Journal of Ovarian Research
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2019
·Vol. 12
·期 1
·1-7
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IF 2.469
Wu Gengxiang,Hu Xue,Ding Jinli,Yang Jing
Background The mechanism of the pathological change of polycystic ovary syndrome (PCOS) is still unclear. Previous studies have shown that PCOS is a chronic nonspecific low-grade inflammatory condition, and that heat shock protein (HSP)70 has a potent anti-inflammatory property. So the aim of this study is to investigate the correlation between HSP70 and the hormones and inflammatory factors and to find out the role of HSP70 in the pathogenesis of PCOS.Methods Twenty female Sprague–Dawley (SD) rats (aged 23 days and weighted 80-90 g) were randomly divided into two groups (n = 10 per group), PCOS group and control group. PCOS group were subcutaneously injected with 6 mg/100 g dehydro-epiandrosterone (DHEA) for 20 consecutive days, the control group were subcutaneously injected with a solvent of equivalent amount. All the samples were collected in the morning fasting state, 12 h after the last administration. Histological examinations of ovarian tissues were analyzed. Hormone levels and inflammatory factors levels were measured by enzyme-linked immunosorbent assay (ELISA) kits.Results Serum concentrations of testosterone (T) and luteinizing hormone (LH) were significantly higher in the PCOS group than the control group (P < 0.001), but the concentrations of estradiol (E2), follicle stimulating hormone (FSH) and insulin didn’t show significant difference between these two groups. All the concentrations of inflammatory factors including C-reactive protein (CRP), interleukin (IL)-6, IL-18, and tumor necrosis factor (TNF)-α. were significantly higher in PCOS group than the control group (P < 0.001). The expressions of HSP70 were significantly lower in serum but higher in ovarian tissues in the PCOS group than the control group. Spearman rank correlation analysis showed strong negative correlation of serum HSP70 levels with T, LH and all the detected inflammatory factors.Conclusion The abnormal expression of HSP70 correlated with testosterone and inflammatory factors, which indicates that HSP70 may play an important role in PCOS pathology.
研究领域:
内分泌学
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生殖生物学
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炎症
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PubMed
高影响因子
Cell Reports
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2023
·Vol. 42
·期 9
·113090-113090
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IF 8.8
Wang D,Zhu Z,Fu Y,Zhang Q,Zhang Y,Wang T,Weng Y,Wen Y,Cao W,Tao G,Wang Y
Polycystic ovary syndrome (PCOS) is an endocrine disorder and the main cause of anovulatory infertility, in which persistent activation of androgen receptor (AR) due to aberrant acetylation modifications of transcription is a potential trigger; however, the precise mechanisms of AR activation are poorly understood. In this study, AR activation in dehydroepiandrosterone- and letrozole-induced rat PCOS ovaries coincided with a marked increase of a chromatin acetylation "reader" BRD4. Further bioinformatic analysis showed that the AR promoter contained highly conserved binding motifs of BRD4 and HIF-1α. BRD4 and HIF-1α inducibly bound to the histone 3/4 acetylation-modified AR promoter, while administration of a BRD4-selective inhibitor JQ1 reduced the binding and AR transcription and improved the adverse expression of the core fibrotic mediators in PCOS ovaries and DHT-treated granulosa cells. Our data indicate that BRD4 upregulation and the resultant AR transcriptional activation constitute an important regulatory pathway that promotes ovarian fibrosis in PCOS.
研究领域:
内分泌学
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生殖医学
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分子生物学
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PubMed
高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
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2020
·Vol. 24
·期 18
·11001-11011
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IF 4.486
Jun Liu,Jinli Ding,Bing Qu,Jiuying Liu,Xiaojie Song,Qingli Suo,Aifen Zhou,Jing Yang
Polycystic ovary syndrome (PCOS), the most common female endocrine disease that causes anovulatory infertility, still lacks promising strategy for the accurate diagnosis and effective therapeutics of PCOS attributed to its unclear aetiology. In this study, we determined the abnormal reduction in circPSMC3 expression by comparing the ovarian tissue samples of PCOS patients and normal individuals. The symptom relief caused by up-regulation of circPSMC3 in PCOS model mice suggested the potential for further study. In vitro functional experiments confirmed that circPSMC3 can inhibit cell proliferation and promote apoptosis by blocking the cell cycle in human-like granular tumour cell lines. Mechanism study revealed that circPSMC3 may play its role through sponging miR-296-3p to regulate PTEN expression. Collectively, we preliminarily characterized the role and possible insights of circPSMC3/miR-296-3p/PTEN axis in the proliferation and apoptosis of KGN cells. We hope that this work provides some original and valuable information for the research of circRNAs in PCOS, not only to better understand the pathogenesis but also to help provide new clues for seeking for the future therapeutic target of PCOS.
研究领域:
妇科学
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分子生物学
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内分泌学
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PubMed
高影响因子
CELLULAR AND MOLECULAR LIFE SCIENCES
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2024
·Vol. 81
·期 1
·1-24
·
IF 6.2
Hong Ling,Xiao Shan,Diao Lianghui,Lian Ruochun,Chen Cong,Zeng Yong,Liu Su
Polycystic ovary syndrome (PCOS) is a complex common endocrine disorder affecting women of reproductive age. Ovulatory dysfunction is recognized as a primary infertile factor, however, even when ovulation is medically induced and restored, PCOS patients continue to experience reduced cumulative pregnancy rates and a higher spontaneous miscarriage rate. Hyperandrogenism, a hallmark feature of PCOS, affects ovarian folliculogenesis, endometrial receptivity, and the establishment and maintenance of pregnancy. Decidualization denotes the transformation that the stromal compart of the endometrium must undergo to accommodate pregnancy, driven by the rising progesterone levels and local cAMP production. However, studies on the impact of hyperandrogenism on decidualization are limited. In this study, we observed that primary endometrial stromal cells from women with PCOS exhibit abnormal responses to progesterone during in vitro decidualization. A high concentration of testosterone inhibits human endometrial stromal cells (HESCs) decidualization. RNA-Seq analysis demonstrated that pyruvate dehydrogenase kinase 4 (PDK4) expression was significantly lower in the endometrium of PCOS patients with hyperandrogenism compared to those without hyperandrogenism. We also characterized that the expression of PDK4 is elevated in the endometrium stroma at the mid-secretory phase. Artificial decidualization could enhance PDK4 expression, while downregulation of PDK4 leads to abnormal decidualization both in vivo and in vitro. Mechanistically, testosterone excess inhibits IGFBP1 and PRL expression, followed by phosphorylating of AMPK that stimulates PDK4 expression. Based on co-immunoprecipitation analysis, we observed an interaction between SIRT1 and PDK4, promoting glycolysis to facilitate decidualization. Restrain of AR activation resumes the AMPK/SIRT1/PDK4 pathway suppressed by testosterone excess, indicating that testosterone primarily acts on decidualization through AR stimulation. Androgen excess in the endometrium inhibits decidualization by disrupting the AMPK/SIRT1/PDK4 signaling pathway. These data demonstrate the critical roles of endometrial PDK4 in regulating decidualization and provide valuable information for understanding the underlying mechanism during decidualization.
研究领域:
生殖内分泌学
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分子生物学
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细胞生物学
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内分泌学
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PubMed
高影响因子
Journal of Ovarian Research
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2024
·Vol. 17
·期 1
·1-13
·
IF 3.8
Jiang Nan-Xing,Zhao Wei-Jie,Shen Hao-Ran,Du Dan-feng,Li Xue-Lian
Background Investigating the underlying molecular mechanisms responsible for endometrial dysfunction in women with PCOS is essential, particularly focusing on the role of hyperinsulinemia.Methods We explored the role of insulin in the decidualization process using a synthetic decidualization assay. To dissect the effects of PI3K/AKT-NR4A signaling, we employed small interfering RNAs (siRNAs) targeting the NR4A genes and inhibitors of the PI3K/AKT pathway. We also investigated the disruption of AKT-NR4A1 signaling in the endometrium of PCOS female rats induced with dehydroepiandrosterone (DHEA). Quantitative real-time PCR (qRT-PCR) and Western blot (WB) analyses were utilized to evaluate gene expression regulation.Results Insulin was found to suppress the expression of decidualization markers in human endometrial stromal cells (hESC) in a dose-dependent manner, concurrently triggering an inappropriate activation of the PI3K/AKT pathway. Members of the NR4A family, as downstream effectors in the PI3K/AKT pathway, were implicated in the insulin-induced disruptions during the decidualization process. Moreover, the endometrium of PCOS models showed significantly elevated levels of phosphorylated (Ser473) AKT, with a corresponding reduction in Nr4a1 protein.Conclusion sOur research demonstrates that insulin negatively regulates decidualization in hESC via the PI3K/AKT-NR4A pathway. In vivo analysis revealed a significant dysregulation of the AKT-NR4A1 pathway in the endometrium of PCOS rats. These findings offer novel insights into the pathogenesis of infertility and endometrial disorders associated with hyperinsulinemia in PCOS.
研究领域:
内分泌学
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生殖生物学
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分子生物学
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妇科学
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PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2024
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IF 4.8
Ting Wang,Xingliang Xiong,Na Xiao,Yizhong Yan,Xiaoyang Liu,Qi Xie,Xian Su,Maosheng Chen,Jing Peng,Siqi Wang,Hua Mei,Ge Lin,Fei Gong,Lamei Cheng
Immune dysregulation has been summarized as a critical factor in the occurrence and development of Polycystic ovary syndrome (PCOS), but potential mediators and mechanisms remain unclear. Our previous study showed that CD19 + B cells were involved in the pathogenesis of dehydroepiandrosterone (DHEA)-induced PCOS mice. Here, we studied the therapeutic potential of anti-CD19 antibody (aCD19 Ab) on DHEA-induced PCOS mice. The results showed that aCD19 Ab treatment improved ovarian pathological structure and function of PCOS mice, manifested by an increased number of corpus luteum, a decreased number of cystic follicles and atretic follicles, and regular estrus cycles. The aCD19 Ab treatment reduced the proportion of splenic CD21 + CD23 low marginal zone B cells as well as the level of serum IgM and decreased the percentage of peripheral blood and splenic neutrophils. In particular, aCD19 Ab treatment reduced the apoptosis of granulosa cells and macrophage infiltration in ovarian secondary follicles of PCOS mice, as well as the expression of TNF-α in ovarian tissue and serum TNF-α levels. Moreover, we confirmed that TNF-α induced the apoptosis of human ovarian granulosa tumor cell line cells in vitro. Thus, our work demonstrates that aCD19 Ab treatment improves ovarian pathological phenotype and function by reducing local and systemic inflammation in PCOS mice, which may provide a novel insight into PCOS therapy.
研究领域:
生殖生物学
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免疫学
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内分泌学
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PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2025
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IF 2.2
Rongyan Zhu,Liu Yang,Yulan Li
Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder in women of reproductive age and is frequently associated with impaired glucose metabolism. Thioredoxin-interacting protein (TXNIP) plays a critical role in cellular metabolic regulation; however, its involvement in PCOS pathogenesis remains unclear. Bioinformatics analysis revealed significantly increased TXNIP expression in both PCOS patients and mouse ovarian granulosa cells (GCs). In vivo experiments using dehydroepiandrosterone (DHEA)-induced PCOS mouse models showed that TXNIP knockdown restored the expression of glycolysis-related enzymes, including HK2, PFKM, and PKM2. This restoration enhanced glycolytic function by suppressing IRS-1 phosphorylation and activating the PI3K signaling pathway. In vitro, dihydrotestosterone (DHT)treatment elevated TXNIP expression and suppressed glycolytic activity in KGN cells. Silencing TXNIP restored glycolytic metabolites such as pyruvate and lactate and promoted glycolytic flux, while TXNIP overexpression further impaired these functions. Additionally, treatment with the IRS-1 inhibitor NT157 confirmed that TXNIP regulates glycolysis in GCs through the IRS-1/PI3K signaling axis. This study is the first to demonstrate that TXNIP contributes to glycolytic dysfunction in PCOS GCs via the IRS-1/PI3K pathway, highlighting a potential target for PCOS diagnosis and therapy.
研究领域:
生殖生物学
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代谢病学
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内分泌学
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DOI
PubMed
高影响因子
JOURNAL OF NUTRITIONAL BIOCHEMISTRY
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2026
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IF 5.2
Jin Yan,Shao-Zhuang Ma,Shuang-Yan Chang,Zheng-Yun Jin,Xi-Xiu Liao,Ming-Xia Jia,Jin-Dan Kang,Lin-Hu Quan
Damaged gut barrier function, ovarian inflammation, and estradiol secretion disorder are observed in PCOS mice. • GLP-1 notably enhances the gut barrier function and alleviates ovarian inflammation. • ETA improves PCOS by regulating GLP-1 levels to restore the intestine and block the ovarian inflammation condition. • Reveal the mechanism by which GLP-1 affects PCOS dual-action for the first time. Polycystic ovary syndrome (PCOS) is a prevalent metabolic and endocrine disorder marked by hormonal imbalances among women, and the specific pathogenesis remains incompletely clarified. Although n-3 polyunsaturated fatty acids (n-3 PUFAs) have been shown to have benefits in managing PCOS through previous studies, the specific mechanisms require further investigation. We found that DHEA-induced PCOS mice exhibited an impaired intestinal barrier, decreased levels of glucagon-like peptide-1 (GLP-1, P <0.05), elevated serum levels of lipopolysaccharides (LPS, P <0.05), and upregulated the ovarian TLR4-NLRP3 inflammatory signaling pathway ( P <0.05). Our in-depth experiments verified that eicosatrienoic acid (ETA) palliated the pathological representative features of PCOS in mice by regulating intestinal GLP-1 levels ( P <0.01). In detail, ETA upregulated GLP-1 receptor (GLP-1R) levels in the colon, restoring intestinal barrier integrity through modulation of the functions of the gut epithelial and mucosal barriers, and reduced serum LPS levels in PCOS mice ( P <0.001). In the ovary, ETA upregulated GLP-1R levels, decreased the expression of the TLR4-NLRP3 signaling pathway ( P <0.05), and reduced the release of inflammatory factors (all P <0.05), thereby ameliorating ovarian inflammation and estradiol secretion disorders ( P <0.01). Here, we propose the mitigation of ovarian inflammation and restoration of intestinal barrier integrity as novel therapeutic targets and strategies for PCOS management, thereby positioning the n-3 PUFA ETA as a promising therapeutic candidate. Download: Download high-res image (227KB) Download: Download full-size image
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MOLECULAR AND CELLULAR ENDOCRINOLOGY
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2024
·
IF 3.8
Yan Li,Hui Song,Jia Xu,Yunping Wang,Lu Bai,Haixu Wang,Jianfang Zhang
This study aimed to elucidate the role of TP53-induced glycolysis and apoptosis regulator (TIGAR) in polycystic ovary syndrome (PCOS). A rat model PCOS was constructed by subcutaneous injection with dehydroepiandrosterone (DHEA). Follicular atresia and reduced granular cells (GCs) in ovaries suggested successful modeling. The low expression of TIGAR was observed in ovarian tissue of PCOS rat. To explore the role of TIGAR in PCOS, lentivirus carrying the TIGAR were used to up-regulate TIGAR expression. TIGAR overexpression reduced the DHEA-induced increase of ovarian weight, the levels of estradiol (E2), and the ratio of luteinizing hormone/follicle-stimulating hormone (LH/FSH) in the serum, as well as improved the morphology of the follicle, especially increased the thickness of the GC layer, which attributed to the inhibition of apoptosis by TIGAR. In addition, high expression of TIGAR inhibited oxidative stress in ovaries of PCOS rat, as evidenced by decreased level of malondialdehyde (MDA), and reactive oxygen species (ROS), and enhanced activity of glutathione peroxidase (GPX) and superoxide dismutase (SOD). Mechanically, Nrf2/OH-1 signal pathway was activated by TIGAR. The effect of TIGAR on PCOS were verified in the primary rat GCs treated with dihydrotestosterone, but also the rescue experiment was performed. Downregulation of Nrf2 reversed the effects of TIGAR, indicating that TIGAR suppressed oxidative stress and GC apoptosis by activating Nrf2/OH-1 pathway in PCOS. Finally, non-targeted metabolomics revealed that TIGAR might affect the energy metabolic pathway, thereby altering the metabolic profile of primary rat GCs. This study provided new insights into the prevention and treatment of PCOS.
研究领域:
生殖生物学
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内分泌学
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分子生物学
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代谢组学
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PubMed
高影响因子
BIOORGANIC CHEMISTRY
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2024
·
IF 4.5
Mingming Wang,Jing Huang,Yue Shi,Richard Mprah,Huanhuan Ding,Shanshan Zhang,Cui Li
Background Wenshentiaojing Decoction (WSTJD), a traditional Chinese herbal prescription, was first recorded in the “Ye Tianshi female department secret recipe for diagnosis and treatment ”. It has been proven effective in treating polycystic ovary syndrome (PCOS). However, the active ingredients and molecular mechanism of WSTJD against PCOS remain unclear. Aim of the study To explore the therapeutic effect and molecular mechanism of WSTJD against PCOS by using network pharmacology and mouse model. Materials and methods Network pharmacology were used to predict active ingredients, potential targets, and pathways of WSTJD against PCOS. Female mice were injected subcutaneously with DHEA (6 mg/100 g body weight) daily to establish a PCOS model and administered with WSTJD and quercetin to observe its therapeutic effect. Thereafter, mouse phenotypes, indicators related to oxidative stress and ferroptosis, and hub genes were determined. Results We identified 144 potential targets for WSTJD in the treatment of PCOS, which were enriched in immune-related signaling pathways such as reactive oxygen species, TNF and IL-17 signaling pathway. Thirteen hub genes were identified by proteinprotein interaction network (PPI) and algorithmic analysis, all of which were oxidative stress-related genes, and five of which, IL6, PTGS2, HIF1A, MTOR and EGFR, were ferroptosis-related genes. Further analysis revealed that quercetin was a key ingredient for WSTJD and that it had superior binding effects with the hub genes. Moreover, WSTJD and quercetin could significantly depress oxidative stress-related indicators and ferroptosis-related gene expression in PCOS mice. Finally, mouse models showed that the expression of the hub genes were consistent with the analysis results. Conclusions WSTJD and quercetin alleviated PCOS by suppressing oxidative stress and ferroptosis. Quercetin was the key ingredient for WSTJD against PCOS.
研究领域:
中药学
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生殖医学
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网络药理学
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PubMed
高影响因子
Frontiers in Endocrinology
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2025
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IF 4.6
Yating Xu,Li Ning,Yu Si,Xiu Li,Ruyue Wang,Qingling Ren
Introduction: Polycystic ovary syndrome (PCOS) is a complex disorder characterized by metabolic and ovulatory dysfunctions, often associated with an imbalance in gut microbiota. Despite current treatments, effective management strategies targeting underlying mechanisms remain limited.Methods: In this study, we used a rat model of PCOS induced by letrozole and a high-fat diet. The effect of intestinal AMP-activated protein kinase (AMPK) activation was evaluated through metformin administration, the most commonly used AMPK activator. We analyzed metabolic parameters, ovulatory functions, gut microbiota composition, and serum levels of Indole-3-carboxaldehyde (I3A), a metabolite involved in inflammation and apoptosis regulation.Results: Metformin treatment significantly reversed metabolic disorders and restored ovulatory functions in PCOS rats. Moreover, metformin treatment led to notable improvements in gut microbiota composition and an increase in serum I3A levels, which have been shown to mitigate inflammation and apoptosis.Discussion: This study highlights the therapeutic potential of targeting intestinal AMPK in managing PCOS. By improving both metabolic and reproductive health, activation of AMPK may offer a promising approach for restoring physiological balance in PCOS patients.
研究领域:
生殖医学
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代谢生物学
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微生物学
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DOI
PubMed
高影响因子
Chinese Herbal Medicines
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2026
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IF 11.2
Aifen Liu,Jingyan Hu,Weili Yu,Chuanyu Cang,Chuanjing Shi,Xi Wang,Rui Wang,Xuanwei Cai,Fengbo Zhao,Lei Zhang
Objective Polycystic ovary syndrome (PCOS) is an endocrine and metabolic disorder characterized by ovulatory dysfunction. Formononetin (FMN), a bioactive compound derived from leguminous plants, including Glycyrrhiza uralensis , Trifolium pratense , and Astragalus membranaceus , exhibits anti-inflammatory and anti-fibrotic properties. This study aimed to evaluate the therapeutic effects of FMN in a PCOS rat model and elucidate its underlying molecular mechanisms. Methods A PCOS-like model was established in 3-week-old female Sprague-Dawley rats by daily dehydroepiandrosterone (DHEA) injections. The efficacy of FMN was assessed by monitoring estrous cycles, hormone levels, glucose tolerance, and ovarian tissue morphology. Network pharmacology and transcriptome sequencing were used to predict the molecular targets and signaling pathways of FMN. The binding and stabilizing effects of FMN on suppressor of cytokine signaling 3 (SOCS3) were confirmed using molecular docking, molecular dynamics (MD) simulations, and cellular thermal shift assay (CETSA)-Western blotting (WB) (CETSA-WB). The expression of SOCS3, inflammation- and fibrosis-related markers, and the components of the transforming growth factor beta1 (TGF- β 1)/Smad pathway were quantified by quantitative polymerase chain reaction (qPCR), Western blotting, and immunohistochemistry. Functional validation was performed using SOCS3 small interfering RNA (siRNA). Results DHEA successfully induced a PCOS-like phenotype, including disrupted estrous cycle, hyperandrogenism, an elevated luteinizing hormone to follicular stimulating hormone (LH/FSH) ratio, insulin resistance, and abnormal ovarian morphology. FMN treatment significantly reversed these abnormalities and reduced ovarian collagen deposition. Network pharmacology and transcriptome analyses indicated that the therapeutic efficacy of FMN was primarily attributable to its anti-fibrotic and anti-inflammatory properties, with SOCS3 identified as a potential key molecule. Molecular docking and MD simulations, along with CETSA-WB, further revealed that FMN directly binds to SOCS3, enhancing its stability and thereby inhibiting ovarian fibrosis in PCOS. Moreover, qPCR, Western blotting, and immunohistochemistry confirmed that FMN regulates the TGF- β 1/Smad signaling pathway. Importantly, SOCS3siRNA abolished fibrotic-related collagen levels and phosphorylated signal transducer and activator of transcription 3 (p-STAT3) expression, supporting the notion that FMN ameliorates PCOS-induced ovarian fibrosis via SOCS3. Conclusion FMN alleviated ovarian dysfunction and hyperandrogenism in DHEA-induced PCOS rats by stabilizing SOCS3 and inhibiting TGF- β 1/Smad signaling, thereby attenuating ovarian fibrosis and inflammation. This reveals a novel SOCS3-centered mechanism for FMN and underscores its therapeutic potential for PCOS.
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高影响因子
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