Phytomedicine : international journal of phytotherapy and phytopharmacology · 2025
Toosendanin-induced liver damage through irreparable DNA damage and autophagy flow blockade.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
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Lin Yifan, Zhang Jian, Gao Xinyue, Wu Zekai, Yang Lele, Tian Kun, Lv Xiaoqi, Li Jiaqi, Chen Kunqi, Zhang Youbo, Hu Hong, Zhu An
Аннотация
OBJECTIVE: The fruit of Melia toosendan Sieb. et Zucc. (MT) is known for its efficacy in relieving pain and treating roundworms. Toosendanin (TO) has been identified as a bioactive marker of MT, with hepatotoxic properties. This study offers a comprehensive investigation into the toxic mechanisms, involving TO-induced remaining DNA damage, cell cycle arrest, and the synergistic effect of autophagy flow disruption. It provides new insights into the clinical applications of MT and TO.
METHODS: TO was prepared at 50, 100, and 200 μM for a 48 h treatment of HepG2 cells, while zebrafish were administered at 50, 75, and 100 μM for 72 h. Transcriptomics and computational molecular simulations, including network pharmacology, molecular docking, and molecular dynamics simulation, were used for target prediction. Fluorescent probes, flow cytometry, quantitative real-time polymerase chain reaction, and western blotting were employed for mechanism verification.
RESULTS: TO disrupted the balance between reactive oxygen species and cellular antioxidant defense, resulting in mitochondrial damage and repression of DNA-dependent protein kinase catalytic subunit. This led to the inability to repair DNA damage and caused cell cycle arrest in the G1/S phase. As shown in computational molecular simulations and transcriptomics analysis, the repression of damaged organelle removal through autophagy flow disruption resulted in excessive injury and hepatocyte death.
CONCLUSION: By impairing DNA damage responses (DDRs) and autophagy, TO causes unrepaired DNA damage, which disrupts cell cycle progression through complex interactions with cyclin proteins and tumour suppressor genes, ultimately contributing to hepatotoxicity.
METHODS: TO was prepared at 50, 100, and 200 μM for a 48 h treatment of HepG2 cells, while zebrafish were administered at 50, 75, and 100 μM for 72 h. Transcriptomics and computational molecular simulations, including network pharmacology, molecular docking, and molecular dynamics simulation, were used for target prediction. Fluorescent probes, flow cytometry, quantitative real-time polymerase chain reaction, and western blotting were employed for mechanism verification.
RESULTS: TO disrupted the balance between reactive oxygen species and cellular antioxidant defense, resulting in mitochondrial damage and repression of DNA-dependent protein kinase catalytic subunit. This led to the inability to repair DNA damage and caused cell cycle arrest in the G1/S phase. As shown in computational molecular simulations and transcriptomics analysis, the repression of damaged organelle removal through autophagy flow disruption resulted in excessive injury and hepatocyte death.
CONCLUSION: By impairing DNA damage responses (DDRs) and autophagy, TO causes unrepaired DNA damage, which disrupts cell cycle progression through complex interactions with cyclin proteins and tumour suppressor genes, ultimately contributing to hepatotoxicity.