The active ingredient β-sitosterol in the anti-inflammatory agents alleviates perianal inflammation in rats by inhibiting the expression of Srebf2, activating the PPAR signaling pathway, and altering the composition of gut microbiota

IF 4.8 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-03-13 DOI:10.1016/j.intimp.2025.114470

Yanlan Wu , Hao Ge , Haoran Zhao , Kaiping Zou , Pei Wang , Yi Wang , Yang Zhang

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引用次数: 0

Abstract

Background

Anti-inflammatory herbal formulations are common in traditional Chinese medicine for clearing heat and detoxifying; however, the specific active components and their mechanisms remain unclear.

Objective

This study investigates the role of Sitosterol in alleviating perianal inflammation and its underlying mechanisms.

Methods

Sitosterol was identified as a key active ingredient through the TCMSP database. Its structure was analyzed using PubChem, target genes were explored with STITCH, and KEGG pathways related to Srebf2 were revealed by STRING. An animal model of perianal inflammation was induced with 75 % acetic acid and treated with Sitosterol, water, normal saline, or antibiotics. The effects on gut microbiota were assessed using 16S rRNA sequencing, and inflammation was evaluated through HE stains, IHC, and TUNEL assays. In vitro, LPS-treated Caco-2 cells were used to measure proliferation, apoptosis, and cytokine levels, with PPAR pathway involvement examined using GW6471.

Results

Sitosterol emerged as the primary active ingredient targeting Srebf2, with KEGG analysis highlighting the PPAR signaling pathway. In rats, Sitosterol reduced weight loss, inflammatory cell infiltration, edema, and vasodilation in perianal tissue. Additionally, it decreased PCNA levels, increased apoptosis, and elevated serum levels of IL-1β, IL-6, and TNF-α, particularly at high doses compared to antibiotics. Sitosterol also restored gut microbiota. Srebf2 knockdown improved tissue conditions and modulated cytokine levels, effects that were countered by GW6471. In LPS-treated Caco-2 cells, Sitosterol reversed reductions in cell viability and proliferation and modulated the expression of proteins and cytokines.

Conclusion

Sitosterol restores gut microbiota composition and further alleviates perianal inflammation in rats by inhibiting Srebf2 expression and activating the PPAR signaling pathway.

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抗炎剂中的有效成分β-谷甾醇通过抑制 Srebf2 的表达、激活 PPAR 信号通路和改变肠道微生物群的组成，缓解大鼠的肛周炎症

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.