Cheng Lei, Zhu Xiaodan, Liu Yang, Zhu Kai, Lin Kang, Li Fujun
Department of Anesthesiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
Ann Transl Med. 2021 Sep;9(18):1454. doi: 10.21037/atm-21-4249.
() has been reported to serve as a major player in the progress of ferroptosis in various diseases. Nevertheless, the functional role and mechanism of in sevoflurane (sev)-induced neuronal death has never been elucidated.
Cell viability was assessed using Cell Counting Kit-8 (CCK-8). Iron levels, reactive oxygen species (ROS) production, and malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), and glutathione (GSH) content were determined to assess ferroptosis level. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blot were undertaken for the measurement of gene expression.
Sev hindered the viability of SH-SY5Y cells and suppression of ferroptosis by ferrostatin-1 (Fer-1) mitigated sev-induced inhibition of SH-SY5Y cell viability. Sev treatment increases the Fe level and decreases the mRNA levels of and in SH-SY5Y cells. Sev increased the expression of . Moreover, silencing of could abrogate sev-induced cell damage, as evidenced by increases in cell viability, GPX4 protein levels, and decreases in iron levels, ROS production, and MDA and 4-HNE content. Remarkably, sev hindered the activation of the 5' AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling, which was diminished by knockdown of . Moreover, inhibition of the AMPK/mTOR signaling by compound C could mitigate the protective effect of silencing against sev-induced ferroptotic cell death.
Downregulation of restrained sev-induced ferroptotic cell death via AMPK/mTOR signaling, providing the basis for an approach to alleviate sev-induced postoperative cognitive dysfunction (POCD).
据报道，（）在多种疾病的铁死亡进程中起主要作用。然而，其在七氟醚（sev）诱导的神经元死亡中的功能作用和机制尚未阐明。
使用细胞计数试剂盒-8（CCK-8）评估细胞活力。测定铁水平、活性氧（ROS）生成量以及丙二醛（MDA）、4-羟基壬烯醛（4-HNE）和谷胱甘肽（GSH）含量，以评估铁死亡水平。采用定量逆转录-聚合酶链反应（qRT-PCR）和蛋白质印迹法检测基因表达。
七氟醚阻碍SH-SY5Y细胞的活力，而铁死亡抑制剂1（Fer-1）抑制铁死亡可减轻七氟醚诱导的SH-SY5Y细胞活力抑制。七氟醚处理可增加SH-SY5Y细胞中的铁水平，并降低（）和（）的mRNA水平。七氟醚增加了（）的表达。此外，沉默（）可消除七氟醚诱导的细胞损伤，表现为细胞活力增加、GPX4蛋白水平升高，以及铁水平、ROS生成量、MDA和4-HNE含量降低。值得注意的是，七氟醚阻碍了5'-AMP激活蛋白激酶（AMPK）/雷帕霉素哺乳动物靶蛋白（mTOR）信号通路的激活，而敲低（）可减弱这种阻碍作用。此外，化合物C抑制AMPK/mTOR信号通路可减轻沉默（）对七氟醚诱导的铁死亡性细胞死亡的保护作用。
（）的下调通过AMPK/mTOR信号通路抑制七氟醚诱导的铁死亡性细胞死亡，为减轻七氟醚诱导的术后认知功能障碍（POCD）提供了一种方法的依据。
