Successful delivery after in vitro fertilization-embryo transfer in a woman with metachronous primary cancer of ovary and endometrium: a case report.

BACKGROUND: The appearance of malignancies at various times in the same individual, excluding metastases of the initial primary cancer, is termed multiple primary cancers. Double primary gynecological cancers cause inevitable damage to female reproductive function, and the preservation of fertility in such patients remains a challenging issue as relatively few cases have been reported. This case report provides management options for dual primary ovarian and endometrial cancers, including the choice of ovulation induction protocols, considerations during pregnancy and parturition, with the aim of providing assistance to clinicians. CASE PRESENTATION: We report a case of a 39-year-old woman with primary infertility and a medical history of right-sided ovarian mucinous borderline tumor with intraepithelial carcinoma, left-sided ovarian mucinous cystadenoma and endometrial cancer, who successfully conceived with in vitro fertilization-embryo transfer (IVF-ET) after three different ovulation induction protocols. During her pregnancy, she was complicated by central placenta praevia with placental implantation and eventually delivered a healthy female infant by caesarean section at 33 gestational weeks. CONCLUSIONS: For patients with double primary gynecological cancers who have an intense desire for fertility, the most appropriate oncological treatment should be applied according to the patient's individual situation, and fertility preservation should be performed promptly. Ovulation induction protocol should be individualized and deliberate, with the aim of ensuring that the patient's hormone levels do not precipitate a recurrence of the primary disease during induction of ovulation and maximizing fertility outcomes. In addition, the risk of postpartum hemorrhage due to placental factors cannot be neglected in such patients.

Successful pregnancy and delivery after ovulation induction therapy in a woman with congenital hypogonadotropic hypogonadism: a case report.

BACKGROUND: Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder resulting from a deficient secretion of the episodic gonadotropin-releasing hormone, leading to delayed or absent puberty and infertility. In female patients with CHH, the most commonly used treatment is gonadotropin (Gn) therapy. Due to the rarity of the disease in females, there are limited case reports available. This article offers a management approach for this unusual disease that can be helpful for clinicians. CASE PRESENTATION: We report the case of a 29-year-old woman who successfully achieved pregnancy and delivered healthy twin girls after ovulation induction therapy. The patient was diagnosed with CHH at 18 years of age due to primary amenorrhea and the absence of secondary sexual characteristics. After experiencing infertility for three years, the patient sought medical assistance for conceiving. The patient was treated with gonadotropin therapy due to anovulation. In her first treatment cycle, the initial dose of HMG used for treatment was 75IU, which was increased to 150IU after six days. However, the cycle was canceled due to follicular dysplasia. In the second cycle, the treatment began with an initial dose of 150IU, and the follicles grew normally, but the estrogen level was low. Consequently, the treatment was interrupted. In a third ovulation stimulation cycle, HMG was adjusted to 150IU, and recombinant LH was added. After 12 days of ovulation, three mature follicles grew, the estrogen level was normal,and the treatment resulted in successful ovulation and subsequent pregnancy. At 35 weeks of gestation, the patient underwent a cesarean section and delivered two healthy female infants weighing 2,405 g and 2,755 g with an Apgar score of 10/10. CONCLUSIONS: Early diagnosis and timely and appropriate hormone replacement therapy are important for future pregnancy. Ovulation induction therapy is necessary to stimulate fertility. Gn therapy is a feasible and effective treatment for reproduction in CHH females, but the selection of Gn type and dosage must be personalized to maximize fertility outcomes. Effective treatment is available not only for inducing estrogenization and promoting fertility, but also for addressing concerns about psychological and emotional well-being.

LINC02190 inhibits the embryo-endometrial attachment by decreasing ITGAD expression.

Recurrent implantation failure (RIF) is a challenge in the field of reproductive medicine, but mechanisms for its occurrence remain still unclear. Long non-coding RNAs (lncRNAs) have been found to play a vital role in many different diseases. In recent years, the differentially expressed lncRNAs have been reported in endometrial tissues. Here, we profiled dysregulated lncRNAs and mRNAs in the endometrial tissues of RIF patients and performed correlation analysis. We found that LINC02190 was upregulated in RIF endometrium and was bound to the integrin αD (ITGAD) mRNA promoter. Immunofluorescence assays were used to detect the location of ITGAD in the Ishikawa cell line and patients' endometrial biopsies. Overexpressed LINC02190 could decrease the expression of ITGAD and the adhesion rate of Ishikawa and JAR cells. Knockdown of the expression of LINC02190 significantly increased the ITGAD level, as well as the adhesion rate of Ishikawa and JAR cells. Furthermore, we demonstrated that the 150-250 bps of LINC02190 were the cis-elements involved in the regulation of ITGAD promoter activities. In conclusion, the results demonstrated that LINC02190 plays an important role in the occurrence of RIF, and the molecular mechanism may be associated with the embryo-endometrial attachment mediated by ITGAD. This study emphasizes the importance of lncRNAs in the occurrence of RIF and provides a potential new biomarker for diagnosis and therapies.

The China birth cohort study (CBCS).

The China birth cohort study (CBCS) is a prospective longitudinal, mega-cohort study and the first national-based birth cohort study, aiming to establish a birth cohort covering representative geographical areas of the whole of China to investigate risk factors for birth defects and develop strategies for their reduction. Pregnant women who are of Chinese nationality, are 6-13+6 weeks of gestation, plan to attend the routine antenatal examination and deliver in the study site, and give their informed, written consent are eligible to participate in this study. All participants are followed-up through an in-person interview at 20-23+6 weeks and again at 28-33+6 weeks of gestation, and at delivery, respectively. CBCS has been divided into three phases from 20th November 2017 to 31st December 2021, and the first two phases have now been completed on 29th February 2020, enrolling 120 377 eligible pregnant women during this period. During the same period a total of 40 837 participants had been followed up to the end of pregnancy. Study recruitment will continue until December 2021 to achieve the target of 500 000 participants. Meanwhile, biological samples including peripheral blood, amniocytes, cord blood, placenta, or umbilical cord tissue have been collected from participants according to various conditions. The incidence of birth defects in this group is 2.5% and congenital heart disease is the most common type of birth defect seen so far. A website is in the advanced stages of planning, to allow seamless data transfer and facilitate collaboration with groups around the world.

Vasomotor tone-associated factors and pregnancy outcomes of women who undergo in vitro fertilization.

Vasomotor tone-associated factors play important roles in normal pregnancy, but their roles in the pregnancy outcome of women who undergo in vitro fertilization and embryo transfer (IVF-ET) remain unclear. A total of 82 infertile women who underwent successful IVF-ET were enrolled, including 18 pregnancy losses, 11 complications, and 53 normal deliveries. The serum NO and iNOS levels were significantly higher in the pregnancy loss group and significantly lower in the complication group than in the normal delivery group (p < 0.05). Significantly increased ET-1 and decreased PGI2 were found in both the pregnancy loss and complication groups compared with those in the normal delivery group (p < 0.05). NO, iNOS, and ET-1 are risk factors and PGI2 is a protective factor for pregnancy loss. ET-1 + PGI2 (AUC, 0.897; sensitivity, 90.6%; specificity, 83.3%) showed a relatively good predictive value for pregnancy loss following IVF-ET.

Progesterone-induced blocking factor-mediated Th1/Th2 balance correlates with fetal arrest in women who underwent in vitro fertilization and embryo transfer.

The role of progesterone-induced blocking factor (PIBF)-mediated Th1/Th2 balance in delivery outcomes of in vitro fertilization and embryo transfer (IVF-ET) has not been fully elucidated. In this study, 73 infertile women with successful IVF-ET were enrolled (16 fetal arrests and 57 live births). PIBF and IL-4 levels were significantly lower in the fetal arrest group than in the live birth group (p < 0.05). TNF-α level and Th1/Th2 ratios were significantly higher in the fetal arrest group than in the live birth group (p < 0.05). High TNF-α level and Th1/Th2 ratios were risk factors for fetal arrest, whereas increased PIBF and IL-4 levels were protective factors (P < 0.05). Increased TNF-α/IL-4 exhibited relatively strong predictive value for fetal arrest (AUC, 0.855; sensitivity, 93.8%; specificity, 71.9%). In summary, the PIBF-mediated Th1/Th2 balance is closely correlated with delivery outcomes of IVF-ET. TNF-α/IL-4 may be a predictive marker of fetal arrest.

Clinical analysis of second-trimester pregnancy termination after previous caesarean delivery in 51 patients with placenta previa and placenta accreta spectrum: a retrospective study.

BACKGROUNDS: Pregnancy termination during the second trimester in patients with placenta previa and placenta accreta spectrum (PAS) is a complex and challenging clinical problem. Based on our literature review, there has been a relative increase in the number of such cases being treated by hysterotomy and/or local uterine lesion resection and repair. In the present study, a retrospective analysis was conducted to compare the clinical outcomes when different management strategies were used to terminate pregnancy in the patients with placenta previa and PAS. METHODS: A total of 51 patients who underwent pregnancy termination in the second trimester in Beijing Obstetrics and Gynecology Hospital between June 2013 and December 2018 were retrospectively analyzed in this study. All patients having previous caesarean delivery (CD) were diagnosed with placenta previa status and PAS. RESULTS: ① Among the 51 patients, 16 cases received mifepristone and misoprostol medical termination, 15 cases received mifepristone and Rivanol medical termination, but 1 of them was transferred to hysterotomy due to failed labor induction, another 20 cases were performed planned hysterotomy. There was no placenta percreta cases and uterine artery embolization (UAE) was all performed before surgery.② There were 31 cases who underwent medical termination and 30 cases were vaginal delivery. Dilation and evacuation (D&E) were used in 20 cases of medical abortion failure and in all 30 cases of difficult manual removal of placental tissue. ③ A statistically significant difference was found among the three different strategies in terms of gestational weeks, the type of placenta previa status, main operative success rate and ß-HCG regression time (P < 0.05). ④ There were 4(7.8%) cases who were taken up for hysterectomy because of life-threatening bleeding or severe bacteremia during or after delivery and hysterotomy. The uterus was preserved with the implanted placenta partly or completely left in situ in 47(92.2%) cases. Combined medical and/or surgical management were used for the residual placenta and the time of menstrual recovery was 52(range: 33 to 86) days after pregnancy termination. CONCLUSIONS: Terminating a pregnancy by vaginal delivery through medical induction of labor may be feasible if clinicians have an overall understanding of gestational age, the type of placenta previa status, the type of placenta accreta, and patients concerns about preserving fertility. A collaborative team effort in tertiary medical centers with a very experience MDT and combined application of multiple methods is required to optimize patient outcomes.

Transforming growth factor-ß1 increases lysyl oxidase expression by downregulating MIR29A in human granulosa lutein cells.

Lysyl oxidase (LOX), a key enzyme in the formation and stabilization of the extracellular matrix, is expressed in granulosa cells and plays a critical role in the regulation of granulosa cell differentiation, oocyte maturation and ovulation. To date, the regulation of LOX expression in human granulosa cells remains largely unknown. In this study, using primary and immortalized human granulosa lutein cells, we demonstrated that transforming growth factor (TGF)-ß1 (TGFB1) upregulated LOX expression and downregulated microRNA-29a (MIR29A) expression via a TGF-ß type I receptor-mediated signaling pathway. Additionally, we showed that MIR29A downregulated the expression of LOX in both types of cells. Furthermore, the downregulation of MIR29A contributed to the TGFB1-induced increase in LOX expression because the inhibition of MIR29A with a MIR29A inhibitor not only reversed the MIR29A-induced downregulation of LOX but also enhanced the TGFB1-induced upregulation of LOX. Our findings suggest that TGFB1 and MIR29A may play essential roles in the regulation of extracellular matrix remodeling during the periovulatory phase.

miR-23a and miR-27a promote human granulosa cell apoptosis by targeting SMAD5.

In mammals, follicular atresia can be partially triggered by granulosa cell apoptosis. However, very little is known about the functions of miRNAs in granulosa cell apoptosis. We previously reported that hsa-mir-23a (miR-23a) and hsa-mir-27a (miR-27a) were highly expressed in the plasma of patients with premature ovarian failure, but the action of these two miRNAs in follicular development was unclear. In this study, we explored the roles of miR-23a and miR-27a in the granulosa cells of women undergoing in vitro fertilization/embryo transfer. Using Hoechst staining, we found that miR-23a and miR-27a promoted apoptosis in human granulosa cells. In addition, the Western blotting results suggested that the miR-23a/miR-27a-mediated apoptosis occurred via the FasL-Fas pathway. Based on the results of a luciferase-reporter assay and quantitative RT-PCR and Western blotting analyses, we found that SMAD5 is a target gene of both miR-23a and miR-27a. Furthermore, knocking down SMAD5 expression increased the rate of apoptosis, as well as the levels of Fas, FasL, cleaved caspase-8, and cleaved caspase-3 protein. Taken together, these data suggest that miR-23a and miR-27a target SMAD5 and regulate apoptosis in human granulosa cells via the FasL-Fas pathway. These findings provide an improved understanding of the mechanisms underlying granulosa cell apoptosis, which could potentially be used for future clinical applications.

The dynamic changes of anti-Mullerian hormone and inhibin B during controlled ovarian hyperstimulation in decreased ovarian reserve women and the effect on clinical outcome.

OBJECTIVE: To investigate the dynamics of anti-Mullerian hormone (AMH) and inhibin B (INHB) levels during controlled ovarian hyperstimulation (COH) in women with decreased ovarian reserve (DOR), and assess the effect of these dynamic changes on the prediction of clinical outcome in in-vitro fertilization (IVF). METHODS: A total of 124 women undergoing IVF cycles were divided into normal ovarian reserve (NOR) and DOR groups. AMH and INHB levels were measured in serum on menstrual cycle day 2 or 3 (D2/3), day 5 of stimulation (D5), hCG day (D-hCG) and follicular fluid (FF) on oocyte retrieval day. RESULTS: Serum AMH levels were gradually decreased while INHB levels were gradually increased from D2/3 to D-hCG during the COH in both groups. Serum AMH, INHB levels on D2/3 and FF AMH, INHB levels were highly positively correlated with AFC and oocytes retrieval. Multivariate logistic regression analysis revealed that clinical pregnancy did not directly correlate with serum and FF AMH and INHB levels. CONCLUSION: Serum AMH and INHB levels were not directly related to clinical pregnancy, dynamic serum AMH and IHNB levels were positively correlated with COH outcomes.

A Case Report of Consecutive Live Birth Twice Through in vitro Fertilization and Embryo Transfer After Endometrial Carcinoma Fertility Preservation Treatment.

Preserving fertility is a vital concern for young women diagnosed with endometrial carcinoma. The clinical management of such patients is often disappointing. It is rare to have two consecutive successful pregnancies. We present a child-bearing-age woman who underwent fertility preservation therapy due to endometrial carcinoma. Following fertility preservation therapy, she underwent in vitro fertilization and embryo transfer. After receiving her first fresh embryo transfer, she successfully conceived and gave birth to a healthy child. Two years after the first embryo transfer and regular follow-up, she had another frozen embryo transfer of two cleavage embryos and successfully gave birth to another healthy baby. After the delivery of her second child, she underwent surgical treatment for endometrial carcinoma. For endometrial carcinoma patients who intend to preserve fertility, high-quality long-term follow-up and personalized treatment are necessary.

In this case report, we share the story of one young woman who had endometrial cancer but desired to have children. She received fertility-sparing treatment and in vitro fertilization to increase her chances of conceiving. She successfully delivered a healthy child after the first embryo transfer. Two years later, she had another healthy child through a second frozen embryo transfer. Rigorous monitoring showed no cancer recurrence throughout the entire treatment. There are currently few reported cases of a patient with endometrial cancer successfully and safely giving birth twice through assisted reproductive technology. This case report emphasizes that, with personalized treatment and monitoring, endometrial cancer patients can have multiple pregnancies safely. In summary, this case report brings hope to young women with early-stage endometrial cancer who aspire to become mothers. With the right support, they can overcome the challenges of cancer and have their own babies.

Aberrantly High FBXO31 Impairs Oocyte Quality in Premature Ovarian Insufficiency.

Premature ovarian insufficiency (POI), which is defined as loss of ovarian function that occurs before the age of 40, causes menstrual disturbances, infertility, and diverse health problems in females. Despite the limited understanding of the molecular basis underlying POI pathology, we had previously demonstrated that the cooperation of miR-106a and FBXO31 plays a pivotal role in diminished ovarian reserve (DOR), with FBXO31 serving as a putative target of miR-106a. In this study, we found that FBXO31 is aberrantly expressed in granulosa cells of POI patients, leading to accumulated reactive oxygen species (ROS) and cell apoptosis via the p53/ROS pathway. Furthermore, our results demonstrated that high levels of FBXO31 in mouse ovaries impair oocyte quality. Our study revealed that FBXO31 may serve as a novel indicator and play a significant role in the etiology of POI.

Premature Ovarian Insufficiency Is Associated with Increased Risk of Depression, Anxiety, and Poor Life Quality: A Systematic Review and Meta-analysis.

Background: Premature ovarian insufficiency (POI) seriously affects the reproductive health of women. Several studies have been conducted to show that POI appears to be associated with psychological and psychosocial problems, but whether POI increases the risk of mental health problems has not been identified. Therefore, this meta-analysis provides a preliminary systematic assessment of the studies published to date on the impact of POI on women's mental health. Methods: We implemented a systematic search for studies on this topic up to October 2022. Pooled odds ratios (ORs) and 95% confident intervals (CIs) of prevalence were used to assess the impacts of POI on various psychological factors, and the publication bias was assessed by Egger's test. Results: A total of 15 articles comprising 5820 participants were included in this meta-analysis. POI was found to be related to higher risk of 13 psychological and psychosocial problems identified and classified into 3 domains: depression (OR = 1.61; 95% CI: 1.11-2.33), anxiety (OR = 3.74; 95% CI: 1.78-7.87), and poor life quality (OR = 2.55, 95% CI: 1.63-3.97). Conclusion: This meta-analysis reveals that women with POI have an increased risk of depression, anxiety, and poor life quality. The marital status of POI may be a possible influencing factor for depression, meaning that the unmarried status in POI is at high risk of psychological and psychosocial problems. We should pay attention to the mental health of women with POI who were unmarried.

Role of the immune-kynurenine pathway in treatment-resistant schizophrenia.

BACKGROUND: The immune-inflammatory response system (IRS) and kynurenine pathway (KP) have been implicated in the pathophysiology of schizophrenia. Studies have shown inflammation-related effects on KP metabolism in patients with schizophrenia. This study investigated the relationship between KP metabolites, IRS, and the compensatory immune-regulatory reflex system (CIRS) in patients with treatment-resistant schizophrenia (TRS). METHODS: Patients with (n = 53) and without TRS (n = 47), and healthy controls (HCs, n = 49) were enrolled. We quantified plasma levels of pro-inflammatory cytokines (interleukin [IL]-1ß, IL-2, IL-6, soluble(s)IL-6 receptor, IL-8, IL-12, IL-17, IL-18, interferon-γ, and tumor necrosis factor[TNF]-α) and anti-inflammatory cytokines (IL-1 receptor antagonist, IL-4, IL-10, tumor growth factor [TGF]-ß1, TGF-ß2, soluble (s) IL-2 receptor subunit α, sIL-2 receptor subunit ß, and sTNF-α receptor 1) and calculated the IRS/CIRS ratio. We also tested serum metabolites of the KP, including kynurenine (KYN), kynurenic acid (KYNA), and quinolinic acid (QUIN), along with the QUIN/KYNA ratio. RESULTS: Patients with TRS had significantly higher IRS/CIRS ratio than non-TRS patients (p = 0.002) and HCs (p = 0.007), and significantly lower KYN (p = 0.001) and KYNA (p = 0.01) levels than HCs. Binary logistic regression analysis revealed that a younger age at illness onset (odds ratio [OR] = 0.91, p = 0.02) and a higher IRS/CIRS ratio (OR = 1.22; p = 0.007) were risk factors for patients with TRS. After further adjusted for age of onset, the QUIN/KYNA ratio (ß = 0.97; p = 0.02) significantly moderated the relationship between IRS/CIRS and TRS, showing that in the higher QUIN/KYNA condition, higher IRS/CIRS ratio were significantly and more likely to be associated with patients with TRS (ß = 0.12, z = 3.19, p = 0.001), whereas in the low QUIN/KYNA condition, the association between IRS/CIRS ratio and TRS was weak and insignificant. CONCLUSIONS: The peripheral immune response was imbalanced in TRS and was preferentially directed towards the IRS compared to patients without TRS and healthy controls, which is likely to play a role in neurotoxicity. Additionally, peripheral KP activation was also imbalanced, as evidenced by significantly reduced KYN and KYNA levels in patients with TRS compared to healthy controls, but none of KP metabolisms were significantly difference in non-TRS patients compared to healthy controls. QUIN/KYNA ratio involving to the degree of activation of NMDA receptors, indicated the neurotoxic level of the KP activation. The interaction between IRS/CIRS and QUIN/KYNA ratio was significant in predicting TRS, and our findings suggest a potential role for the immune-kynurenine pathway in TRS pathogenesis.

Exploration of Serum lipid levels during twin pregnancy.

Objective: This study aims to characterize changes in serum lipid levels throughout twin pregnancies and explore the relationship between lipid levels and gestational diabetes mellitus (GDM) and hypertensive disorders complicating pregnancy (HDCP).Methods: We retrospectively studied 297 twin pregnancies of women who received regular prenatal care and delivered at the Beijing Obstetrics and Gynecology Hospital over a period of two years. Demographic and medical data of the participants were collected by questionnaires and medical records review. Serum lipid levels were measured in the first trimester (6-13 weeks), second trimester (24-28 weeks), and third trimester (34-37 weeks). A multivariate regression model was constructed to examine the association between lipid levels and pregnancy complications. A decision tree was used to explore the relationship between early serum lipid glucose levels and GDM and HDCP in twin pregnancies.Results: Triglyceride (TG), total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels increased significantly from the first trimester to the third trimester, with the exception of high-density lipoprotein cholesterol (HDL-C), which decreased in the third trimester in twin pregnancies (p < 0.001). The levels of TC in the GDM and HDCP group were significantly elevated compared to those in the normal group in early pregnancies (p < 0.05, p < 0.05). In the second trimester, TG in the HDCP group was substantially higher than that in the normal group (p = 0.01). In the third trimester, LDL-C and HDL-C levels in the GDM group are significantly lower than that in the normal group (p < 0.05, p < 0.05). After adjusting for confounders, body mass index (BMI) is independently associated with GDM (odds ratio [OR] = 1.129, 95% confidence interval [CI]: 1.007-1.266) and HDCP(odds ratio [OR] = 1.170, 95% confidence interval [CI]: 1.031-1.329). The variation amplitude of HDL-C in the third trimester is related to the occurrence of GDM and HDCP(GDM:OR = 0.271, 95%CI: 0.095-0.778; HDCP: OR =0.249, 95% CI: 0.075-0.823). TG and TC levels in DCDA twins were significantly higher than that in MCDA twins in the first trimester(TG: p < 0.05, TC: p < 0.05). In the decision tree model for GDM, fasting blood glucose in the first trimester (FBG), TC, and pre-pregnancy BMI were identified as important nodes, while in the HDCP model, pre-pregnancy BMI, TC, and TG were key nodes.Conclusion: Serum lipid levels in twin pregnancies increase gradually during pregnancy. BMI is independently associated with the occurrence of GDM and HDCP. HDL-C may serve as a protective factor for GDM and HDCP. The predictive effect of early blood lipid on GDM and HDCP in twin pregnancy needs further study.

Differentially expressed plasma microRNAs in premature ovarian failure patients and the potential regulatory function of mir-23a in granulosa cell apoptosis.

Recent studies implicate the regulatory function of microRNAs (miRNAs) in oocyte maturation and ovarian follicular development. Differentially expressed miRNAs are found in the plasma of premature ovarian failure (POF) patients and normal cycling women. In this study, miRNA-regulated signaling pathways and related genes were described using Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis. The effect of mir-23a on granulosa cell apoptosis was also studied by examining the protein expression of X-linked inhibitor of apoptosis protein (XIAP) and caspase-3, followed by subsequent counting of apoptotic cells after Hoechst 33258 staining. Both GO analysis and pathway analysis suggested that many signaling pathways, including the AKT signaling pathway, steroid hormone receptor signaling pathways, and others, were regulated by this group of differentially expressed miRNAs. A decrease in XIAP expression (mRNA and protein level) and caspase-3 protein levels and an increase in cleaved caspase-3 protein were observed in human ovarian granulosa cells transfected with pre-mir-23a, along with an increased occurrence of apoptosis. In conclusion, differentially expressed miRNAs in the plasma of POF patients may have regulatory effects on proliferation and apoptosis of granulosa cells by affecting different signaling pathways. Mir-23a may play important roles in regulating apoptosis via decreasing XIAP expression in human ovarian granulosa cells.

Insulin-like growth factor 2 mRNA-binding protein 2-regulated alternative splicing of nuclear factor 1 C-type causes excessive granulosa cell proliferation in polycystic ovary syndrome.

OBJECTIVES: Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disorder. Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) serves as an HMGA2 target gene to promote the proliferation of granulosa cells (GCs). However, it is still unclear whether IGF2BP2 participates in the pathogenesis of PCOS as RNA binding protein (RBP). In this study, we aimed to elucidate IGF2BP2-interacting transcripts, global transcriptome together with alternative splicing in GCs to eventually uncover potential mechanisms of PCOS pathogenesis. MATERIALS AND METHODS: The expression of IGF2BP2 in GCs from PCOS patients was detected using quantitative reverse transcription PCR (RT-qPCR) and western blot. We captured IGF2BP2-interacting transcripts, global transcriptome together with alternative splicing by RNA immunoprecipitation sequencing (RIP-seq) and RNA sequencing (RNA-seq). KGN cells transfected with IGF2BP2 overexpressing plasmids and nuclear factor 1 C-type (NFIC) siRNAs, were applied to CCK-8, EdU and TUNEL assays. RESULTS: IGF2BP2 was highly expressed in GCs from PCOS patients. As an RBP, it preferentially bound to the 3'and 5'UTRs of mRNAs with GGAC motif and a newly found GAAG motif. The overexpression of IGF2BP2 changed the transcriptome profile of KGN cells. IGF2BP2 functioned to regulate alternative splicing events and promote cell proliferation through inhibiting exon skipping events of NFIC. CONCLUSION: In conclusion, we demonstrated that IGF2BP2 promotes GC proliferation via regulating alternative splicing of NFIC in PCOS. The findings help to better understand the roles of IGF2BP2 in the pathogenesis of PCOS.

Bone Mesenchymal Stem Cell-Derived Exosome-Enclosed miR-181a Induces CD4+CD25+FOXP3+ Regulatory T Cells via SIRT1/Acetylation-Mediated FOXP3 Stabilization.

Bone marrow mesenchymal stem cells (BMSCs) have been identified as a potential therapeutic approach to immune-related diseases. Here, we show that BMSC-derived exosomes promote FOXP3 expression and induce the conversion of CD4+ T cells into CD4+CD25+FOXP3+ Treg cells, which is significant for immunosuppressive activity. We found that miR-181a-5p is upregulated in BMSC-derived exosomes and can be transferred to CD4+ T cells. In CD4+ cells, miR-181a directly targets SIRT1 and suppresses its expression. Moreover, downregulated SIRT1 enhances FOXP3 via protein acetylation. In conclusion, our data demonstrated that BMSC-derived exosomal miR-181a is critical in the maintenance of immune tolerance. Furthermore, our results reveal that BMSC-derived exosomal miR-181a induces the production of CD4+CD25+FOXP3+ Treg cells via SIRT1/acetylation/FOXP3.

[Relationship between the Akt-regulated direct p53 mitochondrial translocation and the resistance to cisplatin of ovarian cancer cells].

OBJECTIVE: To explore Akt-regulated direct p53 mitochondrial translocation in cisplatin-induced apoptosis in ovarian cancer cells and the relationship between this and chemoresistance in ovarian cancer. METHODS: Chemosensitive ovarian cancer cell lines (OV2008 and A2780s) and chemoresistant cells (C13(*) and A2780cp) were treated with cisplatin and whole cell and mitochondrial p53 contents were determined by Western blot. The p53 accumulation in mitochondria was determined in purified mitochondrial fractions in cisplatin-sensitive and -resistant ovarian cancer cells. Akt1/2 siRNA were transfected into C13(*) cells. Cisplatin-induced apoptosis was measured by Hoechst staining and p53 translocation was determined by Western blot. RESULTS: Cisplatin induced mitochondrial p53 accumulation and apoptosis in chemosensitive cells (P < 0.05), but not in resistant cells (P > 0.05). Over-expression of active Akt2 inhibited p53 directly translocate to mitochondria, and downregulation of Akt by Akt1/2 siRNA increased p53 mitochondrial accumulation and sensitize C13(*) cells to cisplatin treatment. CONCLUSIONS: Cisplatin induces direct p53 mitochondrial accumulation in chemosensitive cells, and Akt confers resistance in ovarian cancer cells, in part, by regulating the direct action of p53 in mitochondrial death pathway.