托里消毒散调控TLR4/Myd88/NF-κB通路和NLRP3炎性小体抑制对5-Fu所致的CID小鼠肠道损伤研究

Tuoli Xiaodu Powder inhibited 5-fluorouracil-induced CID mice intestinal injury by regulating TLR4/Myd88/NF-κB pathway and inhibiting NLRP3 inflammasome

关键词:  托里消毒散  TLR4/Myd88/NF-κB通路  NLRP3炎性小体  化疗相关性腹泻

Key words:  Tuoli Xiaodu Powder  TLR4/Myd88/NF-κB pathway  NLRP3 inflammasome  chemotherapy-induced diarrhea

摘要:

[目的] 化疗相关性腹泻（CID）是5-氟尿嘧啶（5-Fu）治疗最常见的不良反应。本研究旨在研究托里消毒散对CID的潜在保护作用，并探讨其可能的机制。[方法] 将5-Fu致CID模型小鼠随机分为对照组、空白组、CID模型组、阳性药物（洛哌丁胺）组、托里消毒散-散低剂量组、托里消毒散-中剂量组和托里消毒散-高剂量组。评估各组小鼠腹泻程度、肿瘤生长、肠屏障损伤、肠道炎症和Toll样受体4（TLR4）/骨髓分化主要反应蛋白88（Myd88）/核因子κB（NF-κB）通路活性和NOD样受体热蛋白结构域相关蛋白3（NLRP3）炎性小体活化水平。[结果] 研究表明，托里消毒散能明显抑制5-Fu诱导的CID小鼠腹泻和肿瘤生长。苏木精-伊红（HE）染色结果显示，与CID模型组相比，托里消毒散能改善5-Fu诱导的CID小鼠肠黏膜损伤。此外，与CID模型组相比，托里消毒散导致CID小鼠肠道内炎症因子白细胞介素（IL）-1β、IL-8、IL-6以及肿瘤坏死因子（TNF）-α的表达降低，NLRP3水平也明显下降。[结论] 托里消毒散通过抑制CID小鼠肠道TLR4/Myd88/NF-κB通路活性和NLRP3炎性小体活化水平减轻5-Fu所致CID小鼠的肠道损伤，为CID治疗提供了一种新的方法。

Abstract:

[Objective] Chemotherapy-induced diarrhea(CID) is a common adverse reaction in cancer patients treated with 5-fluorouracil(5-Fu). This study aimed to investigate the potential protective effect of Tuoli Xiaodu Powder on CID and explore its possible mechanism. [Methods] The 5-Fu-induced CID mice were randomly divided into control group,blank group,CID model group,positive drug(loperamide) group,Tuoli Xiaodu Powder-low dose group,Tuoli Xiaodu Powder-medium dose group and Tuoli Xiaodu Powder-high dose group. The severity of diarrhea,tumor growth,intestinal barrier damage,intestinal inflammation,Toll-like receptor 4(TLR4)/Myeloid differentiation primary response protein 88(Myd88)/Nuclear factor kappa-B(NF-κB) pathway activity and NOD-like receptor thermal protein domain associated protein 3(NLRP3) inflammasome activation were evaluated. [Results] The results showed that Tuoli Xiaodu Powder significantly inhibited the diarrhea and tumor growth of 5-Fu-induced CID mice. Hematoxylin and Eosin staining(HE) outcome showed that compared with the CID model group,Tuoli Xiaodu Powder improved the intestinal mucosal injury induced by 5-Fu in CID mice. In addition,compared with the CID model group,Tuoli Xiaodu Powder reduced the expression of inflammatory factors interleukin(IL)-1β,IL-8,IL-6,and tumor necrosis factor(TNF)-α in the intestinal tract of CID mice,and the level of NLRP3 was also significantly decreased. [Conclusion] Tuoli Xiaodu Powder can reduce the intestinal injury of CID mice induced by 5-FU by inhibiting the activity of TLR4/Myd88/NF-κB pathway and the activation level of NLRP3 inflammasome in the intestinal tract of CID mice. These findings provide a new therapeutic strategy for the treatment of 5-Fu-induced CID in cancer patients.