Protective effect of Andrographolide on 5-Fu induced intestinal mucositis by regulating p38 MAPK signaling pathway
Protective effect of Andrographolide on 5-Fu induced intestinal mucositis by regulating p38 MAPK signaling pathway
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穿心莲内酯通过调节p38 MAPK信号通路对5-Fu诱导的肠粘膜炎的保护作用
DOI：
10.1016/j.lfs.2020.117612
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发表时间：
2020-07-01
期刊：
影响因子：
6.1
通讯作者：
Liu，Dong
中科院分区：
文献类型：
--
作者：
Xiang，Dao-Chun;Yang，Jin-Yu;Liu，Dong
目的：肠道黏膜炎是5-氟尿嘧啶（5-Fu）治疗癌症患者最常见的副作用。既往研究表明穿心莲内酯能减轻小鼠结肠炎或腹泻引起的肠道损伤。本研究旨在探讨安德罗对5-Fu诱导的肠黏膜炎的保护作用及其机制。主要方法：给BALB/C小鼠注射5- fu，剂量为100 mg/kg，连续5 d诱导肠黏膜炎。给予不同剂量（25、50、100 mg/kg/天）的Andro。评估体重减轻、腹泻评分、细胞凋亡和增殖。Western blotting检测细胞凋亡相关蛋白。然后利用NCM460细胞在体外探讨其可能的机制。以H22荷瘤小鼠为实验对象，研究了安德罗对5-Fu抗肿瘤作用的影响。主要发现：安德罗显著改善了5-Fu引起的体重减轻和腹泻。在体内和体外均可明显减少肠道细胞的凋亡。此外，Andro显著下调了5- fu诱导的caspase8/3、Bax蛋白的表达和p38的磷酸化。此外，5-Fu显著降低NCM460细胞的活力，并通过Andro预处理恢复细胞活力。此外，p38 MAPK的激动剂asia - acid在NCM460细胞中逆转了Andro的抗凋亡作用。在体内，安德罗对5-Fu的抗h22肿瘤作用没有减弱。意义：我们已经证明p38 MAPK抑制介导Andro对5-Fu诱导的肠黏膜炎的抗凋亡作用，提示Andro可能对接受5-Fu化疗的患者有益。
Aims: Intestinal mucositis is the most common side effect of 5-fluorouracil (5-Fu) treatment in cancer patients. Previous research suggested that andrographolide (Andro) attenuated the intestinal injury in colitis or diarrhea in mice. The present study was aimed at investigating the protective effect of Andro against 5-Fu induced intestinal mucositis and the underlying mechanism.Main methods: BALB/C mice were injected 5-Fu at a dose of 100 mg/kg for 5 days to induce intestinal mucositis. Andro at different doses (25, 50, 100 mg/kg/day) was administered. Weight loss, diarrhea score, cellular apoptosis and proliferation were evaluated. Apoptosis related proteins were detected by Western blotting. Then, NCM460 cells were used to explore the possible mechanism in vitro. The effect of Andro on the anti-tumor efficacy of 5-Fu was investigated in H22 tumor-bearing mice.Key findings: Andro significantly ameliorated the 5-Fu induced weight loss and diarrhea. The apoptosis of intestinal cells was also attenuated by Andro treatment both in vivo and in vitro. Besides, Andro markedly down-regulated the 5-Fu-induced protein expression of caspase8/3, Bax and the phosphorylation of p38. Moreover, 5-Fu significantly reduced the viability of NCM460 cells, which was restored by the Andro pretreatment. Furthermore, asiatic acid, an agonist of p38 MAPK, reversed the anti-apoptotic effect of Andro in NCM460 cells. Andro did not weaken the anti-H22 tumor effect of 5-Fu in vivo.Significance: We have demonstrated that p38 MAPK inhibition mediates anti-apoptotic effects of Andro against 5-Fu induced intestinal mucositis, suggesting that Andro may benefit the patients undergoing 5-Fu based chemotherapy.