Meroterpenoids from Ganoderma sinense protect hepatocytes and cardiomyocytes from oxidative stress induced injuries

Four meroterpenoids, applanatumols F (1), H (3), I (2), and lingzhiol (4) were isolated from the 95% EtOH extract of the fruiting bodies of Ganoderma sinense. Their structures were established on the basis of NMR spectroscopic analyses, optical rotatory dispersion data, ECD spectra, and X-ray crystallography. Compounds 1, 2, 4 existed as racemic mixtures ((+) 1a, 2a, 4a; (-) 1b, 2b, 4b), while 3 as a single enantiomer. Base on the seperated enantiomers, we sought to explicit possible effects of compounds 1-4 on hydrogen peroxide (H₂O₂)-induced cell death and to determine their underlying molecular mechanisms in human normal liver LO2 cells. Among them, compound 2a treatment effectively protected LO2 cells against H₂O₂-induced cell damage and apoptosis. H₂O₂ exposure increased ROS, which was inhibited by 2a treatment. Mitochondrial membrane potential decrease, nuclear fragments, caspase-3 activation and PARP cleavage were also arrested by 2a. Further, increased levels of Nrf2, HO-1, phosphorylation Akt and up-regulation of antioxidant enzymes were detected in 2a treated cells, indicating that the anti-oxidative effects of 2a might protect LO2 cells against oxidative damage via PI3K/Akt-mediated activation of Nrf2/HO-1 pathway. In addition, compound 2a showed potential protective role of cardiomyocyte from ischemia/reperfusion injury, and pretreatment with 2a could decrease CK and LDH levels and increase GSH level.