Investigating the mechanisms of Sini San in alleviating inflammatory responses via multi-omics and the BDNF/TrkB/PI3K/AKT signaling pathway in depressive model rats.

Background: Sini San, from the traditional Chinese medicine classic Aim: This study aimed to evaluate the antidepressant effect and inflammatory profile of Sini San in chronic unpredictable mild stress (CUMS)-induced rats and to explore its potential mechanism. Methods: The primary active ingredients, targets, and pathways of Sini San in treating depression were determined through network pharmacology. The improvement of depression-like behaviors was assessed using behavioral experiments. Tissue inflammatory responses were evaluated through histopathological analysis (HE staining and Nissl staining) and quantitative measurement of inflammatory cytokines by ELISA. Western blotting (WB) was employed to quantify protein expression levels, while RT-qPCR was used to assess mRNA transcription levels. Gut microbial composition was analyzed by 16S rRNA gene amplicon sequencing, with taxonomic classification performed using the Greengenes database. Results: The data indicated that Sini San reduced inflammation related to the NLRP3 inflammasome pathway by inhibiting the expression of NLRP3, ASC, caspase-1, and downstream pro-inflammatory cytokines IL-18, IL-1β, and TNF-α. According to network pharmacology analysis, Sini San mitigated depression via modulation of the PI3K/AKT signaling pathway. Upstream and downstream proteins, including BDNF (brain-derived neurotrophic factor), TrkB (tropomyosin receptor kinase B), and p-CREB (phosphorylated cAMP response element-binding protein), which were decreased after CUMS induction, were regulated by Conclusion: Sini San modulates the gut-brain axis by inhibiting the NLRP3 inflammasome, thereby alleviating CUMS-induced inflammation and gut microbiota dysbiosis in rats. This effect may further contribute to the improvement of depressive symptoms via regulation of the BDNF/TrkB/PI3K/AKT signaling pathway.