Circulating chemerin levels in preeclampsia: a systematic review and meta-analysis.

BACKGROUND: Preeclampsia (PE) is a new-onset pregnancy-specific disorder with a high prevalence that leads to over 70 000 maternal and 500 000 foetal fatalities worldwide each year. The level of chemerin, a newly identified adipokine, is increased in diabetic and obese patients. Currently, there are several studies describing the relationship between maternal circulating chemerin levels and PE. Therefore, this study aimed to assess their association in pooled samples. METHODS: Four databases were systematically searched to identify potential studies that reported circulating chemerin levels in PE and normal pregnancy groups. Standardized mean differences (SMDs), 95% confidence intervals (CIs), and 95% prediction intervals (PIs) were calculated using a random-effects meta-analysis. The probability of heterogeneity was also investigated by sensitivity analysis, subgroup analysis, and meta-regression. RESULTS: Thirteen studies in 11 articles with a total of 860 PE patients and 1309 women with normal pregnancies met the inclusion criteria. The results of the meta-analysis revealed that circulating chemerin, which levels in PE patients were considerably higher than those in controls (SMD = 1.39, 95% CI: 1.02, 1.77, 95% PI: -0.07, 2.86). Moreover, sensitivity analysis determined that the outcomes of the overall pooled results were not affected after the elimination of any study. Notably, subgroup analysis demonstrated a similar expression pattern irrespective of geographic location, severity, timing of sampling, and sample size. Last, there were no factors that significantly impacted the overall estimate, according to meta-regression. CONCLUSIONS: This meta-analysis is the first to assess circulating chemerin levels in PE patients. The findings indicate that circulating chemerin levels may be a potential marker to diagnose PE.

MiR-95-3p/EPM2A/MMP2 contributes to the pathogenesis of severe preeclampsia through the regulation of trophoblast biological behaviour.

OBJECTIVE: Preeclampsia (PE) is a maternal multisystem disease with an unclear mechanism. Data showed that MiR-95-3p promoted cell migration, invasion and proliferation, leading to the occurrence and development of many cancers, and placental trophoblasts and tumor cells had similar migration, invasion and proliferation abilities. Meanwhile we found that MiR-95-3p was differentially expressed in PE and normal placenta. Therefore, this article aimed to explore the biological function and mechanism of miR-95-3p in PE. METHODS: The expression of miR-95-3p in PE and normal placental tissue was explored by high-throughput sequencing and qRT-PCR. The effects of miR-95-3p on trophoblast migration, invasion, proliferation, angiogenesis and apoptosis were investigated by Transwell migration and invasion assays, cell viability assay, tube formation assay and flow cytometry in two trophoblast cell lines (HTR-8/SVneo and JAR). The miR-95-3p target gene EPM2A was identified and verified by unique identifier mRNA next-generation sequencing and dual-luciferase reporter gene experiments. Rescue experiments were conducted to investigate whether miR-95-3p regulated EPM2A to participate in trophoblast migration and invasion. Finally, the effects of miR-95-3p and EPM2A on the expression of angiogenic factors and inflammation-related factors were investigated by ELISA. RESULTS: We found that miR-95-3p was expressed at low levels in the placental tissue of patients with PE and was negatively correlated with EPM2A expression. In vitro upregulation of miR-95-3p and downregulation of EPM2A promote trophoblast migration, invasion and proliferation. Furthermore, EPM2A was confirmed as a target mRNA of miR-95-3p. Upregulation of EPM2A mitigated miR-95-3p-mediated promotion of trophoblast migration and invasion and vice versa. Finally, both miR-95-3p and EPM2A regulate the expression of trophoblast angiogenesis-related factors and inflammation-related factors. CONCLUSION: Our findings demonstrated that miR-95-3p promoted the migration and invasion of trophoblast cells by targeting EPM2A to inhibit the occurrence and development of PE.

Comprehensive analysis of transcriptomic profiling of 5-methylcytosin modification in placentas from preeclampsia and normotensive pregnancies.

Increasing evidence suggests that RNA m5C modification and its regulators have been confirmed to be associated with the pathogenesis of many diseases. However, the distribution and biological functions of m5C in mRNAs of placental tissues remain unknown. we collected placentae from normotensive pregnancies (CTR) and preeclampsia patients (PE) to analyze the transcriptomic profiling of m5C RNA methylation through m5C RNA immunoprecipitation (UMI-MeRIP-Seq). we discovered that overall m5C methylation peaks were decreased in placental tissues from PE patients. And, 2844 aberrant m5C peaks were identified, of which respectively 1304 m5C peaks were upregulated and 1540 peaks were downregulated. The distribution of m5C peaks were mainly located in CDS (coding sequences) regions in placental tissues of both groups, but compared with the CTR group, the m5C peak in PE group before the stop code of CDS was significantly increased and even higher than the peak value after start code in CDS. Differentially methylated genes were mainly enriched in MAPK/cAMP signaling pathway. Moreover, the up-regulated genes with hypermethylated modification were enriched in the processes of hypoxia, inflammation/immune response. Finally, through analyzing the mRNA expression levels of m5C RNA methylation regulators, we found only DNMT3B and TET3 were significantly upregulated in PE samples than in control group. And they are not only negatively correlated with each other, but also closely related to those differentially expressed genes modified by differential methylation.Our findings provide new insights regarding alterations of m5C RNA modification into the pathogenic mechanisms of PE.

The Association Between Season and Hypertensive Disorders in Pregnancy: a Systematic Review and Meta-analysis.

There is increasing and inconsistent evidence of a relationship between hypertensive disorders in pregnancy (HDPs) and season of delivery or conception. In this systematic review and meta-analysis, we assessed the association between season and HDPs. The review protocol was registered in PROSPERO (CRD42021285539). Four databases, the Cochrane Library, PubMed, EMBASE, and Web of Science, were searched until September 29th, 2021. Two authors extracted data independently and used the Newcastle-Ottawa quality assessment scale (NOS) to evaluate study quality. A random effects model and the Mantel-Haenszel method were used to calculate pooled Odds ratios (ORs) and 95% confidence intervals (95% CIs). Subgroup analyses and sensitivity analyses were performed to find the source of heterogeneity and Begg's funnel plot and Egger's test were used to check for the risk of publication bias. Finally, twenty articles were included in the systematic review, and 11 articles were included in the meta-analysis. The quantitative analysis of the association between delivery season and HDPs showed that the odds of HDPs was higher in women who delivered in winter than in those who delivered in summer (OR = 1.18, 95% CI 1.02-1.38, P < 0.001) and all other seasons (OR = 1.17, 95% CI 1.03-1.34, P < 0.001). In the qualitative analysis of the association between conception season and HDPs, four of seven studies suggested that women who conceived in summer had a higher risk of HDPs than those who conceived in other seasons. Based on the evidence to date, we found weakly positive relationships between HDPs and summer conception and winter delivery.

The long noncoding RNA TARID regulates the CXCL3/ERK/MAPK pathway in trophoblasts and is associated with preeclampsia.

BACKGROUND: The widely accepted explanation of preeclampsia (PE) pathogenesis is insufficient trophoblast invasion and impaired uterine spiral artery remodeling. However, the underlying molecular mechanism remains unclear. METHODS: We performed transcriptome sequencing on placentas of normal and PE patients and identified 976 differentially expressed long noncoding RNAs (lncRNAs). TCF21 antisense RNA inducing demethylation (TARID) was one of the most significantly differentially expressed lncRNAs and was negatively correlated with the systolic and diastolic blood pressure in PE patients. Furthermore, we verified the effect of TARID on the biological behavior of trophoblasts and performed UID mRNA-seq to identify the effectors downstream of TARID. Then, co-transfection experiments were used to better illustrate the interaction between TARID and its downstream effector. RESULTS: We concluded that the downregulation of TARID expression may inhibit trophoblast infiltration and spiral artery remodeling through inhibition of cell migration, invasion, and tube formation mediated through the CXCL3/ERK/MAPK pathway. CONCLUSIONS: Overall, these findings suggested that TARID may be a therapeutic target for PE through the CXCL3/ERK/MAPK pathway.

BCAM Deficiency May Contribute to Preeclampsia by Suppressing the PIK3R6/p-STAT3 Signaling.

BACKGROUND: Preeclampsia is a pregnancy syndrome that may utilize multiple pathogenic mechanisms. Insufficient trophoblast invasion and impaired uterine spiral artery remodeling are believed to be the pathological basis; yet the underlying mechanisms remain largely unclear. METHODS: The placental BCAM (basal cell adhesion molecule) expression and important clinical indicators were detected and correlation analysis was performed. MiRNAs directly targeting BCAM were predicted and further verified by dual-luciferase reporter gene, and the downstream molecular mechanisms of BCAM were investigated in both HTR-8/SVneo and JAR cells. In addition, pregnant/nonpregnant rats were treated with adenoviruses containing BCAM shRNA genes (Ad-shBCAM) on gestational 9.5 days to detect the preeclamptic features. RESULTS: The BCAM is highly expressed on the trophoblast membrane and decreased in the preeclamptic placentae. In HTR-8/SVneo and JAR cells, BCAM knockdown inhibited trophoblast proliferation, migration, and invasion, and suppressed phosphorylation on Y705 of STAT3 dependent on the downregulation of PIK3R6. Moreover, miR-199a-5p mediated the degradation of BCAM and also inhibited trophoblast proliferation, migration, and invasion. In vivo, BCAM deficiency induced a preeclampsia-like phenotype included elevated systolic blood pressure, proteinuria, impaired morphology and function of multiple organs (placenta, liver, and kidney), and fetal growth restriction. The expression of placenta BCAM/PIK3R6/p-STAT3 signaling was also downregulated in this preeclampsia rat model. CONCLUSIONS: MiR-199a-5p mediated-BCAM deficiency contributes to the suppression of trophoblast proliferation, migration, and invasion by inhibiting PIK3R6/p-STAT3 signaling, which may lead to poor placentation and result in preeclampsia-like phenotypes. Our study provides a new academic perspective on the pathogenesis of preeclampsia.

Bioinformatics-based screening of key genes between maternal preeclampsia and offspring schizophrenia.

Converging lines of evidence suggest an association between schizophrenia and prenatal neurodevelopmental disorders. Preeclampsia is a multisystem disease based on the coexistence of pregnancy and elevated blood pressure, which increases the risk for offspring abnormal neurodevelopment. Previous studies have showed maternal preeclampsia is associated with an increased risk of offspring schizophrenia, but the molecular mechanism remains unclear. In this study, we sought to identify key protein-coding genes between maternal preeclampsia and offspring schizophrenia. GSE53987 and GSE166846 datasets from Gene Expression Omnibus (GEO) database were analysed to obtain common differentially expressed genes (DEGs) between preeclampsia and schizophrenia. GSE62105 dataset was analysed to identify the DEGs' expressions in neural cells from one control and one schizophrenic patient. GSE92845 dataset was analysed to describe the changes of the DEGs in human neural stem cells. In total, we obtained ten common DEGs. All of them expressed differently in neural cells of the control and schizophrenic patient. We chose the six DEGs that had similar trend in both neural cells and UCB from preeclampsia patients and analysed their expressions in human neural stem cells over time. We found the expressions of CKAP5 and SAT1 in day 30 had significant difference comparing with those in day 0. The KEGG pathway analysis of their interaction proteins showed they were involved with metabolism. Our results may provide a new insight for genetic basis of relationship between maternal preeclampsia and offspring schizophrenia.

Effect of lncRNA-ATB/miR-651-3p/Yin Yang 1 pathway on trophoblast-endothelial cell interaction networks.

Our previous studies have confirmed that lncRNA-ATB may be involved in the pathogenesis of preeclampsia, however, it is uncertain whether lncRNA-ATB influence the interaction between trophoblast and endothelial cells, which is crucial to the uterine spiral artery remodelling. Scratch wound healing and transwell invasion assay were conducted to test the migration and invasion of trophoblast cells. Co-culture model was used to simulate the physiological environment in vivo. The expression levels of lncRNA-ATB were analyzed in placenta tissues from healthy pregnant women and preeclampsia patients. Subsequently, the binding site of lncRNA-ATB and miR-651-3p was verified using dual-luciferase reporter assay, and the rescue experiment was used to study the effects of these two on the biological function. The direct effects of miR-651-3p and Yin Yang 1 (YY1) were verified using similar methods. LncRNA-ATB was found to be down-regulated in the placenta of preeclampsia patients. LncRNA-ATB knockdown decreased trophoblast migration, invasion and colocalisation with human umbilical vein endothelial cells. MiR-651-3p was a direct target of lncRNA-ATB and they had opposite effects. Moreover, the expression of lncRNA-ATB and miR-651-3p in placental tissues was negatively correlated. MiR-651-3p has been confirmed to directly target the 3' untranslated region of YY1. The inhibitory effects of YY1 low expression on biological function was rescued by miR-651-3p depletion. Western blot analysis showed that lncRNA-ATB could regulate YY1 expression by sponging miR-651-3p. LncRNA-ATB functioned as a competitive endogenous RNA of miR-651-3p to regulate YY1 on progress of spiral artery remodelling.

Circulating microRNAs as biomarkers for diagnosis and prediction of preeclampsia: A systematic review and meta-analysis.

OBJECTIVE: We carried out a meta-analysis to quantitatively summarize the overall diagnostic and predictive effects of circulating microRNAs in diagnosis and prediction of preeclampsia, respectively. STUDY DESIGN: We screened selected databases and systematically retrieved articles until September 20th, 2019 for analysis. After literature screening and data extraction, we firstly conducted quality assessment according to QUADAS-2 score system. And then the pooled diagnostic and predictive parameters were calculated using a bivariate random-effect meta-analysis model. We used threshold effect analysis and subgroup analysis to identify the sources of heterogeneity. The clinical utility was validated through the Fagan's Nomogram. Sensitivity analysis was performed to assess the reliability of each included study, and we evaluated publication bias with the Deeks' funnel plot asymmetry test. RESULTS: The meta-analysis included 8 articles comprising 273 preeclampsia patients and 343 normal pregnancies. Pooled results of diagnostic values of 5 articles indicated a sensitivity of 0.88 (95 %CI: 0.80-0.93), specificity of 0.87 (95 %CI: 0.78-0.92) and diagnostic odds ratio of 50.24 (95 %CI: 21.28-118.62). The pooled sensitivity, specificity, DOR of circulating microRNAs for predicting preeclampsia of asymptomatic pregnancies were 0.61 (95 %CI: 0.55-0.68), 0.78 (95 %CI: 0.72-0.83) and 5.7 (95 %CI: 3.7-8.7) across other 3 articles. Subgroup analysis revealed that non-plasma specimen type, non-U6 reference gene and non-Asian had better diagnostic value while due to limited data, we did not conduct a subgroup analysis of predictive value. CONCLUSIONS: Circulating miRNAs distinguish patients with preeclampsia from controls with relatively high diagnostic and predictive accuracy. Then we conclude that circulating miRNAs could be a useful screening tool to diagnose and predict preeclampsia. However, its utility should be judged with caution and large-sample prospective studies are warranted to explore if its implementation improves maternal and neonatal outcomes.

The impact of particulate matter 2.5 on the risk of preeclampsia: an updated systematic review and meta-analysis.

There is increasing and inconsistent evidence of a linkage between maternal exposure to particulate matter 2.5 (PM2.5) and preeclampsia. Therefore, this study was conducted to investigate this relationship. Electronic databases including PubMed, Embase, Web of Science, and Cochrane Library were searched to identify articles published from inception to March 23, 2020, which showed a correlation between PM2.5 and preeclampsia. Finally, 9 of 523 initial studies were deemed eligible for inclusion. A random effect model was adopted to calculate the standardized odds ratio (OR) and 95% confidence interval (CI). Based on potential effect modification, subgroup analyses were further performed. Meta-analysis showed that maternal exposure to PM2.5 (per 10 µg/m3 increment) elevated the risk of preeclampsia (OR = 1.32, 95% CI 1.10 to 1.58%). Compared with other pregnancy trimesters, the third trimester of pregnancy seems to be the period in which women are more susceptible to PM2.5. Significant effect modification of the correlation between PM2.5 exposure and preeclampsia according to multiple pregnancies, pregnancy stage, maternal-related disease history, and sample size was not observed. The results demonstrated that maternal exposure to PM2.5 may predispose pregnant women to develop preeclampsia, especially in the third trimester of pregnancy. Therefore, more efforts should be made to improve air quality to maintain the health of pregnant women.

Clinical features and outcomes of pregnant women with COVID-19: a systematic review and meta-analysis.

BACKGROUND: The recent COVID-19 outbreak in Wuhan, China, has quickly spread throughout the world. In this study, we systematically reviewed the clinical features and outcomes of pregnant women with COVID-19. METHODS: PubMed, Web of Science, EMBASE and MEDLINE were searched from January 1, 2020, to April 16, 2020. Case reports and case series of pregnant women infected with SARS-CoV-2 were included. Two reviewers screened 366 studies and 14 studies were included. Four reviewers independently extracted the features from the studies. We used a random-effects model to analyse the incidence (P) and 95% confidence interval (95% CI). Heterogeneity was assessed using the I2 statistic. RESULTS: The meta-analysis included 236 pregnant women with COVID-19. The results were as follows: positive CT findings (71%; 95% CI, 0.49-0.93), caesarean section (65%; 95% CI, 0.42-0.87), fever (51%; 95% CI, 0.35-0.67), lymphopenia (49%; 95% CI, 0.29-0.70), coexisting disorders (33%; 95% CI, 0.21-0.44), cough (31%; 95% CI, 0.23-0.39), fetal distress (29%; 95% CI, 0.08-0.49), preterm labor (23%; 95% CI, 0.14-0.32), and severe case or death (12%; 95% CI, 0.03-0.20). The subgroup analysis showed that compared with non-pregnant patients, pregnant women with COVID-19 had significantly lower incidences of fever (pregnant women, 51%; non-pregnant patients, 91%; P < 0.00001) and cough (pregnant women, 31%; non-pregnant patients, 67%; P < 0.0001). CONCLUSIONS: The incidences of fever, cough and positive CT findings in pregnant women with COVID-19 are less than those in the normal population with COVID-19, but the rate of preterm labor is higher among pregnant with COVID-19 than among normal pregnant women. There is currently no evidence that COVID-19 can spread through vertical transmission.

Laminins Regulate Placentation and Pre-eclampsia: Focus on Trophoblasts and Endothelial Cells.

Pre-eclampsia is a systemic vascular disease characterized by new-onset hypertension and/or proteinuria at ≥20 weeks of gestation and leads to high rates of maternal and perinatal morbidity and mortality. Despite the incomplete understanding of pre-eclampsia pathophysiology, it is accepted that insufficient spiral artery remodeling and endothelial dysfunction are major contributors. Laminins (LNs) are a vital family of extracellular matrix (ECM) molecules present in basement membranes that provide unique spatial and molecular information to regulate implantation and placentation. LNs interact with cell surface receptors to trigger intracellular signals that affect cellular behavior. This mini-review summarizes the role of LNs in placental development during normal pregnancy. Moreover, it describes how LN deficiency can lead to the pre-eclampsia, which is associated with trophoblast and vascular endothelial dysfunction. New research directions and the prospect of clinical diagnosis of LN deficiency are discussed, and the gaps in basic and clinical research in this field are highlighted.