1,3,5,8‐Tetrahydroxy‐9H‐xanthen‐9‐one exerts its antiageing effect through the regulation of stress‐response genes and the MAPK signaling pathway

Abstract

The antioxidative effects of 30 xanthone derivatives (XDs) (XD‐n, n\u2009=\u20091–30) in HepG2 cells were evaluated by the cellular antioxidant activity assay. Results showed that all XDs were antioxidants and 1,3,5,8‐tetrahydroxy‐9H‐xanthen‐9‐one (XD‐2) was the most active antioxidant. The all‐oxygenated substituted xanthones extended the lifespan of wild‐type N2 nematodes under normal culture conditions and XD‐2 was the best one. XD‐2 eliminated excessive intracellular reactive oxygen species and enhanced the expression levels and activities of the antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase. XD‐2 inhibited the H2O2‐increased phosphorylation levels of c‐JUN N‐terminal kinase, extracellular signal‐regulated kinase, and p38 in HepG2 cells. In vivo, XD‐2 also extended the lifespan of wild‐type N2 nematodes under oxidative stress induced by paraquat, but failed in extending the lifespan of CF1038 (daf‐16 deletion) and AY102 (pmk‐1 deletion) mutant nematodes. It was revealed by real‐time polymerase chain reaction that the genes daf‐16, sir‐2.1, akt‐1, and age‐1 were all inhibited by paraquat stimuli, while XD‐2 reversed these inhibitions; in contrast, paraquat stimuli upregulated both the skn‐1 and pmk‐1 genes. However, treatment by XD‐2 further increased the levels of both genes. These pieces of evidence implied that XD‐2 promotes longevity through endogenous signaling pathways rather than through the antioxidative activity alone. Taken all together, it may be concluded that XD‐2 is a promising antiageing agent.