Decreased microRNA-125b-5p disrupts follicle steroidogenesis through targeting PAK3/ERK1/2 signalling in mouse preantral follicles.


  • 影响因子:5.69
  • DOI:10.1016/j.metabol.2020.154241
  • 作者列表:"Zhang X","Xiao H","Zhang X","E Q","Gong X","Li T","Han Y","Ying X","Cherrington BD","Xu B","Liu X","Zhang X
  • 发表时间:2020-06-01

BACKGROUND:Hyperandrogenism is one of the major characteristics of polycystic ovary syndrome (PCOS). Abnormal miR-125b-5p expression has been documented in multiple diseases, but whether miR-125b-5p is associated with aberrant steroidogenesis in preantral follicles remains unknown. METHODS:Steriod hormone concentrations and miR-125b-5p expression were measured in clinical serum samples from PCOS patients. Using a mouse preantral follicle culture model and a letrozole-induced PCOS mouse model, we investigated the mechanism underlying miR-125b-5p regulation of androgen and oestrogen secretion. RESULTS:The decreased miR-125b-5p expression was observed in the sera from hyperandrogenic PCOS (HA-PCOS) patients. In mouse preantral follicles, inhibiting miR-125b-5p increased the expression of androgen synthesis-related genes and stimulated the secretion of testosterone, while simultaneously downregulating oestrogen synthesis-related genes and decreasing oestradiol release. Ectopically expressed miR-125b-5p reversed the effects on steroidogenesis-related gene expression and hormone release. Mechanistic studies identified Pak3 as a direct target of miR-125b-5p. Furthermore, inhibiting miR-125b-5p facilitated the activation of ERK1/2 in mouse preantral follicles, while inhibiting Pak3 abrogated this activating effect. These results were recapitulated in letrozole-induced PCOS mouse ovaries. Of note, inhibiting PAK3 antagonised the positive effect of miR-125b-5p siRNA on the expressions of androgen synthesis-related enzymes and testosterone secretion. Luteinizing hormone (LH) inhibited miR-125b-5p expression, and stimulated Pak3 expression. CONCLUSION:High serum LH concentrations in PCOS patients repress miR-125b-5p expression, which further increases Pak3 expression, leading to activation of ERK1/2 signalling, thus stimulating the expression of androgen synthesis-related enzymes and testosterone secretion in HA-PCOS.


背景: 高雄激素血症是多囊卵巢综合征 (PCOS) 的主要特征之一。miR-125b-5p的异常表达已在多种疾病中被记录,但miR-125b-5p是否与腔前卵泡中异常类固醇生成相关仍不清楚。 方法: 检测PCOS患者血清中类固醇激素浓度及miR-125b-5p的表达。利用小鼠腔前卵泡培养模型和来曲唑诱导的PCOS小鼠模型,我们研究了雄激素和雌激素分泌miR-125b-5p调节机制。 结果: 高雄激素型PCOS (HA-PCOS) 患者血清中miR-125b-5p表达下降。在小鼠腔前卵泡中,抑制miR-125b-5p增加了雄激素合成相关基因的表达,刺激了睾酮的分泌,同时下调了雌激素合成相关基因,减少了雌二醇的释放。异位表达的miR-125b-5p逆转了对类固醇生成相关基因表达和激素释放的影响。机制研究确定Pak3是miR-125b-5p的直接目标。此外,抑制miR-125b-5p促进了小鼠腔前卵泡中ERK1/2的激活,而抑制Pak3消除了这种激活作用。这些结果在来曲唑诱导的PCOS小鼠卵巢中重现。值得注意的是,抑制PAK3拮抗了miR-125b-5p siRNA对雄激素合成相关酶的表达和睾酮分泌的积极作用。促黄体生成素 (LH) 抑制miR-125b-5p表达,并刺激Pak3表达。 结论: PCOS患者高血清LH浓度抑制miR-125b-5p的表达,进一步增加Pak3的表达,导致ERK1/2信号的激活,从而刺激HA-PCOS雄激素合成相关酶的表达和睾酮分泌。



作者列表:["Ellis RJ","Schlick CJR","Yang AD","Barber EL","Bilimoria KY","Merkow RP"]

METHODS:INTRODUCTION:Cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC) is an effective treatment option for selected patients with peritoneal metastases (PM), but national utilization patterns are poorly understood. The objectives of this study were to (1) describe population-based trends in national utilization of CRS/IPC; (2) define the most common indications for the procedure; and (3) characterize the types of hospitals performing the procedure. METHODS:The National Inpatient Sample (NIS) was used to identify patients from 2006 to 2015 who underwent CRS/IPC, and to calculate national estimates of procedural frequency and oncologic indication. Hospitals performing CRS/IPC were classified based on size and teaching status. RESULTS:The estimated annual number of CRS/IPC cases increased significantly from 189 to 1540 (p < 0.001). Overall, appendiceal cancer was the most common indication (25.7%), followed by ovarian cancer (23.3%), colorectal cancer (22.5%), and unspecified PM (15.0%). Remaining cases (13.5%) were performed for other indications. Most cases were performed in large teaching hospitals (65.9%), compared with smaller teaching hospitals (25.1%), large non-teaching hospitals (5.3%), or small non-teaching hospitals (3.2%). Patients were more likely to undergo CRS/IPC without a diagnosis based on level I evidence (appendiceal, ovarian, or colorectal) at large non-academic hospitals (odds ratio 2.00, 95% confidence interval 1.18-3.38, p = 0.010) compared with large academic hospitals. CONCLUSIONS:Utilization of CRS/IPC is increasing steadily in the US, is performed at many types of facilities, and often for a variety of indications that are not supported by high-level evidence. Given associated morbidity of CRS/IPC, a national registry dedicated to cases of IPC is necessary to further evaluate use and outcomes.

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作者列表:["Grundy A","Ho V","Abrahamowicz M","Parent MÉ","Siemiatycki J","Arseneau J","Gilbert L","Gotlieb WH","Provencher DM","Koushik A"]

METHODS::Results of epidemiologic studies of physical activity and ovarian cancer risk are inconsistent. Few have attempted to measure physical activity over the lifetime or in specific age windows, which may better capture etiologically relevant exposures. We examined participation in moderate-to-vigorous recreational physical activity (MVPA) in relation to ovarian cancer risk. In a population-based case-control study conducted in Montreal, Canada from 2011 to 2016 (485 cases and 887 controls), information was collected on lifetime participation in various recreational physical activities, which was used to estimate MVPA for each participant. MVPA was represented as average energy expenditure over the lifetime and in specific age-periods in units of metabolic equivalents (METs)-hours per week. Odds ratios (OR) and 95% confidence intervals (CI) for the relation between average MVPA and ovarian cancer risk were estimated using multivariable logistic regression models. Confounding was assessed using directed acyclic graphs combined with a change-in-estimate approach. The adjusted OR (95% CI) for each 28.5 MET-hr/week increment of lifetime recreational MVPA was 1.11 (0.99-1.24) for ovarian cancer overall. ORs for individual age-periods were weaker. When examined by menopausal status, the OR (95% CI) for lifetime MVPA was 1.21 (1.00-1.45) for those diagnosed before menopause and 1.04 (0.89-1.21) for those diagnosed postmenopausally. The suggestive positive associations were stronger for invasive ovarian cancers and more specifically for high-grade serous carcinomas. These results do not support a reduced ovarian cancer risk associated with MVPA.

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作者列表:["Çetin M","Tunçdemir P","Karaman K","Yel S","Karaman E","Özgökçe M","Kömüroğlu AU"]

METHODS::The aim of our study was to evaluate whether cardiovascular disease risks seen in adults with polycystic ovary syndrome (PCOS) develop in adolescents with PCOS using conventional Doppler echocardiography (CDE) and tissue Doppler echocardiography (TDE) or not. The other aim was to investigate the association of paraoxonase-1 (PON-1) level with cardiovascular parameters. 30 PCOS patients and 30 control patients were included in the study. All patients were evaluated with TDE and CDE. Paraoxonase-1 levels of both groups were studied. In CDE study, myocardial performance index (MPI) was higher in the PCOS group than in the control group (0.54 ± 0.11, 0.50 ± 0.12, p = .049, respectively). In the TDE study, early diastolic myocardial velocity (E)'/late diastolic myocardial velocity (A') was lower in PCOS group than in the control group (2.07 ± 0.08, 2.44 ± 0.10, p = .008, respectively). PON-1 was higher in PCOS group than in the control group (26.81 ± 3.05, 18.68 ± 1.18, p = .011, respectively). Cardiovascular disease risks, which are among the long-term complications of PCOS, seem to begin from the early stage of PCOS. The high PON-1 level was thought to increase in response to increased oxidative stress in PCOS.Impact statementWhat is already known on this subject? Polycystic ovary syndrome (PCOS) is one of the most commonly seen endocrinopathy in the adolescent age group. PCOS has detrimental effects on the cardiovascular system in the adult population which is reported in many studies.What the results of this study add? The result of this study showed that cardiovascular effects, which are among the long-term complications of PCOS, seem to begin from the early stage of PCOS. And also, serum paraoxonase-1 level increases in response to the oxidative stress in the adolescent with PCOS.What are the implications of these findings for clinical practice and/or further research? The cardiovascular system evaluation should be started in early phases of PCOS development in the adolescent age group. The potential role of oxidative effect of Paraoxonase-1 on the PCOS needs to be elucidated in further studies.

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