Integrated Metabolomics and Network Pharmacology Strategy-Driven Active Traditional Chinese Medicine Ingredients Discovery for the Alleviation of Cisplatin Nephrotoxicity.,Chemical Research in Toxicology

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Integrated Metabolomics and Network Pharmacology Strategy-Driven Active Traditional Chinese Medicine Ingredients Discovery for the Alleviation of Cisplatin Nephrotoxicity.
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2019-11-19 , DOI: 10.1021/acs.chemrestox.9b00180
Lei Xu _{1,

2} , Yuxin Zhang ₃ , Pei Zhang _{1,

4,

5} , Xiaomin Dai ₁ , Yiqiao Gao ₁ , Yingtong Lv ₁ , Siyuan Qin ₁ , Fengguo Xu ₁

Affiliation

Renal injury is the main adverse reaction of cisplatin, and many traditional Chinese medicines (TCMs) were proven active against renal toxicity. Here, an integrated metabolomics and network pharmacology strategy was proposed to discover active TCM ingredients for the alleviation of cisplatin nephrotoxicity. First, by interrogating the Human Metabolome Database (HMDB) we collected targets connected to 149 cisplatin nephrotoxicity-related metabolites. Second, targets of kidney damage were obtained from the Therapeutic Target Database (TTD), PharmGKB, Online Mendelian Inheritance in Man (OMIM), and Genetic Association Database (GAD). Common targets of both dysregulated metabolites and kidney damage were then used for TCM active ingredient screening by applying the network pharmacology approach. Eventually, 22 ingredients passed screening criteria, and their antinephrotoxicity activity was assessed in human kidney tubular epithelial (HK2) cells. As a result, 14 ingredients were found to be effective, in which kaempferol showed relatively better activity. Further metabolomics analysis revealed that kaempferol exerted an antinephrotoxicity effect in rats by regulating amino acid, pyrimidine, and purine metabolism as well as lipid metabolism. Collectively, this proposed integrated strategy would promote the transformation of metabolomics research in the field of drug pair discovery for the purpose of reduced toxicity and increased efficiency.

中文翻译：

综合代谢组学和网络药理学策略驱动的主动中药成分发现，可减轻顺铂肾毒性。

肾损伤是顺铂的主要不良反应，许多中药（TCM）被证明具有抗肾毒性作用。在这里，提出了一种综合的代谢组学和网络药理学策略，以发现有效的中药成分，以减轻顺铂的肾毒性。首先，通过询问人类代谢组数据库（HMDB），我们收集了与149种顺铂肾毒性相关代谢产物相关的靶标。其次，从治疗目标数据库（TTD），PharmGKB，在线孟德尔男性遗传（OMIM）和遗传协会数据库（GAD）获得了肾脏损害的目标。然后通过应用网络药理学方法将代谢失调和肾脏损害的共同靶点用于中药活性成分筛选。最终，有22种成分通过了筛选标准，并在人肾小管上皮（HK2）细胞中评估其抗癌活性。结果，发现14种成分是有效的，其中山fer酚表现出相对更好的活性。进一步的代谢组学分析表明，山fer酚可通过调节氨基酸，嘧啶和嘌呤代谢以及脂质代谢，在大鼠中发挥抗癌作用。总体而言，该拟议的综合策略将促进药物对发现领域的代谢组学研究的转变，以降低毒性和提高效率。进一步的代谢组学分析表明，山fer酚可通过调节氨基酸，嘧啶和嘌呤代谢以及脂质代谢，在大鼠中发挥抗癌作用。总体而言，该拟议的综合策略将促进药物对发现领域的代谢组学研究的转变，以降低毒性和提高效率。进一步的代谢组学分析表明，山fer酚可通过调节氨基酸，嘧啶和嘌呤代谢以及脂质代谢，在大鼠中发挥抗癌作用。总体而言，该拟议的综合策略将促进药物对发现领域的代谢组学研究的转变，以降低毒性和提高效率。

更新日期：2019-11-20

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