Clinical Analysis of Risk Factors and Perinatal Outcomes in Recurrent Pre-Eclampsia with Severe Features.

To analyze the differences in risk factors and pregnancy outcomes between recurrent and initial pre-eclampsia(PE) with severe features. Data from recurrent (n = 128) and initial (n = 904) PE with severe features who terminated their pregnancy or gave birth at 20 weeks of gestation or later at the tertiary teaching hospital (Women's Hospital of Nanjing Medical University, Nanjing Women and Children's Healthcare Hospital) from January 2016 to December 2022 were collected. Risk factors for recurrent PE with severe features and differences in pregnancy outcomes between the two groups were assessed using the chi-square test, student t-test, or nonparametric test. Independent risk factors for recurrent PE with severe features were further analyzed by logistic regression. (1) Logistic regression analysis identified 3 independent risk factors for recurrent PE with severe features: history of cesarean section, rural residence and chronic hypertension. In addition, assisted reproductive technology (ART) is an independent risk factor for initial PE with severe features; (2) The incidence of oligohydramnios, chorioamnionitis, preterm birth, stillbirth, fetal growth restriction (FGR) and abnormal umbilical blood flow was higher in the recurrent PE with severe features group than in the initial PE with severe features group(P < 0.05). In contrast, the incidence of premature rupture of membrane (PROM) and postpartum hemorrhage (PPH) was higher in the group of initial PE with severe features(P < 0.05); (3) In the recurrent PE with severe features group, gestational age(GA) of birth and birth weight were lower than those in the initial PE with severe features group(P < 0.05). Also, the incidence of mild asphyxia, the rate of neonatal intensive care unit (NICU) hospitalization, length of stay in NICU, and the rate of abandoning treatment in the recurrent PE with severe features group were higher than those in the initial PE with severe features group(P < 0.05). 3 independent risk factors was identified for recurrent PE with severe features: history of cesarean section, rural residence and chronic hypertension. Women with recurrent PE with severe features are more likely to have adverse perinatal outcomes than those with initial PE with severe features.

Peptide derived from RAGE efficiently improves oocyte development through attenuating oxidative stress in oocytes of mice with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a common and complex endocrine disorder in reproductive-aged women that frequently leads to infertility due to poor oocyte quality. In this study, we identified a new active peptide (advanced glycation end products receptors RAGE344-355 ) from PCOS follicular fluid using mass spectrometry. We found that supplementing PCOS-like mouse oocytes with RAGE344-355 attenuated both meiotic defects and oxidative stress levels, ultimately preventing developmental defects. Additionally, our results suggest that RAGE344-355 may interact with eEF1a1 to mitigate oxidative meiotic defects in PCOS-like mouse oocytes. These findings highlight the potential for further clinical development of RAGE344-355 as a potent supplement and therapeutic option for women with PCOS. This research addresses an important clinical problem and offers promising opportunities for improving oocyte quality in PCOS patients.

Expression profiles of circular RNAs in spermatozoa from aging men.

BACKGROUND: Advanced paternal age (APA) is associated with decreased fertility, but the mechanism underlying APA remains unknown. CircRNAs have been reported to be ideal candidate biomarkers for diagnostic and therapeutic applications in many diseases and are also involved in spermatogenesis. Hence, we aimed to assess the circRNA expression profile of spermatozoa from aging men. METHODS AND RESULTS: We recruited 6 subjects, including 3 in the younger group (men age < 40) and 3 in the APA group (men age ≥ 40). RNA sequencing was exploited to identify the expression profiles of circRNAs between the two groups. The expression levels of circRNAs were validated using real-time quantitative polymerase chain reaction (RT-qPCR). Kyoto Encyclopedia of Genes and Genomes biological pathway analysis and Gene Ontology analysis were performed to evaluate the functions of differentially expressed circRNAs (DE-circRNAs) between the two groups. In total, 18,787 circRNAs were sequenced in the spermatozoa of two groups. Our analysis revealed that there were 1056 downregulated circRNAs and 1228 upregulated circRNAs between the two groups, and KEGG analysis showed they were mainly involved in pathways including the DNA repair signaling pathway, meiotic recombination signaling pathway, and PI3K/AKT signaling pathway. CONCLUSIONS: In conclusion, our study suggested that circRNAs play a vital role in spermatozoa from aging men and provided a fresh perspective on the specific regulatory mechanism of spermatozoa from aging men.

The COL-4A1 polypeptide destroy endothelial cells through the TGF-ß/PI3K/AKT pathway.

Preeclampsia (PE) is commonly considered as a placental disorder in pregnancy. Until now, the etiology and pathological mechanism of PE have remained ambiguous. Although PE can lead to a variety of maternal and infant complications, there are still no effective treatments. This study aimed to explore the correlation between the novel polypeptide COL-4A1 and PE, and to identify the underlying mechanism by which this polypeptide may function and to explore new therapeutic targets for PE. A rat model of PE was established and used to verify the function of the polypeptide COL-4A1 in vivo. Additionally, human umbilical vascular endothelial cells (HUVECs) were cultured with or without COL-4A1 and TNF-α (20 ng/ml). Cell Counting Kit-8 (CCK-8), wound-healing, Transwell and tube formation assays were used to evaluate cell proliferation, migration and angiopoiesis. RNA sequencing and mass spectrometry were conducted to explore the underlying downstream mechanism of COL-4A1. In vivo, COL-4A1 increased blood pressure and elevated the risk of fetal growth restriction (FGR) which was induced by lipopolysaccharide (LPS) in the rat model. In vitro, COL-4A1 significantly inhibited the proliferation and migration of HUVECs. After culture with COL-4A1, compared to control group the adhesive ability and level of reactive oxygen species (ROS) were enhanced and tube formation ability was decreased. Furthermore, Western blotting (WB) and pull-down assays were conducted to explore the underlying mechanism by which COL-4A1 functions, and the TGF-ß/PI3K/AKT pathway was identified as the potential pathway involved in its effects. In summary, these results revealed that the polypeptide COL-4A1 caused PE-like symptoms in cells and a rat model. Through the TGF-ß/PI3K/AKT pathway, COL-4A1 interferes with the pathogenesis of PE. Thus COL-4A1 is expected to become a potential target of PE, providing a basis for exploring the treatment of PE.

The Association Between ABO Blood Group and Preeclampsia: A Systematic Review and Meta-Analysis.

Objective: This meta-analysis comprehensively evaluated the association between ABO blood group and the risk of preeclampsia (PE). Design: Systematic review and meta-analysis. Data sources: PubMed, Web of Science, and ScienceDirect databases from their inception to September 23, 2020. Methods: Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were obtained through random-effects and fixed-effects models according to heterogeneity. Meta-regression analysis was applied to explore the source of heterogeneity. We conducted a subgroup analysis by the publication year, study design, state, and Newcastle-Ottawa Scale (NOS) score. In addition, we calculated the rate of each ABO blood group in PE by total pooled effects. Results: A total of 12 articles with 714,153 patients were included in our analysis. Compared with people without PE (control group), the O blood group presented a lower risk of PE (OR 0.95, 95% CI 0.93-0.97). The AB (OR 1.46, 95% CI 1.12-1.91) blood group presented a higher risk. However, the total pooled OR and 95% CI for the A (OR 1.02, 95% CI 0.90-1.16) and B (OR 1.02, 95% CI 0.98-1.05) blood groups were not significant. The funnel plot and linear regression equation showed that there was no publication bias for the O, A, or B blood groups (all P > 0.05). However, the funnel plot and linear regression equation for the AB blood group were obviously asymmetric (P < 0.05), and the publication bias persisted even after the trim-and-fill method was applied (P < 0.05). Multivariable meta-regression analysis did not find a specific source of heterogeneity. The A blood group showed an association with early-onset PE (OR 0.53, 95% CI 0.33-0.83), and the other blood groups showed no significant differences. In PE, the rates of the O, A, B, and AB blood groups decreased gradually (0.39, 0.33, 0.19, 0.07). Conclusion: These findings suggest that pregnant women with AB blood group are more likely to develop PE, and more attention should be paid to AB blood group whose blood pressure is high but not sufficient to diagnose PE. Systematic Review Registration: Prospero CRD42021227930.

MiR-141-3p downregulation promotes tube formation, migration, invasion and inhibits apoptosis in hypoxia-induced human umbilical vein endothelial cells by targeting Notch2.

Vascular endothelial cell damage is regarded as the carrier in the progression of the pathological changes of preeclampsia (PE) from the placenta to maternal organs. MicroRNA (miR)-141-3p was aberrantly expressed during PE pathogenesis. We investigated the role of miR-141-3p in regulating the biological behaviors of endothelial cells in PE. Human umbilical vein endothelial cells (HUVECs) were isolated from the human umbilical cords and cultured under hypoxia condition to establish PE models. The binding of miR-141-3p and Notch2 was confirmed by dual-luciferase reporter assay. HUVECs were transfected with miR-141-3p inhibitor and siRNA-Notch2. The viability, vascularization capability, migration, and invasion of HUVECs were evaluated by MTT, tube formation, and Transwell assays. Cell apoptosis was measured via flow cytometry. The expressions of miR-141-3p, Notch2, Bcl-2, Bax and cleaved caspase-3 were assessed by qRT-PCR or Western blot. MiR-141-3p expression was upregulated in the HUVECs isolated from PE tissues and hypoxia-induced HUVECs. Hypoxia treatment inhibited viability, tube formation, migration, and invasion, and promoted apoptosis in HUVECS, as well as increased Bax and cleaved caspase-3 expressions and decreased Bcl-2 expression. Downregulating miR-141-3p expression promoted viability, tube formation, migration and invasion, and inhibited apoptosis in HUVECs, counteracting the effect of hypoxia on HUVECs. MiR-141-3p directly targeted Notch2. Silencing Notch2 reversed the promoting effect of downregulated miR-141-3p expression on HUVECs. In conclusion, downregulating miR-141-3p expression during hypoxia promotes tube formation, migration, and invasion and inhibits apoptosis in HUVECs by targeting Notch2.

Distinct expression profiles of peptides in placentae from preeclampsia and normal pregnancies.

This study sought to identify potential bioactive peptides from the placenta that are involved in preeclampsia (PE) to obtain information about the prediction, diagnosis and treatment of PE. The liquid chromatography/mass spectrometry was used to perform a comparative analysis of placental peptides in normal and PE pregnancies. Gene ontology (GO), pathway analysis and ingenuity pathway analysis (IPA) were used to evaluate the underlying biological function of the differential peptides based on their protein precursors. Transwell assays and qPCR were used to study the effect of the identified bioactive peptides on the function of HTR-8/SVneo cells. A total of 392 upregulated peptides and 420 downregulated peptides were identified (absolute fold change ≥ 2 and adjusted P value < 0.05). The GO analysis, pathway analysis, and IPA revealed that these differentially expressed peptides play a role in PE. In addition, the up-regulated peptide "DQSATALHFLGRVANPLSTA" derived from Angiotensinogen exhibited effect on the invasiveness of HTR-8/SVneo cells. The current preliminary research not only provides a new research direction for studying the pathogenesis of PE, but also brings new insights for the prediction, diagnosis and treatment of PE.

Cys-peptide mediates the protective role in preeclampsia-like rat and cell models.

OBJECTIVE: The present study was designed to investigate whether the novel peptide cysteine-based peptide (Cys-peptide) had protective effects on preeclamptic animal and cell models. METHODS: We investigated effects of Cys-peptide on (1) preeclamptic symptoms (e.g. hypertension, proteinuria, fetal growth restriction (FGR)) in preeclampia-like rat models induced by lipopolysaccharides (LPS), (2) TNFα-induced cytotoxicity of human umbilical vascular endothelial cells (HUVECs) and HTR-8 cells (an immortalised human trophoblast cell line), (3) endothelial dysfunction and injured angiogenesis, (4) migration and invasion of trophoblast cells induced by TNFα. RESULTS: Cys-peptide ameliorated LPS-induced hypertension, proteinuria and FGR and other PE symptoms in preeclampia-like rat models. In addition, Cys-peptide attenuated TNFα-induced cytotoxicity by decreasing soluble fms-like tyrosine kinase-1 (sFlt-1), endothelin-1 (ET-1) and tissue plasminogen activator (tPA) mRNA expression in both cells. Furthermore, Cys-peptide restored endothelial dysfunction and rescued angiogenesis caused by TNFα in vitro. Importantly, Cys-peptide could reverse insufficient ability to invade and migrate of trophoblast cells. CONCLUSIONS: These results suggest Cys-peptide can play beneficial roles in preeclampsia-like rat and cell models. Therefore, we propose that Cys-peptide is probably a novel therapeutic candidate for PE.

In vitro fertilization is associated with the onset and progression of preeclampsia.

OBJECTIVE: We aimed to estimate the risk of preeclampsia (PE) associated with in vitro fertilization (IVF) and potential predisposing factors responsible for the observed association. METHODS: This retrospective cohort study included 114485 pregnant women who delivered at the Nanjing Maternity and Child Health Care Hospital between 2013 and 2018. Of the 114485 women, 4601 (4%) conceived through IVF (IVF group) and 109884 (96%) conceived spontaneously (SC group). We performed logistic regression analysis to evaluate the risk of PE following IVF compared to spontaneous conception (SC). Then, we used propensity score matching analysis to compare the clinical characteristics and pregnancy outcomes between IVF patients with and without PE. RESULT: There were 1339 PE cases in the total study population, with a significantly higher incidence of PE in IVF relative to spontaneous pregnancies (6.1% vs. 1.0%, p < 0.01). Severe PE was more prevalent in singleton IVF-PE group than in singleton SC-PE group (40% vs. 24.1%, p = 0.025). Placenta accreta was more common in singleton preeclamptic patients with IVF than without IVF (12.5vs.2.6%, p = 0.003). Placental hypoxia was more prevalent in twin IVF pregnancies with PE than without PE (6% vs. 12.2%, p = 0.045). Moreover, the IVF-PE group showed more frequent first-trimester bleeding (31.6% vs. 10.5%, p = 0.024) compared to the control group. CONCLUSION: IVF is associated with the onset and progression of PE. Defective placentation and placental insufficiency may predispose IVF patients to PE and may manifest as first-trimester bleeding.

Upregulation of SCNN1A Promotes Cell Proliferation, Migration, and Predicts Poor Prognosis in Ovarian Cancer Through Regulating Epithelial-Mesenchymal Transformation.

Background: There is little knowledge about the biological roles and clinical significance of SCNN1A in ovarian cancer. Thus, the objective of this study was to investigate the biological functions and prognosis value of SCNN1A in ovarian cancer to further seek a potential therapeutic target for patients with ovarian cancer. Materials and Methods: First, the expression level of SCNN1A in ovarian cancer samples obtained from ONCOMINE database was determined, and its expression in cell lines was also investigated. Moreover, correlation analysis was performed to determine the relationship between SCNN1A expression and prognosis in ovarian cancer patients according to the data obtained from GEPIA database and Kaplan-Meier plotter website. The biological roles of SCNN1A on cell growth, migration, and invasion were then examined by knockdown of SCNN1A in ovarian cancer cell line SK-OV-3. Ultimately, Western blotting analysis was carried out to investigate the expression of epithelial-mesenchymal transformation markers (including E-cadherin, N-cadherin, Vimentin, and Snail) after silencing SCNN1A. Results: Based on the ONCOMINE-related data and cell lines, SCNN1A was observed to be overexpressed in ovarian cancer samples and cell lines. Survival analysis showed that high expression of SCNN1A was associated with poor overall survival and progression-free survival in ovarian cancer patients. In addition, SCNN1A silence remarkably blocked SK-OV-3 cell growth ability, migration, and invasion potential. Western blotting results showed that SCNN1A silence led to an increase in E-cadherin, whereas a decrease in N-cadherin, Vimentin, and Snail in SK-OV-3 cells. Increased E-cadherin and decreased N-cadherin, Vimentin, as well as Snail inhibited cell invasion of ovarian cancer. Conclusions: SCNN1A might exert crucial roles in cell growth and invasion and migration in ovarian cancer, and might be a potential indicator for prognosis and a therapeutic target for ovarian cancer patients.