Department of Gastroenterology, Shanghai Tenth People's Hospital Affiliated to Tongji University, Tongji University, School of Medicine, Shanghai 200072, China; Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province; Department of Gastroenterology, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China; Department of Gastroenterology, Gongli Hospital, School of Medicine, Shanghai University, Shanghai 200135, China.
Department of Gastroenterology, Shanghai Tenth People's Hospital Affiliated to Tongji University, Tongji University, School of Medicine, Shanghai 200072, China; Department of Gastroenterology, Gongli Hospital, School of Medicine, Shanghai University, Shanghai 200135, China.
Int Immunopharmacol. 2022 Oct;111:109058. doi: 10.1016/j.intimp.2022.109058. Epub 2022 Jul 26.
Ulcerative colitis (UC) is a chronic, idiopathic relapsing inflammatory bowel disease. Honokiol is a major active component of the traditional Chinese medicinal herb Magnolia officinalis, which has been widely used in traditional prescriptions to treat tumors, inflammation, and gastrointestinal disorders. In this study, we investigated the ability of this polyphenolic compound to suppress UC in mice and the possible regulatory mechanism. A mouse model of UC induced with dextran sulfate sodium (DSS) in 40 male C57BL/6J mice was used for the in vivo study, and in vitro experiments were performed in mouse RAW264.7 macrophages. Lipopolysaccharide was used to induce the inflammatory response. The mouse bodyweights, stool consistency, and bleeding were determined and the disease activity indices calculated. RAW264.7 macrophages were cultured with or without either honokiol or lipopolysaccharide. Gene and protein expression was analyzed with RT-PCR and western blotting, respectively. GW6471 and GW9662 were used to interrupt the transcription of peroxisome proliferator activated receptor alpha (PPAR-α) and peroxisome proliferator activated receptor gamma (PPAR-γ). Both the in vivo and in vitro experimental results showed that the oral administration of honokiol markedly attenuated the severity of UC by reducing the inflammatory signals and restoring the integrity of the colon. Honokiol dramatically reduced the proinflammatory cytokines TNF-α, IL6, IL1β, and IFN-γ in mice with DSS-induced UC. It also upregulated PPAR-γ expression, and downregulated the TLR4-NF-κB signaling pathway. Moreover, honokiol inhibited gasdermin-D-mediated cell pyroptosis. These findings demonstrate for the first time that honokiol exerts a strong anti-inflammatory effect in a mouse model of UC, and that its underlying mechanism is associated with the activation of the PPAR-γ-TLR4-NF-κB signaling pathway and gasdermin-D-mediated macrophage pyroptosis. Therefore, honokiol may be a promising new drug for the clinical management of UC.
溃疡性结肠炎（UC）是一种慢性、特发性复发性炎症性肠病。和厚朴酚是传统中药厚朴的主要活性成分之一，广泛用于传统方剂治疗肿瘤、炎症和胃肠道疾病。本研究旨在探讨该多酚化合物对葡聚糖硫酸钠（DSS）诱导的 UC 小鼠的抑制作用及其可能的调节机制。体内实验采用雄性 C57BL/6J 小鼠 40 只构建 DSS 诱导的 UC 模型，体外实验采用小鼠 RAW264.7 巨噬细胞。采用脂多糖诱导炎症反应。检测小鼠体重、粪便稠度和出血情况，并计算疾病活动指数。RAW264.7 巨噬细胞分别用或不用 honokiol 或脂多糖培养。采用 RT-PCR 和 Western blot 分别分析基因和蛋白表达。用 GW6471 和 GW9662 阻断过氧化物酶体增殖物激活受体α（PPAR-α）和过氧化物酶体增殖物激活受体γ（PPAR-γ）的转录。体内和体外实验结果均表明， honokiol 口服可通过减轻炎症信号和恢复结肠完整性来显著减轻 UC 的严重程度。 honokiol 可显著降低 DSS 诱导的 UC 小鼠促炎细胞因子 TNF-α、IL6、IL1β 和 IFN-γ 的表达。它还上调了 PPAR-γ 的表达，并下调了 TLR4-NF-κB 信号通路。此外， honokiol 抑制了 gasdermin-D 介导的细胞焦亡。这些发现首次证明， honokiol 在 UC 小鼠模型中具有很强的抗炎作用，其作用机制与激活 PPAR-γ-TLR4-NF-κB 信号通路和 gasdermin-D 介导的巨噬细胞焦亡有关。因此， honokiol 可能是治疗 UC 的一种有前途的新药。
