Fragile X-related protein 1 (FXR1) regulates cyclooxygenase-2 (COX-2) expression at the maternal-fetal interface.

Cyclooxygenase-2 (COX-2) is regulated post-transcriptionally by the AU-rich element (ARE) in the 3'-untranslated region (UTR) of its mRNA. However, the mechanism of COX-2 induction in infertility has not been thoroughly elucidated to date. The aim of this study was to examine the association between COX-2 and fragile X-related protein 1 (FXR1) in trophoblasts. Using quantitative reverse transcription polymerase chain reaction, our results showed that FXR1 mRNA expression levels were significantly decreased in trophoblasts from recurrent miscarriage patients compared with healthy controls; conversely, COX-2 mRNA expression levels were increased in patient samples. We also observed that FXR1 was highly expressed in human placental villi during early pregnancy. Furthermore, we used western blotting and immunofluorescence to analyse the expression levels of FXR1 and COX-2 in HTR-8 cells that were treated with tumour necrosis factor α; we observed that the expression of COX-2 was clearly increased in HTR-8 cells treated with FXR1 small interfering RNA, whereas the expression of COX-2 was effectively decreased in HTR-8 cells with FXR1 overexpressed via a plasmid. Importantly, bioinformatics analysis identified FXR1 binding sites in the 3'-UTR region of COX-2 and firefly luciferase reporter assay analysis verified that FXR1 binds directly to the 3'-UTR region of COX-2. ELISA assays showed that overexpression of FXR1 enhanced vascular endothelial growth factor-A and interleukin-8 expression in HTR-8 cells, whereas conversely, knockdown of FXR1 effectively repressed these effects. In conclusion, the results of this study indicate that FXR1 is a novel COX-2 regulatory factor.

Network-Based Analysis Reveals Novel Biomarkers in Peripheral Blood of Patients With Preeclampsia.

WGCNA is a potent systems biology approach that explains the connection of gene expression based on a microarray database, which facilitates the discovery of disease therapy targets or potential biomarkers. Preeclampsia is a kind of pregnancy-induced hypertension caused by complex factors. The disease's pathophysiology, however, remains unknown. The focus of this research is to utilize WGCNA to identify susceptible modules and genes in the peripheral blood of preeclampsia patients. Obtain the whole gene expression data of GSE48424 preeclampsia patients and normal pregnant women from NCBI's GEO database. WGCNA is used to construct a gene co-expression network by calculating correlation coefficients between modules and phenotypic traits, screening important modules, and filtering central genes. To identify hub genes, we performed functional enrichment analysis, pathway analysis, and protein-protein interaction (PPI) network construction on key genes in critical modules. Then, the genetic data file GSE149437 and clinical peripheral blood samples were used as a validation cohort to determine the diagnostic value of these key genes. Nine gene co-expression modules were constructed through WGCNA analysis. Among them, the blue module is significantly related to preeclampsia and is related to its clinical severity. Thirty genes have been discovered by using the intersection of the genes in the blue module and the DEGs genes as the hub genes. It was found that HDC, MS4A2, and SLC18A2 scored higher in the PPI network and were identified as hub genes. These three genes were also differentially expressed in peripheral blood validation samples. Based on the above three genes, we established the prediction model of peripheral blood markers of preeclampsia and drew the nomogram and calibration curve. The ROC curves were used in the training cohort GSE48424 and the validation cohort GSE149437 to verify the predictive value of the above model. Finally, it was confirmed in the collected clinical peripheral blood samples that MS4A2 was differentially expressed in the peripheral blood of early-onset and late-onset preeclampsia, which is of great significance. This study provides a new biomarker and prediction model for preeclampsia.

Effects of low-dose aspirin on the prevention of preeclampsia and pregnancy outcomes: A randomized controlled trial from Shanghai, China.

OBJECTIVES: To evaluate the preventive effects of low-dose aspirin on the incidence of preeclampsia and pregnancy outcomes of women at high-risk for preeclampsia. STUDY DESIGN: This prospective randomized clinical trial was conducted at the Obstetrics Department of The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, China. It analyzed data from 1105 high-risk women who were divided into the control group (placebo group) and the aspirin group (including three subgroups: 25 mg, 50 mg and 75 mg). The aspirin group in this study was instructed to take aspirin daily before bedtime beginning in the 12th week of pregnancy. MAIN OUTCOME MEASURES: The primary outcome is the occurrence of preeclampsia. The secondary outcomes included maternal and neonatal outcomes (such as premature delivery, FGR etc.), maternal serum biomarkers (including d-dimers, platelet aggregation rates, etc.) and uterine arterial blood flow resistance. The onset of preeclampsia and pregnancy outcomes were recorded after all participants delivered. RESULTS: Low-dose aspirin significantly reduced the incidence of preeclampsia and early-onset preeclampsia. Aspirin also showed significant dose dependence in preeclampsia prevention. The results of Mantel-Haenszel trend test showed that there was a linear relationship between the dosage and the incidence of preeclampsia and early preeclampsia (P < 0.05). Pearson's results showed that the incidence of preeclampsia and early preeclampsia was negatively correlated with aspirin dosage. There was also a linear relationship between the dosage and the rates of postpartum hemorrhage, fetal growth restriction, premature births and cesarean section (P < 0.05). There was no evidence to suggest differences in the incidence of fetal distress, miscarriage and placental abruption among the four groups. The blood resistance S/D value of uterine artery in early pregnancy was the only independent factor affecting the efficacy of aspirin (OR = 1.405; 95 %CI,1.058-1.867; P = 0.019). CONCLUSION: Low-dose aspirin can prevent preeclampsia and early-preeclampsia. Its efficacy is dose-dependent. It can reduce the rates of postpartum hemorrhage, fetal growth restriction, premature births and cesarean section. The prophylactic effect of aspirin on preeclampsia seemed to be greater in patients with higher blood resistance S/D value of uterine artery during early pregnancy.

Reference intervals for common thyroid function tests, during different stages of pregnancy in Chinese women.

BACKGROUND: The importance of diagnosis of thyroid dysfunction during pregnancy has been widely recognized. Our study was designed to compare two different detection reagents between Abbott and Roche and to establish the gestational related reference intervals for thyroid function tests (TFT) in Chinese women and to assay the reference ranges with the American Thyroid Association recommended standard. METHODS: Serum samples were collected from 693 normal pregnant Chinese women and divided into five groups according to their gestational age: 9-13, 16-20, 24-28, 32-34 and 37-40 weeks. Thyroid stimulating hormone (TSH) and free thyroxine (FT4) levels were determined by two different detection reagents: Abbott Architect I 2000 and Roche Cobas Elecsys 600. The reference ranges of the TFT indexes were calculated according to the National Academy of Clinical Biochemistry (NACB). The 2.5th and 97.5th percentiles of each stage were calculated, and the results were analyzed by one-way analysis of variances, t-test, and Spearman correlation analysis. RESULTS: Thyroid hormone levels varied greatly among different gestational stages. TSH levels, as assessed via two different TSH ELISA kits showed consistent changing pattern during pregnancy and displayed linear correlation (P < 0.001). In 9-13 gestational weeks, TSH levels were significantly lower than that of other groups; and in 37-40 gestational weeks, it was higher than that of other groups (all P < 0.001). TSH reference ranges determined by Roche detection reagent in each group were higher than those by Abbott detection reagent (P < 0.01 respectively). FT4 levels were higher in 9-13 gestational weeks than that of other groups (P < 0.001). FT4 levels determined by Roche reagent were higher than Abbott reagent in 9-13 weeks, (P < 0.001), and lower in 24-28 and 37-40 weeks (P < 0.001 and P = 0.016, respectively). The TSH level was correlated with FT4 levels in 9-13 gestational weeks by detection reagents (for Abbott reagent, r=-0.319 for FT4 P < 0.001; for Roche reagent, r=-0.352 for FT4, P <0.001). CONCLUSION: Accurate evaluation of TFT in pregnant women should be based on the gestational-related reference intervals in Chinese population, and different detection reagents should also establish their own reference intervals.