Background: Cisplatin's therapeutic potential was limited by its dose-dependent and irreversible sensorineural hearing loss. To date, there were no effective interventions available for cisplatin-induced hearing loss. This study aims to explore traditional Chinese herbal medicines that can alleviate the ototoxicity caused by cisplatin.Methods: We first established a cisplatin-induced injury model in HEI-OC1 cells and intervened with Sulforaphane, Thymol, and Magnolol under both pre-treatment and post-treatment respectively. By comparing their protective effects, we identified Magnolol as the optimal candidate compound. On this basis, we comprehensively utilized multiple databases to predict the potential target of Magnolol, with a focus on PPAR-γ, and further verified the mechanism of related signaling pathways in vitro and in vivo experiments.Results: Whether in the pre-treatment or post-treatment process, Magnolol could significantly increase the survival rate of HEI-OC1 cells, with the pre-treatment strategy exhibiting more prominent advantages in enhancing cell viability. After Magnolol pre-treatment, the SOD level in the cells significantly increased, while the GSSG/GSH ratio and the contents of TNF-α and IL-1β decreased significantly. Among them, the content of TNF-α basically restored to the level of the control group. Further mechanistic investigation revealed that Magnolol, as a preferential agonist of PPAR-γ, effectively reversed the cisplatin-induced suppression of PPAR-γ expression, suggesting that PPAR-γ may be the key molecular target for Magnolol to exert its anti-cisplatin ototoxicity effect.Conclusions: The Magnolol may target PPAR-γ to modulate oxidative stress, thereby delaying the ototoxicity caused by cisplatin.
Icaritin (ICT), a clinically approved natural anti-liver cancer agent, exhibits pharmacological limitations. To enhance its activity, glycosylation was performed at the 3-OH and 7-OH positions using five monosaccharides, and a total of 31 ICT O-glycosylated derivatives were synthesized in a stereoselective manner. In vitro evaluation showed that most glycosides markedly inhibited the proliferation of Hep3B and HepG2 cells. Structure-activity relationship (SAR) analysis indicated that acetylation of the glycosyl moiety could enhance the inhibitory activity. The 3-O-glycosides demonstrated stronger inhibition of Hep3B cells than the 7-O-glycosides, whereas the opposite trend was observed in HepG2 and Huh7 cells, while the doubly substituted 3,7-O-glycosides exhibited consistently weaker activity in three cell lines. Notably, the 7-O-acetyl galactoside 2b (Hep3B: IC50 = 0.18 μM; HepG2: IC50 = 2.60 μM; Huh7: IC50 = 6.66 μM) exhibited superior anti-liver cancer activity across three cell lines compared with ICT and sorafenib (SOR). Further studies demonstrated that 2b induced G0/G1 phase arrest and enhanced oxidative stress in HepG2 cells. Initial mechanistic studies indicated that 2b was able to bind to Ataxia telangiectasia and Rad3-related protein (ATR) in HepG2 cells, inhibit the ATR/Chk1 signaling axis, and induce DNA damage. In zebrafish HepG2 xenografts, 2b displayed exhibited preferential cytotoxicity toward tumor cells and produced a dose-dependent suppression of tumor growth, further confirming its superior in vivo efficacy. These results demonstrate the potential of ICT glycosylated derivatives as lead anti-liver cancer compounds.
