Insufficient migration and invasion during trophoblast epithelial-mesenchymal transition (EMT) results in the occurrence and development of preeclampsia (PE), and our previous study has screened 52 miRNAs, whose expression levels are altered in the placental samples from PE patients, compared with the normal group. Among those, miR-3935 is one of the miRNAs being most significantly down-regulated, indicating its involvement in PE. However, the exact effect and molecular mechanisms remain unknown.In the present study, we investigate the roles and underlying mechanisms of miR-3935 in trophoblast EMT by use of the human extra-villous trophoblast cell line HTR-8/SVneo as well as human placental tissues and maternal blood samples obtained from 15 women with normal pregnancies and 15 women with PE. Experimental methods include transfection, quantitative reverse transcription-PCR (qRT-PCR), western blot, immunofluorescence staining, dual-luciferase assays, in vitro invasion and migration assays, RNA-Seq analysis, bisulfite sequencing and immunohistochemistry staining.MiR-3935 expression is significantly decreased in both placentas and peripheral blood specimens of PE, and functionally, miR-3935 promotes EMT of trophoblast cells. Mechanistically, TRAF6 is identified to be a direct target of miR-3935 and TRAF6 exerts its negative effect on EMT of trophoblast cells by inhibition of RGS2, which down-regulates the methylation status of promoter of CDH1 gene that encodes E-Cadherin protein through induction of ALKBH1, resulting in increase of E-Cadherin and subsequently insufficient trophoblast EMT.Together these results uncover a hitherto uncharacterized role of miR-3935/TRAF6/RGS2 axis in the function of human trophoblasts, which may pinpoint the molecular pathogenesis of PE and may be a prognostic biomarker and therapeutic target for such obstetrical diseases as PE.
Vaginal dysbiosis has been identified to be associated with adverse pregnancy outcomes, such as preterm delivery and premature rupture of membranes. However, the overall structure and composition of vaginal microbiota in different trimesters of the pregnant women has not been fully elucidated. In this study, the physiological changes of the vaginal microbiota in healthy pregnant women were investigated. A total of 83 healthy pregnant participants were enrolled, who are in the first, second, or third pregnancy trimester. Quantitative real-time PCR was used to explore the abundant bacteria in the vaginal microbiota. No significant difference in the abundance of Gardnerella , Atopobium , Megasphaera , Eggerthella , Leptotrichia / Sneathia , or Prevotella was found among different trimesters, except Lactobacillus . Compared with the first pregnancy trimester, the abundance of L. iners decreased in the second and third trimester while the abundance of L. crispatus was increased in the second trimester. Moreover, we also found that vaginal cleanliness is correlated with the present of Lactobacillus , Atopobium , and Prevotella and leukocyte esterase is associated with Lactobacillus , Atopobium , Gardnerella , Eggerthella , Leptotrichia / Sneathia , and Prevotella . For those whose vaginal cleanliness raised or leukocyte esterase became positive, the richness of L. iners increased, while that of L. crispatus decreased significantly. Our present data indicated that the altered vaginal microbiota, mainly Lactobacillus , could be observed among different trimesters of pregnancy and L. iners could be considered as a potential bacterial marker for evaluating vaginal cleanliness and leukocyte esterase.
Acupoint hot compress during the early postpartum period may benefit patients after a vaginal delivery, but the evidence of this effect is limited.
Objective
To assess whether acupoint hot compress involving the abdominal, lumbosacral, and plantar regions could reduce the incidence of postpartum urinary retention, relieve postpartum uterine contraction pain, prevent emotional disorders, and promote lactation.
Design, Setting, and Participants
This multicenter randomized clinical trial was conducted at 12 hospitals in China. Pregnant patients were screened for eligibility (n = 13 949) and enrolled after vaginal delivery (n = 1200) between January 17 and August 15, 2021; data collection was completed on August 18, 2021. After vaginal delivery, these participants were randomized 1:1 to either the intervention group or control group. Statistical analysis was based on per-protocol population.
Interventions
Participants in the control group received routine postpartum care. Participants in the intervention group received routine postpartum care plus 3 sessions of a 4-hour acupoint hot compress involving the abdominal, lumbosacral, and plantar regions within 30 minutes, 24 hours, and 48 hours after delivery.
Main Outcomes and Measures
The primary outcome was the incidence of postpartum urinary retention, defined as the first urination occurring more than 6.5 hours after delivery and/or use of an indwelling catheter within 72 hours after delivery. The secondary outcomes were postpartum uterine contraction pain intensity (assessed with the visual analog scale [VAS]), depressive symptoms (assessed with the Edinburgh Postnatal Depression Scale), and lactation conditions (including lactation initiation time, breastfeeding milk volume, feeding mood and times, and newborn weight).
Results
Of the 1200 participants randomized, 1085 completed the study (537 in the intervention group and 548 in the control group, with a median [IQR] age of 26.0 [24.0-29.0] years). Participants in the intervention group compared with the control group had significantly decreased incidence of postpartum urinary retention (relative risk [RR], 0.58; 95% CI, 0.35-0.98;P = .03); improved postpartum uterine contraction pain when measured at 6.5 hours (median [IQR] VAS score, 1 [1-2] vs 2 [1-2];P < .001), 28.5 hours (median [IQR] VAS score, 1 [0-1] vs 1 [1-2];P < .001), 52.5 hours (median [IQR] VAS score, 1 [0-1] vs 1 [0-1];P < .001), and 76.5 hours (median [IQR] VAS score, 0 [0-1] vs 0 [0-1];P = .01) after delivery; reduced depressive symptoms (RR, 0.73; 95% CI, 0.54-0.98;P = .01); and increased breastfeeding milk volume measured at 28.5, 52.5, and 76.5 hours after delivery. No adverse events occurred in either of the 2 groups.
Conclusions and Relevance
Results of this trial showed that acupoint hot compress after vaginal delivery decreased postpartum urinary retention, uterine contraction pain, and depressive symptoms and increased breastfeeding milk volume. Acupoint hot compress may be considered as an adjunctive intervention in postnatal care that meets patient self-care needs.
Trial Registration
Chinese Clinical Trial Registry Identifier:ChiCTR2000038417
Ovarian cancer is a primary gynecological malignancy with a global 5-year survival rate of 44%. The majority of patients present with advanced disease at initial diagnosis because of the lack of an effective early detection screening test. Circular RNAs (circRNAs) within exosomes in the circulatory system are effective diagnostic and therapeutic biomarkers for many diseases, especially tumors. In this study, we used microarrays to identify 6 circRNAs that were upregulated and 37 circRNAs that were downregulated in exosomes from ovarian cancer patients as compared to healthy volunteers. We validated the accumulation trends for the 6 upregulated circRNAs in the training set using qRT-PCR and found that circ-0001068 was significantly higher in the serum exosomes from the ovarian cancer patients as than healthy volunteers. Circ-0001068 was next evaluated further in a larger cohort. As with the training set, results from the larger cohort revealed that levels of circ-0001068 in the exosomes were significantly higher in ovarian cancer patients than healthy volunteers. Circ-0001068 was also delivered into T cells and induced PD1 expression by acting as a competing endogenous RNA (ceRNA) for miR-28-5p through the exosomes.
Micro-RNAs (miRNAs) are short non-coding single-stranded RNAs that modulate the expression of various target genes after transcription. The expression and distribution of kinds of miRNAs have been characterized in human placenta during different gestational stages. The identified miRNAs are recognized as key mediators in the regulation of placental development and in the maintenance of human pregnancy. Aberrant expression of miRNAs is associated with compromised pregnancies in humans, and dysregulation of those miRNAs contributes to the occurrence and development of related diseases during pregnancy, such as pre-eclampsia (PE), fetal growth restriction (FGR), gestational diabetes mellitus (GDM), recurrent miscarriage, preterm birth (PTB) and small-for-gestational-age (SGA). Thus, having a better understanding of the expression and functions of miRNAs in human placenta during pregnancy and thereby developing novel drugs targeting the miRNAs could be a potentially promising method in the prevention and treatment of relevant diseases in future. Here, we summarize the current knowledge of the expression pattern and function regulation of miRNAs in human placental development and related diseases.
Insufficient trophoblast migration/invasion is associated with the preeclampsia (PE) development. Recently, microRNAs (miRNAs) have been confirmed to be involved in the pathogenesis of PE. The aim of the present study was to evaluate whether miRNAs is involved in the procession of PE by regulating the migration/invasion of trophoblast. First, we compared the expression profiles of miRNAs between normal and preeclamptic placentas using microarray. Validation analysis of miR-20b level in placentas and peripheral blood specimens was performed using quantitative reverse transcription PCR (qRT-PCR). Then, the effects of miR-20b on trophoblast cell migration and invasion were evaluated using wound healing assay and transwell migration assay. Further bioinformatics analysis, luciferase reporter assays and Western blot were performed to identify its target genes. The correlation between miR-20b and matrix metalloproteinase-2 (MMP-2) in placentas was determined by Pearson's correlation coefficient. Finally, HTR8/SVneo cells were co-transfected with miR-20b inhibitor and si-MMP-2 to explore the molecular mechanism by which miR-20b functions in the trophoblast migration/invasion. We found that miR-20b was elevated in placentas and peripheral blood specimens from preeclampsia patients. Further results show that overexpression of miR-20b significantly inhibited the invasiveness of human trophoblast cells, whereas miR-20b knockdown enhanced trophoblast cell invasion. Matrix metalloproteinase-2 (MMP-2), the most common enzymes in remodeling extracellular matrix components for metastasis, was proved to be a direct target of miR-20b. Inhibition of MMP-2 by siRNA could reverse the promoting effect of miR-20b inhibition on the invasion of trophoblast cells. Taken together, our study indicates that miR-20b inhibited trophoblastic invasion by targeting MMP2. The miR-20b/MMP-2 axis may provide novel insights into understanding the molecular pathogenesis of PE and may be a prognostic biomarker and therapeutic target for PE.
An association between circulating pentraxin-3 (PTX3) and the risk of preeclampsia (PE) remains to be established. We performed a meta-analysis of observational studies to evaluate their relationship.The PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, and WanFang databases were searched for related observational studies evaluating PTX3 and PE risk. A random-effects or a fixed-effects model was used in the meta-analysis, depending on the heterogeneity among the included studies.Nine case-control studies were included, with 396 PE patients and 438 controls. The results showed that PTX3 was significantly higher in pregnant women with PE as compared to those without PE (standardized mean difference [SMD] = 2.48, P < .001), with significant heterogeneity (I2 = 98%), particularly for those over 30 years old (SMD = 3.75, P < .001). Subsequent analyses showed that patients with severe or early-onset PE had higher PTX3 levels compared to those with mild or late-onset PE (SMD = 0.93, P = .01), suggesting that PTX3 may be a marker of PE severity. The association between PTX3 and PE was not significantly affected by the statistical method used. Sensitivity analyses by omitting one study at a time did not significantly affect the results. However, the funnel plots were asymmetric, suggesting the potential existence of publication bias.PTX3 may be related to the risk and severity of PE in pregnant women. These results should be evaluated and confirmed in cohort studies.
Abstract Production of estradiol (E2) by the placenta during human pregnancy ensures successful maintenance of placental development and fetal growth by stimulating trophoblast proliferation and the differentiation of cytotrophoblasts into syncytiotrophoblasts. Decreased levels of E2 are closely associated with obstetrical diseases such as preeclampsia (PE) in the clinic. However, the mechanisms underlying the inhibition of placental E2 biosynthesis remain poorly understood. Here, we report that regulator of G-protein signaling 2 (RGS2) affects E2 levels by regulating aromatase, a rate-limiting enzyme for E2 biosynthesis, by using human trophoblast-derived JEG-3 cells and human placental villus tissues. RGS2 enhanced the protein degradation of the transcription factor heart and neural crest derivatives expressed 1 (HAND1) by suppressing ubiquitin-specific protease 14 (USP14)-mediated deubiquitination of HAND1, resulting in the restoration of HAND1-induced trans-inactivation of the aromatase gene and subsequent increases in E2 levels. However, aromatase bound to RGS2 and repressed RGS2 GTPase activating protein (GAP) activity. Moreover, we observed a positive correlation between RGS2 and aromatase expression in clinical normal and preeclamptic placental tissues. Our results uncover a hitherto uncharacterized role of the RGS2-aromatase axis in the regulation of E2 production by human placental trophoblasts, which may pinpoint the molecular pathogenesis and highlight potential biomarkers for related obstetrical diseases.
Esophageal cancer (EC), a common type of malignant tumor, ranks as the sixth highest contributor to cancer-related mortality worldwide. Due to the condition that most patients with EC are diagnosed at advanced or metastatic status, the efficacy of conventional treatments including surgery, chemotherapy and radiotherapy is limited, resulting in a dismal 5-year overall survival rate. In recent years, the application of immune checkpoint inhibitors (ICIs) has presented a novel therapeutic avenue for EC patients. Both ICIs monotherapy and immunotherapy combined with chemotherapy or chemoradiotherapy (CRT) have demonstrated marked benefits for patients with advanced EC. Adjuvant or neoadjuvant therapy incorporating immunotherapy has also demonstrated promising prospects in the context of perioperative treatment. Nonetheless, due to the variable response observed among patients undergoing immunotherapy, it is of vital importance to identify predictive biomarkers for patient stratification, to facilitate identification of subgroups who may derive greater benefits from immunotherapy. In this review, we summarize validated or potential biomarkers for immunotherapy in EC in three dimensions: tumor-cell-associated biomarkers, tumor-immune microenvironment (TIME)-associated factors, and host-associated biomarkers, so as to provide a theoretical foundation to inform tailored therapy for individuals diagnosed with EC.
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