Liao Yi-Fan, Luo Feng-Lin, Tang Shan-Shan, Huang Jing-Wei, Yang Ying, Wang Shuang, Jiang Tang-Yu, Man Qiong, Liu Sha, Wu Yi-Ying
Department of Pharmacology, School of Pharmacy, Chengdu Medical College, Chengdu, Sichuan, China.
Department of Pharmacy, Study on the Structure-Specific Small Molecule Drug in Sichuan Province College Key Laboratory, Chengdu Medical College, Chengdu, Sichuan, China.
Front Pharmacol. 2022 Oct 6;13:1014160. doi: 10.3389/fphar.2022.1014160. eCollection 2022.
5-fluorouracil (5-FU) is one of the most widely used chemotherapy drugs for malignant tumors. However, intestinal mucositis caused by 5-FU is a severe dose-limiting toxic effect and even leads to treatment interruption. Isoliquiritigenin (ISL) is one of the main active compounds of licorice, which is a traditional Chinese herbal medicine commonly used in inflammation and gastrointestinal diseases. It is speculated that ISL have protective effects on intestinal mucositis. However, no such studies have been reported. Therefore, to investigate the impact of ISL on 5-Fu-induced intestinal mucositis, a strategy based on network prediction and pharmacological experimental validation was proposed in this study. Firstly, the targets and mechanism of ISL in alleviating 5-Fu-induced gastrointestinal toxicity were predicted by network analysis. And the results were further confirmed by molecular docking. Then, a mouse model of intestinal mucositis was established by intraperitoneal injection of 5-FU (384 μmol/kg) to verify the prediction of network analysis. The network analysis results suggested that PTGS2 (Prostaglandin G/H synthase 2) and NOS2 (Nitric oxide synthase, inducible) might be the critical targets of ISL for reducing the intestinal toxicity of 5-FU. In addition, KEGG and GO enrichment analysis revealed that the HIF-1, TNF, MAPK, IL-17, PI3K-Akt, Ras, NF-kappa B signaling pathway, and biological processes of the inflammatory response, apoptosis regulation, NO production and NF-kappa B transcription factor activity might be involved in the mechanism of ISL against intestinal mucositis. Subsequent animal experiments showed that ISL could reduce the weight loss, leukopenia and mucosal damage caused by 5-FU. Compared with the intestinal mucositis model, the protein expressions of PTGS2, NOS2, TNFα (Tumor necrosis factor-alpha) and NF-κB p65 (nuclear factor kappa-B P65) were decreased after ISL treatment. In conclusion, this study is the fist time to find that ISL can attenuate 5-FU-induced intestinal mucositis in mice. Its anti-mucositis effect may be through regulating TNF/NF-κB pathway and inhibiting inflammatory mediators PTGS2 and NOS2. It will provide a potential candidate for the prevention and treatment of chemotherapy-induced intestinal mucositis.
5-氟尿嘧啶（5-FU）是治疗恶性肿瘤最常用的化疗药物之一。然而，5-FU引起的肠道黏膜炎是一种严重的剂量限制性毒性反应，甚至会导致治疗中断。异甘草素（ISL）是甘草的主要活性成分之一，甘草是一种常用于治疗炎症和胃肠道疾病的传统中药。据推测，ISL对肠道黏膜炎具有保护作用。然而，尚未见相关研究报道。因此，为了研究ISL对5-氟尿嘧啶诱导的肠道黏膜炎的影响，本研究提出了一种基于网络预测和药理实验验证的策略。首先，通过网络分析预测ISL减轻5-氟尿嘧啶诱导的胃肠道毒性的靶点和机制。并通过分子对接进一步证实结果。然后，通过腹腔注射5-氟尿嘧啶（384 μmol/kg）建立肠道黏膜炎小鼠模型，以验证网络分析的预测结果。网络分析结果表明，PTGS2（前列腺素G/H合酶2）和NOS2（一氧化氮合酶，诱导型）可能是ISL降低5-氟尿嘧啶肠道毒性的关键靶点。此外，KEGG和GO富集分析显示，HIF-1、TNF、MAPK、IL-17、PI3K-Akt、Ras、NF-κB信号通路以及炎症反应、凋亡调控、NO生成和NF-κB转录因子活性等生物学过程可能参与了ISL抗肠道黏膜炎的机制。随后的动物实验表明，ISL可以减轻5-氟尿嘧啶引起的体重减轻、白细胞减少和黏膜损伤。与肠道黏膜炎模型相比，ISL治疗后PTGS2、NOS2、TNFα（肿瘤坏死因子-α）和NF-κB p65（核因子κB P65）的蛋白表达降低。总之，本研究首次发现ISL可减轻5-氟尿嘧啶诱导的小鼠肠道黏膜炎。其抗黏膜炎作用可能是通过调节TNF/NF-κB通路并抑制炎症介质PTGS2和NOS2实现的。这将为化疗诱导的肠道黏膜炎的防治提供一个潜在的候选药物。
