当前位置：
X-MOL 学术
›
J. Adv. Res.
›
论文详情
Our official English website, www.x-mol.net, welcomes your
feedback! (Note: you will need to create a separate account there.)
Disturbance of bile acids profile aggravates the diarrhea induced by capecitabine through inhibiting the Wnt/β-catenin pathway
Journal of Advanced Research ( IF 11.4 ) Pub Date : 2024-07-22 , DOI: 10.1016/j.jare.2024.07.019 Zhipeng Wang 1 , Zhijun Liu 2 , Lili Cui 1 , Jianguo Sun 3 , Chen Bu 1 , Mao Tang 1 , Mingming Li 1 , Shouhong Gao 3 , Wansheng Chen 2 , Xia Tao 3
中文翻译：
胆汁酸谱的紊乱通过抑制 Wnt/β-catenin 途径加重卡培他滨诱导的腹泻
腹泻是卡培他滨 （Cap） 的主要剂量限制性副作用，阻碍了其临床应用，但机制尚不清楚。阐明这一机制可能会提高患者的依从性并改善治疗结果。
评估内源性代谢特征是否可以预测 Cap 诱导的腹泻，并探索和验证潜在机制。
进行非靶向和靶向胆汁酸 （BAs） 代谢组学分析结直肠癌 （CRC） 患者基线样本的代谢特征，并评估与 Cap 诱导的腹泻的相关性。评价 BAs 和 Cap 及其代谢产物单独或其组合对人正常肠上皮细胞 （HIEC） 的毒性，并通过 RNA-seq 发现介导 Cap BAs 增强毒性的关键基因，然后进行验证。构建具有高 BAs 暴露水平的小鼠模型，然后用 Cap 处理以验证 CAP 诱导的腹泻由 BAs 增强。
基线内源性代谢特征显示腹泻和非腹泻 CRC 患者之间存在明显差异，差异代谢物主要富集于 BAs 代谢;选择脱氧胆酸 （DCA） 和石胆酸 （LCA） 作为增强 Cap 代谢物 5-FU 对 HIEC 细胞毒性的关键 BAs;DCA 和 LCA 可抑制 Wnt/β-catenin 信号通路，进而抑制 P-糖蛋白，增加 HIEC 细胞中 5-FU 的暴露水平。动物实验结果证实，过量的 DCA 和 LCA 可通过抑制 Wnt/β-catenin-P-glycoprotein 通路加重 Cap 诱导的腹泻。
BAs 代谢谱紊乱与 Cap 诱导的腹泻密切相关，过量的 DCA 和 LCA 被证明是关键的 BAs，可通过抑制 Wnt/β-catenin-P-糖蛋白通路加重 Cap 诱导的腹泻。
更新日期：2024-07-22
Journal of Advanced Research ( IF 11.4 ) Pub Date : 2024-07-22 , DOI: 10.1016/j.jare.2024.07.019 Zhipeng Wang 1 , Zhijun Liu 2 , Lili Cui 1 , Jianguo Sun 3 , Chen Bu 1 , Mao Tang 1 , Mingming Li 1 , Shouhong Gao 3 , Wansheng Chen 2 , Xia Tao 3
Affiliation
|
Introduction
Diarrhea is the primary dose-limiting side effect of capecitabine(Cap) hindering its clinical application, but the mechanism is unclear. Clarifying this mechanism may enhance the patient compliance and improve the treatment outcome.Objectives
To assess if the endogenous metabolic profile could prodict the diarrhea induced by Cap and explore and validate underlying mechanisms.Methods
Untargeted and targeted bile acids(BAs) metabolomics were performed to analyzed the metabolic profile of baseline samples from colorectal cancer(CRC) patients and the association with the diarrhea induced by Cap was assessed. The toxicity of BAs and Cap and its metabolites alone or their combinations to the human normal intestinal epithelial cell(HIEC) was assessed, and the key genes that mediated the BAs-enhanced toxicity of Cap were discovered by RNA-seq and then validated. A mouse model with high exposure levels of BAs was constructed and then treated with Cap to verify the Cap-induced diarrhea enhanced by BAs.Results
The baseline endogenous metabolic profile showed obviously difference between diarrhea and non-diarrhea CRC patients, and the differential metabolites mainly enriched in BAs metabolism; the deoxycholic acid(DCA) and lithocholic acid(LCA) were selected to be the key BAs that enhanced the toxicity of Cap metabolite 5-FU to the HIEC cell; the DCA and LCA could inhibit the Wnt/β-catenin signaling pathway, which then suppressed the P-glycoprotein and increased the exposure level of 5-FU in the HIEC cell. The results of animal experiment verified that the excessive DCA and LCA could aggravate the Cap-induced diarrhea through inhibiting Wnt/β-catenin-P-glycoprotein pathway.Conclusions
The disordered BAs metabolic profile showed close relationship with diarrhea induced by Cap, and excessive DCA and LCA were proved to be the key BAs, which could aggravate the Cap-induced diarrhea through inhibiting Wnt/β-catenin-P-glycoprotein pathway.中文翻译：
胆汁酸谱的紊乱通过抑制 Wnt/β-catenin 途径加重卡培他滨诱导的腹泻
介绍
腹泻是卡培他滨 （Cap） 的主要剂量限制性副作用，阻碍了其临床应用，但机制尚不清楚。阐明这一机制可能会提高患者的依从性并改善治疗结果。
目标
评估内源性代谢特征是否可以预测 Cap 诱导的腹泻，并探索和验证潜在机制。
方法
进行非靶向和靶向胆汁酸 （BAs） 代谢组学分析结直肠癌 （CRC） 患者基线样本的代谢特征，并评估与 Cap 诱导的腹泻的相关性。评价 BAs 和 Cap 及其代谢产物单独或其组合对人正常肠上皮细胞 （HIEC） 的毒性，并通过 RNA-seq 发现介导 Cap BAs 增强毒性的关键基因，然后进行验证。构建具有高 BAs 暴露水平的小鼠模型，然后用 Cap 处理以验证 CAP 诱导的腹泻由 BAs 增强。
结果
基线内源性代谢特征显示腹泻和非腹泻 CRC 患者之间存在明显差异，差异代谢物主要富集于 BAs 代谢;选择脱氧胆酸 （DCA） 和石胆酸 （LCA） 作为增强 Cap 代谢物 5-FU 对 HIEC 细胞毒性的关键 BAs;DCA 和 LCA 可抑制 Wnt/β-catenin 信号通路，进而抑制 P-糖蛋白，增加 HIEC 细胞中 5-FU 的暴露水平。动物实验结果证实，过量的 DCA 和 LCA 可通过抑制 Wnt/β-catenin-P-glycoprotein 通路加重 Cap 诱导的腹泻。
结论
BAs 代谢谱紊乱与 Cap 诱导的腹泻密切相关，过量的 DCA 和 LCA 被证明是关键的 BAs，可通过抑制 Wnt/β-catenin-P-糖蛋白通路加重 Cap 诱导的腹泻。
京公网安备 11010802027423号