Exploring the molecular mechanisms by which per- and polyfluoroalkyl substances induce polycystic ovary syndrome through in silico toxicogenomic data mining.

The pathogeny of polycystic ovary syndrome (PCOS) is intricate, with endocrine disruptors (EDCs) being acknowledged as significant environmental factors. Research has shown a link between exposure to per- and polyfluoroalkyl substances (PFAS) and the development and progression of PCOS, although the precise mechanism is not fully understood. This study utilized toxicogenomics and comparative toxicogenomics databases to analyze data and investigate how PFAS mixtures may contribute to the development of PCOS. The results indicated that 74 genes are associated with both PFAS exposure and PCOS progression. Enrichment analysis suggested that cell cycle regulation and steroid hormone synthesis may be crucial pathways through which PFAS mixtures participate in the development of PCOS, involving important genes such as CCNB1 and SRD5A1. Furthermore, the study identified transcription factors (TFs) and miRNAs that may be involved in the onset and progression of PCOS, constructing regulatory networks encompassing TFs-mRNA interactions and miRNA-mRNA relationships to elucidate their regulatory roles in gene expression. By utilizing data mining techniques based on toxicogenomic databases, this study provides relatively comprehensive insights into the association between exposure factors and diseases compared to traditional toxicology studies. These findings offer new perspectives for further in vivo or in vitro investigations and contribute to understanding the pathogenesis of PCOS, thereby providing valuable references for identifying clinical treatment targets.

The Wnt/ß-catenin pathway is involved in 2,5-hexanedione-induced ovarian granulosa cell cycle arrest.

N-Hexane causes significant ovarian toxicity, and its main active metabolite 2,5-hexanedione (2,5-HD) can induce ovarian injury through mechanisms such as inducing apoptosis in ovarian granulosa cells (GCs); however, the specific mechanism has not been fully elucidated. In this study, we investigated the effects on the cell cycle of rat ovarian GCs exposed in vitro to different concentrations of 2,5-HD (0 mM, 20 mM, 40 mM, and 60 mM) and further explored the mechanism by mRNA and miRNA microarray analyses. The flow cytometry results sindicated that compared with control cells, in ovarian GCs, there was significant cell cycle arrest after 2,5-HD treatment. Cell cycle- and apoptosis- related gene (Cdk2, Ccnd1, Bax, Bcl-2, Caspase3, and Caspase9) expression was altered. The mRNA and miRNA microarray results suggested that 5678 mRNAs and 32 miRNAs were differentially expressed in the 2,5-HD-treated group. A total of 262 target mRNAs were obtained by miRNA and mRNA coexpression analysis, forming 368 miRNA-mRNA coexpression relationship pairs with 27 miRNAs. GO and KEGG analyses showed that differentially expressed genes were significantly enriched in the cell cycle and Wnt signaling pathways. Furthermore, significant changes in the expression of Wnt signaling pathway and cell cycle- related genes (Fzd1, Lrp6, Tcf3, Tcf4, Fzd6, Lrp5, ß-catenin, Lef1, GSK3ß, and Dvl3) after 2,5-HD treatment were confirmed by qRT-PCR and Western blotting. Ther results of dual-luciferase assays indicated decreased ß-catenin/TCF transcriptional activity after 2,5-HD treatment. In addition, Wnt pathway-related miRNAs (rno-miR-145-5p, rno-miR-143-3p, rno-miR-214-3p, rno-miR-138-5p, and rno-miR-199a-3p) were changed significantly after 2,5-HD treatment. In summary, 2,5-HD induced cell cycle arrest in ovarian GCs, and the Wnt/ß-catenin signaling pathway may play a very critical role in this process. Alterations in the expression of miRNAs such as rno-miR-145-5p may have significant implications.

Dimeric Matrine-Type Alkaloids from the Roots of Sophora flavescens and Their Anti-Hepatitis B Virus Activities.

Six unusual matrine-type alkaloid dimers, flavesines A-F (1-6, respectively), together with three proposed biosynthetic intermediates (7-9) were isolated from the roots of Sophora flavescens. Compounds 1-5 were the first natural matrine-type alkaloid dimers, and compound 6 represented an unprecedented dimerization pattern constructed by matrine and (-)-cytisine. Their structures were elucidated by NMR, MS, single-crystal X-ray diffraction, and a chemical method. The hypothetical biogenetic pathways of 1-6 were also proposed. Compounds 1-9 exhibited inhibitory activities against hepatitis B virus.

The effect of SGLT2i on the GH/IGF1 axis in newly diagnosed male T2D patients - a prospective, randomized case-control study.

PURPOSE: To investigate the effect of SGLT2i on the GH/IGF1 axis in male patients with newly diagnosed type 2 diabetes (T2D). METHODS: Sixty male patients with newly diagnosed T2D were recruited, and randomly assigned to Metformin+SGLT2i group or Metformin group after baseline assessment. All patients received standard lifestyle interventions, and blood indices were obtained before and after 12 weeks of treatment. RESULTS: After 12 weeks of treatment with Metformin+SGLT2i, there were noteworthy improvements in patients' FPG (Fasting plasma glucose), HBA1c, HOMA-IR, HOMA-ß, TyG (Triglyceride-glucose) index and UACR (P < 0.05). Both IGF1 (P = 0.01) and the IGF1/IGFBP3 ratio (P < 0.01) considerably increased, while GH and IGFBP3 did not show significant changes. When comparing Metformin+SGLT2i group to Metformin group, SGLT2i significantly improved HOMA-IR [P = 0.04], and elevated IGF1/IGFBP3 ratio [P = 0.04], SGLT2i showed a tendency of increasing IGF1 (P = 0.10), but this was not statistically meaningful. There was no effect on GH and IGFBP3. Correlation analysis showed that blood IGF1 was negatively correlated with FPG, HBA1c, HOMA-IR, TyG index and positively correlated with IGFBP3. Regression analysis indicated that FPG and testosterone had a negative effect on blood IGF1 level, while HOMA-IR had no obvious effect. CONCLUSION: In male patients with newly diagnosed T2D, SGLT2i can increase IGF1/IGFBP3 ratio, alleviate insulin resistance, but has no significant effect on GH and IGF1 levels. Additionally, our study showed that Metformin+SGLT2i treatment resulted in an increase in blood IGF1 levels and improved insulin resistance, suggesting a potentially beneficial role of IGF1 in newly diagnosed T2D.