Identification and verification of diagnostic biomarkers based on mitochondria-related genes related to immune microenvironment for preeclampsia using machine learning algorithms.

Preeclampsia is one of the leading causes of maternal and fetal morbidity and mortality worldwide. Preeclampsia is linked to mitochondrial dysfunction as a contributing factor in its progression. This study aimed to develop a novel diagnostic model based on mitochondria-related genes(MRGs) for preeclampsia using machine learning and further investigate the association of the MRGs and immune infiltration landscape in preeclampsia. In this research, we analyzed GSE75010 database and screened 552 DE-MRGs between preeclampsia samples and normal samples. Enrichment assays indicated that 552 DE-MRGs were mainly related to energy metabolism pathway and several different diseases. Then, we performed LASSO and SVM-RFE and identified three critical diagnostic genes for preeclampsia, including CPOX, DEGS1 and SH3BP5. In addition, we developed a novel diagnostic model using the above three genes and its diagnostic value was confirmed in GSE44711, GSE75010 datasets and our cohorts. Importantly, the results of RT-PCR confirmed the expressions of CPOX, DEGS1 and SH3BP5 were distinctly increased in preeclampsia samples compared with normal samples. The results of the CIBERSORT algorithm revealed a striking dissimilarity between the immune cells found in preeclampsia samples and those found in normal samples. In addition, we found that the levels of SH3BP5 were closely associated with several immune cells, highlighting its potential involved in immune microenvironment of preeclampsia. Overall, this study has provided a novel diagnostic model and diagnostic genes for preeclampsia while also revealing the association between MRGs and immune infiltration. These findings offer valuable insights for further research and treatment of preeclampsia.

Landscape of somatic alterations in large-scale solid tumors from an Asian population.

Extending the benefits of tumor molecular profiling for all cancer patients requires a comprehensive analysis of tumor genomes across distinct patient populations worldwide. In this study, we perform deep next-generation DNA sequencing (NGS) from tumor tissues and matched blood specimens from over 10,000 patients in China by using a 450-gene comprehensive assay, developed and implemented under international clinical regulations. We perform a comprehensive comparison of somatically altered genes, the distribution of tumor mutational burden (TMB), gene fusion patterns, and the spectrum of various somatic alterations between Chinese and American patient populations. Here, we show 64% of cancers from Chinese patients in this study have clinically actionable genomic alterations, which may affect clinical decisions related to targeted therapy or immunotherapy. These findings describe the similarities and differences between tumors from Chinese and American patients, providing valuable information for personalized medicine.

Length of stay in the ward following a preeclamptic pregnancy.

To date, data on postpartum management of preeclampsia including the optimal time for discharge are limited. The aims of this study were to investigate the appropriate time for discharge after delivery, and factors that could affect the time for discharge. Data on 210 preeclamptic women including the severity or time of onset and days in the ward after delivery were collected and analysed. In total, 167 (73%) patients were followed up for at least 16 months and none of them developed any complications after delivery. The mean days in the ward after delivery in preeclamptic women with vaginal delivery or with caesarean section was 3.4 or 5.8 days, respectively. After adjusting for delivery modes and parity, women with severe or early onset preeclampsia or preeclamptic women complicated with IUGR were in the ward longer than women with mild or late onset of preeclampsia or preeclamptic women without IUGR. In addition, women with severe preeclampsia or with IUGR delayed the time for blood pressure to return to normal range. Our descriptive data reported that preeclamptic women stayed in the ward for 4-6 days after delivery, dependent on the delivery modes. Preeclamptic women with severe or early onset form or complicated with IUGR delayed the improvement of clinical symptoms after delivery. We further found that women with severe preeclampsia, and preeclampsia complicated with IUGR delayed blood pressure returning to normal range. These pre-discharge checklists may help obstetricians and midwives decide when to discharge.

Short-Term Prediction of Preeclampsia in Chinese Women Using the Soluble fms-Like Tyrosine Kinase 1/Placental Growth Factor Ratio: A Sub-Analysis of the PROGNOSIS Asia Study.

The diagnosis of preeclampsia in China currently relies on limited clinical signs and unspecific laboratory findings. These are inadequate predictors of preeclampsia development, limiting early diagnosis and appropriate management. Previously, the Prediction of Short-Term Outcome in Pregnant Women with Suspected Preeclampsia Study (PROGNOSIS) and PROGNOSIS Asia demonstrated that a soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) ratio of ≤38 can be used to rule out preeclampsia within 1 week, with negative predictive values of 99.3 and 98.6%, respectively. This is an exploratory sub-analysis of the Chinese cohort (n = 225) of the PROGNOSIS Asia study. The primary objectives were to assess the predictive performance of using the sFlt-1/PlGF ratio to rule out preeclampsia within 1 week and to rule in preeclampsia within 4 weeks. The sFlt-1/PlGF ratio was also examined for short-term prediction of fetal adverse outcomes, maternal adverse outcomes, and time to delivery. The overall prevalence of preeclampsia was 17.3%. With the use of an sFlt-1/PlGF ratio of ≤38, the negative predictive value for ruling out preeclampsia within 1 week was 97.3% [95% confidence interval (CI), 93.8-99.1], with a sensitivity of 64.3% and specificity of 85.3%. With the use of an sFlt-1/PlGF ratio of >38, the positive predictive value for ruling in preeclampsia within 4 weeks was 35.0% (95% CI, 20.6-51.7), with a sensitivity of 50.0% and specificity of 86.8%. In the analyses of the sFlt-1/PlGF ratio and fetal adverse outcomes, the area under the receiver operating characteristic curve was 92.8% (95% CI, 83.5-98.7) for ruling out fetal adverse outcomes within 1 week and 79.9% (95% CI, 68.1-90.3) for ruling in fetal adverse outcomes within 4 weeks. An sFlt-1/PlGF ratio of >38 increased the likelihood of imminent delivery 3.3-fold compared with a ratio of ≤38 [hazard ratio, 3.3 (95% CI, 2.1-5.1)]. This sub-analysis confirms the high predictive performance of the sFlt-1/PlGF ratio cutoff of 38 for short-term prediction of preeclampsia in Chinese women, which may help prevent unnecessary hospitalization of women with low risk of developing preeclampsia.

Expectant or outpatient management of preeclampsia before 34 weeks: safe for mother but associated with increased stillbirth risk.

Today the only effective "treatment" for preeclampsia is to deliver at the optimal time for both maternal and foetal well-being. Studies reported that severe preeclampsia can benefit from the expectant management including mild preeclampsia between 34 and 37 weeks. However it is unclear whether mild preeclampsia before 34 weeks also benefits from the expectant management. Data on 274 women with mild preeclampsia before 37 weeks of gestation were retrospectively collected and analysed. Blood pressure and proteinuria at time of onset were not clinically associated with delivery time. For women who developed preeclampsia before 34 weeks, the median latency from onset to delivery or from onset to admission to hospital or from admission to hospital to delivery was 27 or 21 or 3 days, respectively. There were four women (2%) who delivered within 48 h after onset, 28 (14%) FGR and 14 (7%) stillbirths. The median birth-weight was 2240 g. For women who developed preeclampsia between 34 and 37 weeks, the median latency from onset to delivery or from onset to admission to hospital or from admission to hospital to delivery was 11 or 7 or 2 days, respectively. There were seven women (10%) who delivered within 48 h after onset and eight (12%) FGR. The median birth-weight was 2880 g. Our study demonstrates that mild preeclampsia before 37 weeks has benefits from expectant or outpatient management with a median prolongation of over 11 days dependent on the time of onset, but it increases the risk for stillbirths before 34 weeks.

MicroRNA-30a-3p is overexpressed in the placentas of patients with preeclampsia and affects trophoblast invasion and apoptosis by its effects on IGF-1.

OBJECTIVE: Preeclampsia (PE) affects many women globally and remains a primary cause of neonatal and maternal morbidity and mortality. Aberrant placental microRNA (miRNA) expression might be associated with PE. Previously, 33 PE-related miRNAs, 11 up-regulated and 23 down-regulated, were detected in placentas of women with severe PE when compared with those of normal patients. One of the most up-regulated miRNAs in PE is miR-30a-3p. The predicted target of it is insulin-like growth factor 1 (IGF-1), which has been reported to have a relatively low expression level in PE patients. This study was conducted to determine the aberrant increased of miR-30a-3p in the placentas of women with preeclampsia and to elucidate the target and function of it in trophoblast cells. STUDY DESIGN: miR-30a-3p expression in placenta tissues was compared between women with preeclampsia (n = 25) and normal pregnant women (n = 20). The miRNA target was studied by in silico and functional assay. The effects of the miRNA were verified by apoptosis assay and invasion assay in the trophoblast cell line. RESULTS: miR-30a-3p was increased significantly in the placenta of women with preeclampsia when compared to those with normal pregnancies. Luciferase assay confirmed direct regulation of miR-30a-3p on the expression of IGF-1. Forced expression of miR-30a-3p suppressed IGF-1 protein expression in the HTR-8/SVneo cells. The functional assay suggests that the over-expression of miR-30a-3p alter the invasive capacity of JEG-3 cells and induce the apoptosis of HTR-8/SVneo cells (Figure). CONCLUSION: Expression of miR-30a-3p was significantly increased in the placentas of patients with preeclampsia. miR-30a-3p might be involved in the pathogenesis of preeclampsia by targeting IGF-1 and regulating the invasion and apoptosis of trophoblast cells.

FAM3A Protects Against Glutamate-Induced Toxicity by Preserving Calcium Homeostasis in Differentiated PC12 Cells.

BACKGROUND/AIMS: Stroke is the leading cause of adult disability, and glutamate-induced dysregulation of intracellular Ca2+ homeostasis is a key mechanism. FAM3A is the first member of the family with sequence similarity 3 (FAM3) gene family, and its biological function remains largely unknown. We have recently reported that FAM3A exerts protective effects against oxidative stress and mitochondrial dysfunction in HT22 cells. METHODS: Here, we investigated the protective effects of FAM3A using a glutamate-induced neuronal injury model in nerve growth factor (NGF)-differentiated PC12 cells. The protective effects were determined by measuring lactate dehydrogenase (LDH) release, apoptosis and mitochondrial oxidative stress. Ca2+ imaging was performed to detect changes in intracellular Ca2+ concentration in PC12 cells. The related molecular mechanisms were investigated by fluorescence staining, coimmunoprecipitation (Co-IP) and western blotting. RESULTS: Upregulation of FAM3A by lentivirus transfection markedly decreased LDH release, inhibited apoptosis and reduced mitochondrial oxidative stress, which were accompanied by alleviated intracellular Ca2+ levels as measured by calcium imaging. The results of western blotting showed that FAM3A significantly decreased the surface expression of metabotropic glutamate receptor 1/5 (mGluR1/5), with no effect on the expression of N-methyl-d-aspartic acid receptor (NMDAR) or α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) subunits. FAM3A overexpression also inhibited the intracellular Ca2+ release mediated by mGluR1/5 and inositol 1,4,5-trisphosphate receptor (IP3R), but not the ryanodine receptor (RyR). In addition, FAM3A significantly attenuated the store-operated calcium entry (SOCE) induced by thapsigargin (Tg), but the expression of SOCE-related proteins was not altered. The results of coimmunoprecipitation (Co-IP) showed that FAM3A disrupted the interaction of stromal interaction molecule 1 (STIM1) with Orai1 triggered by glutamate. CONCLUSION: These results suggest that the upregulation of FAM3A protects against glutamate-induced dysfunction of Ca2+ homeostasis not only by inhibiting mGluR1/5-dependent endoplasmic reticulum (ER) Ca2+ release, but also by attenuating SOCE mediated by the STIM1-Orai1 interaction.

Proteinuria in preeclampsia: Not essential to diagnosis but related to disease severity and fetal outcomes.

Preeclampsia is a leading cause of maternal and perinatal morbidity and mortality globally and proteinuria can be one of the cardinal features of this disease. However, studies about the association of the amount of proteinuria and the severity of preeclampsia, and perinatal outcomes are limited. Data on 239 women with preeclampsia were retrospectively collected from a university teaching hospital from September 2011 to June 2013 and analysed. Data included all clinical parameters and proteinuria in a 24h urine collection. In cases of severe preeclampsia, significantly fewer patients had proteinuria levels <0.3g/L in comparison to any of the other groups with proteinuria >0.3g/L, but there was no difference in cases of severe preeclampsia when proteinuria levels were >0.3g/L. Furthermore, when proteinuria levels were >0.3g/L, the frequency of severe preeclampsia in each group was significantly higher than the frequency of mild pre-eclampsia cases. Time of onset was significantly earlier in patients with proteinuria >3g/L in a 24h urine collection, but time between the onset of preeclampsia and delivery was not correlated with the amount of proteinuria. The birth weight was significantly lower in patients with proteinuria >3g/L. The incidence of fetal growth restriction or stillbirth was significantly higher in patients with proteinuria >5g/L. Our data demonstrate that the amount of proteinuria is not associated with the severe of preeclampsia, once proteinuria is detected, but is related to the severity of preeclampsia. The adverse fetal outcomes appear to be the function of prematurity rather than proteinuria itself.

Autoantibodies against glucose-regulated protein 78 as serological biomarkers in metastatic and recurrent hepatocellular carcinoma.

PURPOSE: To identify Heptocellular carcinoma (HCC) associated antigens by proteomics, and validate whether autoantibodies against tumor-associated antigens (TAAs) could be used for diagnosis and conditional monitoring. RESULTS: The 78 kDa glucose regulated protein (GRP78) was selected as a candidate TAA. The titers of autoantibodies against 78 kDa glucose regulated protein (GRP78) from patients with HCC, liver cirrhosis (LC), and chronic hepatitis (CH) were significantly higher than that from normal controls (P<0.05, P<0.001, and P<0.01, respectively). The expression of autoantibodies against GRP78 was associated with clinical stage (P<0.01), portal vein invasion (P<0.05), and metastasis (P<0.05). The expression of anti-GRP78 antibodies was significantly higher 1 month after surgery in recurrent patients who had accepted hepatic resection 1 month after surgery compared to patients who had surgery before surgery or within 1 week after surgery (P<0.01 and P<0.001). Immunohistochemistry (IHC) showed higher expression of GRP78 in HCC compared to the non-HCC liver tissues (P <0.05). MATERIALS AND METHODS: HCC serum with high titer of autoantibodies against TAAs were screened and used for a proteome-based approach to identify HCC associated antigens. Indirect enzyme-linked immunoassay (ELISA) was used to detect the corresponding autoantibodies against TAAs. CONCLUSION: GRP78 is an autoantigen that could stimulate autoimmune responses and serve as a potential marker for recurrent and metastatic progression in HCC.

Zinc improves learning and memory abilities of fetal growth restriction rats and promotes trophoblast cell invasion and migration via enhancing STAT3-MMP-2/9 axis activity.

Fetal growth restriction (FGR) is a well-known risk factor for cognitive dysfunction, especially for learning and memory abilities. However, knowledge about prevention and treatment methods of learning and memory abilities of fetal are limit. Here, Morris water maze and passive avoidance tests showed zinc supplementation could protect the impairment of the learning and memory abilities caused by FGR. As accumulating evidence suggested that insufficiency of placental trophoblast cell invasion was closely related to FGR fetal neurodevelopmental dysplasia, we further explored the relationship between zinc supplementation during pregnancy and placental trophoblast. Microarray identified 346 differently expressed genes in placental tissues with and without zinc supplementation, and GO and KEGG analyses showed these differently expressed genes were highly enriched in cell invasion and migration and STAT3 pathway. Protein-protein interaction(PPI) analysis found that STAT3 interacted with matrix metalloproteinase-2/9 (MMP-2/9). In vivo, western blot results authenticated that the expression levels of phospho-STAT3, STAT3, MMP-2 and MMP-9 were up-regulated in placental tissues after zinc treatment. To validate whether zinc could promotes trophoblast cell invasion and migration via enhancing STAT3-MMP-2/9 activity. In vitro, Transwell assay was performed, and we observed that abilities of invasion and migration were obviously increased in zinc treated trophoblast cells. And phospho-STAT3, STAT3, MMP-2 and MMP-9 expression levels were correspondingly increased in zinc treated trophoblast cells, which were dose-dependent. Moreover, gain-of-function and loss-of-function of STAT3 confirmed that zinc promotes cell invasion and migration via regulating STAT3 mediated up-regulation of MMP-2/9 activity. We propose that activation of MMP-2/9 mediated by STAT3 may contribute to invasion and migration of trophoblast cells, which improved neurodevelopmental impairment of FGR rats probably via contributing to placental development. Our findings are the first to show a possible mechanism of reversing neurodevelopmental impairment of FGR rats by zinc supplementation, holding promise for the development of novel therapeutic modalities for learning and memory abilities impairment caused by FGR.

Clinical characteristics of fetal and neonatal outcomes in twin pregnancy with preeclampsia in a retrospective case-control study: A STROBE-compliant article.

The aim of our study was to compare the clinical characteristics of fetal and neonatal outcomes in twin pregnancies between women with preeclampsia (PE) and those with normotension in a Chinese population.There were 143 preeclamptic women and 367 normotensive women with twin pregnancies included in this retrospective case-control study. The baseline characteristics and perinatal outcomes were collected and compared between the groups. Multiple logistic regression and linear regression were used to assess the correlations between PE and the outcomes.Significant increases were observed in the frequencies of preterm delivery (OR = 2.75, P < 0.001), iatrogenic preterm birth (OR = 3.52, P < 0.001), and IUGR (OR = 2.94, P = 0.001) in the PE group, and the PE group had more than a 2-fold risk of adverse neonatal outcomes. Preeclamptic twin neonates had lower birth weights (ß = -147.34, P = 0.005; ß = -169.47, P = 0.001). The comparison on the discordance of intertwin weight was not significantly different.Twin pregnancies with PE are associated with worse perinatal outcomes. The adverse outcomes of preeclamptic twin pregnancies may be associated with lower birth weights rather than the discordance of the intertwin weight, which requires further confirmation. The results may provide helpful references for better clinical assessments, evaluations of prognosis, and a deeper understanding of preeclamptic twin pregnancies.

FAM3A attenuates ER stress-induced mitochondrial dysfunction and apoptosis via CHOP-Wnt pathway.

Endoplasmic reticulum (ER) stress is linked to several neurological disorders, and neuronal injury cascades initiated by excessive ER stress are mediated, in part, via mitochondrial dysfunction. In the present study, we identified FAM3A as an important regulator of ER stress-induced cell death in neuronal HT22 cells. The ER stress inductor tunicamycin (TM) significantly decreased the expression of FAM3A at both mRNA and protein levels, which was shown to be dependent on the induction of reactive oxygen species (ROS). Overexpression of FAM3A attenuated TM-induced apoptosis and activation of ER stress factors, but had no effect on ER calcium metabolism in HT22 cells. We also found decreased mitochondrial ROS generation, inhibited cytochrome c release and preserved mitochondrial membrane potential (MMP) in FAM3A overexpressed cells. In addition, the experiments using isolated mitochondria showed that overexpression of FAM3A attenuated mitochondrial swelling and loss of mitochondrial Ca(2+) buffering capacity after TM exposure. By using specific targeted small interfering RNA (siRNA) to knockdown the expression of the C/EBP homologous protein (CHOP), we found that FAM3A-induced protection and inhibition of ER stress was mediated by inverting TM-induced decrease of Wnt through the CHOP pathway. Our study demonstrates a pivotal role of FAM3A in protecting against TM-induced cytotoxicity via regulating CHOP-Wnt pathway, and suggests the therapeutic values of FAM3A overexpression against ER stress-associated neuronal injury.

FAM3A Protects HT22 Cells Against Hydrogen Peroxide-Induced Oxidative Stress Through Activation of PI3K/Akt but not MEK/ERK Pathway.

BACKGROUND/AIMS: Oxidative stress-induced cell damage is involved in many neurological diseases. FAM3A is the first member of family with sequence similarity 3 (FAM3) gene family and its biological function remains largely unknown. METHODS: This study aimed to determine its role in hydrogen peroxide (H2O2) induced injury in neuronal HT22 cells. The protective effects were measured by cell viability, lactate dehydrogenase (LDH) release and apoptosis, and oxidative stress was assayed by reactive oxygen species (ROS) generation, ATP synthesis and lipid peroxidation. By using selective inhibitors, the involvement of PI3K/Akt and MEK/ERK pathways were also investigated. RESULTS: The results of fluorescence staining revealed that H2O2 significantly decreased the expression of FAM3A protein, which was shown to be subcellularly located in mitochondria. Up-regulation of FAM3A by lentivirus transfection markedly increased cell viability and decreased LDH release after H2O2 treatment. The anti-apoptotic activity of FAM3A was demonstrated by the reduced mitochondrial cytochrome c release, decreased activation of caspase-3 and the results of flow cytometry. Overexpression of FAM3A attenuated intracellular ROS generation and loss of ATP production induced by H2O2, and subsequently inhibited lipid peroxidation. In addition, overexpression of FAM3A significantly increased the activation of Akt and ERK in H2O2 injured HT22 cells. By using Akt and ERK specific inhibitors, we found that inhibition of PI3K/Akt, but not MEK/ERK pathway, partially prevented FAM3A-induced protection against H2O2. CONCLUSION: These results suggest that FAM3A has protective effects against H2O2-induced oxidative stress by reducing ROS accumulation and apoptosis, and these protective effects are dependent on the activation of PI3K/Akt pathway.

Insights into the mechanism of CXCL12-mediated signaling in trophoblast functions and placental angiogenesis.

The chemokine CXCL12 and its receptor CXCR4 are important signaling components required for human blastocyst implantation and the progression of pregnancy. Growing evidence indicates that the CXCL12/CXCR4 axis can regulate trophoblast function and uterine spiral artery remodeling, which plays a fundamental role in placentation and fetal outcome. The orphan receptor CXCR7 is also believed to partly regulate the function of the CXCL12/CXCR4 axis. Additionally, the CXCL12/CXCR4/CXCR7 axis can enhance the cross-talk between trophoblasts and decidual cells such as uterine natural killer cells and decidual stromal cells which are involved in regulation of trophoblast differentiation and invasion and placental angiogenesis. In addition, recent studies proved that CXCL12 expression is elevated in the placenta and mid-trimester amniotic fluid of pregnant women with preeclampsia, implying that dysregulation of CXCL12 plays a role in the pathogenesis of preeclampsia. Further understanding of the regulatory mechanisms of CXCL12-mediated signaling in trophoblast functions and placental angiogenesis may help to design novel therapeutic approaches for pregnancy-associated diseases.

An ovarian cancer model with positive ER: Reversion of ER antagonist resistance by Src blockade.

Approximately 60% of ovarian cancers are positive for the estrogen receptor (ER); however, ER-targeted treatment is disappointing due to drug resistance as compared with breast cancer. In estrogen-sensitive cancers, estrogen activates Src to phosphorylate p27 promoting its degradation and increasing cell cycle progression. Since Src is frequently activated in ovarian cancers, we investigated whether combined Src and ER blockade by saracatinib and fulvestrant would circumvent anti-estrogen resistance. In 20 out of 40 enrolled patients with immunohistochemically ER-positive ovarian cancer, phosphorylated Src (p-Src) at the site of 416 tyrosine was expressed with a propensity for metastasis and a poorer disease-free survival (DFS) at 3 years following ER antagonist treatment. The effects of ER and Src blockade on cell cycle were assayed in estrogen receptor α (ERα)-positive ovarian cancer. We observed that Src activity was fairly greater in anti-estrogen-resistant ovarian cancer cells than that in the anti-estrogen-sensitive cell line. Estrogen activated Src via ER-Src binding and ER translocation from cytoplasm to nucleus. Mitogenesis was mediated via ERα, not ERß. Combined saracatinib and fulvestrant increased p27 and inhibited cell cycle progression. Furthermore, dual therapy induced autophagy and inhibited ovarian cancer xenograft growth more effectively than monotherapy. Saracatinib facilitated the therapeutic effects of fulvestrant by antagonizing the estrogen-mediated Src activation. These are supportive of further preclinical assessment of combined fulvestrant and saracatinib in patients with ovarian cancer.

MicroRNA-155 inhibits migration of trophoblast cells and contributes to the pathogenesis of severe preeclampsia by regulating endothelial nitric oxide synthase.

The aim of the present study was to characterize the role of microRNA (miR)-155 in the pathogenesis of severe preeclampsia (PE). A total of 19 severe preeclampsic and 22 normal placentas were collected to measure miR-155 and endothelial nitric oxide synthase (eNOS) expression using quantitative (q)PCR and western blot analysis. The results demonstrated a significant increase in the levels of miR-155 and decreased eNOS expression in the severe preeclampsic placentas, as compared with the normal controls. In order to examine the function of miR-155 in the human placenta, the HTR8/Svneo cell line was transiently transfected with an miR-155 mimic or its inhibitor, anti-miR-155. It was confirmed that miR-155 may suppress the expression of eNOS in HTR-8/SVneo cells. Furthermore, a transwell insert invasion assay demonstrated that miR-155 inhibited cell invasion in trophoblast cells, and the effect was rescued by over expression of eNOS. The present study revealed that miR-155 has a negative regulatory role in the migratory behavior of HTR-8/SVneo cells via modulating eNOS.

High temperature requirement A1 in placental tissues and serum from pre-eclamptic pregnancies with or without fetal growth restriction.

INTRODUCTION: Pre-eclampsia (PE) is the most serious syndrome of human pregnancy and it is potentially life-threatening for both mother and fetus. The aim of the study was to identify the role of high temperature requirement A1 (HtrA1) in pre-eclampsia. MATERIAL AND METHODS: One hundred consecutive pregnancies complicated by PE and 100 normal controls were included in our study. The changes in serum HtrA1 and fetal growth restriction were recorded. The placentae after delivery was also obtained for laboratory analyses. RESULTS: High temperature requirement A1 expressed positively in all placenta tissues, but showed higher expression from control, PE with AGA (pre-eclamptic pregnancies with appropriate-for-gestational-age newborns) to PE with fetal growth restriction (FGR) groups. Early-onset PE happened more frequently while in PE with AGA, late-onset PE was more common. Additionally, we found that only during ∼28-32 gestational weeks, sera HtrA1 level of PE with AGA and PE with FGR was increased significantly compared with the control group (p < 0.05). In contrast, there was no significant difference between groups in other gestational ages in the third trimester (p > 0.05). CONCLUSIONS: HtrA1 could potentially affect trophoblast migration and invasion during placentation, resulting in the shallow invasion noted in pre-eclampsia. HtrA1 may play an important role in the etiology and severity of PE and FGR. But the actual mechanism still needs deep research.

Changes in the level of serum high-temperature requirement A1 (HtrA1) during pregnancy and its relationship to preeclampsia.

OBJECTIVE: To investigate the expression and changes of high-temperature requirement A1 (HtrA1) during pregnancy and the use of this value in predicting preeclampsia. METHOD: Serum samples were collected from pregnant mothers at different gestational weeks, and double-antibody sandwich enzyme-linked immunosorbent assay was employed to describe the changes in HtrA1 in serum during pregnancy. RESULTS: (i) In Xi'an area of China, the incidence of preeclampsia was 4.95%, including 0.85% of early-onset type and 4.10% of late-onset type; (ii) the HtrA1 showed a lognormal distribution during pregnancy in the maternal serum, with the peak at 17-20 weeks of pregnancy; (iii) the HtrA1 levels in preeclampsia mothers peaked at 13-16 weeks of pregnancy, followed by acute decline until 21-24 weeks, then remained stable; (iv) the HtrA1 levels in preeclampsia mothers were higher than the control group in 13-16 weeks and lower than that in 21-24 weeks (p < 0.05); (v) the criteria using lgHtrA1 level at 1.684 during 13-16 weeks of pregnancy could predict hypertension disorders complicating pregnancy (HDCP) with sensitivity of 62.1% and specificity of 53.7%. This could be improved to 85 and 83%, respectively, when combined with body mass index as well as education background of the mother. CONCLUSION: (i) HtrA1 showed lognormal distribution during pregnancy for all populations; (ii) HtrA1 level peaked at 17-20 weeks in normal group of pregnant mothers, and the increase of HtrA1 level in 13-16 weeks could predict the risk of preeclampsia; (iii) the risk calculation formula for preeclampsia: p (%) = eY/(1 + eY) (Y = -15.87 + 3.706 × lgHtrA1 + 0.134 × mean arterial pressure (MAP) - 1.4 × education level code); e = 2.718.

Difference between 2 h and 3 h 75 g glucose tolerance test in the diagnosis of gestational diabetes mellitus (GDM): results from a national survey on prevalence of GDM.

The possibility of the 2 h oral glucose tolerance test (OGTT) as an alternative to the 3 h OGTT was investigated based on data from a national survey on pregnancy-associated diabetes. Data were retrieved from 4179 pregnant women who had OGTT performed after an abnormal 50 g glucose challenge test (GCT). All of the 4 glucose levels during their OGTT were collected and analyzed. According to American Diabetes Association (ADA) gestational diabetes mellitus (GDM) diagnostic criteria, among the 4179 pregnant women who required OGTT, 3429 (82.1%) were normal and 750 (17.9%) were diagnosed as GDM. If the 3rd h glucose levels were omitted from OGTT, 79 cases of GDM (10.5%) would be overlooked. No trend was shown where women with more risk factors were more likely to be overlooked if the 3rd h test was omitted (χ2 for trend=0.038, P>0.05). No significant differences were found in the rate of cesarean section (CS), preterm births or macrosomia between the 79 cases and those with normal OGTT results and in the gestational weeks when OGTT was performed. It shows that in order to diagnose one woman with GDM, another 52 pregnant women would have an innocent 3rd h glucose test. Omission of the 3rd h glucose test in OGTT might be reasonable due to its convenience, better compliance and a small number of possibly miss-diagnosed cases, and their pregnancy outcomes have no significant difference from those of normal pregnant women.

[Effect of behavioral training on learning and memory capacity and changes of hippocampal NR2B and GluR1 expressions in FGR offspring rats].

OBJECTIVE: To study the effect of behavioral training on the learning and memory abilities and changes of NR2B and GluR1 expressions in the hippocampus of offspring rats with fetal growth retardation (FGR). METHODS: A FGR model was established in SD rats by passive smoking. The offspring rats were divided into FGR group and control group, each then randomized into training and untrained group. Morris water maze behavioral training was carried out in postnatal months 2 and 4, and the learning and memory abilities of the young rats were assessed using dark-avoidance test and step-down test. NR2B and GluR1 expression in the hippocampus of the rats were detected by immunohistochemistry. RESULTS: In the dark-avoidance and step-down tests, the FGR rats showed deteriorated learning and memory performance in comparison with the control group, but behavioral training resulted in improved performance of the rats. The performance in FGR group was much improved after behavioral training, and the model factor and the training factor showed a significant interaction (P<0.05). The expression of NR2B and GluR1 in CA1 and CA3 regions of the hippocampus decreased in FGR group, then the their expressions in the CA1 region increased after training in both FGR and control groups, and the increment was especially obvious in GluR1 expression in the CA1 region at postnatal month 2. The two factors showed a significant interaction (P<0.05). CONCLUSION: Behavioral training can improve the learning and memory abilities of FGR offspring rats, the mechanism of which is probably related to increased expression of NR2B and GluR1 in the CA1 region of the hippocampus.