Wu Zhijun, Li Haijiao, Zhang Yizhe, Ding Chunguang, Zhao Wenjin, Dai Jing, Yu Chengmin, Yao Qunmei, Zheng Fenshuang, Fan Jingguang, Sun Chengye
Chinese Center for Disease Control and Prevention, National Institute for Occupational Health and Poison Control, Beijing, 100050, China.
National Center for Occupational Safety and Health, Beijing, 202300, China.
Arch Toxicol. 2022 Jun;96(6):1751-1766. doi: 10.1007/s00204-022-03278-2. Epub 2022 Apr 6.
Approximately 70-90% of mushroom poisoning deaths are caused by α-amanitin-induced liver injury resulting from RNA polymerase II (RNAP II) inhibition. Liver regeneration ability may contribute greatly to individual survival after α-amanitin poisoning. However, it is unclear what cellular pathways are activated to stimulate regeneration. We conducted dose-effect and time-effect studies in mice that were intraperitoneally injected with 0.33-0.66 mg/kg α-amanitin to establish a poisoning model. The liver/body weight ratio, serological indices, and pathology were evaluated to characterize the liver injury. In the time-effect study, the liver transcriptome was analyzed to explore the mRNA changes resulting from RNAP II inhibition and the underlying pathways associated with recovery. Based on the two animal studies, we established a poisoning model with three sequential liver states: early injury, regulation, and recovery. The mRNA changes reflected by the differentially expressed genes (DEGs) in the transcriptome could be used to illustrate the inhibition of RNAP II by α-amanitin. DEGs at four key time points were well matched with the three liver states, including 8-h downregulated genes in the early injury state, 16-h and 72-h upregulated genes in the regulation state, and 96-h upregulated/downregulated genes in the recovery state. By clustering analysis, the mTOR signaling pathway was screened out as the most promising potential pathway promoting recovery. The results of our investigations of the pathways and events downstream of the mTOR pathway indicated that the activation of mTOR probably contributes crucially to liver regeneration, which could be a promising basis for drug development.
约70-90%的蘑菇中毒死亡是由α-鹅膏毒肽抑制RNA聚合酶II（RNAP II）导致的肝损伤引起的。肝脏再生能力可能对α-鹅膏毒肽中毒后的个体存活有很大贡献。然而，尚不清楚激活了哪些细胞途径来刺激再生。我们对腹腔注射0.33-0.66 mg/kg α-鹅膏毒肽的小鼠进行了剂量效应和时间效应研究，以建立中毒模型。评估肝脏/体重比、血清学指标和病理学特征以表征肝损伤。在时间效应研究中，分析肝脏转录组以探索RNAP II抑制导致的mRNA变化以及与恢复相关的潜在途径。基于这两项动物研究，我们建立了一个具有三个连续肝脏状态的中毒模型：早期损伤、调节和恢复。转录组中差异表达基因（DEG）反映的mRNA变化可用于说明α-鹅膏毒肽对RNAP II的抑制作用。四个关键时间点的DEG与三个肝脏状态高度匹配，包括早期损伤状态下8小时下调的基因、调节状态下16小时和72小时上调的基因以及恢复状态下96小时上调/下调的基因。通过聚类分析，mTOR信号通路被筛选为最有希望促进恢复的潜在途径。我们对mTOR通路下游途径和事件的研究结果表明，mTOR的激活可能对肝脏再生起关键作用，这可能是药物开发的一个有前景的基础。
