Therapeutic application of natural products: NAD+ metabolism as potential target

Background: Nicotinamide adenine dinucleotide (NAD(+)) metabolism is involved in the entire physiopathological process and is critical to human health. Long-term imbalance in NAD(+) homeostasis is associated with various diseases, including non-alcoholic fatty liver disease, diabetes mellitus, cardiovascular diseases, neurodegenerative disorders, aging, and cancer, making it a potential target for effective therapeutic strategies. Currently, several natural products that target NAD(+) metabolism have been widely reported to have significant therapeutic effects, but systematic summaries are lacking. Purpose: To summarize the latest findings on the prevention and treatment of various diseases through the regulation of NAD(+) metabolism by various natural products in vivo and in vitro models, and evaluate the toxicities of the natural products. Methods: PubMed, Web of Science, and ScienceDirect were searched using the keywords "natural products sources," "toxicology," "NAD(+) clinical trials," and "NAD(+)," and/or paired with "natural products" and "diseases" for studies published within the last decade until January 2023. Results: We found that the natural products mainly include phenols (curcumin, cyclocurcumin, 4-hydroxybenzyl alcohol, salvianolic acid B, pterostilbene, EGCG), flavonoids (pinostrobin, apigenin, acacetin, tilianin, kaempferol, quercetin, isoliquiritigenin, luteolin, silybin, hydroxysafflor yellow A, scutellarin), glycosides (salidroside), quinones (emodin, embelin, beta-LAPachone, shikonin), terpenoids (notoginsenoside R1, ginsenoside F2, ginsenoside Rd, ginsenoside Rb1, ginsenoside Rg3, thymoquinone, genipin), pyrazines (tetramethylpyrazine), alkaloids (evodiamine, berberine), and phenylpropanoids (ferulic acid). These natural products have antioxidant, energy-producing, anti-inflammatory, anti-apoptotic and anti-aging effects, which mainly influence the NAMPT/NAD(+)/SIRT, AMPK/SIRT1/PGC-1 alpha, Nrf2/HO-1, PKCs/PARPs/NF-kappa B, and AMPK/Nrf2/mTOR signaling pathways, thereby regulating NAD(+) metabolism to prevent and treat various diseases. These natural products have been shown to be safe, tolerable and have fewer adverse effects in various in vivo and in vitro studies and clinical trials. Conclusion: We evaluated the toxic effects of natural products and summarized the available clinical trials on NAD(+) metabolism, as well as the recent advances in the therapeutic application of natural products targeting NAD(+) metabolism, with the aim to provide new insights into the treatment of multiple disorders.