Current knowledge on the role of extracellular vesicles in endometrial receptivity.

Endometrial receptivity has been widely understood as the capacity of the endometrium to receive implantable embryos. The establishment of endometrial receptivity involves multiple biological processes including decidualization, tissue remodeling, angiogenesis, immune regulation, and oxidative metabolism. Extracellular vesicles (EVs) are lipid-bilayer-membrane nanosized vesicles mediating cell-to-cell communication. Recently, EVs and their cargo have been proven as functional factors in the establishment of endometrial receptivity. In this review, we comprehensively summarized the alteration of endometrium/embryo-derived EVs during the receptive phase and retrospected the current findings which revealed the pivotal role and potential mechanism of EVs to promote successful implantation. Furthermore, we highlight the potentiality and limitations of EVs being translated into clinical applications such as biomarkers of endometrial receptivity or reproductive therapeutic mediators, and point out the direction for further research.

Young women were associated with higher risk of hypertensive disorders of pregnancy and cesarean section from hormone replaced cycles in frozen-thawed embryo transfer: a retrospective study of 5316 singleton deliveries.

Background: The utilization of frozen-thawed embryo transfer (FET) cycles has been linked to heightened risks of adverse perinatal outcomes. However, the potential association between adverse perinatal outcomes and distinct endometrial preparation regimens remains unclear. Therefore, we aim to investigate the maternal and neonatal outcomes after hormone replacement treatment (HRT) cycles, natural cycles (NC) and HRT cycles with pretreatment using GnRHa (HRT + GnRHa) for ovulatory women undergoing FET cycles. Methods: A large sample retrospective cohort study was carried out from 2016 to 2020. The data included a total of 5316 women who had singleton deliveries undergoing FET cycles and which were divided into three groups based on different endometrial preparation protocols: 4399 patients in HRT groups, 621 in GnRHa+HRT groups, 296 in NC groups. The outcomes consisted of maternal outcomes (cesarean section, hypertensive disorders of pregnancy (HDP), placenta previa, gestational diabetes mellitus (GDM));and neonatal outcomes (preterm birth, newborn birthweight, low birthweight, small for gestational age (SGA), macrosomia, large for gestational age (LGA), fetal malformation). Results: After adjusting for a series of confounding variables, we found an increased risk of HDP (aOR=3.362; 95%CI, 1.059-10.675) and cesarean section (aOR=1.838; 95%CI, 1.333-2.535) in HRT cycles compared with NC, especially for ovulatory women under 35 years old. However, in all three groups, newborn birth weight was not significantly different. Meanwhile, perinatal outcomes did not differ significantly in terms of perinatal outcomes in HRT +GnRHa cycles compared with HRT cycles solely. Conclusion: During FET cycles, singletons from HRT were related to higher risks of HDP and cesarean section, particularly for young women. GnRHa pretreatment didn't bring any benefit to perinatal outcomes compared with HRT cycles alone. Therefore, the natural cycle may be a more appropriate and safer option for young ovulatory women.

Nomogram for predicting the risk of preterm delivery after IVF/ICSI treatment: an analysis of 11513 singleton births.

Background: There is a higher risk of preterm delivery (PTD) in singleton live births conceived after in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) compared with spontaneously conceived pregnancies. The objective of our study was to build a predictive nomogram model to suggest the possibility of PTD in singleton pregnancies after IVF/ICSI treatment. Method: 11513 IVF/ICSI cycles with singleton live births were enrolled retrospectively. These cycles were randomly allocated into a training group (80%) and a validation group (20%). We used the multivariate logistics regression analysis to determine prognostic factors for PTD in the training group. A nomogram based on the above factors was further established for predicting PTD. Receiver operating characteristic curves (ROC), areas under the ROC curves (AUC), concordance index (C-index), and calibration plots were analyzed for assessing the performance of this nomogram in the training and validation group. Results: There were fourteen risk factors significantly related to PTD in IVF/ICSI singleton live births, including maternal body mass index (BMI) > 24 kg/m2, smoking, uterine factors, cervical factors, ovulatory factors, double embryo transferred (DET), blastocyst transfer, FET, vanishing twin syndrome (VTS), obstetric complications (placenta previa, placenta abruption, hypertensive of pregnancies, and premature rupture of membrane), and a male fetus. These factors were further incorporated to construct a nomogram prediction model. The AUC, C-index, and calibration curves indicated that this nomogram exhibited fair performance and good calibration. Conclusions: We found that the occurrence of PTD increased when women with obesity, smoking, uterine factors, cervical factors, ovulatory factors, DET, VTS, and obstetric complications, and a male fetus. Furthermore, a nomogram was constructed based on the above factors and it might have great value for clinic use.

Ursolic Acid Alleviates Cancer Cachexia and Prevents Muscle Wasting via Activating SIRT1.

Skeletal muscle wasting is the most remarkable phenotypic feature of cancer cachexia that increases the risk of morbidity and mortality. However, there are currently no effective drugs against cancer cachexia. Ursolic acid (UA) is a lipophilic pentacyclic triterpene that has been reported to alleviate muscle atrophy and reduce muscle decomposition in some disease models. This study aimed to explore the role and mechanisms of UA treatment in cancer cachexia. We found that UA attenuated Lewis lung carcinoma (LLC)-conditioned medium-induced C2C12 myotube atrophy and muscle wasting of LLC tumor-bearing mice. Moreover, UA dose-dependently activated SIRT1 and downregulated MuRF1 and Atrogin-1. Molecular docking results revealed a good binding effect on UA and SIRT1 protein. UA rescued vital features wasting without impacting tumor growth, suppressed the elevated spleen weight, and downregulated serum concentrations of inflammatory cytokines in vivo. The above phenomena can be attenuated by Ex-527, an inhibitor of SIRT1. Furthermore, UA remained protective against cancer cachexia in the advanced stage of tumor growth. The results revealed that UA exerts an anti-cachexia effect via activating SIRT1, thereby downregulating the phosphorylation levels of NF-κB and STAT3. UA might be a potential drug against cancer cachexia.

An autophagy-related diagnostic biomarker for uterine fibroids: FOS.

Uterine fibroids (UFs) are the most common benign gynecologic tumors in reproductive-aged women. The typical diagnostic strategies of UFs are transvaginal ultrasonography and pathological feature, while molecular biomarkers are considered conventional options in the assessment of the origin and development of UFs in recent years. Here, we extracted the differential expression genes (DEGs) and differential DNA methylation genes (DMGs) of UFs from the Gene Expression Omnibus (GEO) database, GSE64763, GSE120854, GSE45188, and GSE45187. 167 DEGs with aberrant DNA methylation were identified, and further Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed by the relevant R package. We next discerned 2 hub genes (FOS, and TNFSF10) with autophagy involvement by overlapping 167 DEGs and 232 autophagic regulators from Human Autophagy Database. FOS was identified as the most crucial gene through the Protein-Protein Interactions (PPI) network with the correlation of the immune scores. Moreover, the down-regulated expression of FOS in UFs tissue at both mRNA and protein levels was validated by RT-qPCR and immunohistochemistry respectively. The area under the ROC curve (AUC) of FOS was 0.856, with a sensitivity of 86.2% and a specificity of 73.9%. Overall, we explored the possible biomarker of UFs undergoing DNA-methylated autophagy and provided clinicians with a comprehensive assessment of UFs.

PLP1 may serve as a potential diagnostic biomarker of uterine fibroids.

Objective: We aim to identify the crucial genes or potential biomarkers associated with uterine fibroids (UFs), which may provide clinicians with evidence about the diagnostic biomarker of UFs and reveal the mechanism of its progression. Methods: The gene expression and genome-wide DNA methylation profiles were obtained from Gene Expression Omnibus database (GEO). GSE45189, GSE31699, and GSE593 datasets were included. GEO2R and Venn diagrams were used to analyze the differentially expressed genes (DEGs) and extract the hub genes. Gene Ontology (GO) analysis was performed by the online tool Database for Annotation, Visualization, and Integrated Discovery (DAVID). The mRNA and protein expression of hub genes were validated by RT-qPCR, western blot, and immunohistochemistry. The receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value. Results: We detected 22 DEGs between UFs and normal myometrium, which were enriched in cell maturation, apoptotic process, hypoxia, protein binding, and cytoplasm for cell composition. By finding the intersection of the data between differentially expressed mRNA and DNA methylation profiles, 3 hub genes were identified, including transmembrane 4 L six family member 1 (TM4SF1), TNF superfamily member 10 (TNFSF10), and proteolipid protein 1 (PLP1). PLP1 was validated to be up-regulated significantly in UFs both at mRNA and protein levels. The area under the ROC curve (AUC) of PLP1 was 0.956, with a sensitivity of 79.2% and a specificity of 100%. Conclusion: Overall, our results indicate that PLP1 may be a potential diagnostic biomarker for uterine fibroids.

Single-Cell Transcriptomics of Proliferative Phase Endometrium: Systems Analysis of Cell-Cell Communication Network Using CellChat.

The endometrium thickness increases by which endometrial angiogenesis occurs in parallel with the rapid growth of endometrium during the proliferative phase, which is orchestrated by complex cell-cell interactions and cytokine networks. However, the intercellular communication has not been fully delineated. In the present work, we studied the cell-cell interactome among cells of human proliferative phase endometrium using single-cell transcriptomics. The transcriptomes of 33,240 primary endometrial cells were profiled at single-cell resolution. CellChat was used to infer the cell-cell interactome by assessing the gene expression of receptor-ligand pairs across cell types. In total, nine cell types and 88 functionally related signaling pathways were found. Among them, growth factors and angiogenic factor signaling pathways, including EGF, FGF, IGF, PDGF, TGFb, VEGF, ANGPT, and ANGPTL that are highly associated with endometrial growth, were further analyzed and verified. The results showed that stromal cells and proliferating stromal cells represented cell-cell interaction hubs with a large number of EGF, PDGF incoming signals, and FGF outgoing signals. Endothelial cells exhibited cell-cell interaction hubs with a plenty of VEGF, TGFb incoming signals, and ANGPT outgoing signals. Unciliated epithelial cells, ciliated epithelial cells, and macrophages exhibited cell-cell interaction hubs with substantial EGF outgoing signals. Ciliated epithelial cells represented cell-cell interaction hubs with a large number of IGF and TGFb incoming signals. Smooth muscle cells represented lots of PDGF incoming signals and ANGPT and ANGPTL outgoing signals. This study deconvoluted complex intercellular communications at the single-cell level and predicted meaningful biological discoveries, which deepened the understanding of communications among endometrial cells.

Therapeutic Role of Mesenchymal Stem Cell-Derived Extracellular Vesicles in Female Reproductive Diseases.

Reproductive disorders, including intrauterine adhesion (IUA), premature ovarian insufficiency (POI), and polycystic ovary syndrome (PCOS), are great threats to female reproduction. Recently, mesenchymal stem cells derived-extracellular vesicles (MSC-EVs) have presented their potentials to cure these diseases, not only for the propensity ability they stemmed from the parent cells, but also for the higher biology stability and lower immunogenicity, compared to MSCs. EVs are lipid bilayer complexes, functional as mediators by transferring multiple molecules to recipient cells, such as proteins, microRNAs, lipids, and cytokines. EVs appeared to have a therapeutic effect on the female reproductive disorder, such as repairing injured endometrium, suppressing fibrosis of endometrium, regulating immunity and anti-inflammatory, and repressing apoptosis of granulosa cells (GCs) in ovaries. Although the underlying mechanisms of MSC-EVs have reached a consensus, several theories have been proposed, including promoting angiogenesis, regulating immunity, and reducing oxidate stress levels. In the current study, we summarized the current knowledge of functions of MSC-EVs on IUA, POI, and PCOS. Given the great potentials of MSC-EVs on reproductive health, the critical issues discussed will guide new insights in this rapidly expanding field.

The Effect of Endometrial Thickness on Pregnancy, Maternal, and Perinatal Outcomes of Women in Fresh Cycles After IVF/ICSI: A Systematic Review and Meta-Analysis.

Background: Thin endometrium on ovulation triggering day is associated with impaired pregnancy outcomes in women after in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI), but the role of thick endometrium on pregnancy outcomes remains controversial. Moreover, there has been insufficient evidence currently to analyze the influence of endometrial thickness (EMT) on obstetric complications and perinatal outcomes. Thus, we performed this meta-analysis to evaluate the effect of EMT on pregnancy, maternal, and perinatal outcomes in an enlarged sample size. Methods: The databases Pubmed, Embase, Cochrane Libraries, and Web of Science were searched for English articles evaluating the correlation between EMT and pregnancy, maternal, or perinatal outcomes in women who underwent IVF/ICSI. We included studies that depicted a clear definition of outcomes and EMT grouping on ovulation triggering day. The EMT effect was analyzed in fresh cycle. Qualities of studies were assessed by the Newcastle-Ottawa Scale (NOS). Odds ratios (ORs) and weighted mean difference (WMD) with 95% confidence intervals (CIs) were calculated for analyzing dichotomous and continuous outcomes respectively, under a fixed or random effect model. Results: A total of 22 pieces of literature were included for the final meta-analysis. A decreased trend towards pregnancy outcomes was observed, such as live birth rate (LBR), clinical pregnancy rate (CPR), and implantation rate (IR) in the thin endometrium groups (EMT <7 mm). In contrast, thick endometrium (EMT >14 mm) had no effect on pregnancy outcomes compared to medium EMT groups (EMT 7-14 mm). Moreover, thin endometrium (EMT <7.5 mm) enhanced the incidence of hypertensive disorders of pregnancy (HDP) and small-for-gestational-age (SGA) infants, and decreased the birthweight (BW) of babies. Conclusions: Our studies indicated that thin endometrium not only had detrimental effect on pregnancy outcomes, but also increased the risk of HDP in women and SGA of babies, or decreased BW of babies. The thick endometrium does not have an adverse effect on IVF outcomes. Therefore, patients need to be informed on possible obstetric complications and perinatal outcomes caused by thin endometrium and are encouraged to actively cooperate with perinatal care. Systematic Review Registration: (https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=242637), identifier CRD42021242637.

Studies on the Ecological Adaptability of Growing Rice with Floating Bed on the Dilute Biogas Slurry.

This study aimed to explore the ecological adaptability and the possibility of growing rice with floating bed on the dilute biogas slurry. The results of the experiments show that the growth stage, rice plant height, and rice yield and quality were significantly affected by multiple dilutions; rice plants cultivated with 45 multiple dilutions had better ecological adaptability than others. In the 45 multiple dilutions' group, the yield of rice was 13.3 g/bucket (8 rice plants), milled rice rate was 63.1%, and the content of crude protein in the rice was 6.3%. The concentrations of heavy metals in the rice cultivated with 30 multiple dilutions' slurry, such as total lead, cadmium, mercury, chromium, and arsenic, were all below the national standard. The study shows that it is possible and safe to cultivate rice plants with no soil but diluted biogas slurry. In the experiments, the yield, milled rice rate, and crude protein of the rice cultivated with slurry were not as much as those of rice cultivated with regular way in soil. This study provides the basic theoretical support for the development of biogas projects and the potential achievement of organic farming in special agricultural facilities and circular economy.