PDF(Pubmed)
Abstract：
Cisplatin-induced acute kidney injury (AKI) increases the patient mortality dramatically and results in an unfavorable prognosis. A strong correlation between AKI and ferroptosis, which is a notable type of programmed cell death, was found in recent studies. Myricitrin is a natural flavonoid compound with diverse pharmacological properties. To investigate the protective effect of myricitrin against cisplatin induced human tubular epithelium (HK-2) cell injury and the underlying anti-ferroptic mechanism by this study. Firstly, a pharmacology network analysis was proposed to explore the myricitrin\'s effect. HK-2 cells were employed for in vitro experiments. Ferroptosis was detected by cell viability, quantification of iron, malondialdehyde, glutathione, lipid peroxidation fluorescence, and glutathione peroxidase (GPX4) expression. Ferritinophagy was detected by related protein expression (NCOA4, FTH, LC3II/I, and SQSTM1). In our study, GO enrichment presented that myricitrin might be effective in eliminating ferroptosis. The phenomenon of ferroptosis regulated by ferritinophagy was observed in cisplatin-activated HK-2 cells. Meanwhile, pretreatment with myricitrin significantly rescued HK-2 cells from cell death, reduced iron overload and lipid peroxidation biomarkers, and improved GPX4 expression. In addition, myricitrin downregulated the expression of LC3II/LC3I and NCOA4 and elevated the expression of FTH and SQTM. Furthermore, myricitrin inhibited ROS production and preserved mitochondrial function with a lower percentage of green JC-1 monomers. However, the protection could be reserved by the inducer of ferritinophagy rapamycin. Mechanically, the Hub genes analysis reveals that AKT and NF-κB are indispensable mediators in the anti-ferroptic process. In conclusion, myricitrin ameliorates cisplatin induced HK-2 cells damage by attenuating ferritinophagy mediated ferroptosis.
摘要：
顺铂诱导的急性肾损伤(AKI)显著增加患者死亡率并导致不良预后。AKI与铁凋亡之间有很强的相关性，这是一种值得注意的程序性细胞死亡，在最近的研究中发现。杨梅苷是一种具有多种药理特性的天然黄酮类化合物。本研究探讨杨梅苷对顺铂诱导的人肾小管上皮细胞（HK-2）损伤的保护作用及其潜在的抗铁作用机制。首先,提出了一个药理学网络分析来探讨杨梅素的作用。HK-2细胞用于体外实验。通过细胞活力检测铁凋亡，铁的定量，丙二醛，谷胱甘肽,脂质过氧化荧光，和谷胱甘肽过氧化物酶（GPX4）的表达。通过相关蛋白表达（NCOA4，FTH，LC3II/I,和SQSTM1）。在我们的研究中,GO富集表明，杨梅苷可能有效消除铁死亡。在顺铂激活的HK-2细胞中观察到铁细胞自噬调节的铁凋亡现象。同时,用杨梅素预处理显着挽救了HK-2细胞的细胞死亡，减少铁过载和脂质过氧化生物标志物，并改善GPX4的表达。此外,杨梅苷下调LC3II/LC3I和NCOA4的表达，并升高FTH和SQTM的表达。此外，肉豆蔻素以较低的绿色JC-1单体百分比抑制ROS的产生并保留线粒体功能。然而,这种保护作用可以通过磷酸铁肽雷帕霉素的诱导剂来保留。机械上,Hub基因分析显示，AKT和NF-κB是抗铁过程中不可或缺的介质。总之,杨梅苷通过减弱铁细胞吞噬介导的铁凋亡来改善顺铂诱导的HK-2细胞损伤。
