. In this study, metabolomics and chemometrics approaches were integrated to accelerate and unravel signature-altered metabolites involved pre- and post-exercise. Metabolites profiling revealed a total of 57 signatures and the identified signature altered metabolites belonging to carboxylic acids, ketone, alcohols, aldehydes, aromatics, alkenes, hexoses, hydroxy fatty acids, tetracyclic N-heterocycles, aldopentose, benzenes, alkanes, phenols, and heterocyclic. Niacin is the most downregulated and abundant pre-induced exercise, which can employ its effects through energy metabolism as a precursor for nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). Significant alterations were also specifically observed in the Alanine, aspartate and glutamate, Valine, leucine and isoleucine, Pantothenate and CoA biosynthesis, and Galactose metabolisms following exercise. Full article

Increased acetylation or “hyperacetylation” of mitochondrial (MITO) proteins can lead to abnormalities of the electron transport chain (ETC) and oxidative phosphorylation. In this study we examined the levels of proteins that regulate acetylation. Studies were performed in isolated MITO fractions from left ventricular (LV) myocardium of seven healthy normal (NL) dogs and seven dogs with coronary microembolization-induced heart failure (HF, LV ejection fraction ~35%). Protein levels of drivers of hyperacetylation, namely sirtuin-3 (Sirt-3), a MITO deacetylase, and CD38, a regulator of nicotinamide adenine dinucleotide (NAD⁺), were measured by Western blotting, and the bands were quantified in densitometric units (du). To assess MITO function, MITO components directly influenced by a hyperacetylation state, namely the protein level of cytophillin-D (CyPD), a regulator of MITO permeability transition pore and MITO Complex-I activity, were also measured. Protein level of Sirt-3 and amount of NAD⁺ were decreased in HF compared to NL dogs. Protein levels of CD38 and CyPD were increased in HF compared to NL dogs. Complex-I activity was decreased in HF compared to NL dogs. The results support the existence of a protein hyperacetylation state in mitochondria of failing LV myocardium compared to NL. This abnormality can contribute to MITO dysfunction as evidenced by reduced Complex-I activity and opening of MITO permeability pores. Full article