杭州师范大学Yi Wang等研究人员合作发现，一种丹参酮IIA和salviadione的衍生物15a通过直接结合和抑制RIPK2抑制炎症并减轻小鼠的DSS诱导结肠炎。2024年10月23日，国际知名学术期刊《中国药理学报》在线发表了这一成果。

研究人员表示，炎症性肠病（IBD）是一种主要影响胃肠道的慢性炎症性疾病。先前的研究确立了NF-κB信号通路在IBD发展中的作用，表明抗炎疗法可能是一种可行的治疗策略。丹参酮IIA和salviadione均源自丹参（Salviae Miltiorrhizae Radix et Rhizoma），具有抗炎和抗氧化活性。通过将salviadione与丹参酮结合，一系列新化合物被合成。其中，化合物15a在LPS诱导的急性肺损伤和糖尿病诱导的肾损伤小鼠模型中显示出有益效果。

研究人员探讨了化合物15a在急性和慢性结肠炎模型中的治疗效果及其潜在机制。研究人员建立了DSS诱导的结肠炎小鼠模型，急性结肠炎用化合物15a（5或10 mg/kg每天）治疗8天，而慢性结肠炎小鼠在2.5% DSS给药期间接受化合物15a（5或10 mg/kg每天，口服）。15a处理显著减轻了急性和慢性结肠炎小鼠模型中的DSS诱导的病理和炎症损伤。在小鼠肠上皮细胞系MODE-K中，预处理化合物15a（5或10 μM）显著抑制了LPS + L18-MDP诱导的炎症反应。

通过微阵列和重组人蛋白识别出受体相互作用丝氨酸/苏氨酸激酶2（RIPK2）是化合物15a的直接结合靶点。此外，15a能够直接结合并抑制RIPK2的磷酸化，从而抑制NF-κB和MAPK信号通路。此外，在RIPK2的KD结构域中识别出LEU153和VAL32作为15a结合的关键氨基酸残基。总之，目前的研究结果表明，化合物15a作为管理急性和慢性结肠炎的治疗剂具有良好的前景。

附：英文原文

Title: A derivative of tanshinone IIA and salviadione, 15a, inhibits inflammation and alleviates DSS-induced colitis in mice by direct binding and inhibition of RIPK2

Author: Hu, Cheng-hong, Chen, Yue, Jin, Tian-yang, Wang, Zhe, Jin, Bo, Liao, Jing, Ding, Chun-yong, Zhang, Ao, Tang, Wei-yang, Zhang, Ling-xi, Xu, Lei-yu, Ning, Fang-min, Liang, Guang, Wei, Xiao-hong, Wang, Yi

Issue&Volume: 2024-10-23

Abstract: Inflammatory bowel diseases (IBDs) are chronic inflammatory conditions primarily affecting the gastrointestinal tract. Previous studies established the role of the NF-κB signaling pathway in the development of IBDs, suggesting that anti-inflammatory therapies might offer a viable treatment strategy. Tanshinone IIA and salviadione, both derived from Salviae Miltiorrhizae Radix et Rhizoma, possess anti-inflammatory and anti-oxidative activities. A series of new compounds were synthesized by hybridizing salviadione with tanshinone. Among these compounds, 15a showed beneficial effects in LPS-induced acute lung injury and diabetes-induced renal injury mouse models. The current study explored the therapeutic efficacy of 15a using both acute and chronic colitis models and elucidated the underlying mechanisms. DSS-induced colitis models were established in mice, where acute colitis was treated with compound 15a (5 or 10mg·kg1·d1) for 8 days, while chronic colitis mice received compound 15a (5 or 10mg·kg1·d1, i.g.) during 2.5% DSS administration. The 15a treatment significantly alleviated DSS-induced pathological and inflammatory damages in both acute and chronic colitis mouse models. In mouse intestinal epithelial cell line MODE-K, pretreatment with compound 15a (5 or 10μM) significantly suppressed LPS+L18-MDP-induced inflammatory responses. The receptor-interacting serine/threonine kinase 2 (RIPK2) was identified as a direct binding target of compound 15a using microarrays and recombinant human proteins. Moreover, 15a could directly bind to and inhibit the phosphorylation of RIPK2, leading to the suppression of the NF-κB and MAPK signaling pathways. Furthermore, LEU153 and VAL32 were identified within the KD domain of RIPK2 as critical amino residues for the binding of 15a. Briefly, the current findings demonstrate that compound 15a holds promise as a therapeutic agent for managing acute and chronic colitis.

DOI: 10.1038/s41401-024-01399-1

Source: https://www.nature.com/articles/s41401-024-01399-1