Swertiamarin通过PI3K/AKT/mTOR信号通路诱导自噬，促进屏障功能，缓解溃疡性结肠炎
Swertiamarin promotes barrier function to alleviate ulcerative colitis by inducing autophagy via the PI3K/AKT/mTOR-signaling pathway.
摘要(中文译文)
溃疡性结肠炎（UC）是一种以结肠黏膜炎症为特征的慢性炎症性肠病。维持肠黏膜屏障完整性是管理UC的基本治疗目标。獐牙菜苦苷（STM）具有多种生物活性，有望用于UC的治疗。自噬是保护肠黏膜屏障完整性的关键机制，但STM是否通过调节自噬来改善UC并保护该屏障仍不确定。通过在饮水中给予葡聚糖硫酸钠（DSS）诱导急性结肠炎小鼠模型。通过监测体重变化、疾病活动指数（DAI）、结肠长度、脾脏指数、组织学评分和AB-PAS染色，评估不同浓度STM对结肠炎的保护作用。使用ELISA和qPCR评估结肠炎症严重程度，同时通过FITC-葡聚糖通透性实验、Western blotting和免疫组织化学评估肠道通透性。用2% DSS处理Caco-2/HIEC-6细胞单层，并使用Western blotting、qPCR和FITC-葡聚糖通透性实验评估STM对细胞炎症和屏障功能的影响。使用在线数据库和网络药理学分析预测STM通过肠上皮细胞缓解UC的潜在机制和靶点。这些预测随后通过Western blotting进行验证。为阐明自噬和PI3K/AKT/mTOR通路在STM保护作用中的角色，进行了功能挽救实验。这些实验使用了自噬抑制剂3-甲基腺嘌呤（3-MA）和PI3K特异性激动剂740YP。通过透射电子显微镜（TEM）直接观察自噬结构。STM剂量依赖性地缓解了DSS诱导的小鼠结肠炎。它逆转了体重下降，改善了DAI评分，并抑制了结肠缩短。治疗还降低了脾脏指数，减轻了结肠病理损伤，增加了杯状细胞计数，抑制了细胞因子产生，并保护了上皮屏障功能。体外实验表明，STM有效保护了肠上皮屏障并减轻了炎症反应。网络药理学分析揭示，STM通过促进肠上皮细胞自噬来保护肠道屏障，并通过PI3K/AKT/mTOR信号通路缓解UC。DSS处理升高了结肠组织中p62表达并抑制了LC3-II水平，提示自噬受损。相反，STM在体内和体外模型中均诱导了自噬并抑制了PI3K/AKT/mTOR信号通路。TEM显示STM治疗组中自噬体数量显著增多。使用自噬抑制剂3-MA处理显著削弱了STM的保护作用。使用PI3K激动剂740YP处理显著增加了PI3K、AKT和mTOR的磷酸化水平。这伴随着p62积累、LC3-II表达降低和紧密连接蛋白（ZO-1和Occludin）水平降低，表明PI3K激活抵消了STM对自噬和屏障功能的保护作用。STM通过降低促炎细胞因子水平减轻DSS诱导结肠炎小鼠的结肠炎症。该效应可能通过抑制PI3K/AKT/mTOR通路增强自噬来介导，最终改善肠道屏障功能障碍。
Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by mucosal inflammation in the colon. Maintaining intestinal mucosal barrier integrity is a fundamental therapeutic objective in managing UC. Swertiamarin (STM) exhibits diverse biological activities and holds promise for the treatment of UC. Autophagy is a critical mechanism that safeguards the integrity of the intestinal mucosal barrier, yet it remains uncertain whether STM ameliorates UC and modulates autophagy to preserve this barrier. An acute colitis mouse model was induced by administering dextran sulfate sodium (DSS) in drinking water. The protective effects of different concentrations of STM against colitis were evaluated by monitoring body weight changes, disease activity index (DAI), colon length, spleen index, histological score, and AB-PAS staining. Colonic inflammation severity was assessed using ELISA and qPCR, while intestinal permeability was evaluated through FITC-dextran permeability assays, Western blotting, and immunohistochemistry. Caco-2/HIEC-6 cell monolayers were treated with 2% DSS, and the effects of STM on cellular inflammation and barrier function were assessed using Western blotting, qPCR, and a FITC-dextran permeability assay. Potential mechanisms and targets of STM for alleviating UC through intestinal epithelial cells were predicted using online databases and network pharmacology analysis. These predictions were subsequently validated through Western blotting. To elucidate the roles of autophagy and the PI3K/AKT/mTOR pathway in STM's protective effects, functional rescue experiments were conducted. These experiments utilized the autophagy inhibitor 3-methyladenine (3-MA) and the PI3K-specific agonist 740YP. Autophagic structures were directly visualized by transmission electron microscopy (TEM). STM dose-dependently alleviated DSS-induced colitis in mice. It reversed body weight loss, improved the DAI score, and inhibited colon shortening. Treatment also reduced the spleen index, attenuated colonic pathological damage, increased goblet cell counts, suppressed cytokine production, and protected epithelial barrier function. In vitro experiments demonstrated that STM effectively protected the intestinal epithelial barrier and mitigated inflammatory responses. Network pharmacology analysis revealed that STM safeguards the intestinal barrier by promoting intestinal epithelial cell autophagy and mitigating UC through the PI3K/AKT/mTOR-signaling pathway. DSS treatment elevated p62 expression and suppressed LC3-II levels in colonic tissues, suggesting impaired autophagy. Conversely, STM induced autophagy and inhibited the PI3K/AKT/mTOR-signaling pathway in both in vivo and in vitro models. TEM revealed a significantly higher number of autophagosomes in the STM-treated group. Treatment with the autophagy inhibitor 3-MA significantly abrogated the protective effects of STM. Treatment with the PI3K agonist 740YP significantly increased phosphorylation levels of PI3K, AKT, and mTOR. This was accompanied by p62 accumulation, decreased LC3-II expression, and reduced tight junction protein (ZO-1 and Occludin) levels, indicating that PI3K activation counteracts the protective effects of STM on autophagy and barrier function. STM mitigates colonic inflammation in DSS-induced colitis mice by reducing pro-inflammatory cytokine levels. This effect is likely mediated through enhanced autophagy, achieved by inhibiting the PI3K/AKT/mTOR pathway, ultimately ameliorating intestinal barrier dysfunction.
如何引用
AMA
Yaohui Ma, Hang Gong, Na Wei, Tong Lu, Wen Yin, Jinwu Wei, et al. Swertiamarin promotes barrier function to alleviate ulcerative colitis by inducing autophagy via the PI3K/AKT/mTOR-signaling pathway.. International immunopharmacology. 2026; doi:10.1016/j.intimp.2026.116975.
APA
Yaohui Ma, Hang Gong, Na Wei, Tong Lu, Wen Yin, Jinwu Wei, et al (2026). Swertiamarin promotes barrier function to alleviate ulcerative colitis by inducing autophagy via the PI3K/AKT/mTOR-signaling pathway.. International immunopharmacology. https://doi.org/10.1016/j.intimp.2026.116975
GB/T 7714
Yaohui Ma, Hang Gong, Na Wei, Tong Lu, Wen Yin, Jinwu Wei, et al. Swertiamarin promotes barrier function to alleviate ulcerative colitis by inducing autophagy via the PI3K/AKT/mTOR-signaling pathway.[J]. International immunopharmacology, 2026 doi:10.1016/j.intimp.2026.116975.
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