经过加工的五环三萜类化合物通过肿瘤坏死因子-α/核因子-κB信号通路预防结肠癌，并结合网络药理学、分子模拟动力学和实验验证。
The processed L. triterpenoids prevent colon cancer through the TNF-/NF-κB signaling pathway, combined with network pharmacology, molecular simulation dynamics and experimental verification.
作者信息
Gan Chunli, Mu Yuanqiu, Ali Shah Syed Faizan, Shi Xuepeng, Jiang Shuang, Wang Zhengyang, Wu Xiaotian, Wang Xiaotong, Wang Zhibin, Zhang Shulu, Feng Zheng, Yang Chunjuan
机构信息
Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, Harbin Medical University, Harbin, China.
Department of Pharmaceutical Analysis and Analytical Chemistry, College of Pharmacy, Harbin Medical University, Harbin, China.
出版信息
Front Immunol. 2025 Jun 18;16:1605326. doi: 10.3389/fimmu.2025.1605326. eCollection 2025.
BACKGROUND
L. (S.L.), a traditional Chinese medicine from the Rosaceae family, is recognized for its rich content of triterpenoids, which are known for their antioxidant, anti-inflammatory, and anti-tumor properties. Although its traditional uses and biological activities are well known, its role in preventing colon cancer and the underlying mechanisms remain unclear. This study aims to elucidate the preventive mechanisms of triterpenoids in both raw (TR) and processed (TP) forms of S.L. against colon cancer.
METHODS
The AOM/DSS-induced mouse model of colon cancer was employed to elucidate the mechanism underlying the preventive effects of L. triterpenoids (ST) against colon cancer. A comprehensive suite of techniques, including hematoxylin-eosin staining (H&E), immunohistochemistry (IHC), TUNEL staining, Western blotting (WB), and DNA methylation analysis, was utilized to investigate the preventive effects of ST on colon cancer. The main active compounds were identified using UPLC-Q-TOF-MS, and potential active compounds were screened through network pharmacology and molecular docking. The stability of the protein-ligand complexes was further assessed using molecular dynamics simulations.
RESULTS
experiments, treatment with ST significantly improved the clinical manifestations, Disease Activity Index (DAI) scores, and pathological lesions associated with colon cancer, with all drug administration groups outperforming the model group. Additionally, ST markedly enhanced gut barrier function by downregulating the levels of TNF-, p65, COX-2, and iNOS. Furthermore, ST dramatically ameliorated the colonic immune-inflammatory state, which was associated with decreased expression of proliferative proteins and increased expression of apoptotic proteins. Among the identified triterpenoids, compound 27 May be the main active compound. Notably, compound 27 can form a stable complex with TNF-.
CONCLUSION
These results suggest that TP has a more pronounced colon cancer prevention effect than TR. TP play a role in preventing colon cancer by down-regulating TNF- and thereby inhibiting the NF-κB signaling pathway. This research not only fills the mechanism gap of S.L. in the field of colon cancer prevention, but also provides methodological support and theoretical foundation for its transition from traditional Chinese medicine to clinical practice through the integration of multi-disciplinary technologies and the verification of precise targets.
背景
L.（S.L.）是蔷薇科的一种传统中药，以其丰富的三萜类化合物含量而闻名，这些三萜类化合物具有抗氧化、抗炎和抗肿瘤特性。尽管其传统用途和生物学活性广为人知，但其在预防结肠癌中的作用及潜在机制仍不清楚。本研究旨在阐明S.L.的生品（TR）和炮制品（TP）中三萜类化合物预防结肠癌的机制。
方法
采用AOM/DSS诱导的小鼠结肠癌模型来阐明S.L.三萜类化合物（ST）预防结肠癌的潜在机制。运用了一套综合技术，包括苏木精-伊红染色（H&E）、免疫组织化学（IHC）、TUNEL染色、蛋白质印迹法（WB）和DNA甲基化分析，以研究ST对结肠癌的预防作用。使用超高效液相色谱-四极杆飞行时间质谱联用仪（UPLC-Q-TOF-MS）鉴定主要活性成分，并通过网络药理学和分子对接筛选潜在活性化合物。使用分子动力学模拟进一步评估蛋白质-配体复合物的稳定性。
结果
实验中，ST治疗显著改善了与结肠癌相关的临床表现、疾病活动指数（DAI）评分和病理损伤，所有给药组均优于模型组。此外，ST通过下调肿瘤坏死因子-α（TNF-α）、p65、环氧化酶-2（COX-2）和诱导型一氧化氮合酶（iNOS）的水平，显著增强肠道屏障功能。此外，ST显著改善结肠免疫炎症状态，这与增殖蛋白表达降低和凋亡蛋白表达增加有关。在所鉴定的三萜类化合物中，化合物27可能是主要活性成分。值得注意的是，化合物27可与TNF-α形成稳定复合物。
结论
这些结果表明，TP比TR具有更显著的预防结肠癌作用。TP通过下调TNF-α从而抑制核因子κB（NF-κB）信号通路来发挥预防结肠癌的作用。本研究不仅填补了S.L.在结肠癌预防领域的机制空白，还通过多学科技术整合和精确靶点验证，为其从传统中药向临床实践的转化提供了方法学支持和理论基础。
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