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微小 RNA-101 通过调控 mTOR 信号通路抑制自噬从而减轻肝缺血/再灌注损伤。

MicroRNA-101 inhibits autophagy to alleviate liver ischemia/reperfusion injury via regulating the mTOR signaling pathway.

机构信息

First Central Clinical College, Tianjin Medical University, Tianjin 300070, P.R. China.

出版信息

Int J Mol Med. 2019 Mar;43(3):1331-1342. doi: 10.3892/ijmm.2019.4077. Epub 2019 Jan 24.

Abstract

Liver ischemia/reperfusion injury (LIRI) is a common complication of liver surgery, and affects liver function post‑transplantation. However, the precise mechanism underlying LIRI has not yet been completely elucidated. Previous studies have demonstrated the involvement of a number of microRNAs (miRNAs/miRs) in liver pathophysiology. The objective of the present study was to determine the potential function and mechanism of miR‑101‑mediated regulation of autophagy in LIRI. Compared with the sham‑treated group, a significant decrease in miR‑101 and mechanistic target of rapamycin (mTOR) expression levels following ischemia/reperfusion (IR) were observed, along with an increased number of autophagosomes (P<0.001). The exogenous overexpression of miR‑101 has been demonstrated to inhibit autophagy during the LIRI response and the levels of mTOR and phosphorylated (p)‑mTOR expression are correspondingly elevated. However, compared with the miR‑NC group, miR‑101 silencing was associated with reduced mTOR and p‑mTOR levels and increased autophagy, as indicated by the gradual increase in the levels of the microtubule‑associated protein 1 light II (LC3II). The peak levels of LC3II were observed 12 h subsequent to reperfusion, which coincided with the lowest levels of miR‑101. In addition, inhibition of autophagy by 3‑methyladenine significant enhanced the protective effect of miR‑101 against LIRI, compared with the IR group (P<0.001). Altogether, miR‑101 attenuates LIRI by inhibiting autophagy via activating the mTOR pathway.

摘要

肝缺血/再灌注损伤(LIRI)是肝外科的常见并发症,会影响肝移植后的肝功能。然而,LIRI 的确切机制尚未完全阐明。先前的研究表明,许多 microRNAs(miRNAs/miRs)参与了肝脏病理生理学过程。本研究旨在确定 miR-101 介导的自噬调控在 LIRI 中的潜在功能和机制。与假手术处理组相比,在缺血/再灌注(IR)后,miR-101 和雷帕霉素靶蛋白(mTOR)表达水平显著下降,同时自噬体数量增加(P<0.001)。外源性过表达 miR-101 可抑制 LIRI 反应中的自噬,同时 mTOR 和磷酸化(p)-mTOR 表达水平相应升高。然而,与 miR-NC 组相比,miR-101 沉默与 mTOR 和 p-mTOR 水平降低以及自噬增加有关,这表明微管相关蛋白 1 轻链 2(LC3II)的水平逐渐升高。LC3II 的峰值水平在再灌注后 12 小时观察到,此时 miR-101 水平最低。此外,与 IR 组相比,3-甲基腺嘌呤抑制自噬显著增强了 miR-101 对 LIRI 的保护作用(P<0.001)。总之,miR-101 通过激活 mTOR 通路抑制自噬来减轻 LIRI。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28ac/6365072/068781f7f6c8/IJMM-43-03-1331-g00.jpg

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