Background: The incidence of threatened abortion (TA) is increasing due to poor diet and living habits, which brings great pressure to pregnant women and their families. Huangqin-Baizhu herb pair recorded in ancient books of traditional Chinese medicine has been widely used in the treatment of TA with remarkable effect. In this study, we will use the network pharmacology method to predict the target and mechanism of Huangqin-Baizhu herb pair. Methods: Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform database was used to screen the active components of Huangqin-Baizhu herb pair. Pubchem and Swiss Target Prediction databases were used to predict the action targets. Genecards, OMIM, and Drugbank databases were used to predict the related targets of TA. The intersection of drug target and disease target was selected and the intersection genes were uploaded to STRING database to construct protein–protein interaction network and conduct module analysis. Metascape database was used for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, which was imported into Cytoscape software to construct component-pathway-gene network and finally verified by molecular docking. Ethical approval and informed consent of patients are not required because the data used in this study is publicly available and does not involve individual patient data or privacy. Results: The main active components of the herb pair are baicalein, flavanone, and norwogonin, etc. The main targets are AKT1, VEGFA, STAT3, MAPK1, SRC, etc. Cluster module analysis shows that the targets are related to cell metabolism, immune regulation and hormone level regulation. There were 2073, 3169, and 161 KEGG pathways involved in the biological processes, cell components, and molecular functions of Gene Ontology analysis, respectively. The main KEGG pathways involved in the intervention were HIF1 signaling pathway, PI3K-Akt signaling pathway, and Rap1 signaling pathway. Molecular docking showed that the main active components of the herb pair were well combined with the key targets. Conclusions: In this study, 42 active components, 152 potential targets and 11 key targets of Huangqin-Baizhu herb pair for the treatment of TA were revealed, participating in multiple signaling pathways such as PI3K-Akt, providing a theoretical basis for further experimental research.

Background: Observational studies have revealed associations between birth weight, childhood obesity, age at menarche, and ovarian dysfunction. However, these studies are susceptible to unavoidable confounding factors, leading to ongoing debates regarding their conclusions and making causal relationships challenging to infer. In light of these challenges, Mendelian randomization was employed in this study to investigate the causal relationships between birth weight, childhood obesity, age at menarche, and ovarian dysfunction. Methods: This study employed a two-sample Mendelian randomization approach using genetic variation as instrumental variables to investigate causal relationships. Genetic variation data were sourced from summary data of genome-wide association studies in European populations. Instrumental variables were selected based on the principles of Mendel’s three assumptions. The study utilized the inverse variance weighted method to assess the relationships between birth weight, childhood obesity, age at menarche, and ovarian dysfunction. Supplementary analyses were conducted using MR-Egger regression, the weighted median method, and the weighted median mode to complement the IVW results. Furthermore, the study conducted heterogeneity, horizontal pleiotropy, and sensitivity analyses to evaluate the robustness of the results. Results: Based on the inverse variance weighted method, it was found that there exists a causal relationship between childhood obesity (OR = 1.378, 95% CI: 1.113∼1.705, p = 0.003), age at menarche (OR = 0.639, 95% CI: 0.468∼0.871, p = 0.005), and ovarian dysfunction, while no causal relationship was observed between birth weight and ovarian dysfunction. Heterogeneity tests, multiplicity tests, and leave-one-out sensitivity analyses did not detect any heterogeneity or multiplicity effects in the estimated impact of these three exposure factors on the risk of ovarian dysfunction. Conclusions: This study represents the first evidence suggesting a potential causal relationship between childhood obesity, age at menarche, and ovarian dysfunction. Childhood obesity was found to increase the risk of ovarian dysfunction, while a later age at menarche was associated with a reduced risk of ovarian dysfunction.

Background: Pelvic inflammatory disease (PID) is a common gynecological disorder that seriously affects women’s physical and mental health, yet there are few effective therapeutic options. Objective: Mendelian randomization (MR) has been used to repurpose existing drugs and identify new therapeutic targets. Therefore, we performed a systematic drugable genome-wide MR analysis to explore potential therapeutic targets for PID. Methods: We utilized cis-expressed quantitative trait loci (cis-eQTL) of druggable genes and PID Genome-Wide Association Study (GWAS) data to perform MR analysis and colocalization analysis, screened candidate drugs through drug prediction, identified the most stable druggable genes with the highest binding affinity through molecular docking, and finally constructed a PID rat model to validate gene expression. Results: MR analysis, colocalization analysis, and protein interaction analysis identified six key genes. Drug enrichment analysis and molecular docking revealed two potential drugs (Sunitinib and Everolimus) targeting Albumin (ALB), Interleukin 6 (IL6), and Cluster of Differentiation 4 (CD4). In the PID rat model, ALB and IL6 expression decreased, while CD4 expression increased. Conclusion: Our MR analysis provides genetic evidence supporting ALB, IL6, and CD4 as druggable genes for PID treatment. Among the drug candidates with repurposing opportunities targeting the above genes, Sunitinib and Everolimus were effective. Subsequent in vivo experiments validated the differential expression of ALB, IL6, and CD4 in PID rats.

Background: Due to the complex pathogenesis of sequelae of pelvic inflammatory disease (SPID), targeted therapeutic agents are still lacking. Here, we investigated the interactions between neutrophils and uterine fibroblasts (FBs) in developing tissue fibrosis in SPID. Methods: A rat model of SPID was constructed to assess the roles of autophagy and neutrophil extracellular traps (NETs) in SPID rats. Single‐cell sequencing data from the public database GSE223639 were utilized to identify the specific cell cluster FBs where NETs act. A DMSO‐induced HL‐60‐driven neutrophil‐like (dHL‐60) cell model was established, and neutrophil‐like cells were treated with rapamycin and MHY1485 to activate and inhibit autophagy, respectively, to observe the differences in the production of NETs. NETs were cocultured with FBs to observe the effects on FB proliferation, migration, apoptosis, and phenotypic transformation. Results: In vivo experiments revealed that there was a consistency in the expression of autophagy and NETs in the adherent tissues of rats with the SPID model and that autophagy promotes the generation of NETs, which are collectively involved in the fibrosis of pelvic tissues in SPID. Single‐cell sequencing identified FBs, the cells in which NETs play a major role in aseptic inflammation. Further in vitro studies confirmed that NETs inhibit FB apoptosis while promoting horizontal and longitudinal migration, phenotypic transformation, and hyperproliferation of FBs, thereby exacerbating tissue fibrosis. Conclusions: Autophagy promotes the generation of NETs, which facilitates FB transformation and hyperproliferation and exacerbates the degree of adhesion and fibrosis in the pelvic tissue of SPID.