Abstract
ObjectiveTo 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 methodsOvarian 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.ResultsThe 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.ConclusionsThis 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.
Highlights
Premature ovarian failure (POF) is characterized by amenorrhoea, low oestrogen, high gonadotropin and a lack of mature follicles in females aged below 40 years and leads to infertility.[1,2,3,4] The pathogenesis of POF is closely associated with the health and quality of ovarian granulosa cells (OGCs).[1,5,6] Ageing and apoptosis of the OGCs contribute to a decline in ovarian reserve function.[5,6] Previously, we demonstrated that oxidative stress-induced injury adversely affects OGC health.[1]
We found that high fat diet could induce development of mouse atherosclerosis by promoting the expression of the DAB2 interaction protein (DAB2IP)/apoptosis signal-regulating kinase 1 (ASK1) pathway in vascular endothelial cells
Compared with the phosphate-buffered saline (PBS)-supplemented group, adenosine triphosphate (ATP) content and superoxidase dismutase (SOD) activity were significantly lower and reactive oxygen species (ROS) was significantly higher in the high-fat and highsugar (HFHS)-supplemented group (Figure 1E-G). These results indicated that HFHS supplementation could induce oxidative stress injury in OGCs, resulting in cell cycle arrest and growth inhibition
Summary
Premature ovarian failure (POF) is characterized by amenorrhoea, low oestrogen, high gonadotropin and a lack of mature follicles in females aged below 40 years and leads to infertility.[1,2,3,4] The pathogenesis of POF is closely associated with the health and quality of ovarian granulosa cells (OGCs).[1,5,6] Ageing and apoptosis of the OGCs contribute to a decline in ovarian reserve function.[5,6] Previously, we demonstrated that oxidative stress-induced injury adversely affects OGC health.[1]. The major function of miRs is downregulation of target gene expression by binding to the 3′-untranslated coding region (3′ -UTR) of the target gene mRNA.[1,2,19] miRs regulate many physiological and pathological processes, including the cell cycle, organ development, tumour development, neurodegenerative diseases, ageing and apoptosis.[1,2,19] Previously, we demonstrated that miR-15 negatively regulates the expression of α-Klotho and Lats[1], which leads to induction of mouse OGC death and POF.[1,2] This indicated that the development of POF is closely associated with the abnormal regulation of microRNAs. In this study, the role of the Dab2ip/Ask1/p38-Mapk pathway in mediating oxidative stress in OGCs and maintaining OGC health was examined using a HFHS diet-induced POF mouse model. The role of miR-146b-5p (miR-146) in regulating p38Mapk[14] expression and γH2A.X phosphorylation, which promote ageing and apoptosis of the OGCs, was examined in the model mice
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