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BackgroundOvarian cancer (OC) is the most lethal gynecologic malignancy, yet the clinical results for OC patients are still variable. Therefore, we examined how elafin expression affects the patients’ prognoses and immunotherapy responses in OC, which may facilitate treatment selection and improve prognosis.MethodsThe elafin mRNA expression profile was downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus. Elafin’s prognostic potential and its relationship with clinical variables were investigated using Kaplan–Meier survival curves, time-dependent receiver operating characteristic curves as well as univariate and multivariate Cox regression models. As validation, protein expression in the tumor and adjacent tissues of OC patients was investigated by using immunohistochemistry (IHC). Comprehensive analyses were then conducted to explore the correlation between immune infiltration and elafin expression.ResultsA higher mRNA expression of elafin was associated with an unfavorable prognosis in TCGA cohort and was validated in GSE31245 and IHC. Moreover, elafin was indicated as an independent risk factor for OC. A significantly higher protein expression of elafin was detected in the adjacent tissues of OC patients with shorter overall survival (OS). The immune-related pathways were mainly enriched in the high-elafin-mRNA-expression group. However, the mRNA expression of elafin was favorably correlated with indicators of the immune filtration and immunotherapy response, which also proved better immunotherapy outcomes.ConclusionThe high elafin expression was associated with an unfavorable OS, while it also indicated better immunotherapy responses. Thus, the detection of elafin is beneficial to diagnosis and treatment selection.

Numerous studies have suggested the possibility of explaining the etiology of metabolic syndrome through DNA methylation. DNA methyltransferase 3B (DNMT3B) plays an important role in de novo DNA methylation. There was an alteration in maternal (F0) endometrial function, which might lead to growth and developmental disorder in offspring (F1). In this study, we investigated the effect of maternal endometrial DNMT3B deficiency on the metabolism in offspring. We constructed endometrial DNMT3B conditional knockout female mice (cKO) which were mated with normal C57BL/6 male mice to obtain the F1 generation. Further, to study the development of these offspring, we observed them at three different life stages which included the 6-week-old juvenile, 9-week-old sub-adult and 12-week-old adult. Follow the detection of a range of metabolism-related indicators, we found that in the cKO F1 generation, liver triglyceride level was significantly elevated in 9-week-old female mice, lipid droplet deposition was significantly increased in 9-week-old and 12-week-old mice, and the expression of lipid metabolism key factors in the liver was markedly decreased except of 6-week-old male mice. These results indicate that maternal endometrial DNMT3B conditional knockout leads to imbalance in hepatic metabolism in F1 generation, the mechanism of which requires further discussion.

Polycystic ovary syndrome (PCOS) exerts negative effects on females of childbearing age. It is important to identify more suitable models for fundamental research on PCOS. We evaluated animal models from a novel perspective with the aim of helping researchers select the best model for PCOS. RNA sequencing was performed to investigate the mRNA expression profiles in the ovarian tissues of mice with dehydroepiandrosterone (DHEA) plus high-fat diet (HFD)-induced PCOS. Meanwhile, 14 datasets were obtained from the Gene Expression Omnibus (GEO), including eight studies on humans, three on rats and three on mice, and genes associated with PCOS were obtained from the PCOSKB website. We compared the consistency of each animal model and human PCOS in terms of DEGs and pathway enrichment analysis results. There were 239 DEGs shared between prenatally androgenized (PNA) mice and PCOS patients. Moreover, 1113 genes associated with PCOS from the PCOSKB website were identified among the DEGs of PNA mice. A total of 134 GO and KEGG pathways were shared between PNA mice and PCOS patients. These findings suggest that the PNA mouse model is the best animal model to simulate PCOS.

BackgroundOvarian cancer (OC) is one of the most lethal gynecologic malignancies and a leading cause of death in the world. Thus, this necessitates identification of prognostic biomarkers which will be helpful in its treatment.MethodsThe gene expression profiles from The Cancer Genome Atlas (TCGA) and GSE31245 were selected as the training cohort and validation cohort, respectively. The Kaplan–Meier (KM) survival analysis was used to analyze the difference in overall survival (OS) between high and low RB transcriptional corepressor 1 (RB1) expression groups. To confirm whether RB1 was an independent risk factor for OC, we constructed a multivariate Cox regression model. Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analyses were conducted to identify the functions of differentially expressed genes (DEGs). The associations of RB1 with immune infiltration and immune checkpoints were studied by the Tumor Immune Estimation Resource (TIMER 2.0) and the Gene Expression Profiling Interactive Analysis (GEPIA). The immunohistochemistry (IHC) was performed to compare the expression level of RB1 in normal tissues and tumor samples, and to predict the prognosis of OC.ResultsThe KM survival curve of the TCGA indicated that the OS in the high-risk group was lower than that in the low-risk group (HR = 1.61, 95% CI: 1.28-2.02, P = 3×10-5), which was validated in GSE31245 (HR = 4.08, 95% CI: 1.21–13.74, P = 0.01) and IHC. Multivariate Cox regression analysis revealed that RB1 was an independent prognostic biomarker (HR = 1.66, 95% CI: 1.31-2.10, P = 2.02×10-5). Enrichment analysis suggested that the DEGs were mainly involved in cell cycle, DNA replication, and mitochondrial transition. The infiltration levels of fibroblast, neutrophil, monocyte and macrophage were positively correlated with RB1. Furthermore, RB1 was associated with immune checkpoint molecules (CTLA4, LAG3, and CD274). The IHC staining revealed higher expression of RB1 in tumor tissues as compared to that in normal tissues (P = 0.019). Overexpression of RB1 was associated with poor prognosis of OC (P = 0.01).ConclusionThese findings suggest that RB1 was a novel and immune-related prognostic biomarker for OC, which may be a promising target for OC treatment.

AimRecurrent miscarriage (RM) is associated with numerous clinical factors. However, some RM occurred without specific factors. It has been revealed that some molecules such as hormones, miRNAs, and transcription factors are involved in RM by regulating proliferation, apoptosis, etc. However, the mechanism of RM has yet to be identified clearly. Circular RNAs (circRNAs) are a class of endogenous non-coding RNAs that often act as sponges for miRNAs or binds to proteins involved in biological processes. However, the functional role of circRNAs in the uterine decidua of patients with early RM is still unclear. In this study, we aimed to investigate the mechanisms of circ-CYP24A1 in RM.MethodsThe Dual-Luciferase Activity Assay was designed to analyze the bonding between circ-CYP24A1 and miR-224, and miR-224 and prolactin receptor (PRLR) mRNA 3′UTR. In situ hybridization (ISH) and immunohistochemistry (IHC) were used to observe the expression of circ-CYP24A1 and PRLR in the decidua. Rescue experiments were performed to investigate the regulating effects of circ-CYP24A1, miR-224, and PRLR. Western blotting was conducted to test the expression level of PRLR. The proliferation and apoptosis-related markers in Ishikawa cells were analyzed using CCK8, immunofluorescence staining, and the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay.ResultsIn this study, based on the microarray analysis data, we identified a high level of circ-CYP24A1 and PRLR in the decidua of patients with early RM. Based on the bioinformatics prediction, the binding relationship between circ-CYP24A1 and miR-224, as well as miR-224 and PRLR, were verified. Functional experiments demonstrated that circ-CYP24A1 regulated proliferation and apoptosis by binding to and inhibiting miR-224, resulting in increased PRLR expression. Taken together, this study provides new insights into the mechanism of RM.ConclusionIn this study, we found that circ-CYP24A1 plays a role in RM by impairing the balance of cell proliferation and apoptosis by sponging miR-224, thereby regulating PRLR.

The association between the accumulation of synthetic chemicals with estrogenic activity and risks to oogenesis has become a growing concern. This study indicates that in utero estrogen exposure can affect homologous recombination in early oogenesis and influence the reproductive potential and lifespan of female offspring. We conducted this study in developing mouse ovaries using two different models: oral doses administered to the mother, and fetal ovary cultures. Our analyses of meiotic fetal oocytes suggest that 17-β-estradiol induces gross aberrations in prophase I events, including delayed meiotic progression, increased unrepaired DNA damage, and altered homologous recombination levels. These effects were mainly mediated by estrogen receptor 2 (ESR2) activation. Mid-gestation exposure to estrogen also led to delayed primordial folliculogenesis after birth, impaired follicle development after prepuberty, and ultimately reduced the total litter size of the offspring. This raises the concern that maternal exposures to substances activating ESR2 may compromise the fertility of the exposed female fetus.

Alzheimer’s disease (AD) is an age-related neurodegenerative disease characterized by the deposition of amyloid-β (Aβ) peptides and neurofibrillary tangles (NFTs) and massive loss of neuronal cells in the brain. Adult hippocampus continuously generates new neurons throughout life to shape brain function and impaired neurogenesis may contribute to a series of cognitive deterioration associated with AD. Enhancing endogenous neurogenesis represents a promising strategy that may ameliorate AD-associated cognitive defects. However, neurogenesis-enhancing approaches and underlying mechanisms are still not well studied. Here, using a mouse model of AD amyloid precursor protein (APP/PS1/Nestin-GFP triple transgenic mice, 3xTgAD), we examined the effects of 4 weeks of valproic acid (VPA) treatment on hippocampal neurogenesis in 2- and 6-month-old mice. VPA treatment promoted cell proliferation and increased the density of immature neurons in the dentate gyrus (DG) of the hippocampus of 3xTgAD mice. Consistent with enhanced neurogenesis, behavioral and morphological analysis showed that VPA treatment improved the learning and memory ability of 3xTgAD mice. Mechanistically, VPA treatment increased β-catenin levels, accumulated the inactive form of glycogen synthase kinase-3β (GSK-3β), and induced the expression of NeuroD1, a Wnt target gene involved in neurogenesis, suggesting the activation of the Wnt signaling pathway in the hippocampus of 3xTgAD mice. This study indicates that VPA stimulates neurogenesis in the adult hippocampus of AD mice model through the Wnt pathway, highlighting VPA as a potential therapeutic for treating AD and related diseases.