Comparative effectiveness of prophylactic strategies for preeclampsia: a network meta-analysis of randomized controlled trials.

OBJECTIVE: Preeclampsia is a common disease during pregnancy that leads to fetal and maternal adverse events. Few head-to-head clinical trials are currently comparing the effectiveness of prophylactic strategies for preeclampsia. In this network meta-analysis, we aimed to compare the efficacy of prophylactic strategies for preventing preeclampsia in pregnant women at risk. DATA SOURCES: Articles published in or before September 2021 from PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov, references of key articles, and previous meta-analyses were manually searched. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials comparing prophylactic strategies preventing preeclampsia with each other or with negative controls were included. METHODS: Two reviewers independently extracted data, assessed the risk of bias, and assessed evidence certainty. The efficacy of prophylactic strategies was estimated by frequentist and Bayesian network meta-analysis models. The primary composite outcome was preeclampsia/ pregnancy-induced hypertension. RESULTS: In total, 130 trials with a total of 112,916 patients were included to assess 13 prophylactic strategies. Low-molecular-weight heparin (0.60; 95% confidence interval, 0.42-0.87), vitamin D supplementation (0.65; 95% confidence interval, 0.45-0.95), and exercise (0.68; 95% confidence interval, 0.50-0.92) were as efficacious as calcium supplementation (0.71; 95% confidence interval, 0.62-0.82) and aspirin (0.79; 95% confidence interval, 0.72-0.86) in preventing preeclampsia/pregnancy-induced hypertension, with a P score ranking of 85%, 79%, 76%, 74%, and 61%, respectively. In the head-to-head comparison, no differences were found between these effective prophylactic strategies for preventing preeclampsia and pregnancy-induced hypertension, except with regard to exercise, which tended to be superior to aspirin and calcium supplementation in preventing pregnancy-induced hypertension. Furthermore, the prophylactic effects of aspirin and calcium supplementation were robust across subgroups. However, the prophylactic effects of low-molecular-weight heparin, exercise, and vitamin D supplementation on preeclampsia and pregnancy-induced hypertension varied with different risk populations, dosages, areas, etc. The certainty of the evidence was moderate to very low. CONCLUSION: Low-molecular-weight heparin, vitamin D supplementation, exercise, calcium supplementation, and aspirin reduce the risk of preeclampsia/pregnancy-induced hypertension. No significant differences between effective prophylactic strategies were found in preventing preeclampsia. These findings raise the necessity to reevaluate the prophylactic effects of low-molecular-weight heparin, vitamin D supplementation, and exercise on preeclampsia.

Decidual small extracellular vesicles induce trophoblast invasion by upregulating N-cadherin.

Small extracellular vesicles (sEVs) are important mediators of cell-to-cell communication involved in the successful establishment of a pregnancy. Human decidual stromal cells play a key role in regulating trophoblast invasion. Nevertheless, the regulatory functions of decidual stromal cells-derived sEVs in human trophoblast cells are still unclear. In this study, primary human decidual stromal cells were isolated, and immortalized human endometrial stromal cell line (HESCs) were decidualized into human decidual stromal cells (HDSCs) using hormonal cocktail containing medroxy progesterone 17-acetate (MPA), estrogen and cAMP analog. HDSC-sEVs were isolated from both primary human decidual stromal cells and immortal HDSCs, respectively, and identified by transmission electron microscopy and western blotting. EV uptake assay indicated that HDSC-sEVs could be uptaken by trophoblast cells. HDSC-sEVs could increase the invasiveness and the expression level of N-cadherin of trophoblast cells with elevated phosphorylation of SMAD2 and SMAD3 in the cells. Silencing of N-cadherin could block cell invasion induced by HDSC-sEVs, while knockdown of SMAD2 and SMAD3 could inhibit the upregulation of N-cadherin in trophoblast cells. Taken together, our results suggested a regulatory effect of HDSC-sEVs in the invasion of trophoblast cells, and HDSC-sEVs may be important mediators of trophoblasts during embryo implantation and placentation.

Comparison of Dinoprostone and Oxytocin for the Induction of Labor in Late-Term Pregnancy and the Rate of Cesarean Section: A Retrospective Study in Ten Centers in South China.

BACKGROUND Dinoprostone is the recommended primary option for induction of labor (IOL) in late-term pregnancies (LTPs). However, oxytocin is used in developing and rural areas, and studies have supported similar effectiveness for oxytocin and dinoprostone in reducing the rate of cesarean delivery of LTPs with a Bishop's score of between 4-6. This study aimed to compare dinoprostone and oxytocin for IOL in LTPs and the rate of cesarean section in ten centers in South China. MATERIAL AND METHODS A retrospective study included 1,408 women with LTP, with subgroups including a Bishop's score of 0-3 and 4-6. Rates of cesarean delivery were compared between women given vaginal dinoprostone and intravenous oxytocin for IOL. Secondary outcomes included the duration of labor, and maternal and fetal complications. RESULTS Comparison between women who received oxytocin (N=365) and dinoprostone (N=1,043) showed significantly lower rates of cesarean delivery with dinoprostone, but no significant difference between the subgroups with Bishop's scores of 0-3 and 4-6. The interval between induction to labor and duration of the active phase of labor were significantly reduced in the dinoprostone group with a Bishop's score of between 4-6. CONCLUSIONS For LTPs with a Bishop's score of 0-3, dinoprostone was superior to oxytocin for IOL with a lower rate of cesarean delivery, but both agents had a similar outcome for women with a Bishop's score of 4-6. These findings may have implications for the choice of agent used in IOL when dinoprostone is unavailable.

The CSRP2BP histone acetyltransferase drives smooth muscle gene expression.

The expression of nearly all smooth muscle genes are controlled by serum response factor binding sites in their promoter regions. However, SRF alone is not sufficient for regulating smooth muscle cell development. It associates with other cardiovascular specific cofactors to regulate smooth muscle gene expression. Previously, we showed that the transcription co-factor CRP2 was a regulator of smooth muscle gene expression. Here, we report that CSRP2BP, a coactivator for CRP2, is a histone acetyltransferase and a driver of smooth muscle gene expression. CSRP2BP directly interacted with SRF, CRP2 and myocardin. CSRP2BP synergistically activated smooth muscle gene promoters in an SRF-dependent manner. A combination of SRF, GATA6 and CRP2 required CSRP2BP for robust smooth muscle gene promoter activity. Knock-down of Csrp2bp in smooth muscle cells resulted in reduced smooth muscle gene expression. We conclude that the CSRP2BP histone acetyltransferase is a coactivator for CRP2 that works synergistically with SRF and myocardin to regulate smooth muscle gene expression.

Novel Risk Biomarker for Infective Endocarditis Patients With Normal Left Ventricular Ejection Fraction　- Monocyte to High-Density Lipoprotein Cholesterol Ratio.

BACKGROUND: The monocyte to high-density lipoprotein cholesterol ratio (MHR) appears to be a newly emerging inflammatory marker. However, its prognostic value in patients with infective endocarditis (IE) and normal left ventricular ejection fraction (LVEF) has been unclear.Methods and Results:We enrolled consecutive patients with IE and normal LVEF and divided into 3 groups based on the tertiles of MHR. Of 698 included patients, 44 (6.3%) died while in hospital. The occurrence of in-hospital death (3.9%, 4.3%, and 10.8%, P=0.003) and of major adverse clinical events (MACEs) (15.6%, 20.9%, and 30.6%, P<0.001) increased from the lowest to the highest MHR tertiles, respectively. Receiver-operating characteristic analysis demonstrated that MHR had good predictive value for in-hospital death (area under the curve [AUC] 0.670, 95% confidence interval [CI] 0.58-0.76, P<0.001) and was similar to C-reactive protein (AUC 0.670 vs. 0.702, P=0.444). Furthermore, MHR >21.3 had a sensitivity of 74.4% and specificity of 57.6% for predicting in-hospital death. Multiple analysis showed that MHR >21.3 was an independent predictor of both in-hospital (odds ratio 3.98, 95% CI 1.91-8.30, P<0.001) and long-term death (hazard ratio 2.29, 95% CI 1.44-3.64, P<0.001) after adjusting for age, female, diabetes mellitus, estimated glomerular filtration rate <90 mL/min/1.73 m2, and surgical treatment. Kaplan-Meier survival curves showed that patients with MHR >21.3 had an increased rate of long-term death compared to those without (P=0.002). CONCLUSIONS: Elevated MHR was independently associated with in-hospital and long-term death in patients with IE and normal LVEF.

Evaluation of a modified "Triple-P" procedure in women with morbidly adherent placenta after previous caesarean section.

AIM: To describe a modified "Triple-P" procedure and evaluate its outcome in women with morbidly adherent placenta (MAP) after previous caesarean section (CS). METHODS: A retrospective cohort study of 96 women with MAP after CS was recruited with 45 women receiving the modified "Triple-P" procedure as study group and the other 51 cases receiving the conventional managements as the control. The maternal outcomes were compared. RESULTS: The modified "Triple-P" procedure was described in step by step. Women in study group demonstrated reduction of blood loss, transfusion blood volume and operation time, as well as less hospital days and lower hospitalization cost (P < 0.05). In addition, there was no difference in uterine healing rate, hysterectomy rate, and ICU transferring rate (P > 0.05). CONCLUSION: Our modified "Triple-P" procedure for MAP after previous CS maintained the advantages of Chandraharan's "Triple-P" procedure in preservation of uterus for further fertility, less intraoperative blood loss, shorter hospital stays, and lower hospitalization cost but also advanced in feasibility and convenience during introducing into routine clinical practice.

TRPV6 is a prognostic marker in early-stage cervical squamous cell carcinoma.

Transient receptor potential vanilloid 6 (TRPV6) has been shown to promote caner proliferation in several solid tumors, leading to unfavorable clinical outcomes. Our study aimed to elucidate the clinical significance of TRPV6 in patients with early-stage cervical squamous cell carcinoma (CSCC). The mRNA expression of TRPV6 was measured in 12 paired early-stage CSCC specimens and six cervical carcinoma cell lines using quantitative real-time PCR (qRT-PCR). Western blotting and immunohistochemistry (IHC) were employed to examine the protein expression level of TRPV6 in four paired specimens, 175 paraffin-embedded early-stage CSCC specimens, and 50 normal cervical tissues (NCTs), respectively. Statistical analyses were performed to evaluate the clinical significance of TRPV6 expression. The expressions of TRPV6 mRNA and protein were both significantly downregulated in early-stage CSCC tissues and cervical cancer cell lines. IHC analyses revealed that TRPV6 was downregulated in 136 (77.7 %) of 175 early-stage CSCC specimens. Moreover, TRPV6 expression in early-stage CSCC was significantly correlated with the tumor stage (P < 0.001), tumor growth type (P < 0.001), tumor size (P = 0.008), and differentiation grade (P = 0.003). The early-stage CSCC patients with a low TRPV6 expression level had a short progress-free survival (PFS) and overall survival (OS) duration. Univariate and multivariate analyses identified TRPV6 as an independent prognostic factor for early-stage CSCC patients' survival. We demonstrated that TRPV6 was downregulated in CSCC, which was correlated with unfavorable survival outcomes of early-stage CSCC patients. TRPV6 may be used as a novel prognostic marker for early-stage CSCC.

Acylglycerol kinase is over-expressed in early-stage cervical squamous cell cancer and predicts poor prognosis.

Acylglycerol kinase (AGK) had been shown to contribute to cancer progression and unfavorable clinical outcomes of patients. Our study aimed to investigate the expression pattern and clinical significance of AGK in patients with early-stage cervical squamous cell cancer (CSCC). The protein and messenger RNA (mRNA) expression of AGK was analyzed in six cervical cancer cell lines and four paired early-stage CSCC specimens and normal cervical tissues (NCT), using Western blotting and real-time PCR (RT-PCR). And we investigated the AGK protein expression in paraffin-embedded specimens from 140 patients with early-stage CSCC and 30 cases of NCT by immunohistochemistry (IHC). Statistical analyses were performed to evaluate the clinicopathological significance of AGK expression. The expressions of AGK protein and mRNA were significantly up-regulated in cervical cancer cell lines and cancer tissues. IHC analyses revealed that AGK was highly expressed in 93 (66.4 %) of 140 early-stage CSCC specimens, but in none of the NCT. Moreover, AGK expression in early-stage CSCC was significantly correlated with tumor stage (P < 0.001), tumor size (P < 0.001), and tumor type (P < 0.001). Early-stage CSCC patients with high AGK expression level had shorter progress-free survival (PFS) and overall survival (OS) time compared with patients with low AGK expression levels. Univariate and multivariate analyses identified AGK expression level as an independent prognostic factor for survival of early-stage CSCC patients. We showed that AGK was over-expressed in cervical cancer cell lines and clinical tissues, and over-expression of AGK was associated with poor survival outcomes of early-stage CSCC patients. AGK can be used as an independent prognostic marker for early-stage CSCC.

Study on the Crystallization Behavior of Neodymium Rare-Earth Butadiene Rubber Blends and Its Effect on Dynamic Mechanical Properties.

Utilizing neodymium-based butadiene rubber as a baseline, this study examines the effect of eco-friendly aromatic TDAE oil, fillers, and crosslinking reactions on neodymium-based rare-earth butadiene rubber (Nd-BR) crystallization behavior. The findings suggest that TDAE oil hinders crystallization, resulting in decreased crystallization temperatures and heightened activation energies (Ea). The crystallization activation energies for 20 parts per hundreds of rubber (PHR) and 37.5 PHR oil stand at -116.8 kJ/mol and -48.1 kJ/mol, respectively, surpassing the -264.3 kJ/mol of the unadulterated rubber. Fillers act as nucleating agents, hastening crystallization, which in turn elevates crystallization temperatures and diminishes Ea. In samples containing 20 PHR and 37.5 PHR oil, the incorporation of carbon black and silica brought the Ea down to -224.9 kJ/mol and -239.1 kJ/mol, respectively. Crosslinking considerably restricts molecular motion and crystallization potential. In the examined conditions, butadiene rubber containing 37.5 PHR oil displayed no crystallization following crosslinking, albeit crystallization was discernible with filler inclusion. Simultaneously, the crystallinity level sharply declined, manifesting cold crystallization behavior. The crosslinking process elevates Ea, while the equilibrium melting point (Tm0) noticeably diminishes. For instance, the Tm0 of pure Nd-BR is approximately -0.135 °C. When blended with carbon black and silica, the Tm0 values are -3.13 °C and -5.23 °C, respectively. After vulcanization, these values decrease to -21.6 °C and -10.16 °C. Evaluating the isothermal crystallization kinetics of diverse materials via the Avrami equation revealed that both the oil and crosslinking process can bring about a decrease in n values, with the Avrami index n for various samples oscillating between 1.5 and 2.5. Assessing the dynamic mechanical attributes of different specimens reveals that Nd-BR crystallization notably curtails its glass transition, marked by a modulus shift in the transition domain and a decrement in loss factor. The modulus in the rubbery state also witnesses a substantial augmentation.

The Crystallization and Melting Behavior of Neodymium-Based Butadiene Rubber Blends.

This study investigates the influence of poly(butadiene-isoprene) copolymer rubber (BIR) and TDAE oil on the crystallization and melting behavior of neodymium-based butadiene rubber (Nd-BR). The study demonstrates that the melting points of Nd-BR and its blends decrease with lower crystallization temperatures. Below the critical crystallization temperature (Tc,c), the melting behavior shows dual peaks in distinct temperature ranges, which are attributed to different spherulitic sizes. The addition of BIR or TDAE oil lowers the Tc,c, with TDAE oil exerting a more substantial effect. These diluents mainly influence the nucleation temperature and crystallinity level of Nd-BR while having a minimal effect on the crystallization mechanism. A master curve, which overlaps for various samples, is developed by correlating the peak melting temperature (Tm,peak) with the Tc. This curve facilitates a quantitative assessment of the effects of BIR and TDAE oil on Nd-BR, highlighting the greater influence of TDAE oil on the crystalline structure compared with BIR at equivalent mass fractions. By applying the Lorentz equation and multi-peak fitting, a relationship between the melting points and crystallization temperatures is established, enabling the calculation of the equilibrium melting points (Tm0) for different samples. The findings show a reduction in the Tm0 due to the diluents; specifically, the Tm0 is approximately 0 °C for pure Nd-BR, and it decreases to -4.579 °C and -6.579 °C for samples with 50 PHR TDAE oil and 60 wt.% BIR, respectively.

Protocol to derive human trophoblast stem cells directly from primed pluripotent stem cells.

Human trophoblast stem cells (hTSCs) are useful for studying human placenta development and diseases, but primed human pluripotent stem cells (hPSCs) routinely cultured in most laboratories do not support hTSC derivation. Here, we present a protocol to derive hTSCs directly from primed hPSCs. This approach, containing two strategies either with or without bone morphogenetic protein 4 (BMP4), provides a simple and accessible tool for deriving hTSCs to study placenta development and disease modeling without ethical limitations or reprogramming process. For complete details on the use and execution of this protocol, please refer to Wei et al. (2021).

Preeclampsia associated changes in volume density of fetoplacental vessels in Chinese women and mouse model of preeclampsia.

INTRODUCTION: Preeclampsia (PE) is associated with abnormal placental vascular structure. However, the volume density of fetoplacental vessels in PE remains unclear. Additionally, manually annotated CT angiography, which is widely used to analyze placental vessels, has issues regarding inaccuracy. Thus, computer-aided CT angiography for analyzing the volume density of fetoplacental vessels would facilitate the understanding of PE pathogenesis. METHODS: We performed computer-aided CT angiography to compare differences in placentas among 17 women with PE and 34 normotensive women. The contrast ratio in CT angiography was significantly enhanced using a three-dimensional (3-D) Hessian matrix algorithm. The PE-like mouse model was established by administration of 125 mg/kg/day NG-nitro-l-arginine methyl ester (l-NAME) for 10 days. The presence of endothelial marker CD31 was confirmed by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). The expression of angiogenic factors (PlGF, VEGFA, and sFlt1) in placentas was detected using qRT-PCR and western blotting. RESULTS: The volume density in fetoplacental vessels and CD31 expression were significantly reduced in women with PE and l-NAME-induced mice. Additionally, the downregulation of angiogenic factors (PlGF/VEGFA) and upregulation of an anti-angiogenic factor (sFlt1) were determined in a mouse model. DISCUSSION: Contrast-enhanced CT angiography with the aid of a 3-D Hessian matrix algorithm was performed. PE significantly affects the formation of vascular vessels, resulting in a lower volume density of fetoplacental vessels in humans and mice. This may be explained by the abnormal release of angiogenic factors during PE.

Different transcriptional profiles of human embryonic stem cells grown in a feeder-free culture system and on human foreskin fibroblast feeder layers.

Feeder cells provide an optimal microenvironment for the propagation of human embryonic stem cells (hESCs) by supplying currently known or unknown factors. However, the hESCs grown on feeder cells are not suitable for the purpose of clinical application because of the risk of contamination. In recent years, the feeder-free culture method has been developed to eliminate contamination, but some studies show that hESCs exhibit poor growth patterns in a feeder-free culture system. Regarding this phenomenon, we speculate that some genes related to hESC propagation were differently expressed in hESCs grown on feeder cells. To test this hypothesis, 3 hESC lines (NF4, NF5 and P096) were efficiently expanded in a feeder-free culture system or on human foreskin fibroblast (HFF) cells. The different gene expression patterns of hESCs in these 2 conditions were analyzed through microarrays. The results revealed that the hESCs cultured in both conditions maintained the expression of stemness markers and the ability to spontaneously differentiate into the 3 germ layers. The analysis of gene expression profiles revealed that 23 lncRNA and 15 genes were significantly differentially expressed in these two culture conditions. Furthermore, GO analyses showed that these genes were involved in such biological processes as growth factor stimuli, cell growth, and stem cell maintenance. To summarize, our study demonstrated that the hESCs grown on the HFF showed different gene expression patterns compared to those grown in a feeder-free culture system, suggesting that these differently expressed lncRNAs and genes played important roles in maintaining hESC propagation.

Establishment of a CRISPR/Cas9-mediated ANP32A homozygous knockout human embryonic stem cell line.

ANP32A is a member of acidic leucine-rich nuclear phosphoprotein 32 family, which is involved in diverse biochemical processes, including chromatin modification and remodeling. Here, we established the CRISPR/Cas9-mediated ANP32A homozygous knockout human embryonic stem cell (ESC) line to investigate the roles of ANP32A in pluripotency maintenance and differentiation process of human ESCs. This cell line shows the normal karyotype and typical stem cell morphology, in accordance with high expression of pluripotent genes and the differentiation potential in vitro. Consequently, the ANP32A knockout cell line provides a promising approach for investigating the roles of ANP32A in human ESC cell fate decisions.

Coordination of EZH2 and SOX2 specifies human neural fate decision.

Polycomb repressive complexes (PRCs) are essential in mouse gastrulation and specify neural ectoderm in human embryonic stem cells (hESCs), but the underlying molecular basis remains unclear. Here in this study, by employing an array of different approaches, such as gene knock-out, RNA-seq, ChIP-seq, et al., we uncover that EZH2, an important PRC factor, specifies the normal neural fate decision through repressing the competing meso/endoderm program. EZH2-/- hESCs show an aberrant re-activation of meso/endoderm genes during neural induction. At the molecular level, EZH2 represses meso/endoderm genes while SOX2 activates the neural genes to coordinately specify the normal neural fate. Moreover, EZH2 also supports the proliferation of human neural progenitor cells (NPCs) through repressing the aberrant expression of meso/endoderm program during culture. Together, our findings uncover the coordination of epigenetic regulators such as EZH2 and lineage factors like SOX2 in normal neural fate decision.

ACE2 Is Expressed in Immune Cells That Infiltrate the Placenta in Infection-Associated Preterm Birth.

COVID-19 is associated with increased incidence of preterm birth (PTB). We assessed pathways by which SARS-CoV-2 could access the placenta. Placentae, from PTB with or without chorioamnionitis (ChA), or from term pregnancies (n = 12/13/group) were collected. Peripheral blood was collected from healthy pregnant women (n = 6). Second trimester placental explants (16-20 weeks, n = 5/group) were treated with lipopolysaccharide (LPS, to mimic bacterial infection) and ACE2, CCL2, IL-6/8 and TNFα mRNA was assessed. ChA-placentae exhibited increased ACE2 and CCL2 mRNA expression (p < 0.05). LPS increased cytokine and ACE2 mRNA in placental explants. Placental ACE2 protein localized to syncytiotrophoblast, fetal endothelium, extravillous trophoblast and in immune cells-subsets (M1/M2 macrophage and neutrophils) within the villous stroma. Significantly increased numbers of M1 macrophage and neutrophils were present in the ChA-placenta (p < 0.001). Subsets of peripheral immune cells from pregnant women express the ACE2 mRNA and protein. A greater fraction of granulocytes was positive for ACE2 protein expression compared to lymphocytes or monocytes. These data suggest that in pregnancies complicated by ChA, ACE2 positive immune cells in the maternal circulation have the potential to traffic SARS-CoV-2 virus to the placenta and increase the risk of vertical transmission to the placenta/fetus.

Efficient derivation of human trophoblast stem cells from primed pluripotent stem cells.

Human trophoblast stem cells (hTSCs) provide a valuable model to study placental development and function. While primary hTSCs have been derived from embryos/early placenta, and transdifferentiated hTSCs from naïve human pluripotent stem cells (hPSCs), the generation of hTSCs from primed PSCs is problematic. We report the successful generation of TSCs from primed hPSCs and show that BMP4 substantially enhances this process. TSCs derived from primed hPSCs are similar to blastocyst-derived hTSCs in terms of morphology, proliferation, differentiation potential, and gene expression. We define the chromatin accessibility dynamics and histone modifications (H3K4me3/H3K27me3) that specify hPSC-derived TSCs. Consistent with low density of H3K27me3 in primed hPSC-derived hTSCs, we show that knockout of H3K27 methyltransferases (EZH1/2) increases the efficiency of hTSC derivation from primed hPSCs. Efficient derivation of hTSCs from primed hPSCs provides a simple and powerful model to understand human trophoblast development, including the pathogenesis of trophoblast-related disorders, by generating disease-specific hTSCs.

TNF-related apoptosis-inducing ligand (TRAIL) promotes trophoblast cell invasion via miR-146a-EGFR/CXCR4 axis: A novel mechanism for preeclampsia?

INTRODUCTION: Preeclampsia (PE) is associated with failure of uterovascular transformation due to impaired trophoblast invasion. Previously, TNF-related apoptosis-inducing ligand (TRAIL) has been controversially reported to correlate with PE, but whether it regulates trophoblast invasion yet to be defined. METHODS: We treated HTR8/SVneo cells with sTRAIL at concentrations of 0.1 ng/mL, 1 ng/mL and 10 ng/mL for a 72-h time course and compared cell proliferation, apoptosis and invasion ability by CCK8 assay, flow cytometry analysis and Matrigel cell invasion assay, respectively. The expressions levels of miR-146a, CXCR4, EGFR and MMP2 were quantified by qRT-PCR and Western blot. Moreover, HTR8/SVneo cells were transfected with miR-146a mimics and miR-146a inhibitor, followed by analyzing invasion ability and gene expressions of CXCR4, EGFR and MMP2. Finally, both serum and placental samples from preeclamptic and gestational week-matched normotensive women were collected and assessed for the expression levels of TRAIL by ELISA assay and immunochemistry staining. RESULTS: sTRAIL treatment of HTR8/SVneo cells resulted in no change in proliferation or apoptosis, but dose- and time-dependently enhanced invasion. TRAIL downregulated the expressions of miR-146a and upregulated CXCR4, EGFR and MMP2. Transfection of miR-146a resulted in the inhibition of invasion and downregulation of CXCR4, EGFR and MMP2. Lastly, the expression levels of TRAIL decreased in both serum and placenta of preeclamptic pregnancies and correlated with the disease severity. DISCUSSION: TRAIL regulated miR-146a-CXCR/EGFR axis to promote the invasion of trophoblast like cells. Its deceased levels in preeclamptic sera and placenta, suggest that low levels of TRAIL might contribute to the pathogenesis of preeclampsia.