Aerobic cellular respiration provides chemical energy, adenosine triphosphate (ATP), to maintain multiple cellular functions. Sirtuin 1 (SIRT1) can deacetylate peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) to promote mitochondrial biosynthesis. Targeting energy metabolism is a potential strategy for the prevention and treatment of various diseases, such as cardiac and neurological disorders. Ginsenosides, one of the major bioactive constituents of Panax ginseng, have been extensively used due to their diverse beneficial effects on healthy subjects and patients with different diseases. However, the underlying molecular mechanisms of total ginsenosides (GS) on energy metabolism remain unclear. In this study, oxygen consumption rate, ATP production, mitochondrial biosynthesis, glucose metabolism, and SIRT1-PGC-1α pathways in untreated and GS-treated different cells, fly, and mouse models were investigated. GS pretreatment enhanced mitochondrial respiration capacity and ATP production in aerobic respiration-dominated cardiomyocytes and neurons, and promoted tricarboxylic acid metabolism in cardiomyocytes. Moreover, GS clearly enhanced NAD+-dependent SIRT1 activation to increase mitochondrial biosynthesis in cardiomyocytes and neurons, which was completely abrogated by nicotinamide. In addition, GS had protective effects against hypoxia- or oxygen-glucose deprivation-induced cardiomyocyte damage through activation of the SIRT1-PGC-1α pathway. Importantly, ginsenoside monomers, such as Rg1, Re, Rf, Rb1, Rc, Rh1, Rb2, and Rb3, were found to activate SIRT1 and promote energy metabolism. This study may provide new insights into the extensive application of ginseng for cardiac and neurological protection in healthy subjects and patients with ischemic disorders.

Background and Purpose: Humans have been fighting vitiligo for centuries but still being inferior due to the lack of efficiency drugs and therapies. While some research has implied the therapeutic potential of Wnt/β-catenin signalling on curing vitiligo but correlation mechanism is not clear and no Wnt-specific anti-vitiligo drug has been reported. Here, We identified how vitiligo could be treated by regulating Wnt and two lead compounds of new anti-vitiligo drugs have been found. Experimental Approach: Wnt agonists were rational synthesized and then be evaluated their effects on vitiligo in B16 cells and C57B/L mouse. Furthermore, Co-IP and Site-directed mutagenesis were employed to indicate the mechanism and the target of the compounds. Key Results: HCJA121 and HCJA404 could significantly promote the synthesis of melanin, restore the pigmented function of skin, and improve the symptoms of vitiligo. Mechanism studies indicated that HCJA121 and HCJA404 target the DAX domain of Axin by binding to LYS781 and LEU784 then potentiate the Axin-LRP6 association and eventually promoted melanogenesis. Conclusions and Implications: These findings imply an alternative regulatory mechanism of melanogenesis and the Axin protein could be a new target for anti-vitiligo agents which reveal a therapeutic strategy for vitiligo. Besides, HCJA121 and HCJA404 may represent potential compounds for vitiligo treatment.