Objective
Polycystic ovary syndrome (PCOS) is characterized by follicular dysplasia. An insufficient glycolysis-derived energy supply of granulosa cells (GCs) is an important cause of follicular dysplasia in PCOS. Follicular fluid (FF) exosomal microRNAs (miRNAs) have been proven to regulate the function of GCs. In this study, exosomes extracted from clinical FF samples were used for transcriptome sequencing (RNA-seq) analysis, and a human ovarian granulocyte tumour cell line (KGN cells) was used for in vitro mechanistic studies.
Methods and results
In FF exosomal RNA-seq analysis, a decrease in glycolysis-related pathways was identified as an important feature of the PCOS group, and the differentially expressed miR-143-3p and miR-155-5p may be regulatory factors of glycolysis. By determining the effects of miR-143-3p and miR-155-5p on hexokinase (HK) 2, pyruvate kinase muscle isozyme M2 (PKM2), lactate dehydrogenase A (LDHA), pyruvate, lactate and apoptosis in KGN cells, we found that upregulated miR-143-3p expression in exosomes from the PCOS group inhibited glycolysis in KGN cells; knockdown of miR-143-3p significantly alleviated the decrease in glycolysis in KGN cells in PCOS. MiR-155-5p silencing attenuated glycolytic activation in KGN cells; overexpression of miR-155-5p significantly promoted glycolysis in KGN cells in PCOS. In this study, HK2 was found to be the mediator of miR-143-3p and miR-155-5p in FF-derived exosome-mediated regulation of glycolysis in KGN cells. Reduced glycolysis accelerated apoptosis of KGN cells, which mediated follicular dysplasia through ATP, lactate and apoptotic pathways.
Conclusions
In conclusion, these results indicate that miR-143-3p and miR-155-5p in FF-derived exosomes antagonistically regulate glycolytic-mediated follicular dysplasia of GCs in PCOS.
Polycystic ovary syndrome (PCOS) is a lifelong reproductive, metabolic, and psychiatric disorder that affects 5-18% of women, which is associated with a significantly increased lifetime risk of concomitant diseases, including type 2 diabetes, psychiatric disorders, and gynecological cancers. Posttranslational modifications (PTMs) play an important role in changes in protein function and are necessary to maintain cellular viability and biological processes, thus their maladjustment can lead to disease. Growing evidence suggests the association between PCOS and posttranslational modifications. This article mainly reviews the research status of phosphorylation, methylation, acetylation, and ubiquitination, as well as their roles and molecular mechanisms in the development of PCOS. In addition, we briefly summarize research and clinical trials of PCOS therapy to advance our understanding of agents that can be used to target phosphorylated, methylated, acetylated, and ubiquitinated PTM types. It provides not only ideas for future research on the mechanism of PCOS but also ideas for PCOS treatments with therapeutic potential.
Endometriosis (EMS) is a common gynecological disease leading to chronic pelvic pain and infertility in women of reproductive age, but its underlying pathogenic genes and effective treatment are still unclear. To date, abnormal expression of NLRP3 activation-related genes has been identified in EMS patients and mouse models. Therefore, this study sought to identify the key genes that could affect the diagnosis and treatment of EMS. The GSE7307 dataset was downloaded from the Gene Expression Omnibus (GEO) database, including 18 EMS samples and 23 control samples. 14 differential genes related to NLRP3 activation and EMS were obtained from the endometrial samples of GSE7307 by differential analysis. GO and KEGG analysis showed that these genes were mainly involved in the production and regulation of the cytokine IL-1β, and the NOD-like receptor signaling pathway. Random Forest (RF) and support vector machine recursive feature elimination (SVM-RFE) algorithms were used to select four diagnostic markers related to NLRP3 activation (NLRP3, IL-1β, LY96 and PDIA3) to construct the EMS diagnostic model. The four diagnostic markers were verified using western blotting and validated in the GSE7305 and GSE23339 datasets. The AUC values showed that the model had a good diagnostic performance. In addition, the infiltration of immune cells in the samples and the correlation between different immune factors and diagnostic markers were further discussed. These results suggest that four diagnostic markers may also play an important role in the immunity of EMS. Finally, 10 drugs targeting to four diagnostic markers were retrieved from the DrugBank database, of which niclosamide proved useful for treating EMS. Overall, we identified four key diagnostic genes for EMS. In addition, large-scale and multicenter prospective cohort studies are necessary to confirm whether these four genes also have valid diagnostic value in blood samples from EMS patients.
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