Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China; The First School of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China.
J Ethnopharmacol. 2024 Jan 30;319(Pt 3):117323. doi: 10.1016/j.jep.2023.117323. Epub 2023 Oct 16.
The Qi-Qin-Hu-Chang Formula (QQHCF) is a traditional Chinese medicine prescription that is clinically used at the Affiliated Hospital of Nanjing University of Chinese Medicine for the treatment of colitis-associated colorectal cancer (CAC).
To evaluate the potential therapeutic effects of QQHCF on a CAC mouse model and investigate its underlying mechanisms using network pharmacology and experimental validation.
The active components and potential targets of QQHCF were obtained from Traditional Chinese Medicine Systems Pharmacology (TCMSP) and herb-ingredient-targets gene network were constructed by Cytoscape 3.9.2. Target genes of CAC were obtained from GeneCards, Online Mendelian Inheritance in Man, and DrugBank database. The drug disease target protein-protein interaction (PPI) network was constructed and the core targets were visualized and identified using Cytoscape. The Metascape database was used for GO and KEGG enrichment analysis. UHPLC-MS/MS was used to further identify the active compounds in QQHCF. Subsequently, the therapeutic effects and potential mechanism of QQHCF against CAC were investigated in AOM/DSS-induced CAC mouse in vivo, and HT-29 and HCT116 cells in vitro. Finally, interactions between JNK, p38, and active ingredients were assessed by molecular docking.
A total of 176 active compounds, 273 potential therapeutic targets, and 2460 CAC-related target genes were obtained. The number of common targets between QQHCF and CAC were 165. KEGG pathway analysis indicated that the MAPK signaling pathway was closely associated with CAC, which may be the potential mechanism of QQHCF against CAC. Network pharmacology and UHPLC-MS/MS analyses showed that the active compounds of QQHCF included quercetin, kaempferol, luteolin, wogonin, oxymatrine, lupanine, and baicalin. Animal experiments demonstrated that QQHCF reduced tumor load, number, and size in AOM/DSS-treated mice, and induced apoptosis in colon tissue. In vitro experiments further showed that QQHCF induced apoptosis and inhibited cell viability, migration, and invasion in HCT116 and HT-29 cells. Notably, QQHCF activated the JNK/p38 MAPK signaling pathway both in vivo and in vitro. Molecular docking analysis revealed an ability for the main components of QQHCF and JNK/p38 to bind.
The present study demonstrated that QQHCF could ameliorate AOM/DSS-induced CAC in mice by activating the JNK/p38 MAPK signaling pathway. These results have important implications for the development of effective treatment strategies for CAC.
齐秦胡昌配方（QQHCF）是一种中药方剂，临床上用于南京中医药大学附属医院治疗结肠炎相关结直肠癌（CAC）。
使用网络药理学和实验验证方法，评估 QQHCF 对 CAC 小鼠模型的潜在治疗作用及其潜在机制。
从中药系统药理学（TCMSP）获得 QQHCF 的活性成分和潜在靶点，并通过 Cytoscape 3.9.2 构建草药-成分-靶点基因网络。CAC 的靶基因从 GeneCards、在线 Mendelian 遗传在线和 DrugBank 数据库中获得。构建药物疾病靶蛋白-蛋白相互作用（PPI）网络，并使用 Cytoscape 可视化和识别核心靶点。使用 Metascape 数据库进行 GO 和 KEGG 富集分析。使用 UHPLC-MS/MS 进一步鉴定 QQHCF 中的活性化合物。随后，在体内 AOM/DSS 诱导的 CAC 小鼠和体外 HT-29 和 HCT116 细胞中研究 QQHCF 对 CAC 的治疗效果和潜在机制。最后，通过分子对接评估 JNK、p38 与活性成分之间的相互作用。
共获得 176 种活性化合物、273 个潜在治疗靶点和 2460 个 CAC 相关靶基因。QQHCF 和 CAC 之间的共同靶点数为 165 个。KEGG 通路分析表明，MAPK 信号通路与 CAC 密切相关，这可能是 QQHCF 治疗 CAC 的潜在机制。网络药理学和 UHPLC-MS/MS 分析表明，QQHCF 的活性化合物包括槲皮素、山奈酚、木犀草素、白杨素、氧化苦参碱、羽扇豆碱和黄芩苷。动物实验表明，QQHCF 可减少 AOM/DSS 处理小鼠的肿瘤负荷、数量和大小，并诱导结肠组织凋亡。体外实验进一步表明，QQHCF 诱导 HCT116 和 HT-29 细胞凋亡，并抑制细胞活力、迁移和侵袭。值得注意的是，QQHCF 在体内和体外均激活了 JNK/p38 MAPK 信号通路。分子对接分析表明，QQHCF 的主要成分与 JNK/p38 具有结合能力。
本研究表明，QQHCF 通过激活 JNK/p38 MAPK 信号通路，可改善 AOM/DSS 诱导的 CAC 小鼠的病情。这些结果对开发 CAC 的有效治疗策略具有重要意义。
