Frontiers in Endocrinology
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2022
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IF 6.055
Wang Xuejiao,Gu Liping,Zhang Yahui,Xiong Chuanhao,Peng Yongde,Ding Xiaoying
Objective: Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine and metabolic disease. The gut microbiota is highly correlated with androgen secretion and insulin resistance (IR), which are two potential major pathogenic mechanisms of PCOS. Currently, an antibiotic cocktail (ABX) is often used to construct pseudo germ-free mouse models for studies on the gut microbiota and PCOS. Our work aimed to study the effects of dehydroepiandrosterone (DHEA), a high-fat diet (HFD) and ABX on the heterogeneous phenotypes of PCOS mouse models by regulating the gut microbiota.Methods: PCOS mouse models were established by subcutaneous injection of DHEA alone or in combination with a HFD in wild-type and pseudo germ-free mice. The changes in ovary morphology and sex hormonal and glycolipid metabolic parameters were evaluated.Results: Wild-type mice treated with DHEA or DHEA+HFD showed a PCOS-like phenotype of hyperandrogenism, anovulation and polycystic ovaries. The former was combined with hyperinsulinemia and IR, while the latter was combined with glucolipid metabolic disorders, extremely heterogeneous hyperinsulinemia and IR. The phenotype of PCOS mice, especially the metabolic parameters, was correlated with the gut microbiota. The pseudo germ-free mice treated with DHEA or DHEA+HFD also showed a PCOS-like phenotype. However, DHEA could not induce hyperinsulinemia or IR in pseudo germ-free mice. Pseudo germ-free mice treated with DHEA+HFD exhibited decreased serum AMH level, glucolipid metabolic disorders and IR. Compared with the wild-type mice, the pseudo germ-free mice treated with DHEA showed significantly higher testosterone and lipid levels and lower blood glucose levels, and they did not present with hyperinsulinemia or IR.Conclusion: A better and stabilized mouse model simulating the pathophysiological defects of PCOS was induced by DHEA alone rather than by DHEA+HFD. The ABX intervention improved glucose metabolic disorders and hyperinsulinemia but aggravated the hyperandrogenism and lipid metabolic disorders of the PCOS mice. This study suggests that the gut microbiota plays an important role in the heterogeneous phenotypes of PCOS mouse models.
研究领域:
内分泌学
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代谢学
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生殖生物学
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微生物学
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DOI
PubMed
高影响因子
Journal of Ovarian Research
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2025
·Vol. 18
·期 1
·1-14
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IF 4.2
Zheng Xiufen,Chen Zikai,Liang Miao,Zhou Liting,Wang Miaoru,Zhang Silin,Zhang Shuyun,Ma Lei,Yi Wei,Liu Xiawen
Background Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder among women of reproductive age. It is characterized by hyperandrogenism, ovulatory dysfunction, and the presence of polycystic ovarian morphology (PCOM) on ultrasound, often accompanied by metabolic disturbances such as insulin resistance and obesity. Current treatments, including oral contraceptives and anti-androgen medications, often yield limited efficacy and undesirable side effects. This study investigates the role of UGT2B15, an essential enzyme for androgen metabolism, in PCOS pathogenesis and its potential as a therapeutic target.Methods We used RNA sequencing to examine the effects of UGT2B15 knockdown in KGN cells. To modulate UGT2B15 expression, we employed siRNA and (R)/(S)-NAF (naftopidil), a chemical inducer of UGT2B15 identified in our previous studies on a prostate hyperplasia model. The effects of siRNA and (R)/(S)-NAF on dihydrotestosterone (DHT) levels, cell apoptosis, and the expression of apoptosis-related proteins in KGN cells were evaluated. In a PCOS mouse model, we assessed the effects of (R)-NAF and (S)-NAF on serum androgen levels, menstrual cycles, ovarian morphology, and UGT2Bs expression. Additionally, luciferase reporter and ChIP assays were utilized to study UGT2B15 regulation by NR1H4.Results Elevated androgens were found to suppress UGT2B15 expression in ovarian granulosa cells, leading to DHT accumulation and apoptosis. (R)-NAF and (S)-NAF treatments reversed these effects, alleviating PCOS symptoms in mice such as hyperandrogenism, irregular menstrual cycles, and the presence of ovarian cysts. NR1H4 negatively regulated the transcription of UGT2B15 in KGN cells. (R)-NAF and (S)-NAF disrupted NR1H4 binding to the UGT2B15 promoter without affecting its protein levels, indicating direct interference with its regulation.Conclusion sUGT2B15 represents a promising target for novel PCOS therapies by modulating androgen metabolism and protecting ovarian granulosa cells from apoptosis. (R)-NAF and (S)-NAF regulate UGT2B15 by disrupting NR1H4's binding to its promoter, implying potential therapeutic compounds for PCOS treatment.
研究领域:
内分泌学
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生殖医学
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药理学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Endocrinology
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2022
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IF 6.055
Liu Shuowen,Zhang Yao,Yang Fang,Gu Jingna,Zhang Ruyue,Kuang Yingying,Mai Wantong,Zheng Chengbo,Yu Yang,Lu Ruling,Zeng Lei,Cao Hongying,Long Yongling
This study explored the possible connection between the insulin resistance-targeting protein adipokine lipocalin-2 (LCN-2) and NF-κB signaling pathway in the inflammatory microenvironment in PCOS-IR model rats to determine the pharmacological mechanism of modified Cangfu Daotan decoction (MCDD) intervention for PCOS-IR. We used a high-fat diet (42 days) combined with letrozole (1 mg/kg/day, 42 days) to establish a PCOS-IR rat model. From the third week after modeling, the rats were given continuous administration of MCDD (high dose with 31.68 g/kg, medium dose with 15.84 g/kg, and low dose with 7.92 g/kg) for 28 days. Serum, ovarian tissue, liver, and adipose tissue were collected after the last gavage. Enzyme-linked immunosorbent assay, hematoxylin-eosin (HE) staining, Masson staining, qRT-PCR, and Western blot experiments were performed to detect various indicators. Our results showed that MCDD could reduce body weight and abdominal fat weight; restore normal estrous cycle and ovarian function; alleviate fatty liver; regulate HOMA-IR and OGTT index; reduce serum inflammatory factor levels, LCN-2 level, and gene expression; and regulate the insulin signal transduction and NF-κB pathways in PCOS-IR rats. Thus, MCDD may play a role in improving ovarian function in PCOS-IR rats by downregulating NF-κB/LCN-2 proteins and upregulating the gene expression of Insr/Irs-1/Glut4 in the insulin signaling pathway in the inflammatory environment.
研究领域:
药理学
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内分泌学
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妇科学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FOLIA HISTOCHEMICA ET CYTOBIOLOGICA
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2022
·Vol. 60
·期 3
·260-270
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IF 1.49
Ying Wang Yu Wang Yao Chen Qianqian Gao Lihui Hou Xiaoling Feng
Introduction. Abnormal ovarian angiogenesis is a common feature of polycystic ovary syndrome (PCOS), a typical endocrine disorder affecting women of reproductive age. Histone deacetylase 5 (HDAC5) has been documented as a suppressor of angiogenesis. The aim of this study was to explore the effect of HDAC5 on ovarian angiogenesis in a PCOS mouse model. Material and methods. PCOS was induced in female C57BL/6 mice by 20-day administration of dehydroepiandrosterone (DHEA). HDAC5 was over-expressed in PCOS mice by corresponding adenovirus injection. In total, 120 mice were used in this study. Western-blotting, real-time PCR, hematoxylin and eosin staining, enzyme-linked immunosorbent assay (ELISA), immunohistochemical staining, flow cytometry, and co-immunoprecipitation were respectively used to evaluate the effect of HDAC5 on PCOS mice. Results. PCOS ovaries showed a compensatory increase in HDAC5 expression, while HDAC5 over-expression alleviated abnormalities in ovarian morphology and serum hormone levels after PCOS modeling. HDAC5 inhibited ovarian angiogenesis in PCOS mice by regulating angiogenesis-related factors, such as VEGFA, platelet-derived growth factors B and D (PDGFB/D), and angiopoietins 1 and 2 (ANGPT1/2) and CD31. HDAC5 over-expression decreased levels of reactive oxygen species (ROS) and malondialdehyde, while promoting activities of catalase and superoxide dismutase in ovaries of PCOS mice, suggesting its suppressive effects on oxidative stress, an inducer of uncontrolled angiogenesis. Moreover, HDAC5 suppressed activation of angiogenesis-related HIF-1α/VEGFA/VEGFR2 signaling in PCOS ovaries partly via inhibiting VEGFR2 acetylation. Conclusions. This study reveals the protective role of HDAC5 in PCOS by inhibiting ovarian angiogenesis and provides a molecular candidate for PCOS therapy in the future.
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
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Reproductive Biology
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2022
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IF 2.089
Juan Zhao,Yong Tan,Zhe Feng,Yahong Zhou,Feihong Wang,Ge Zhou,Jing Yan,Xiaowei Nie
Oxidative stress plays a central role in polycystic ovary syndrome (PCOS). Catalpol (CAT) is the active ingredient of Rehmannia glutinosa Libosch which has therapeutic effect on PCOS. However, little is known about the mechanism of CAT in PCOS. PCOS rats were induced by subcutaneous injection of dehydroepiandrosteronec for four weeks and then were treated with CAT (50 mg/kg) or carboxyl methyl cellulose (the solvent of CAT) or normal saline for another 4 weeks. Histopathological observation of ovarian tissues, the levels of testosterone, estradiol and progesterone in rat plasma samples, the oxidative stress related-indexes and the expressions of NF-κB pathway-related proteins were determined. KGN cell (human ovarian granulosa cell line) was used as PCOS cell model and was transfected with siSIRT1 in the presence of CAT. The viability, proliferation and apoptosis of cells and the levels of SIRT1 and NF-κB pathway-related proteins were measured. CAT lessened the anthropometric indices and improved ovarian damage in PCOS model rats, and reduced the levels of testosterone, estradiol, progesterone and MDA , increased GSH content, and elevated the activities of catalase, GSH-Px and SOD in ovarian tissues of PCOS model rats. CAT up-regulated SIRT1 level and inhibited the activation of NF-κB signaling pathway in PCOS rat model and KGN cells. Silencing SIRT1 increased the viability and proliferation, whilst decreased the apoptosis of CAT-treated KGN cells. Silencing SIRT1 counteracted the effect of CAT on the level of oxidative stress-related factors and NF-κB signaling pathway in KGN cells. CAT attenuated PCOS by regulating SIRT1 mediated NF-κB signaling pathway.
研究领域:
药理学
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内分泌学
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细胞生物学
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分子生物学
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生殖医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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