MicroRNA-146b-5p overexpression attenuates premature ovarian failure in mice by inhibiting the Dab2ip/Ask1/p38-Mapk pathway and γH2A.X phosphorylation

被引：45

作者：

Liu, Te ^{[1
,2
]}

Lin, Jiajia ^{[1
]}

Chen, Chuan ^{[1
]}

Nie, Xiaoli ^{[1
]}

Dou, Fangfang ^{[1
]}

Chen, Jiulin ^{[1
]}

Wang, Zhenxin ^{[3
,4
]}

Gong, Zhangbin ^{[5
]}

机构：

[1] Shanghai Univ Tradit Chinese Med, Shanghai Geriatr Inst Chinese Med, Shanghai, Peoples R China

[2] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA

[3] Fudan Univ, Zhongshan Hosp, Dept Lab Med, Shanghai, Peoples R China

[4] Fudan Univ, Inst Biomed Sci, Shanghai, Peoples R China

[5] Shanghai Univ Tradit Chinese Med, Coll Basic Med, Dept Biochem, Shanghai 201203, Peoples R China

来源：

CELL PROLIFERATION | 2021年 / 54卷 / 01期

基金：

中国国家自然科学基金;

关键词：

GRANULOSA-CELLS; NANOPARTICLES; ASK1; APOPTOSIS; FRUCTOSE; SURVIVAL; DELIVERY; TARGETS; GROWTH; MODEL;

D O I：

10.1111/cpr.12954

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Objective: To examine the role of high-fat and high-sugar (HFHS) diet-induced oxidative stress, which is a risk factor for various diseases, in premature ovarian failure (POF). Materials and methods: Ovarian granulosa cells (OGCs) were isolated from mice and cultured in medium supplemented with HFHS and poly (lactic-co-glycolic acid) (PLGA)-cross-linked miR-146b-5p nanoparticles (miR-146@PLGA). RNA and protein expression levels were examined using quantitative real-time polymerase chain reaction and Western blotting, respectively. HFHS diet-induced POF model mice were administered miR-146@PLGA. Results: The ovarian tissue of mice fed a HFHS diet exhibited the typical pathological characteristics of POF. HFHS supplementation induced oxidative stress injury in the mouse OGCs, activation of the Dab2ip/Ask1/p38-Mapk signalling pathway and phosphorylation of gamma H2A.X in vitro and in vivo. The results of the luciferase reporter assay revealed that miR-146 specifically downregulated p38-Mapk14 expression. Meanwhile, co-immunoprecipitation and Western blot analyses revealed that HFHS supplementation upregulated nuclear p38-Mapk14 expression and consequently enhanced gamma H2A.X (Ser139) phosphorylation. The HFHS diet-induced POF mouse model treated with miR-146@PLGA exhibited downregulated p38-Mapk14 expression in the OGCs, mitigated OGC ageing and alleviated the symptoms of POF. Conclusions: This study demonstrated that HFHS supplementation activates the Dab2ip/Ask1/p38-Mapk signalling pathway and promotes gamma H2A.X phosphorylation by inhibiting the expression of endogenous miR-146b-5p, which results in OGC ageing and POF development.

引用

页数：14