Preeclampsia, a relatively common pregnancy disorder, is a major contributor to maternal mortality and morbidity worldwide. An elevation in microRNA-210 (miR-210) expression in the placenta has been reported to be associated with preeclampsia. Our bioinformatic analysis showed that thrombospondin type I domain containing 7A (THSD7A) is a predicted target for miR-210. The aim of this study was to determine whether miR-210 is involved in preeclampsia through its targeting of THSD7A in human placental trophoblasts. In preeclamptic placental tissues, THSD7A levels were significantly downregulated, and were inversely correlated with the levels of miR-210. THSD7A was validated as a direct target of miR-210 using quantitative real time PCR (qRT-PCR), Western blotting, and dual luciferase assays in HTR8/SVneo cells. Transwell insert invasion assays showed that THSD7A mediated the invasion-inhibitory effect of miR-210 in HTR8/SVneo cells. Interestingly, hypoxia markedly increased miR-210 expression while suppressing THSD7A expression in a time-dependent manner in HTR8/SVneo cells. This study provides novel data on the function of THSD7A in human placental cells, and extends our knowledge of how miR-210 is involved in the development of the preeclampsia.

During pregnancy, the appropriate allocation of nutrients between the mother and the fetus is dominated by maternal–fetal interactions, which is primarily governed by the placenta. The syncytiotrophoblast (STB) lining at the outer surface of the placental villi is directly bathed in maternal blood and controls feto–maternal exchange. The STB is the largest multinucleated cell type in the human body, and is formed through syncytialization of the mononucleated cytotrophoblast. However, the physiological advantage of forming such an extensively multinucleated cellular structure remains poorly understood. Here, we discover that the STB uniquely adapts to nutrient stress by inducing the macropinocytosis machinery through repression of mammalian target of rapamycin (mTOR) signaling. In primary human trophoblasts and in trophoblast cell lines, differentiation toward a syncytium triggers macropinocytosis, which is greatly enhanced during amino acid shortage, induced by inhibiting mTOR signaling. Moreover, inhibiting mTOR in pregnant mice markedly stimulates macropinocytosis in the syncytium. Blocking macropinocytosis worsens the phenotypes of fetal growth restriction caused by mTOR-inhibition. Consistently, placentas derived from fetal growth restriction patients display: 1) Repressed mTOR signaling, 2) increased syncytialization, and 3) enhanced macropinocytosis. Together, our findings suggest that the unique ability of STB to undergo macropinocytosis serves as an essential adaptation to the cellular nutrient status, and support fetal survival and growth under nutrient deprivation.

Decidual NK (dNK) cells, identified as CD56CD16CD3, account for ~70% of lymphocytes within the uterine wall during early pregnancy. Accumulating evidence suggests that tight interactions between placental trophoblasts and dNK cells are critical for trophoblast cell differentiation. However, the underlying mechanism remains to be explored in detail. In the present study, conditioned medium (CM) was collected from cultured primary human dNK cells. Primary cytotrophoblasts (CTBs) or the human trophoblast cell line HTR8/SVneo was treated with dNK-CM and co-cultured with human umbilical vein endothelial cells (HUVECs) in a three-dimensional Matrigel scaffold, and the formation of tube structures was dynamically monitored with live cell imaging. Trophoblast invasion was analyzed with a transwell invasion assay. The data demonstrated that the treatment of HTR8/SVneo cells or CTBs with dNK-CM remarkably promoted trophoblast invasion and tube formation in the presence of HUVECs. The epithelial marker E-cadherin was reduced, while the expression of endothelial markers NCAM, VE-cadherin and integrin β1 was significantly promoted in the HTR8/SVneo cells upon treatment with dNK-CM. Antibody blocking experiments revealed that the dNK cells promoted trophoblast invasion through the production of IL-8 and HGF, and they induced trophoblast differentiation toward endothelial phenotype by producing VEGF-C and HGF. These results provide new evidence to clarify the finely tuned interactions between trophoblasts and dNK cells at the maternal-fetal interface.

Background Metformin has been reported to decrease insulin resistance and is associated with a lower risk of pregnancy-induced hypertension and preeclampsia. It is widely accepted that the placenta plays a crucial role in the development of preeclampsia. Our aim is to explore the effect of metformin on preeclampsia. Study Design We examined control diet-fed (isocaloric diet) pregnant mice (CTRL group), pregnant mice fed a high-fat diet (HF group), and high-fat-diet-fed pregnant mice treated with metformin (HF-M group). The HF mice were fed a high-fat diet six weeks before pregnancy to establish a preeclampsia-like model; then, the group was randomly divided into a HF group and a HF-M group after pregnancy. Blood pressure, urine protein, pregnancy outcomes, protein expression, and histopathological changes in the placentas of all groups were examined and statistically analysed. Results We observed that metformin significantly improved high blood pressure, proteinuria, and foetal and placental weights in the HF-M group compared with the HF group. Metformin significantly improved placental labyrinth and foetal vascular development in preeclampsia. In addition, metformin effectively increased matrix metalloproteinase-2 (MMP-2) and vascular endothelial growth factor (VEGF) levels in the placenta. Conclusions Our results suggest that metformin can improve preeclamptic symptoms and pregnancy outcomes.

The findings reveal a tight correlation between the imbalanced steroid hormone production and the procoagulation factor in E-PE patients, which provide potential biomarkers to predict preeclampsia, and bring new insight into the pathogenesis of preeclampsia.

Ovarian cancer is the most lethal gynecological malignant tumor because of its high recurrence rate. In the present work, in order to find new therapeutic targets, we identified 8480 proteins in thirteen pairs of ovarian cancer tissues and normal ovary tissues through quantitative proteomics. 498 proteins were found to be differentially expressed in ovarian cancer, which involved in various cellular processes, including metabolism, response to stimulus and biosynthetic process. The expression levels of chloride intracellular channel protein 1 (CLIC1) and lectin galactoside-binding soluble 3 binding protein (LGALS3BP) in epithelial ovarian cancer tissues were significantly higher than those in normal ovary tissues as confirmed by western blotting and immunohistochemistry. The knockdown of CLIC1 in A2780 cell line downregulated expression of CTPS1, leading to the decrease of CTP and an arrest of cell cycle G1 phase, which results into a slower proliferation. CLIC1-knockdown can also slow down the tumor growth in vivo. Besides, CLIC1-knockdown cells showed an increased sensitivity to hydrogen peroxide and cisplatin, suggesting that CLIC1 was involved in regulation of redox and drug resistance in ovarian cancer cells. These results indicate CLIC1 promotes tumorgenesis, and is a potential therapeutic target in epithelial ovarian cancer treatment.

Insufficient trophoblast invasion is associated with preeclampsia (PE) development. Retinol-binding protein 4 (RBP4) is important for regulating cell differentiation, migration and invasion. The aim of the present study was to determine RBP4 expression and function in the human placenta and to examine the underlying mechanisms. In the present study, RBP4 expression was determined in serum samples from 35 pregnant women with PE and 30 healthy pregnant women using enzyme-linked immunosorbent assays. Cell proliferation was assessed by Cell Counting Kit-8 assays, and cell invasion was examined with transwell assays. RBP4 concentrations were significantly lower in the PE group when compared with the control group. RBP4 overexpression enhanced HTR8/SVneo cell proliferation and invasion, and the levels of phosphorylated (p-) phosphoinositide 3-kinase (PI3K) and p-protein kinase B (AKT) in HTR8/SVneo cells. RBP4 knockdown significantly inhibited HTR8/SVneo cell proliferation and invasion, and repressed the expression of matrix metalloproteinases. In addition, RBP4 knockdown significantly reduced the levels of p-PI3K and p-AKT in HTR8/SVneo cells. Taken together, the results of the present study demonstrated that RBP4 overexpression increased HTR8/SVneo cell proliferation and invasion by suppressing PI3K/AKT signaling and RBP4 knockdown induced the opposite effects.

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