MicroRNA-146b-5p overexpression attenuates premature ovarian failure in mice by inhibiting the Dab2ip/Ask1/p38-Mapk pathway and γH2A.X phosphorylation.
MicroRNA-146b-5p overexpression attenuates premature ovarian failure in mice by inhibiting the Dab2ip/Ask1/p38-Mapk pathway and γH2A.X phosphorylation.
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MicroRNA-146b-5p过表达通过抑制Dab2ip/Ask1/p38-MAPK通路和γH_2A.X磷酸化来减轻小鼠卵巢早衰。
DOI：
10.1111/cpr.12954
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发表时间：
2021-01
影响因子：
8.5
通讯作者：
Gong Z
中科院分区：
文献类型：
--
作者：
Liu T;Lin J;Chen C;Nie X;Dou F;Chen J;Wang Z;Gong Z
研究高脂高糖（HFHS）饮食诱导的氧化应激在卵巢早衰（POF）中的作用，氧化应激是各种疾病的危险因素。从小鼠中分离卵巢颗粒细胞（OGC），并在补充有HFHS和聚（乳酸-共-乙醇酸）（PLGA）-交联的miR-146 b-5 p纳米颗粒（miR-146@PLGA）的培养基中培养。分别使用定量真实的时间聚合酶链反应和蛋白质印迹法检查RNA和蛋白质表达水平。对HFHS饮食诱导的POF模型小鼠施用miR-146@PLGA。HFHS饲料喂养的小鼠卵巢组织表现出典型的POF病理特征。HFHS补充在体外和体内诱导小鼠OGC中的氧化应激损伤、Dab 2 ip/Ask 1/p38‐Mapk信号通路的激活和γH2A.X的磷酸化。荧光素酶报告基因检测结果显示，miR-146特异性下调p38-Mapk 14表达。同时，免疫共沉淀和Western blot分析显示，HFHS补充上调核p38-Mapk 14表达，从而增强γH2A.X（Ser 139）磷酸化。经miR-146@PLGA处理的HFHS饮食诱导的POF小鼠模型显示OGC中p38-Mapk 14表达下调，减轻OGC衰老并缓解POF症状。该研究表明，HFHS补充剂通过抑制内源性miR-146 b-5 p的表达激活Dab 2 ip/Ask 1/p38-Mapk信号通路并促进γH2A.X磷酸化，从而导致OGC老化和POF发展。研究高脂高糖（HFHS）饮食诱导的氧化应激在卵巢早衰（POF）中的作用，氧化应激是各种疾病的危险因素。从小鼠中分离卵巢颗粒细胞（OGC），并在补充有HFHS和聚（乳酸-共-乙醇酸）（PLGA）-交联的miR-146纳米颗粒（miR-146@PLGA）的培养基中培养。分别使用定量真实的时间聚合酶链反应和蛋白质印迹法检查RNA和蛋白质表达水平。对HFHS饮食诱导的POF模型小鼠施用miR-146@PLGA。HFHS饲料喂养的小鼠卵巢组织表现出典型的POF病理特征。HFHS补充在体外和体内诱导小鼠OGC中的氧化应激损伤、Dab 2 ip/Ask 1/p38‐Mapk信号通路的激活和γH2A.X的磷酸化。荧光素酶报告基因检测结果显示，miR-146特异性下调p38-Mapk 14表达。同时，免疫共沉淀和Western blot分析显示，HFHS补充上调核p38-Mapk 14表达，从而增强γH2A.X（Ser 139）磷酸化。经miR-146@PLGA处理的HFHS饮食诱导的POF小鼠模型显示OGC中p38-Mapk 14表达下调，减轻OGC衰老并缓解POF症状。这项研究表明，HFHS补充剂激活Dab 2 ip/Ask 1/p38-Mapk信号通路，并通过抑制内源性miR-146的表达促进γ H2 A. X磷酸化，从而导致OGC老化和POF发展。
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). 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. 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 γH2A.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 γH2A.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. This study demonstrated that HFHS supplementation activates the Dab2ip/Ask1/p38‐Mapk signalling pathway and promotes γH2A.X phosphorylation by inhibiting the expression of endogenous miR‐146b‐5p, which results in OGC ageing and POF development. 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). 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‐146 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. 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 γH2A.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 γH2A.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 aging and alleviated the symptoms of POF. This study demonstrated that HFHS supplementation activates the Dab2ip/Ask1/p38‐Mapk signalling pathway and promotes γH2A.X phosphorylation by inhibiting the expression of endogenous miR‐146, which results in OGC aging and POF development.
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影响因子：
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