MiRNA-26a-5p inhibits preterm labor initiation by targeting and regulating TRPC3 ion channel protein expression.

The incidence of preterm birth (PTB) is increasing annually worldwide, leading to various health problems or even fetal deaths. Our previous work demonstrated the activation of transient receptor potential cation channel subfamily C 3 (TRPC3) in mice with PTB, and its activation could promote inward flow of calcium ions and uterine smooth muscle (USM) contraction via regulation of Cav3.2, Cav3.1, and Cav1.2. However, the upstream regulators of TRPC3 and its mechanisms remain unknown. In the present study, the binding of miR-26a-5p to the 3' untranslated region of TRPC3 was predicted by bioinformatics databases (TargetScanHuman and starBase v3.0) and confirmed by a dual-luciferase assay. MiR-26a-5p was downregulated, while TRPC3 was upregulated in the USM tissues of patients with PTB compared to people without PTB. The results showed that miR-26a-5p mimic transfection markedly reduced TRPC3 expression in LPS-stimulated USM cells. Additionally, miR-26a-5p regulated intracellular Ca2+ levels in USM cells by targeting TRPC3. Furthermore, miR-26a-5p inhibited the CPI17/PKC/PLCγ signaling pathway and reduced the expression of Cav3.2, Cav3.1, and Cav1.2. In conclusion, miR-26a-5p regulated the initiation of PTB by targeting TRPC3 and regulating intracellular Ca2+ levels. This study provides a promising diagnostic biomarker and therapeutic target for PTB.

Melatonin for prevention of fetal lung injury associated with intrauterine inflammation and for improvement of lung maturation.

Inflammation is associated with injury to immature lungs, and melatonin administration to preterm newborns with acute respiratory distress improves pulmonary outcomes. We hypothesized that maternally administered melatonin may reduce inflammation, oxidative stress, and structural injury in fetal lung and help fetal lung maturation in a mouse model of intrauterine inflammation (IUI). Mice were randomized to the following groups: control (C), melatonin (M), lipopolysaccharide (LPS; a model of IUI) (L), and LPS with melatonin (ML). Pro-inflammatory cytokines, components of the Hippo pathway, and Yap1/Taz were analyzed in the fetal lung at E18 by real-time RT-qPCR. Confirmatory histochemistry and immunohistochemical analyses (surfactant protein B, vimentin, HIF-1ß, and CXCR2) were performed. The gene expression of IL1ß in the fetal lung was significantly increased in L compared to C, M, and ML. Taz expression was significantly decreased in L compared to C and M. Taz gene expression in L was significantly decreased compared with those in ML. Immunohistochemical analyses showed that the expression of HIF-1ß and CXCR2 was significantly increased in L compared to C, M, and ML. The area of surfactant protein B and vimentin were significantly decreased in L than C, M, or ML in the fetal and neonatal lung. Antenatal maternally administered melatonin appears to prevent fetal lung injury induced by IUI and to help lung maturation. The results from this study results suggest that melatonin could serve as a novel safe preventive and/or therapeutic medicine for preventing fetal lung injury from IUI and for improving lung maturation in prematurity.

Maternal inflammation leads to different mTORC1 activity varied by anatomic locations in mouse placenta†.

Maternal inflammation (MI) is associated with many adverse perinatal outcomes. The placenta plays a vital role in mediating maternal-fetal resource allocation. Studies have shown that MI contributes to placental dysfunction, which then leads to adverse birth outcomes and high health risks throughout childhood. Placental mammalian target of rapamycin complex 1 (mTORC1) signaling pathway links maternal nutrient availability to fetal growth; however, the impact of MI on mTORC1 signaling in the placenta remains unclear. In this study, we sought to explore the changes of mTORC1 signaling in the mouse placenta at late gestation by using two models of MI employing lipopolysaccharide (LPS) and interleukin-1ß (IL-1ß) to mimic acute (aMI) and sub-chronic (cMI) inflammatory states, respectively. We determined placental mTORC1 activity by measuring the activity of mTORC1 downstream molecules, including S6k, 4Ebp1, and rpS6. In the aMI model, we found that mTORC1 activity was significantly decreased in the placental decidual and junctional zone at 2 and 6 h after LPS surgery, respectively; however, mTORC1 activity was significantly increased in the placental labyrinth zone at 2, 6, and 24 h after LPS treatment, respectively. In the cMI model, we observed that mTORC1 activity was increased only in the placental labyrinth zone after consecutive IL-1ß exposure. Our study reveals that different parts of the mouse placenta react differently to MI, leading to variable mTORC1 activity throughout the placenta. This suggests that different downstream molecules of mTORC1 from different parts of the mouse placenta may be used in clinical research to monitor the fetal well-being during MI.

Melatonin for prevention of placental malperfusion and fetal compromise associated with intrauterine inflammation-induced oxidative stress in a mouse model.

Melatonin has been shown to reduce oxidative stress and mitigate hypercoagulability. We hypothesized that maternally administered melatonin may reduce placental oxidative stress and hypercoagulability associated with exposure to intrauterine inflammation (IUI) and consequently improve fetoplacental blood flow and fetal sequelae. Mice were randomized to the following groups: control (C), melatonin (M), lipopolysaccharide (LPS; a model of IUI) (L), and LPS with melatonin (ML). The expression of antioxidant mediators in the placenta was significantly decreased, while that of pro-inflammatory mediators was significantly increased in L compared to C and ML. The systolic/diastolic ratio, resistance index, and pulsatility index in uterine artery (UtA) and umbilical artery (UA) were significantly increased in L compared with other groups when analyzed by Doppler ultrasonography. The expression of antioxidant mediators in the placenta was significantly decreased, while that of pro-inflammatory mediators was significantly increased in L compared to C and ML. Vascular endothelial damage and thrombi formation, as evidenced by fibrin deposits, were similarly increased in L compared to other groups. Maternal pretreatment with melatonin appears to modulate maternal placental malperfusion, fetal cardiovascular compromise, and fetal neuroinflammation induced by IUI through its antioxidant properties.

Moderate mammalian target of rapamycin inhibition induces autophagy in HTR8/SVneo cells via O-linked ß-N-acetylglucosamine signaling.

AIM: Autophagy, a highly regulated process with a dual role (pro-survival or pro-death), has been implicated in adverse pregnancy outcomes. The aim of this study was to explore the mechanism whereby mammalian target of rapamycin (mTOR) signaling regulates autophagy by modulating protein O-GlcNAcylation in human trophoblasts. METHODS: HTR8/SVneo cells were incubated in serum-free medium for different time intervals or treated with varying doses of Torin1. Protein expression and cell apoptosis were detected by immunoblotting and flow cytometry, respectively. RESULTS: Short-term serum starvation or slight suppression of mTOR signaling promoted autophagy and decreased apoptosis in HTR8/SVneo cells. Conversely, prolonged serum starvation or excessive inhibition of mTOR reduced autophagy and enhanced cell apoptosis. Both serum starvation and mTOR signaling suppression reduced protein O-GlcNAcylation. Upregulation and downregulation of O-linked ß-N-acetylglucosamine (O-GlcNAc) levels attenuated and augmented autophagy, respectively. Moderate mTOR inhibition-induced autophagy was blocked by upregulation of protein O-GlcNAcylation. Furthermore, immunoprecipitation studies revealed that Beclin1 and synaptosome associated protein 29 (SNAP29) could be O-GlcNAcylated, and that slight mTOR inhibition resulted in decreased O-GlcNAc modification of Beclin1 and SNAP29. Notably, we observed an inverse correlation between phosphorylation (Ser15) and O-GlcNAcylation of Beclin1. CONCLUSION: mTOR signaling inhibition played dual roles in regulating autophagy and apoptosis in HTR8/SVneo cells. Moderate mTOR suppression might induce autophagy via modulating O-GlcNAcylation of Beclin1 and SNAP29. Moreover, the negative interplay between Beclin1 O-GlcNAcylation and phosphorylation (Ser15) may be involved in autophagy regulation by mTOR signaling.

[Analysis of emergency obstetric hysterectomy: the change of indications and the application of intraoperative interventions].

OBJECTIVE: To investigate the change of indications of emergency obstetric hysterectomy and the clinical application of intraoperative interventions. And to provide evidence for prevention of hysterectomy and improvement of obstetric quality. METHODS: Clinical data were collected from 97 patients who received emergency obstetric hysterectomy at Shengjing Hospital of China Medical University between January 1st, 2004 and December 31st, 2013. The patients were divided into two groups by the time point of January 1st, 2009: the first group was cases treated between January 1st, 2004 and December 31st, 2008, while the second group was cases treated between January 1st, 2009 and December 31st, 2013. The clinical indicators, surgical indications, intraoperative interventions, and blood loss between the two groups were analyzed retrospectively. RESULTS: (1) Incidence: 54 857 women delivered at Shengjing Hospital of China Medical University between January 1st, 2004 and December 31st, 2013. Of them, 97 patients received emergency obstetric hysterectomy, with an incidence of 0.177% (97/54 857). (2) The 17 patients delivered vaginally (18%,17/97) and 80 by caesarean section (83%,80/97). Forty-nine patients experienced repregnancy with scar uterus (51% , 49/97). About 41 patients underwent abdominal total hysterectomy (42%,41/97) and 56 received subtotal hysterectomy (58%, 56/97). (3) The number of patients were comparable between the two groups (50 vs 47; P > 0.05). (4) The main surgical indication was uterine inertia (45%, 44/97). The main causes of uterine inertia were excessive uterine tension (45%, 20/44) and placental abruption due to gestational hypertension (32%, 14/44). Of all the indications, 29 patients in the first group (58%, 29/50) and 15 patients in the second group (32%, 15/47) suffered from postpartum hemorrhage. Pathological placenta embedment occurred in 15 patients in the first group (30%, 15/50) and 25 patients in the second group (53%, 25/47). The incidences of postpartum hemorrhage due to uterine inertia or pathological placenta embedment were significantly different between the two groups (both P < 0.05), respectively. (5) In the first group, the average preoperative blood loss was (2 900±1 900) ml, and the average intraoperative amount of infused white & red blood cells was (5.9±3.5) U, with the average operation time of (2.2±1.8) hours and the average in-hospital duration of (7.8±2.3) days. In the second group, the average preoperative blood loss was (3 100± 2 200) ml, and the intraoperative amount of infused white & red blood cells was (6.2±5.2) U, with the average operation time of (2.5±2.1) hours and the average in-hospital duration of (7.9±2.9) days. There was no significant difference between the two groups in any of these indicators (P > 0.05). Postpartum hemorrhage was usually treated with uterine packing in the first group, but was preferentially treated with potent uterine contraction agents, arterial ligation, uterine balloon compression or B-Lynch suture in the second group. The therapeutic effects of these new treatments were significantly better than uterine packing (P < 0.05). CONCLUSIONS: The incidence of emergency obstetric hysterectomy did not change significantly in the past decade. However, the indications and intraoperative interventions have changed significantly in the second five years compared with the first five years. The main surgical indications were uterine inertia and postpartum hemorrhage due to pathological placenta embedment. Therefore, strict control of caesarean section indications was important to reduce emergency obstetric hysterectomy.

RhoGDI2 is expressed in human trophoblasts and involved in their migration by inhibiting the activation of RAC1.

The invasion of placental trophoblast cells into the maternal decidua is an essential aspect of placental embedment. The process of placentation bears several striking similarities to tumor cell metastasis. However, trophoblastic migration during implantation and placentation is stringently controlled both in space and time. RhoGDI2 belongs to a family of Rho guanosine diphosphate dissociation inhibitors (RhoGDIs), and RhoGDI2 is a metastasis suppressor gene and a marker of aggressive human cancer. We evaluated whether RhoGDI2 has a physiological role in embryo implantation, particularly trophoblast migration. The mRNA and protein expression levels of RhoGDI2 were higher in term placentas compared with first-trimester placentas as detected by real-time PCR and Western blot. Immunohistochemical studies indicated that RhoGDI2 localized to the cytotrophoblast layer and extravillous trophoblast in first-trimester placentas and was distributed in the syncytiotrophoblast layers of term placentas. Overexpression of RhoGDI2 in HTR-8/SVneo cells was associated with reduced RAC1-guanosine triphosphate (GTP) levels and inhibited cell migration. Conversely, small interfering RNA-mediated downregulation of RhoGDI2 resulted in significantly increased RAC1-GTP levels. Altered RhoGDI2 expression had no significant effects on cell proliferation. In conclusion, RhoGDI2 inhibits trophoblast cell migration, and this function may involve suppression of RAC1 activation.

Altered Expression of miR-518b and miR-519a in the placenta is associated with low fetal birth weight.

OBJECTIVES: Previous studies have suggested that the expression and function of placenta-specific microRNAs (miRNAs) are associated with placenta trophoblastic proliferation and invasion. This study investigated whether the altered expression of placenta-specific miRNAs was involved in the development of fetal growth. METHODS: Placenta tissues were obtained from pregnant women with large for gestational age (LGA), intrauterine growth retardation (IUGR), and appropriate for gestational age (AGA) infants (n = 30 in each group). Real-time quantitative reverse transcription-polymerase chain reaction was used to analyze the expression of relative placenta-specific miRNAs in human placental tissues from three different groups. RESULTS: Compared with the LGA and healthy control (AGA) groups; the expression of miR-518b was decreased, whereas miR-519a was significantly increased in the placentas from the IUGR group (p < 0.05). CONCLUSION: This study suggests that altered expression of placenta-specific miRNAs (miR-518b and miR-519a) may be involved in the development of IUGR.

Umbilical Cord Blood-Derived Exosomes in Maternal-Fetal Disease: a Review.

The nutrients and other factors transported by umbilical cord blood, which is vital for fetal survival, play crucial roles in fetal development. There are various communication modes between the fetal-placental system and the maternal-placental system, and these communication modes are all mediated by umbilical cord blood. During the process of umbilical cord blood transportation, the changes of some nutrients and factors may play a key role in fetal development. Exosomes, which are members of the extracellular vesicle family, are present in the umbilical cord blood and play roles in information transmission as a result of their efficient cellular communication activity. The study of umbilical cord blood-derived exosomes provides a new approach for research on the etiology of maternal-fetal diseases and they may be useful for the development of intrauterine treatments. This review summarizes specific functions and research directions regarding umbilical cord blood-derived exosomes, and their potential associations with pregnancy complications.

Prevention of Preterm Birth by Cervical Pessary Combined with Vaginal Progesterone: a Systematic Review and Meta-analysis with Trial Sequential Analysis.

This study was to assess the effectiveness of cervical pessary combined with vaginal progesterone for the prevention of preterm birth (PTB). Ten studies about singleton [five randomized controlled trials (RCTs), vs vaginal progesterone; four cohorts, vs vaginal progesterone; two cohorts, vs cervical cerclage + vaginal progesterone] and two cohort studies about multiple pregnancies (vs vaginal progesterone) were included after searching electronic databases. For singleton pregnancies, the meta-analysis of three non-RCTs [relative risk (RR) = 0.41, p = 0.001] or total trials in non-Asian country (RR = 0.56, p = 0.03) revealed that compared with vaginal progesterone alone, cervical pessary + vaginal progesterone treatment had significant effectiveness on preventing PTB < 34 weeks, but not for five RCTs; meta-analysis of two trials showed that cervical pessary + vaginal progesterone had no significant prevention effects of PTB compared with cervical cerclage + vaginal progesterone. For multiple pregnancies, meta-analysis of two trials showed that compared with vaginal progesterone, cervical pessary + vaginal progesterone treatment increased neonatal birth weight (standardized mean difference = 0.50, p = 0.01). Trial sequential analysis implied additional studies were required. Four studies vs other controls (pessary, three-combined, tocolysis, conservative or no treatment; one study, each) were selected for systematic review. In conclusion, cervical pessary combined with vaginal progesterone may be safe and effective to prevent PTB in singleton pregnancies and increase neonatal birth weight in the multiple pregnancies compared with vaginal progesterone alone.

Functionalized TMC and ε-CL elastomers with shape memory and self-healing properties.

Introduction: Smart elastomers, which possess self-healing and shape memory capabilities, have immense potential in the field of biomedical applications. Polycarbonates and polyesters have gained widespread interest due to their remarkable biocompatibility over the last century. Nevertheless, the lack of functional versatility in conventional polyesters and polycarbonates means that they fall short of meeting the ever-evolving demands of the future. Methods: This paper introduced a new smart elastomer, named mPEG43-b-(PMBC-co-PCL)n, developed from polyester and polycarbonate blends, that possessed shape memory and self-heal capabilities via a physical crosslinking system. Results: The material demonstrated a significant tensile strength of 0.38 MPa and a tensile ratio of 1155.6%, highlighting its favorable mechanical properties. In addition, a conspicuous shape retrieval rate of 93% was showcased within 32.5 seconds at 37°C. Remarkably, the affected area could be repaired proficiently with no irritation experienced during 6h at room temperature, which was indicative of an admirable repair percentage of 87.6%. Furthermore, these features could be precisely modified by altering the proportion of MBC and ε-CL to suit individual constraints. Discussion: This innovative elastomer with exceptional shape memory and self-heal capabilities provides a solid basis and promising potential for the development of self-contracting intelligent surgical sutures in the biomedical field.

Underexpression of 4 placenta-associated microRNAs in complete hydatidiform moles.

OBJECTIVE: Several placental microRNAs (miRNAs) have been identified as placenta-associated miRNAs with the potential of estimating the condition of the placenta. However, our understanding of these miRNAs is limited. The aim of this study was to determine the expression of 8 placenta-associated miRNAs (miR-512-3p, miR-517a, miR-517b, miR-518b, miR-519a, miR-1185, miR-1283, and miR-1323) in complete hydatidiform mole (CHM). METHODS: Samples were obtained from patients with CHM (CHM group, n = 12) and elective terminations of normal pregnancy (control group, n = 20). We detected differentially expressed placenta-associated miRNAs in placenta by quantitative real-time reverse transcriptase-polymerase chain reaction analysis. Subsequently, we assessed the expression location of differentially expressed miRNAs by in situ hybridization analysis. RESULTS: Four placenta-associated miRNAs (miR-517a, miR-517b, miR-518b, and miR-519a) were underexpressed in the CHM group, compared with the control group (P < 0.01). When further investigating these 4 miRNAs with regard to in vivo localization by in situ hybridization, we found that 2 miRNAs (miR-517b and miR-518b) were detected exclusively in the trophoblast layer, with little signal (if any) observed in villous stroma cells. CONCLUSIONS: The results show that 4 miRNAs (miR-517a, miR-517b, miR-518b, and miR-519a) are deregulated in CHM, which suggests the involvement of these miRNAs in the functions of CHM placenta.

Successful treatment of two patients with postpartum disseminated intravascular coagulation complicated by abdominal compartment syndrome.

Disseminated intravascular coagulation (DIC) and abdominal compartment syndrome (ACS) are rare complications of pregnancy, and even more rare are cases with both complications occurring concomitantly. Obstetricians are relatively unfamiliar with these types of cases, the majority of which are fatal. We describe here a primigravida with acute fatty liver of pregnancy and a multipara with placental abruption who each developed uterine inertia complicated by postpartum DIC that required total hysterectomy. They developed ACS postoperatively and required decompressive laparotomy to alleviate increased intra-abdominal pressure and end-organ dysfunction. After timely decompressive laparotomy, both patients recovered without any additional complications and were discharged within 4 weeks of their initial admission. These 2 cases serve to remind obstetricians to consider the possibility of ACS whenever there is a fresh wound in the abdominal cavity of a patient with postpartum DIC. However, even when there is severe deterioration in the condition of a patient with ACS, immediate decompressive laparotomy may not be appropriate; the timing of the procedure is very important.

The emerging roles of placenta-specific microRNAs in regulating trophoblast proliferation during the first trimester.

In the human placenta, eight 'placenta-specific' microRNAs (miRNAs) are exclusively expressed and are associated with high cloning frequencies. The expression of placenta-specific miRNAs is known to be involved in preeclampsia, but the understanding of these miRNAs is still limited. The goal of this study was to investigate the levels and localisations of eight placenta-specific miRNAs in placental villi with different proliferative abilities during the first trimester. Immunohistochemical analyses indicated that placental trophoblast proliferation ability was associated with the weight of villi in the same gestational week during the first trimester. Of the eight placenta-specific miRNAs, quantitative real-time RT-PCR demonstrated that the expression of miR-517b and miR-1283 was increased in the lightest villi and decreased in the heaviest one, the expression of miR-519a was increased in the heaviest villi and decreased in the lightest one. In situ hybridisation analysis showed that miR-517b and miR-519a were located primarily in the trophoblast layer, while miR-1283 were expressed not only in the villous trophoblasts but also in some villous stroma cells. These findings suggest that miR-517b and miR-519a may play an important role in trophoblast proliferation during the first trimester.

Dendrimer-Based N-Acetyl Cysteine Maternal Therapy Ameliorates Placental Inflammation via Maintenance of M1/M2 Macrophage Recruitment.

Intrauterine inflammation (IUI) is the primary cause of spontaneous preterm birth and predisposes neonates to long-term sequelae, including adverse neurological outcomes. N-acetyl-L-cysteine (NAC) is the amino acid L-cysteine derivative and a precursor to the antioxidant glutathione (GSH). NAC is commonly used clinically as an antioxidant with anti-inflammatory properties. Poor bioavailability and high protein binding of NAC necessitates the use of high doses resulting in side effects including nausea, vomiting, and gastric disruptions. Therefore, dendrimer-based therapy can specifically target the drug to the cells involved in inflammation, reducing side effects with efficacy at much lower doses than the free drug. Towards development of the new therapies for the treatment of maternal inflammation, we successfully administered dendrimer-based N-Acetyl Cysteine (DNAC) in an animal model of IUI to reduce preterm birth and perinatal inflammatory response. This study explored the associated immune mechanisms of DNAC treatment on placental macrophages following IUI, especially on M1/M2 type macrophage polarization. Our results demonstrated that intraperitoneal maternal DNAC administration significantly reduced the pro-inflammatory cytokine mRNA of Il1ß and Nos2, and decreased CD45+ leukocyte infiltration in the placenta following IUI. Furthermore, we found that DNAC altered placental immune profile by stimulating macrophages to change to the M2 phenotype while decreasing the M1 phenotype, thus suppressing the inflammatory responses in the placenta. Our study provides evidence for DNAC therapy to alleviate IUI via the maintenance of macrophage M1/M2 imbalance in the placenta.

Placental Macrophages Demonstrate Sex-Specific Response to Intrauterine Inflammation and May Serve as a Marker of Perinatal Neuroinflammation.

Preterm birth (PTB) is considered to be one of the most frequent causes of neonatal death. Prompt and effective measures to predict adverse fetal outcome following PTB are urgently needed. Placenta macrophages are a critical immune cell population during pregnancy, phenotypically divided into M1 and M2 subsets. An established mouse model of intrauterine inflammation (IUI) was applied. Placenta (labyrinth) and corresponding fetal brain were harvested within 24 hours post injection (hpi). Flow cytometry, Western blot, real-time qPCR, and regular histology were utilized to examine the cytokines, macrophage polarization, and sex-specificity. Placental exposure to LPS led to significantly reduced labyrinth thickness compared to PBS-exposed controls as early as 3 hpi, accompanied by apoptosis and necrosis. Pro-inflammatory M1 markers, Il-1ß, and iNOS, and anti-inflammatory M2 marker Il-10 increased significantly in placentas exposed to IUI. Analysis of flow cytometry revealed that fetal macrophages (Hofbauer cell, HBCs) were mostly M1-like and that maternal inter-labyrinth macrophages (MIM) were M2-like in their features in IUI. Male fetuses displayed significantly decreased M2-like features in HBCs at 3 and 6 hpi, while female fetuses showed significant increase in M2-like features in MIM at 3 and 6 hpi. Furthermore, there was a significant correlation between the frequency of HBCs and corresponding microglial marker expression at 3 and 6 hpi. Placental macrophages demonstrated sex-specific features in response to IUI. Specifically, HBCs may be a potential biomarker for fetal brain injury at preterm birth.

Contribution of MRI to detect further anomalies in fetal ventriculomegaly.

OBJECTIVES: The purpose of this study was to determine the contribution of magnetic resonance imaging (MRI) in detecting further anomalies in fetal ventriculomegaly (VM). METHODS: From March 2006 to March 2008, fasting MRI scanning was performed on 70 women in whom ultrasonography (US) diagnosed fetal VM at Shengjing Hospital affiliated to the China Medical University. The US and MRIs were then compared. RESULT: US diagnosed 41 cases of unilateral VM and 29 cases of bilateral VM; 51 cases (72.86%) being mild, 17 cases moderate and 2 cases severe VM. Eight fetuses showed additional brain hemorrhage and other anomalies on MRI. Among these 8 cases, 1 (2.44%, 1/41) had unilateral VM, whereas 7 (24.13%, 7/29) had bilateral VM (Fisher's exact test, p = 0.007). On the other hand, 2 of 8 cases (25%) had mild VM, whereas 6 of 8 cases (75%) had moderate/severe VM (Fisher's exact test, p = 0.002). CONCLUSION: MRI mainly modified the US diagnoses when the fetus had bilateral VM or moderate/severe VM. The most common additional diagnosis was brain hemorrhage.

The Role of circRNA-SETD2/miR-519a/PTEN Axis in Fetal Birth Weight through Regulating Trophoblast Proliferation.

Abnormal birth weight is the one of the major causes of adulthood diseases such as obesity, metabolic syndrome, cardiovascular disease, type 2 diabetes, and hypertension. Accumulating evidence has suggested that the placental trophoblast is one of the most important reasons that influence birth weight. Our previous study showed that miR-519a are correlated with low fetal birth weight through regulating trophoblast proliferation. To further clarify the detailed mechanisms on how it is regulated, we screened the placental-specific circular RNAs (circRNAs) via microarray assay. The result identified that circ-SETD2 was highly expressed in the placenta of the patients with fetal macrosomia compared with healthy donors. Furthermore, bioinformatic analyses and the luciferase reporter assay revealed that miR-519a possessing the binding sites for both circ-SETD2 and phosphate and tensin homolog was deleted on chromosome 10 (PTEN). Interestingly, upregulation of circ-SETD2 enhanced the proliferation and invasion of the human trophoblast-like cell line HTR8/SVneo cell. A parallel study performed by Western blotting showed that overexpression of circ-SETD2 reduced miR-519a levels and increased PTEN levels in HTR8/SVneo cells. Importantly, the enhancement of HTR8/SVneo cell activity by circ-SETD2 overexpression was nullified when the cells were cotransfected by circ-SETD2 and miR-519a, suggesting the involvement of the circ-SETD2/miR-519a/PTEN axis in trophoblast activity. Taken together, we illustrate the role of circ-SETD2, as an upstream signaling of miR-519a/PTEN, in placenta development via regulating trophoblast proliferation and invasion. These findings improve our understanding of the mechanisms of progression of fetal macrosomia and will guide future development of therapeutic strategies against the disease by targeting the circ-SETD2/miR-519a/PTEN axis.

Human umbilical cord mesenchymal stem cell-derived exosome-mediated transfer of microRNA-133b boosts trophoblast cell proliferation, migration and invasion in preeclampsia by restricting SGK1.

OBJECTIVE: Exosomes have been documented to function in human diseases, yet their transfer of microRNA (miRNA) in preeclampsia (PE) has seldom been reported. This study intends to discuss the role of miR-133b derived from exosomes in human umbilical cord mesenchymal stem cells (hUC-MSCs) in trophoblast cell development in PE. METHODS: Placentas from PE patients and normal pregnant women were collected. The hUC-MSCs and their exosomes were obtained and identified. Trophoblast cell HPT-8 and HTR8-S/Vneo were obtained and co-cultured with hUC-MSCs-derived exosomes that had been transfected with different miR-133b plasmids. MiR-133b and glucocorticoid-regulated kinase 1 (SGK1) expression in placental tissues and HPT-8 and HTR8-S/Vneo cells was determined. HTR8-S/Vneo and HPT-8 cell proliferation, cell cycle distribution, apoptosis rate, migration and invasion were detected. RESULTS: MiR-133b was down-regulated and SGK1 was up-regulated in placental tissues of PE patients. MiR-133b expression was inversely related to SGK1 expression in HTR8-S/Vneo and HPT-8 cells co-cultured with hUC-MSC-derived exosomes. Exosomes promoted HTR8-S/Vneo and HPT-8 cell proliferation, migration and invasion abilities, cell cycle entry and inhibited apoptosis. Elevated exosome-derived miR-133b from hUC-MSCs boosted HTR8-S/Vneo and HPT-8 cell proliferation, cell cycle progression, migration and invasion and limited cell apoptosis. MiR-133b targeted SGK1. CONCLUSION: Collectively, we demonstrate that miR-133b is down-regulated and SGK1 is up-regulated in PE, and miR-133b derived from exosomes in hUM-MSCs facilitates trophoblast cell proliferation, migration and invasion in PE via constraining SGK1.

Case Report: Compound Heterozygous Phosphatidylinositol-Glycan Biosynthesis Class N (PIGN) Mutations in a Chinese Fetus With Hypotonia-Seizures Syndrome 1.

Multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1) caused by phosphatidylinositol-glycan biosynthesis class N (PIGN) mutations is an autosomal recessive disease involving many systems of the body, such as the urogenital, cardiovascular, gastrointestinal, and central nervous systems. Here, compound heterozygous variants NM_012327.6:c.2427-2A > G and c.963G > A in PIGN were identified in a Chinese proband with MCAHS1. The features of the MCAHS1 family proband were evaluated to understand the mechanism of the PIGN mutation leading to the occurrence of MCAHS1. Ultrasound was conducted to examine the fetus, and his clinical manifestations were evaluated. Genetic testing was performed by whole-exome sequencing and the results were verified by Sanger sequencing of the proband and his parents. Reverse transcription-polymerase chain reaction was performed, and the products were subjected to Sanger sequencing. Quantitative PCR (Q-PCR) was conducted to compare gene expression between the patient and wild-type subjects. The compound heterozygous mutation NM_012327.6:c.2427-2A > G and c.963G > A was identified by whole-exome sequencing and was confirmed by Sanger sequencing. The NM_012327.6:c.2427-2A > G mutation led to skipping of exon 26, which resulted in a low expression level of the gene, as measured by Q-PCR. These findings provided a basis for genetic counseling and reproduction guidance in this family. Phenotype-genotype correlations may be defined by an expanded array of mutations.