Danhua Pu

Premature ovarian insufficiency (POI) is defined as the depletion of ovarian function before the age of 40 years. The global prevalence of POI is 3.5%. To date, genetic factors account for 23.5% of the etiology of POI. Herein, a previously uncharacterized pathogenic homozygous variant of the chromosome segregation–1–like gene (CSE1L) was identified in POI patients via targeted panel sequencing. It is reported that dysregulated iron metabolism is involved in many reproductive endocrine disorders; however, its precise role in POI remains obscure. In this study, we identified CSE1L as a potential candidate gene that plays an important role in maintaining iron homeostasis. Deficiency of CSE1L led to ferroptosis in human granulosa cells, which was confirmed by transmission electron microscopy. Mechanistically, coimmunoprecipitation identified the direct interaction between CSE1L and FoxO1. Inhibition of CSE1L led to the excessive accumulation of FoxO1 in the nucleus via nucleocytoplasmic transport. Then, FoxO1 bound to the promoter region of NCOA4 and promoted its transcription, which was verified by a chromatin immunoprecipitation assay. Moreover, inhibition of CSE1L in cumulus cell monolayer could impede oocyte maturation, which might be associated with oxidative stress. Consequently, our study first revealed that CSE1L participated in ferroptosis in human ovarian granulosa cells via nucleocytoplasmic transportation, which might be helpful in revealing the molecular mechanism of CSE1L in the development of POI. Importantly, these findings might provide new insights into the application of ferroptosis inhibitors in the treatment of POI.

Background: Helicase for meiosis 1 (HFM1), a putative DNA helicase expressed in germ-line cells, has been reported to be closely associated with premature ovarian insufficiency (POI). However, the underlying molecular mechanism has not been clearly elucidated. The aim of this study was to investigate the function of HFM1 in the first meiotic prophase of mouse oocytes. Results: The results suggested that the deficiency of HFM1 resulting in increased apoptosis and depletion of oocytes in mice, while the oocytes were arrested in the pachytene stage of the first meiotic prophase. In addition, impaired DNA double-strand break repair and disrupted synapsis were observed in the absence of HFM1. Further investigation revealed that knockout of HFM1 promoted ubiquitination and degradation of FUS protein mediated by FBXW11. Additionally, the depletion of HFM1 altered the intranuclear localization of FUS and regulated meiotic- and oocyte development-related genes in oocytes by modulating the expression of BRCA1. Conclusions: These findings elaborated that the critical role of HFM1 in orchestrating the regulation of DNA double-strand break repair and synapsis to ensure meiosis procession and primordial follicle formation. This study provided insights into the pathogenesis of POI and highlighted the importance of HFM1 in maintaining proper meiotic function in mouse oocytes.

Helicase for meiosis 1 (HFM1), a putative DNA helicase expressed in germ-line cells, has been reported to be closely associated with premature ovarian insufficiency (POI). However, the underlying molecular mechanism has not been elucidated. The aim of this study was to investigate the function of HFM1 in the first meiotic prophase of mouse oocytes. In our study, we found that the deficiency of HFM1 resulted in increased apoptosis and depletion of oocytes in mice. Interestingly, the oocytes were arrested in the first meiotic prophase in the pachytene stage. In addition, impaired DNA double-strand break repair and impaired synapsis were observed in the absence of HFM1. Further investigation revealed that knockout of HFM1 promoted ubiquitination and degradation of FUS protein mediated by FBXW11. Additionally, the depletion of HFM1 altered the intranuclear localization of FUS and regulated meiotic- and oocyte development-related genes in oocytes by regulating the expression of BRCA1. These findings uncovered the critical role of HFM1 in orchestrating the regulation of DNA double-strand break repair and synapsis to ensure meiosis procession and primordial follicle formation, which provided clues for pathogenesis of POI.

Purpose The aim of this systematic review and meta-analysis is to evaluate the efficacy of stem cell therapy in mouse models of POI and patients with POI. Methods The PubMed, Web of Science, and Embase databases were searched from inception to February 2022 for relevant animal and clinical studies. The reference lists of the included reviews were manually searched to identify additional eligible studies. Data were independently extracted by two investigators, and disagreements were resolved by discussion. SYRCLE’s risk of bias tool and the MINORS tool were used to assess the quality of animal and clinical studies by two independent investigators. All statistical analyses were conducted using Review Manager 5.3 software. Results A total of twenty animal studies and six clinical studies were included in this meta-analysis. In animal studies, the results showed that stem cells could improve hormone levels, follicle count, estrous cycle and pregnancy outcome. For hormone levels, stem cells increased serum E₂ and AMH levels and decreased serum FSH and LH levels compared with the control group (serum E₂ level: SMD: 5.05, 95% CI 4.21–5.90, P < 0.00001; serum AMH level: SMD: 4.42, 95% CI 3.06–5.79, P < 0.00001; serum FSH level: SMD: − 3.79, 95% CI − 4.87 to – 2.70, P < 0.00001; serum LH level: SMD: − 1.31, 95% CI − 1.65 to − 0.96, P < 0.00001). All follicle counts, except for the antral follicle count, were significantly changed compared with the control group. (primordial follicle count: SMD: 4.61, 95% CI 3.65–5.56, P < 0.00001; primary follicle count: SMD: 3.35, 95% CI 1.08–5.63, P = 0.004; secondary follicle count: SMD: 3.23, 95% CI 1.92–4.55, P < 0.00001; total follicle count: SMD: 4.84, 95% CI 2.86–6.83, P < 0.00001; oocyte count: SMD: 7.56, 95% CI 5.92–9.20, P < 0.00001; atretic follicle count: SMD: − 1.79, 95% CI − 2.59 to − 1.00, P < 0.00001). For the estrous cycle, stem cell therapy increased the number of estrous cycles (WMD: 2.72, 95% CI 2.07–3.37, P < 0.00001) and decreased the duration of the estrous cycle (WMD: − 1.26, 95% CI − 1.84 to − 0.69, P < 0.0001) compared with the control group. For pregnancy outcomes, stem cell therapy increased the fertility rate (RR: 3.00, 95% CI 1.74–5.17, P < 0.0001) and litter size (WMD: 3.82, 95% CI 0.36–7.28, P = 0.03) compared with the control group. In animal studies, the asymmetric funnel plot of serum E₂ and FSH levels indicated the possibility of publication bias. Unpublished and negative studies may be the source of publication bias. In clinical studies, the results showed that stem cell therapy could decrease serum FSH level (MD: − 30.32, 95% CI − 59.03 to − 1.01, P = 0.04) and increase AFC (MD: 1.07, 95% CI 0.70–1.43, P < 0.00001), pregnancy rate (RD: 0.19, 95% CI 0.04–0.34, P = 0.01) and live birth rate (RD: 0.19, 95% CI 0.07–0.31, P = 0.001) in POI patients. In addition, there was no significant difference in menstrual function regained (RD: 0.22, 95% CI − 0.03–0.46, P = 0.09), oocytes retrieved (MD: 1.00, 95% CI − 0.64–2.64, P = 0.23) and embryos (MD: 0.80, 95% CI − 0.15–1.76, P = 0.10) between different groups. Conclusion This meta-analysis suggested that stem cell therapy might be effective in POI mouse models and patients and could be considered a potential treatment to restore fertility capability in POI patients.

Association between Folic Acid Supplementation and Hypertensive Disorder Complicating Pregnancy in Jiangsu Province: A Cross-Sectional Study: Objectives. To investigate the association of folic acid (FA) supplementation with hypertensive disorder complicating pregnancy (HDCP) and preeclampsia in Jiangsu Province, China. Materials and Methods. In this cross-sectional study, a total of 10,662 women with infants born between January 2017 and December 2018 were enrolled in Jiangsu Province, China. Maternal women with and without FA supplement intake were compared in this study. FA supplementation included 0.4 mg FA (0.4 FA), multivitamins with 0.4 mg FA (multivitamin (MV)+0.4 FA), and multivitamins with 0.8 mg FA (MV + 0.8 FA). Associations between FA intake, FA supplement dose or duration, (MV + FA) dosage per weight, and HDCP were analysed using ANOVA, the chi-square test, and logistic regression analysis. Results. Over the study follow-up period, the incidences of HDCP and preeclampsia were 3.5%, 1.4%, and 2.2%, 0.6% in the non-FA supplementation and FA supplementation groups, but only 1.5% and 0.1% in the MV + 0.8 FA group in early pregnancy. Compared with the non-FA group, HDCP and preeclampsia had the lowest risk in the MV + 0.8 FA group among the seven FA supplementation groups (HDCP: RR = 0.42, 95% CI = 0.27-0.68, ; preeclampsia: RR = 0.09, 95% CI = 0.03–0.33, ) in early pregnancy. Compared with the 0.4 FA alone group, the risk of HDCP and preeclampsia in women taking MV + 0.8 FA was significantly reduced (RR = 0.60, 95% CI = 0.41–0.87, ; preeclampsia: RR = 0.18, 95% CI = 0.06–0.60, ) in early pregnancy. (MV + FA)/BMI supplementation was associated with the risk of HDCP in early pregnancy ( trend = 0.002). Conclusions. MV supplement with 0.8 mg FA during early pregnancy may be effective in reducing HDCP and preeclampsia risk. The study provided the viewpoint that (MV + FA)/BMI could be used as a reference for FA intake in pregnant women of different weights.

Recent studies have shown that two common methylenetetrahydrofolate reductase ( MTHFR ) gene polymorphisms (C677T and A1298C) might correlate with thyroid dysfunction, but the results remain inconsistent. We carried out a meta-analysis aiming to assess the relationship of both polymorphisms with thyroid dysfunction. The PubMed, EMBASE, CNKI (China National Knowledge Infrastructure), CBMdisc (China Biology Medicine disc), WeiPu and Wanfang databases were searched up to September 2021. Case-control and cohort studies on MTHFR polymorphism and thyroid dysfunction were identified. Eight [...] ABSTRACT Recent studies have shown that two common methylenetetrahydrofolate reductase ( MTHFR ) gene polymorphisms (C677T and A1298C) might correlate with thyroid dysfunction, but the results remain inconsistent. We carried out a meta-analysis aiming to assess the relationship of both polymorphisms with thyroid dysfunction. The PubMed, EMBASE, CNKI (China National Knowledge Infrastructure), CBMdisc (China Biology Medicine disc), WeiPu and Wanfang databases were searched up to September 2021. Case-control and cohort studies on MTHFR polymorphism and thyroid dysfunction were identified. Eight

Animal studies have demonstrated that myeloid cell leukemia-1 (Mcl-1) gene deficiency leads to premature ovarian failure and decreased reproductive ability in mice. This study investigated the rela... 目的：动物研究表明, Mcl-1基因缺陷导致小鼠卵巢早衰和生殖能力下降。本研究调查了中国女性 MCL-1 基因变异与早发性卵巢功能不全（POI）之间的关系。方法：本研究共招募200名早发性卵巢功能不全患者和100名健康对照者, 采集外周血。首先, 从外周白细胞中提取基因组 DNA。然后, 通过聚合酶链反应扩增 MCL-1 基因的整个编码区和剪接位点。卡方检验用于比较 POI 组和对照组之间单...

HFM1 (helicase for meiosis 1) is widely recognized as an ATP-dependent DNA helicase and is expressed mainly in germ-line cells. HFM1 is a candidate gene of premature ovarian failure (POF), hence it is also known as POF9. However, the roles of HFM1 in mammalian oocytes remain uncertain. To investigate the functions of HFM1, we established a conditional knockout (cKO) mouse model. Specific knockout of Hfm1 in mouse oocytes from the primordial follicle stage resulted in depletion of ovarian follicular reserve and subfertility of mice. In particular, abnormal spindle, misaligned chromosomes, loss of cortical actin cap, and failing polar body extrusion were readily observed in Hfm1-cKO oocytes. Further studies indicated that in addition to its cytoplasmic distribution, Hfm1 accumulated at the spindle poles, colocalized with the Golgi marker protein, GM130. Generally, GM130 signals overlapped with p-Mapk at the two spindle poles to regulate meiotic spindle assembly and asymmetric division. In this research, centrosome associated proteins, such as GM130 and p-Mapk, detached from the spindle poles in Hfm1-cKO oocytes. In conclusion, our data suggest that Hfm1 participates in Golgi-associated spindle assembly and division in mouse oocyte meiosis. These findings provide clues for pathogenesis of POF.