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Integrated Metabolomics and Network Pharmacology Strategy-Driven Active Traditional Chinese Medicine Ingredients Discovery for the Alleviation of Cisplatin Nephrotoxicity
journal contribution
posted on 2019-11-19, 17:08 authored by Lei Xu, Yuxin Zhang, Pei Zhang, Xiaomin Dai, Yiqiao Gao, Yingtong Lv, Siyuan Qin, Fengguo XuRenal 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.
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Genetic Association DatabaseOMIMingredientHuman Metabolome Database149 cisplatin nephrotoxicity-related metabolitesTherapeutic Target DatabaseHKTCMHMDBdrug pair discoveryTTDmetabolomickaempferolnetwork pharmacology approachMedicine Ingredients Discoveryantinephrotoxicitymetabolismscreeningnetwork pharmacology strategykidney damageGADOnline Mendelian InheritanceNetwork Pharmacology Strategy-DrivenCisplatin Nephrotoxicity Renal injury
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