Paris saponin VII inhibits triple-negative breast cancer by targeting the MEK/ERK/STMN1 signaling axis.

BACKGROUND: Triple-negative breast cancer (TNBC) is a category of breast cancer characterized with high molecular heterogeneity. Owing to the lack of effective therapeutic strategies, patients with TNBC have a poor prognosis. Paris saponin VII (PSⅦ), a steroidal saponin extracted from the rhizome of Trichillium tschonoskii Maxim, exhibits excellent anti-cancer activity in a variety of solid tumors. However, the role and potential mechanism of PSⅦ against TNBC remain unexplored. PURPOSE: This study aimed to elucidate the therapeutic effects of PSⅦ against TNBC and explore the potential mechanism of action. METHODS: We combined the analysis of public single-cell sequencing data with weighted gene co-expression network analysis (WGCNA) to identity differentially expressed genes (DEGs) that distinguished malignant and normal epithelial cells in TNBC. Subsequently, the biological features of DEGs in TNBC were evaluated. Gene set enrichment analysis (GSEA) was used to define potential pathways associated with the DEGs. The pharmacological activity of PSⅦ for TNBC was evidenced via in vitro and in vivo experiments, and molecular docking, molecular dynamics (MD), surface plasmon resonance (SPR) assay and western blotting were employed to confirm the relative mechanisms. RESULTS: Single-cell sequencing and WGCNA revealed STMN1 as a pivotal biomarker of TNBC. STMN1 overexpression in TNBC was associated with poor patient prognosis. GSEA revealed a significant accumulation of STMN1 within the MAPK signaling pathway. Furthermore, In vitro experiments showed that PSⅦ showed significantly suppressive actions on the proliferation, migration and invasion abilities for TNBC cells, while inducing apoptosis. Molecular docking, MD analysis and SPR assay indicated a robust interaction between PSⅦ and the MEK protein. Western blotting revealed that PSⅦ may inhibit tumor progression by suppressing the phosphorylation of MEK1/2 and the downstream phosphorylation of ERK1/2 and STMN1. Intraperitoneal injection of PSⅦ (10 mg/kg) notably reduced tumor growth by 71.26 % in a 4T1 xenograft model. CONCLUSION: In our study, the systems biology method was used to identify potential therapeutic targets for TNBC. In vitro and in vivo experiments demonstrated PSⅦ suppresses cancer progression by targeting the MEK/ERK/STMN1 signaling axis. For the first time, the inhibition of STMN1 phosphorylation has been indicated as a possible mechanism for the anticancer effects of PSⅦ. These results emphasize the potential value of PSⅦ as a promising anti-cancer drug candidate for further development in the field of TNBC therapeutics.

Cholestyramine alleviates bone and muscle loss in irritable bowel syndrome via regulating bile acid metabolism.

Irritable bowel syndrome (IBS) is a widespread gastrointestinal disorder known for its multifaceted pathogenesis and varied extraintestinal manifestations, yet its implications for bone and muscle health are underexplored. Recent studies suggest a link between IBS and musculoskeletal disorders, but a comprehensive understanding remains elusive, especially concerning the role of bile acids (BAs) in this context. This study aimed to elucidate the potential contribution of IBS to bone and muscle deterioration via alterations in gut microbiota and BA profiles, hypothesizing that cholestyramine could counteract these adverse effects. We employed a mouse model to characterize IBS and analysed its impact on bone and muscle health. Our results revealed that IBS promotes bone and muscle loss, accompanied by microbial dysbiosis and elevated BAs. Administering cholestyramine significantly mitigated these effects, highlighting its therapeutic potential. This research not only confirms the critical role of BAs and gut microbiota in IBS-associated bone and muscle loss but also demonstrates the efficacy of cholestyramine in ameliorating these conditions, thereby contributing significantly to the field's understanding and offering a promising avenue for treatment.