NAD+

NAD+ is a coenzyme that transfers hydrogen ions and participates in many enzymatic reactions. It is composed of ribosyl nicotinamide 5'-diphosphate coupled to 5'-adenosine phosphate through a pyrophosphate bond^[1]. NAD⁺ is the oxidized form of nicotinamide adenine dinucleotide (NAD), and the reduced form of NAD is NADH. The intracellular NAD⁺/NADH reflects the metabolic activity and health of the cell^[2]. NAD⁺ is a key redox carrier that plays an irreplaceable role in glycolysis, gluconeogenesis, tricarboxylic acid cycle and respiratory chain^[3]. NAD⁺ is also a substrate of the nuclear enzyme poly (ADP-ribose) polymerase-1 (PARP-1)^[4].

In vitro, NAD⁺ (100µM) treatment of naive CD4⁺ T cells for 72h induced naive CD4⁺ T cells to produce a large amount of cytokines, promoted cell differentiation into helper T cells (Th1, Th2 and Th17 cells), but prevented differentiated cells from producing cytokines^[5].

In vivo, intravenous administration of NAD⁺ (10, 60 mg/kg) to ART2^−/− and wild-type (WT) mice reduced the inhibitory effect of CD4⁺ CD25⁺ FoxP3⁺ regulatory T cells (T reg cells) in WT mice in a dose-dependent manner, but had no effect on the T reg cell function in ART2^−/− mice. It also regulated the size and phenotype of the T reg cell pool in vivo^[6]. Intravenous administration of NAD⁺ (10-20 mg/kg) to rats subjected to ischemia/reperfusion (I/R) dose-dependently reduced I/R-induced myocardial infarction, reduced the levels of TUNNEL signaling, Box and cleaved caspase-3, and increased Bcl-XL levels^[7].

References:
[1] Pietrowska-Borek M, Dobrogojski J, Sobieszczuk-Nowicka E, et al. New insight into plant signaling: extracellular ATP and uncommon nucleotides[J]. Cells, 2020, 9(2): 345.
[2] Belenky P, Bogan K L, Brenner C. NAD⁺ metabolism in health and disease[J]. Trends in biochemical sciences, 2007, 32(1): 12-19.
[3] Guo C, Huang Q, Wang Y, et al. Therapeutic application of natural products: NAD⁺ metabolism as potential target[J]. Phytomedicine, 2023, 114: 154768.
[4] Alano C C, Tran A, Tao R, et al. Differences among cell types in NAD⁺ compartmentalization: a comparison of neurons, astrocytes, and cardiac myocytes[J]. Journal of neuroscience research, 2007, 85(15): 3378-3385.
[5] Tullius S G, Biefer H R C, Li S, et al. NAD⁺ protects against EAE by regulating CD4⁺ T-cell differentiation[J]. Nature communications, 2014, 5(1): 5101.
[6] Hubert S, Rissiek B, Klages K, et al. Extracellular NAD⁺ shapes the Foxp3⁺ regulatory T cell compartment through the ART2–P2X7 pathway[J]. Journal of Experimental Medicine, 2010, 207(12): 2561-2568.
[7] Zhang Y, Wang B, Fu X, et al. Exogenous NAD⁺ administration significantly protects against myocardial ischemia/reperfusion injury in rat model[J]. American journal of translational research, 2016, 8(8): 3342.