Exploring the role of exosomal MicroRNAs as potential biomarkers in preeclampsia.

The complex pathogenesis of preeclampsia (PE), a significant contributor to maternal and neonatal mortality globally, is poorly understood despite substantial research. This review explores the involvement of exosomal microRNAs (exomiRs) in PE, focusing on their impact on the protein kinase B (AKT)/hypoxia-inducible factor 1-α (HIF1α)/vascular endothelial growth factor (VEGF) signaling pathway as well as endothelial cell proliferation and migration. Specifically, this article amalgamates existing evidence to reveal the pivotal role of exomiRs in regulating mesenchymal stem cell and trophoblast function, placental angiogenesis, the renin-angiotensin system, and nitric oxide production, which may contribute to PE etiology. This review emphasizes the limited knowledge regarding the role of exomiRs in PE while underscoring the potential of exomiRs as non-invasive biomarkers for PE diagnosis, prediction, and treatment. Further, it provides valuable insights into the mechanisms of PE, highlighting exomiRs as key players with clinical implications, warranting further exploration to enhance the current understanding and the development of novel therapeutic interventions.

Establishment of a placental lncRNA-mRNA expression network for early-onset preeclampsia.

BACKGROUND: This study aimed to establish a placental long non-coding RNA (lncRNA)-mRNA expression network for early-onset preeclampsia (early-onset PE). METHODS: The RNA sequencing data of the GSE14821 dataset were acquired. Several crucial lncRNAs and mRNAs were exerted based on the differential expression analysis of lncRNA and mRNA. By analyzing the differentially expressed lncRNA and mRNA, we constructed a regulatory network to explore the mechanism of the lncRNA in early onset preeclampsia. RESULTS: A total of 4436 differentially expressed lncRNAs (DElncRNAs) were identified in early-onset PE placenta samples compared with control placenta samples. Pearson correlation analysis revealed significant correlations between 3659 DElncRNAs and 372 DEmRNAs. KEGG analysis showed that the DEmRNAs were enriched in cytokine-cytokine receptor and hypoxia-inducible factor (HIF)-1 pathways. Several well-known early-onset PE-related mRNAs, such as vascular endothelial growth factor A (VEGFA) and VEGF receptor 1 (FLT1), were involved in the two pathways. Weighted gene co-expression network analysis and cis-regulatory analysis further suggested the involvement of the two pathways and potential DElncRNA-DEmRNA interactions in early-onset PE. Moreover, the upregulation of representative DElncRNAs, such as RP11-211G3.3 and RP11-65J21.3, and DEmRNAs, such as VEGFA and FLT1, were validated in clinical placenta samples from patients with early-onset PE by quantitative reverse transcription PCR. Importantly, overexpression of RP11-65J21.3 significantly promoted the proliferation of HTR-8 trophoblast cells at 72 h after transfection. CONCLUSIONS: In conclusion, we identified placental DElncRNAs of early-onset PE and established a DElncRNA-DEmRNA network that was closely related to the cytokine-cytokine receptor and HIF-1 pathways. Our results provide potential diagnostic markers and therapeutic targets for early-onset PE management.

Single cell RNA-sequencing reveals the cellular senescence of placental mesenchymal stem/stromal cell in preeclampsia.

INTRODUCTION: Preeclampsia (PE) is a severe obstetric complication closely associated with placental dysfunction. Placental mesenchymal stem/stromal cells (PMSCs) modulate placental development while PE PMSCs are excessively senescent to disturb placental function. Nevertheless, the senescence mechanism of PE PMSCs remains unclear. METHODS: PE-related single-cell RNA sequencing datasets (GSE173193), data of chip detection (GSE99007) and bulk transcriptome RNA sequencing datasets (GSE75010) were extracted from the GEO database. Firstly, the functional enrichment analyses of the differentially expressed genes (DEGs) in PMSCs were conducted. Then, the clusters of PE PMSCs were distinguished according to the expressions of senescence-related genes (SRGs) by consensus clustering analysis. Cell cycle analysis, senescence ß-galactosidase, Transwell, and tube formation were conducted. Next, the expressions of the senescence-associated secretory phenotype (SASPs) were displayed. The characteristic genes of PE were screened by the least absolute shrinkage and selection operator analysis. CTSZ was suppressed in PMSCs and the cellular senescence levels were evaluated. RESULTS: In this study, The DEGs in PMSCs were closely associated with cellular senescence. The score of SRGs was significantly higher and most of the SASPs were abnormally expressed in the senescent group. Seven characteristic genes of PE were identified, thereinto, CTSZ reduction may accelerate the senescence in PMSCs in vitro. DISCUSSION: Combined with bioinformatic analysis and lab experiments, our study emphatically revealed the abnormal cellular senescence in PE PMSCs, in which CTSZ, one of the PE characteristic genes, regulated the cellular senescence levels in PMSCs. These findings might help to deepen the understanding of the senescence mechanism of PMSCs in PE.

Lysosome-related biomarkers in preeclampsia and cancers: Machine learning and bioinformatics analysis.

BACKGROUND: Lysosomes serve as regulatory hubs, and play a pivotal role in human diseases. However, the precise functions and mechanisms of action of lysosome-related genes remain unclear in preeclampsia and cancers. This study aimed to identify lysosome-related biomarkers in preeclampsia, and further explore the biomarkers shared between preeclampsia and cancers. MATERIALS AND METHODS: We obtained GSE60438 and GSE75010 datasets from the Gene Expression Omnibus database, pre-procesed them and merged them into a training cohort. The limma package in R was used to identify the differentially expressed mRNAs between the preeclampsia and normal control groups. Differentially expressed lysosome-related genes were identified by intersecting the differentially expressed mRNAs and lysosome-related genes obtained from Gene Ontology and GSEA databases. Gene Ontology annotations and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed using the DAVID database. The CIBERSORT method was used to analyze immune cell infiltration. Weighted gene co-expression analyses and three machine learning algorithm were used to identify lysosome-related diagnostic biomarkers. Lysosome-related diagnostic biomarkers were further validated in the testing cohort GSE25906. Nomogram diagnostic models for preeclampsia were constructed. In addition, pan-cancer analysis of lysosome-related diagnostic biomarkers were identified by was performed using the TIMER, Sangebox and TISIDB databases. Finally, the Drug-Gene Interaction, TheMarker and DSigDB Databases were used for drug-gene interactions analysis. RESULTS: A total of 11 differentially expressed lysosome-related genes were identified between the preeclampsia and control groups. Three molecular clusters connected to lysosome were identified, and enrichment analysis demonstrated their strong relevance to the development and progression of preeclampsia. Immune infiltration analysis revealed significant immunity heterogeneity among different clusters. GBA, OCRL, TLR7 and HEXB were identified as lysosome-related diagnostic biomarkers with high AUC values, and validated in the testing cohort GSE25906. Nomogram, calibration curve, and decision curve analysis confirmed the accuracy of predicting the occurrence of preeclampsia based on OCRL and HEXB. Pan-cancer analysis showed that GBA, OCRL, TLR7 and HEXB were associated with the prognosis of patients with various tumors and tumor immune cell infiltration. Twelve drugs were identified as potential drugs for the treatment of preeclampsia and cancers. CONCLUSION: This study identified GBA, OCRL, TLR7 and HEXB as potential lysosome-related diagnostic biomarkers shared between preeclampsia and cancers.

Expression and influence of KATP in umbilical artery smooth muscle cells of patients with hypertensive disorders of pregnancy.

The objective of this study is to investigate the expression and influence of adenosine triphosphate-sensitive potassium channel (KATP) in human umbilical arterial smooth muscle cells (HUASMCs) of patients with hypertensive disorders of pregnancy (HDP). Western blotting was used to detect the protein expression levels of KATP inwardly rectifying potassium channel (Kir)6.1 and sulphonylurea receptor (SUR)2B subunits in HUASMCs from patients with normal parturients (NP), gestational hypertension (GH), chronic hypertension (CH), preeclampsia (PE) and chronic hypertension with superimposed preeclampsia (CHSP), respectively. There was no significant difference in the protein expression of Kir6.1 subunit in NP group, GH group, CH group, PE group and CHSP group (P > 0.05). The protein expression of SUR2B subunit was gradually decreased in NP group, GH group, CH group, PE group and CHSP group, with statistically significant difference among the groups (P < 0.05). The altered expression level of KATP SUR2B subunit may be involved in the pathogenesis of HDP. The severity of HDP may be related to the degree of decrease of SUR2B subunit.

Exosomal small RNA profiling in first-trimester maternal blood explores early molecular pathways of preterm preeclampsia.

Introduction: Preeclampsia (PE) is a severe obstetrical syndrome characterized by new-onset hypertension and proteinuria and it is often associated with fetal intrauterine growth restriction (IUGR). PE leads to long-term health complications, so early diagnosis would be crucial for timely prevention. There are multiple etiologies and subtypes of PE, and this heterogeneity has hindered accurate identification in the presymptomatic phase. Recent investigations have pointed to the potential role of small regulatory RNAs in PE, and these species, which travel in extracellular vesicles (EVs) in the circulation, have raised the possibility of non-invasive diagnostics. The aim of this study was to investigate the behavior of exosomal regulatory small RNAs in the most severe subtype of PE with IUGR. Methods: We isolated exosomal EVs from first-trimester peripheral blood plasma samples of women who later developed preterm PE with IUGR (n=6) and gestational age-matched healthy controls (n=14). The small RNA content of EVs and their differential expression were determined by next-generation sequencing and further validated by quantitative real-time PCR. We also applied the rigorous exceRpt bioinformatics pipeline for small RNA identification, followed by target verification and Gene Ontology analysis. Results: Overall, >2700 small RNAs were identified in all samples and, of interest, the majority belonged to the RNA interference (RNAi) pathways. Among the RNAi species, 16 differentially expressed microRNAs were up-regulated in PE, whereas up-regulated and down-regulated members were equally found among the six identified Piwi-associated RNAs. Gene ontology analysis of the predicted small RNA targets showed enrichment of genes in pathways related to immune processes involved in decidualization, placentation and embryonic development, indicating that dysregulation of the induced small RNAs is connected to the impairment of immune pathways in preeclampsia development. Finally, the subsequent validation experiments revealed that the hsa_piR_016658 piRNA is a promising biomarker candidate for preterm PE associated with IUGR. Discussion: Our rigorously designed study in a homogeneous group of patients unraveled small RNAs in circulating maternal exosomes that act on physiological pathways dysregulated in preterm PE with IUGR. Therefore, our small RNA hits are not only suitable biomarker candidates, but the revealed biological pathways may further inform us about the complex pathology of this severe PE subtype.

Impact of physical activity on preeclampsia and angiogenic markers in the Finnish Genetics of Pre-eclampsia Consortium (FINNPEC) cohort.

INTRODUCTION: Effect of physical activity in pregnancy on preeclampsia (PE) and angiogenic markers is not well understood. We studied the association of physical activity and PE in a case-control setting and assessed whether exercise in PE and non-PE women associate with maternal serum concentrations of soluble fms-like tyrosine kinase 1 (s-Flt-1), placental growth factor (PlGF) and soluble endoglin (sEng) and sFlt-1/PlGF ratio in the Finnish Genetics of Pre-eclampsia Consortium (FINNPEC) cohort. MATERIALS AND METHODS: Participants completed a questionnaire on their background information and serum samples were collected from a subset. Questionnaire data on physical activity were available from 708 PE women and 724 non-PE women. Both first trimester serum samples and questionnaire data on physical activity were available from 160 PE women and 160 non-PE women, and second/third trimester serum samples and questionnaire data on physical activity were available from 139 PE women and 47 non-PE women. The PE and non-PE women were divided into categories of physically active (exercise 2 - 3 times/week or more) and physically inactive (exercise less than 2 - 3 times/week). RESULTS: A total of 43.4% of the PE women and 42.4% of the non-PE women were categorized as physically active. There were no differences in physical activity and exercise habits between the groups. The physically active women were more often nulliparous and non-smokers and had a lower body mass index. There were no differences in the concentrations of angiogenic markers (sFlt-1, PlGF and sEng and sFlt-1/PlGF ratio) between the groups who exercised more or less than 2 - 3 times/week. CONCLUSIONS: In the FINNPEC study cohort, there was no association between physical activity and PE and no associations of physical activity in pregnant women with and without PE with maternal serum concentrations of sFlt-1, PlGF and sEng and sFlt-1/PlGF ratio.

This is the first study to investigate the association of physical activity in pregnancy with concentrations of angiogenic markers while comparing pregnant women with and without preeclampsia.There were no differences in the physical activity and exercise habits in pregnancy between women with and without preeclampsia in the FINNPEC cohort.Physical activity of pregnant women with or without preeclampsia did not associate with the concentrations of angiogenic markers (sFlt-1, PlGF and sEng and sFlt-1/PlGF ratio).

Overexpression of Human sFLT1 in the Spongiotrophoblast Is Sufficient to Induce Placental Dysfunction and Fetal Growth Restriction in Transgenic Mice.

Preeclampsia (PE) is characterized by maternal hypertension and placental dysfunction, often leading to fetal growth restriction (FGR). It is associated with an overexpression of the anti-angiogenic sFLT1 protein, which originates from the placenta and serves as a clinical biomarker to predict PE. To analyze the impact of sFLT1 on placental function and fetal growth, we generated transgenic mice with placenta-specific human sFLT1 (hsFLT1) overexpression. Immunohistochemical, morphometrical, and molecular analyses of the placentas on 14.5 dpc and 18.5 dpc were performed with a focus on angiogenesis, nutrient transport, and inflammation. Additionally, fetal development upon placental hsFLT1 overexpression was investigated. Dams exhibited a mild increase in serum hsFLT1 levels upon placental hsFLT1 expression and revealed growth restriction of the fetuses in a sex-specific manner. Male FGR fetuses expressed higher amounts of placental hsFLT1 mRNA compared to females. FGR placentas displayed an altered morphology, hallmarked by an increase in the spongiotrophoblast layer and changes in labyrinthine vascularization. Further, FGR placentas showed a significant reduction in placental glycogen storage and nutrient transporter expression. Moreover, signs of hypoxia and inflammation were observed in FGR placentas. The transgenic spongiotrophoblast-specific hsFLT1 mouse line demonstrates that low hsFLT1 serum levels are sufficient to induce significant alterations in fetal and placental development in a sex-specific manner.

Bioinformatics analysis identifies potential autophagy key genes and immune infiltration in preeclampsia.

BACKGROUND: Preeclampsia (PE) is a disease that seriously threatens maternal and fetal health. Appropriate autophagy can shield the placenta from oxidative stress, but its role in PE is unclear. OBJECTIVE: To identify potential autophagy-related genes in PE. METHODS: Microarray datasets from the Gene Expression Omnibus database, compassing the test dataset GSE10588, along with validation datasets GSE4707 and GSE60438 GPL10558, were utilized. Differentially expressed genes (DEGs) were identified using the limma R package, intersected with autophagy-related genes. Hub genes were obtained using the Cytoscape software and analyzed via gene set enrichment analysis (GSEA). The diagnostic capability of hub genes was evaluated using receiver operating characteristic (ROC) curve analysis. Analysis of immune cell infiltration was conducted using single-sample gene set enrichment analysis (ssGSEA) and CIBERSORT methods. Placental tissues were collected from 10 normal pregnant women and 10 preeclamptic pregnant women, and the expression of hub genes was validated through immunohistochemistry and western blot analysis. RESULTS: Analysis of the microarray data identified 2224 DEGs, among which 26 were autophagy-related DEGs identified through intersection with autophagy genes. Ten hub genes were identified. Immune cell infiltration analysis suggested the potential involvement of T regulatory cells (Tregs), natural killer cells, neutrophils, and T follicular helper cells in the pathogenesis of PE. ROC curve analysis indicated promising diagnostic capabilities for EGFR and TP53. Additionally, levels of EGFR and TP53 were significantly higher in placental tissue from PE pregnancies compared to normal pregnancies. CONCLUSION: EGFR and TP53 may play a role in PE by influencing autophagy.

Down-Regulation of CPEB4 Alleviates Preeclampsia through the Inhibition of Ferroptosis by PFKFB3.

Gestational diabetes mellitus (GDM) complicated with preeclampsia can lead to polyhydramnios, ketosis. Herein, we explored that CPEB4 in cancer progression of preeclampsia and its underlying mechanism. All the serum samples were collected from patients with preeclampsia. These was the induction of CPEB4 in patients with preeclampsia. The serum of CPEB4 mRNA expression was positive correlation with Proteinuria, systolic blood pressure and diastolic blood pressure in patients. The serum of CPEB4 mRNA expression was also negative correlation with body weight of infant in patients. The serum of CPEB4 mRNA expression also was negative correlation with GPX4 level and GSH activity level in patients. The serum of CPEB4 mRNA expression was positive correlation with iron content in patients. CPEB4 gene inhibited trophoblast cell proliferation. CPEB4 gene promoted trophoblast cell ferroptosis by mitochondrial damage. CPEB4 gene induced PFKFB3 expression by the inhibition of PFKFB3 Ubiquitination. PFKFB3 inhibitor reduced the effects of CPEB4 on cell proliferation and ferroptosis of trophoblast cell. Taken together, the CPEB4 promoted trophoblast cell ferroptosis through mitochondrial damage by the induction of PFKFB3 expression, CPEB4 as an represents a potential therapeutic strategy for the treatment of preeclampsia or various types of GDM.

Investigating the progression of preeclampsia through a comprehensive analysis of genes associated with per- and polyfluoroalkyl substances.

Per- and Polyfluoroalkyl Substances (PFAS) are synthetic chemicals utilized in the production of various products that possess water and dirt-repellent properties. Exposure to PFAS has been linked to numerous diseases, such as cancer and preeclampsia (PE). However, whether PFAS contributes to the advancement of PE remains uncertain. In this study, we conducted an extensive bioinformatics analysis using the Comparative Toxicogenomics Database (CTD) and Gene Expression Omnibus (GEO) databases, leading us to discover a connection between PE and four specific PFAS. Moreover, further examination revealed that six genes associated with PFAS exhibited significant diagnostic potential for individuals with PE. By employing receiver operating characteristic (ROC) curves, our PFAS-related gene-based nomogram model demonstrated outstanding predictive efficacy for diagnosing PE. Immune infiltration analysis showed that six PFAS-related genes were significantly associated with the level of immune cell infiltration. The expression of PFAS-related genes in PE patients was confirmed by collecting clinical samples. This research has offered fresh perspectives on comprehending the impact of PFAS on PE, drawing attention to the connection between environmental factors and the risks and development of PE.

Circ_0030042 inhibits trophoblast cell growth, invasion and epithelial-mesenchymal transition process in preeclampsia via miR-942-5p/LITAF.

BACKGROUND: There is increasing evidence that circular RNAs (circRNAs) are involved in the processes of preeclampsia (PE). Circ_0030042 was found to be abnormally expressed in PE patients. However, the role and molecular mechanism of circ_0030042 in PE progression remains unclear. METHODS: Quantitative real-time PCR was used for determining the expression of circ_0030042, microRNA (miR)- 942-5p and lipopolysaccharide induced TNF-α factor (LITAF). Trophoblast cell functions were determined using cell counting kit 8 assay, EdU assay, flow cytometry and transwell assay. The protein levels of epithelial-mesenchymal transition (EMT)-related markers and LITAF were examined using western blot analysis. Dual-luciferase reporter assay and RNA pull-down assay were used to verify RNA interaction. RESULTS: Circ_0030042 had an elevated expression in PE patients, and its overexpression inhibited trophoblast cell growth, invasion, and EMT process. Circ_0030042 served as miR-942-5p sponge, and miR-942-5p inhibitor also reversed the regulation of circ_0030042 on trophoblast cell growth, invasion and EMT process. LITAF was targeted by miR-942-5p, and its knockdown abolished the inhibition effect of miR-942-5p on trophoblast cell growth, invasion, and EMT process. Also, circ_0030042 regulated LITAF expression via sponging miR-942-5p. CONCLUSION: Circ_0030042 regulated trophoblast cell growth, invasion, and EMT process via the miR-942-5p/LITAF axis, providing a novel insight for PE treatment.

Mediating Factors in the Association of Maternal Educational Level With Pregnancy Outcomes: A Mendelian Randomization Study.

Importance: Lower educational attainment is associated with increased risk of adverse pregnancy outcomes, but it is unclear which pathways mediate this association. Objective: To investigate the association between educational attainment and pregnancy outcomes and the proportion of this association that is mediated through modifiable cardiometabolic risk factors. Design, Setting, and Participants: In this 2-sample mendelian randomization (MR) cohort study, uncorrelated (R2 < 0.01) single-nucleotide variants (formerly single-nucleotide polymorphisms) associated with the exposure (P < 5 × 10-8) and mediators and genetic associations with the pregnancy outcomes from genome-wide association studies were extracted. All participants were of European ancestry and were largely from Finland, Iceland, the United Kingdom, or the US. The inverse variance-weighted method was used in the main analysis, and the weighted median, weighted mode, and MR Egger regression were used in sensitivity analyses. In mediation analyses, the direct effect of educational attainment estimated in multivariable MR was compared with the total effect estimated in the main univariable MR analysis. Data were extracted between December 1, 2022, and April 30, 2023. Exposure: Genetically estimated educational attainment. The mediators considered were genetically estimated type 2 diabetes, body mass index, smoking, high-density lipoprotein cholesterol level, and systolic blood pressure. Main Outcomes and Measures: Ectopic pregnancy, hyperemesis gravidarum, gestational diabetes, preeclampsia, preterm birth, and offspring birth weight. Results: The analyses included 3 037 499 individuals with data on educational attainment, and those included in studies on pregnancy outcomes ranged from 141 014 for ectopic pregnancy to 270 002 with data on offspring birth weight. Each SD increase in genetically estimated educational attainment (ie, 3.4 years) was associated with an increased birth weight of 42 (95% CI, 28-56) g and an odds ratio ranging from 0.53 (95% CI, 0.46-0.60) for ectopic pregnancy to 0.81 (95% CI, 0.71-0.93) for preeclampsia. The combined proportion of the association that was mediated by the 5 cardiometabolic risk factors ranged from -17% (95% CI, -46% to 26%) for hyperemesis gravidarum to 78% (95% CI, 10%-208%) for preeclampsia. Sensitivity analyses accounting for pleiotropy were consistent with the main analyses. Conclusions and Relevance: In this MR cohort study, intervening for type 2 diabetes, body mass index, smoking, high-density lipoprotein cholesterol level, and systolic blood pressure may lead to reductions in several adverse pregnancy outcomes associated with lower levels of education. Such public health interventions would serve to reduce health disparities attributable to social inequalities.

Investigation of the linkage between TNF-alfa rs1800629 polymorphism and preeclampsia risk: A meta-analysis.

BACKGROUND: Preeclampsia is a serious medical condition that significantly affects expectant mothers. Growing research showed an inconsistent association between TNF-alfa rs1800629 polymorphism and preeclampsia. The current meta-analysis was aimed at examining the potential impact of rs1800629 variant on preeclampsia. METHODS: The Cochrane Library, Google Scholar, PubMed, EMBASE, Web of Science, and other databases were searched extensively to locate and select articles up to October 30, 2023. The PRISMA 2020 recommendations were followed to perform this study. Data analysis was done by using Comprehensive Meta analysis (v 3). RESULTS: We have included 32 articles containing 35 studies with 3,883 patients and 5,821 controls for qualitative and quantitative data analysis. We found a strong relationship between rs1800629 variant with the increased preeclampsia risk in co-dominant model 1 (OR = 1.33, p = 0.019), co-dominant model 2 (OR = 1.43, p = 0.014), dominant model (OR = 1.25, p = 0.044), over-dominant model (OR = 1.31, p = 0.021), and allelic model (OR = 1.24, p = 0.018). This study also revealed a significantly higher risk among the Asian population in the dominant (OR = 2.31, p = 0.036) and allelic model (OR = 2.02, p = 0.028). For the Caucasian population, an increased association between the rs1800629 variant and preeclampsia risk was reported in co-dominant model 1 (OR = 1.37, p = 0.011), co-dominant model 2 (OR = 1.77, p = 0.007), dominant model (OR = 1.32, p = 0.030), recessive (OR = 1.50, p = 0.047), over-dominant (OR = 1.34, p = 0.009), and allelic model (OR = 1.32, p = 0.004). Though our study showed the protective link of the TNF-alfa polymorphism to the preeclampsia risk among the Black population, no significant outcomes were observed in any genetic models (p > 0.05). CONCLUSION: Overall, the present meta-analysis explored a consistent linkage of the TNF-alfa rs1800629 variant to the preeclampsia risk in different ethnic groups. Additional research is required to confirm the precise relationship between the rs1800629 variant and preeclampsia risk.

Novel Insights into Prokineticin 1 Role in Pregnancy-related Diseases.

Prokineticin 1 (PROK1) is a secreted protein involved in a range of physiological activities such as cell proliferation, migration, angiogenesis, and neuronal cell proliferation. Emerging evidences show that PROK1/PROK receptors (PROKRs) are expressed by trophoblasts, and decidual stroma cells at the maternal-fetal interface. PROK1 plays a critical role in successful pregnancy establishment by regulating the decidualization, implantation and placental development. Dysregulation of prokineticin signaling has been described in certain pathological states associated with pregnancy, including pre-eclampsia, recurrent miscarriage and fetal growth restriction. In this review, the expression and pleiotropic roles of PROK1 under physiological and pathological pregnancy conditions are discussed.

Suppression of circular RNA serum and glucocorticoid-induced kinase 1 elevates antioxidant molecules and angiogenesis in trophoblast cells to attenuate preeclampsia via microRNA-508-3p to target and restrain PUM homolog 1.

AIM: Preeclampsia (PE) is a pregnancy-specific syndrome characterized by hypertension and proteinuria. Recently, multiple circular RNAs (circRNAs) were considered latent clinical diagnostic markers or therapeutic targets. This study was to explore the impact of circRNA serum and glucocorticoid-induced kinase 1 (SGK1) on PE via influencing the microRNA (miR)-508-3p/PUM homolog 1 (PUM1) axis. METHODS: Placental tissues of 34 pregnant women with PE and 34 normal pregnant women were collected to measure circRNA SGK1 (circSGK1), miR-508-3p, and PUM1. Human placental trophoblasts HTR-8/SVneo were transfected with plasmids, thereafter to observe proliferation, migration, invasion, and apoptosis, analyze antioxidant molecules Troxerutin (TXN), Glutamate-cysteine ligase catalytic subunit (GCLC), NAD (P) H-quinone oxidoreductase 1 (NQO1), and determine angiogenesis. After the construction of the PE rat model, antioxidant molecules TXN, GCLC, and NQO1, vascular-associated factor vascular endothelial growth factor A (VEGF-A), and histopathological conditions were tested. Examination of the binding of circSGK1 and miR-508-3p with PUM1 was performed. RESULTS: Our data showed that circSGK1 expression was elevated in the placenta of patients with PE. Silenced circSGK1 or elevated miR-508-3p promoted the growth and antioxidant molecules and angiogenesis in trophoblast cells; CircSGK1 combined with miR-508-3p, and miR-508-3p targeted PUM1. CONCLUSIONS: In summary, suppression of circSGK1 augments antioxidant molecules and angiogenesis in trophoblast cells to attenuate PE via miR-508-3p to target PUM1.

Upregulation of SEMP1 Contributes to Improving the Biological Functions of Trophoblast via the PI3K/AKT Pathway in Preeclampsia.

Disturbance of extravillous trophoblast infiltration is associated with preeclampsia (PE), a severe condition of pregnancy characterized by hypertension and proteinuria. Senescence-associated epithelial membrane protein 1 (SEMP1), an integral membrane protein, is a vital component of tight junction strands in epithelial or endothelial cells, with no clear function reported in PE. Gene Expression Omnibus (GEO) datasets showed that SEMP1 expression was downregulated in the placental tissues of PE patients, which was confirmed by assessing SEMP1 levels in placental samples collected in our hospital. Furthermore, less SEMP1 was detected in cytokeratin 7 positive trophoblast cells in the spiral arteries of rat placentas post L-arginine methyl ester hydrochloride (L-NAME) treatment. Trophoblast cells acquired robust ability of proliferation, migration, and invasion when SEMP1 was overexpressed. Such capability was weakened in SEMP1-silenced cells. Trophoblast cells overexpressing SEMP1 secreted more vascular endothelial growth factor A (VEGFA), which facilitated the tube formation of human umbilical vein endothelial cells. Blockade of PI3K/AKT signaling transduction with LY294002 dampened the effects of SEMP1 on trophoblast cells. Collectively, we firstly indicated that SEMP1 inhibition is a potential driver for PE, which may be associated with the deactivation of the PI3K/AKT pathway.

Down-regulated Wnt7a and GPR124 in early-onset preeclampsia placentas reduce invasion and migration of trophoblast cells.

OBJECTIVES: Preeclampsia (PE) is a disease specific to pregnancy that causes 9-10 % of maternal deaths. Early-onset PE (<34 weeks' gestation) is the most dangerous category of PE. Wnt7a and GPR124 (G protein-coupled receptor 124) are widely expressed in the human reproductive process. Especially during embryogenesis and tumorigenesis, Wnt7a plays a crucial role. However, few studies have examined the association between Wnt7a-GPR124 and early-onset PE. The aim of this study was to examine the significance of Wnt7a and GPR124 in early-onset PE as well as Wnt7a's role in trophoblast cells. METHODS: Immunohistochemistry (IHC), real-time PCR, and western blotting (WB) were used to investigate Wnt7a and GPR124 expression in normal and early-onset PE placentas. Additionally, FACS, Transwell, and CCK-8 assays were used to diagnose Wnt7a involvement in migration, invasion, and proliferation. RESULTS: In the early-onset PE group, Wnt7a and GPR124 expression was significantly lower than in the normal group, especially in the area of syncytiotrophoblasts (STBs) and extravillous trophoblasts (EVTs). A negative correlation was found between Wnt7a RNA and GPR124 expression (r=-0.42, p<0.01). However, the Wnt7a RNA expression level was positive correlated with PE severity. In further cellular functional experiments, knockdown of Wnt7a inhibits HTR8/SVeno cells invasion and migration but has little effect on proliferation and apoptosis. CONCLUSIONS: Through the Wnt pathway, Wnt7a regulates trophoblast cell invasion and migration, and may contribute to early-onset preeclampsia pathogenesis. A molecular level study of Wnt7a will be needed to find downstream proteins and mechanisms of interaction.

IL-6, IL-10 and TNF-α gene polymorphisms in preeclampsia: a case-control study in a Mexican population.

OBJECTIVES: We focused our study on examining the genotype and allele frequency of IL-6 (rs1800795), TNF-α (rs1800629) and IL-10 (rs1800872) single nucleotide polymorphisms (SNP) on preeclampsia (PE) diagnosed Mexican pregnant women. MATERIAL AND METHODS: A case-control study was designed including 86 preeclampsia patients and 100 normotensives pregnancies from Women's Hospital of Culiacan, Mexico. Genotyping of IL-6, TNF-α and IL-10 was performed using TaqMan SNP Genotyping. RESULTS: Not significant association was found between development of PE and genotypic (p > 0.05) and allelic (p > 0.05) frequencies of IL-6, TNF-α and IL-10 SNPs. Genotype distributions of IL-6 (p = 0.599), TNF-α (p = 0.721) and IL-10 (p = 0.761) polymorphisms in the two groups were in agreement with Hardy-Weinberg equilibrium. CONCLUSIONS: According to the findings, the IL-6, TNF-α and IL-10 SNPs are not exponents of susceptibility to developing PE.

Association between expression levels of p53, miRNA-21, and lncRNA-TCL6 and the risk of preeclampsia in pregnant women.

BACKGROUND: Preeclampsia is a hypertensive pregnancy-related disorder. The etiology of preeclampsia is still not fully elucidated. Genetic factors are suggested to play a vital role. AIM: The association between p53, miRNA-21, and lncRNA-TCL6 expression levels and the risk of preeclampsia and its onset and severity in pregnant women was evaluated. METHOD: Expression levels of the analyzed RNAs were assessed in the serum samples from 75 preeclamptic pregnant women and 75 volunteer pregnant women with an uncomplicated pregnancy. RESULTS: Cases showed upregulated p53, lnc-TCL6, and downregulated miRNA-21. P53 expression and preeclampsia severity were substantially correlated, while miRNA-21 and lnc-TCL6 were not. None of them was associated with preeclampsia onset. In diagnosing preeclampsia, p53 had the best sensitivity (98.67 %), followed by miRNA-21 (97.33 %) and lnc-TCL6 (92 %). P53 had the highest sensitivity (68.42 %) for distinguishing mild from severe cases. Lnc-TCL6 exhibited 52.63 % sensitivity, while miRNA-21 had 52.63 % sensitivity. Finally, for discriminating early and late-onset cases, miRNA-21 demonstrated the highest sensitivity (66 %), followed by p53 (62 %) and lnc-TCL6 (54 %). P53 expression was inversely correlated with proteinuria. Parity, TLC, platelet count, AST, and ALT were positively correlated, while lnc-TCL6 expression was negatively correlated with miRNA-21 expression. However, parity negatively correlated with lnc-TCL6 expression. CONCLUSION: P53, miRNA-21, and lnc-TCL6 were dysregulated in preeclampsia compared to normal pregnancy, highlighting the role of apoptosis in its development. P53 can be a prognostic marker for preeclampsia, discriminating between mild and severe cases.