Search Results (5)

Dietary vitamin B3 components, such as nicotinamide and nicotinic acid, are precursors to the ubiquitous redox cofactor nicotinamide adenine dinucleotide (NAD⁺). NAD⁺ levels are thought to decline with age and disease. While the drivers of this decline remain under intense investigation, strategies have emerged seeking to functionally maintain NAD⁺ levels through supplementation with NAD⁺ biosynthetic intermediates. These include marketed products, such as nicotinamide riboside (NR) and its phosphorylated form (NMN). More recent developments have shown that NRH (the reduced form of NR) and its phosphorylated form NMNH also increases NAD⁺ levels upon administration, although they initially generate NADH (the reduced form of NAD⁺). Other means to increase the combined levels of NAD⁺ and NADH, NAD(H), include the inhibition of NAD⁺-consuming enzymes or activation of biosynthetic pathways. Multiple studies have shown that supplementation with an NAD(H) precursor changes the profile of NAD(H) catabolism. Yet, the pharmacological significance of NAD(H) catabolites is rarely considered although the distribution and abundance of these catabolites differ depending on the NAD(H) precursor used, the species in which the study is conducted, and the tissues used for the quantification. Significantly, some of these metabolites have emerged as biomarkers in physiological disorders and might not be innocuous. Herein, we review the known and emerging catabolites of the NAD(H) metabolome and highlight their biochemical and physiological function as well as key chemical and biochemical reactions leading to their formation. Furthermore, we emphasize the need for analytical methods that inform on the full NAD(H) metabolome since the relative abundance of NAD(H) catabolites informs how NAD(H) precursors are used, recycled, and eliminated. Full article

Despite the intensive investigation of the molecular mechanism of skeletal muscle hypertrophy, the underlying signaling processes are not completely understood. Therefore, we used an overload model, in which the main synergist muscles (gastrocnemius, soleus) of the plantaris muscle were surgically removed, to cause a significant overload in the remaining plantaris muscle of 8-month-old Wistar male rats. SIRT1-associated pro-anabolic, pro-catabolic molecular signaling pathways, NAD and H₂S levels of this overload-induced hypertrophy were studied. Fourteen days of overload resulted in a significant 43% (p < 0.01) increase in the mass of plantaris muscle compared to sham operated animals. Cystathionine-β-synthase (CBS) activities and bioavailable H₂S levels were not modified by overload. On the other hand, overload-induced hypertrophy of skeletal muscle was associated with increased SIRT1 (p < 0.01), Akt (p < 0.01), mTOR, S6 (p < 0.01) and suppressed sestrin 2 levels (p < 0.01), which are mostly responsible for anabolic signaling. Decreased FOXO1 and SIRT3 signaling (p < 0.01) suggest downregulation of protein breakdown and mitophagy. Decreased levels of NAD⁺, sestrin2, OGG1 (p < 0.01) indicate that the redox milieu of skeletal muscle after 14 days of overloading is reduced. The present investigation revealed novel cellular interactions that regulate anabolic and catabolic processes in the hypertrophy of skeletal muscle. Full article

Anxiety–depressive disorders (ADD) are a risk factor of cardiovascular mortality in patients with coronary artery disease (CAD). Acute coronary syndrome (ACS) is the main clinical manifestation of a progressing CAD. Metabolic processes disorder in platelets can be one of the causes of cardiovascular complications in patients with ACS and concomitant ADD. We studied platelets metabolism and prognostic informativity of NAD(P)-dependent dehydrogenases of platelets in ACS patients with ADD in terms of forecasting cardiovascular complications development over a year of observation. The levels of NAD- and NADP-dependent dehydrogenases of platelets were determined by means of a bioluminescent method during the first 24 h after admission to hospital and in dynamics in 10 days. Among 315 examined patients, ADD was found in 161 (51.1%). ACS patients with concomitant ADD had both cytoplasmic and mitochondrial processes impairment in platelets that consisted in a decrease of energy metabolism intensity, inhibition of anaerobic glycolysis reactions and lipid catabolism. After 12 months of follow-up, 41 (25.5%) cardiovascular complications were detected in the group of ACS patients with ADD and 20 (13.0%) in the group of ACS patients without ADD. According to the results of the analysis of the neural network based on NAD(P)-dependent dehydrogenases of platelets activity in ACS patients with ADD, indicators were obtained that are informative for predicting the development of recurrent cardiovascular complications. Full article

N¹-methylnicotinamide (N¹-MN) and N¹-methyl-2-pyridone-5-carboxamide (2Py) are successive end products of NAD⁺ catabolism. N¹-MN excretion in 24-h urine is the established biomarker of niacin nutritional status, and recently shown to be reduced in renal transplant recipients (RTR). However, it is unclear whether 2Py excretion is increased in this population, and, if so, whether a shift in excretion of N¹-MN to 2Py can be attributed to kidney function. Hence, we assessed the 24-h urinary excretion of 2Py and N¹-MN in RTR and kidney donors before and after kidney donation, and investigated associations of the urinary ratio of 2Py to N¹-MN (2Py/N¹-MN) with kidney function, and independent determinants of urinary 2Py/N¹-MN in RTR. The urinary excretion of 2Py and N¹-MN was measured in a cross-sectional cohort of 660 RTR and 275 healthy kidney donors with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Linear regression analyses were used to investigate associations and determinants of urinary 2Py/N¹-MN. Median 2Py excretion was 178.1 (130.3–242.8) μmol/day in RTR, compared to 155.6 (119.6–217.6) μmol/day in kidney donors (p < 0.001). In kidney donors, urinary 2Py/N¹-MN increased significantly after kidney donation (4.0 ± 1.4 to 5.2 ± 1.5, respectively; p < 0.001). Smoking, alcohol consumption, diabetes, high-density lipoprotein (HDL), high-sensitivity C-reactive protein (hs-CRP) and estimated glomerular filtration rate (eGFR) were identified as independent determinants of urinary 2Py/N¹-MN in RTR. In conclusion, the 24-h urinary excretion of 2Py is higher in RTR than in kidney donors, and urinary 2Py/N¹-MN increases after kidney donation. As our data furthermore reveal strong associations of urinary 2Py/N¹-MN with kidney function, interpretation of both N¹-MN and 2Py excretion may be recommended for assessment of niacin nutritional status in conditions of impaired kidney function. Full article

Glutamate dehydrogenase (GDH) is a hexameric enzyme that catalyzes the reversible conversion of glutamate to α-ketoglutarate and ammonia while reducing NAD(P)⁺ to NAD(P)H. It is found in all living organisms serving both catabolic and anabolic reactions. In mammalian tissues, oxidative deamination of glutamate via GDH generates α-ketoglutarate, which is metabolized by the Krebs cycle, leading to the synthesis of ATP. In addition, the GDH pathway is linked to diverse cellular processes, including ammonia metabolism, acid-base equilibrium, redox homeostasis (via formation of fumarate), lipid biosynthesis (via oxidative generation of citrate), and lactate production. While most mammals possess a single GDH1 protein (hGDH1 in the human) that is highly expressed in the liver, humans and other primates have acquired, via duplication, an hGDH2 isoenzyme with distinct functional properties and tissue expression profile. The novel hGDH2 underwent rapid evolutionary adaptation, acquiring unique properties that enable enhanced enzyme function under conditions inhibitory to its ancestor hGDH1. These are thought to provide a biological advantage to humans with hGDH2 evolution occurring concomitantly with human brain development. hGDH2 is co-expressed with hGDH1 in human brain, kidney, testis and steroidogenic organs, but not in the liver. In human cerebral cortex, hGDH1 and hGDH2 are expressed in astrocytes, the cells responsible for removing and metabolizing transmitter glutamate, and for supplying neurons with glutamine and lactate. In human testis, hGDH2 (but not hGDH1) is densely expressed in the Sertoli cells, known to provide the spermatids with lactate and other nutrients. In steroid producing cells, hGDH1/2 is thought to generate reducing equivalents (NADPH) in the mitochondria for the biosynthesis of steroidal hormones. Lastly, up-regulation of hGDH1/2 expression occurs in cancer, permitting neoplastic cells to utilize glutamine/glutamate for their growth. In addition, deregulation of hGDH1/2 is implicated in the pathogenesis of several human disorders. Full article