{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T16:22:11Z","timestamp":1791390131623,"version":"4.3.3"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2019,8,29]],"date-time":"2019-08-29T00:00:00Z","timestamp":1567036800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"},{"start":{"date-parts":[[2020,8,7]],"date-time":"2020-08-07T00:00:00Z","timestamp":1596758400000},"content-version":"am","delay-in-days":344,"URL":"http:\/\/rsc.li\/journals-terms-of-use"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81573825"],"award-info":[{"award-number":["81573825"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81573825"],"award-info":[{"award-number":["81573825"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["rsc.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2019,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Triptolide (TP) is one of the important active components in Tripterygium wilfordii Hook. F., which shows strong anti-inflammatory and immunomodulatory effects. However, a large number of literature studies have reported that TP is the main component causing nephrotoxicity, and the mechanism of nephrotoxicity has not yet been revealed. Therefore, it is of great practical significance to clarify the toxicity mechanism of TP. This study integrated network pharmacology and targeted metabolomics to reveal the nephrotoxicity mechanism of TP. Firstly, network pharmacology screening of 61 action targets related to TP induced nephrotoxicity, with 39 direct targets and 22 indirect targets, was performed. Subsequently, based on a large-scale protein\u2013protein interaction (PPI) and molecular docking validation, the core targets were identified. Based on the above targets and enrichment analysis, the purine metabolism, Toll-like receptor signaling pathway and NF-\u03baB signaling pathway were found play a pivotal role in TP-induced nephrotoxicity. Literature investigation showed that purine and pyrimidine metabolism pathways were closely related to kidney diseases. Therefore, by using the quantitative method of determining endogenous purine and pyrimidine previously established in the laboratory, a targeted metabolomic analysis of TP was carried out. Finally, six nephrotoxicity biomarkers, dihydroorotate, thymidine, 2-deoxyinosine, uric acid, adenosine and xanthine, were found. Combining the above results, the mechanisms underlying the nephrotoxicity of TP were speculated to be due to the over-consumption of xanthine and uric acid, which would result in enormous ROS being released in response to oxidative stress in the body. Furthermore, activation of the Toll-like receptor signalling pathway can promotes the phosphorylation of the downstream protein NF-\u03baB and causes an inflammatory response that ultimately leads to nephrotoxicity.<\/jats:p>","DOI":"10.1039\/c9tx00067d","type":"journal-article","created":{"date-parts":[[2019,8,7]],"date-time":"2019-08-07T10:29:08Z","timestamp":1565173748000},"page":"850-861","update-policy":"https:\/\/doi.org\/10.1039\/rsc_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Integrated network pharmacology and targeted metabolomics to reveal the mechanism of nephrotoxicity of triptolide"],"prefix":"10.1093","volume":"8","author":[{"given":"Wei","family":"Huang","sequence":"first","affiliation":[{"name":"School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Jian Kang Chan Ye Yuan, Jinghai Dist., Tianjin 301617, China. Fax: +86-22-59596223; Tel: +86-22-59596223"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanxin","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Beijing University of Chinese Medicine, Liangxiang Town, Fangshan District, Beijing 102488, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijuan","family":"Xie","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Jian Kang Chan Ye Yuan, Jinghai Dist., Tianjin 301617, China. Fax: +86-22-59596223; Tel: +86-22-59596223"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuming","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Jian Kang Chan Ye Yuan, Jinghai Dist., Tianjin 301617, China. Fax: +86-22-59596223; Tel: +86-22-59596223"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanyan","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Jian Kang Chan Ye Yuan, Jinghai Dist., Tianjin 301617, China. Fax: +86-22-59596223; Tel: +86-22-59596223"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0455-0969","authenticated-orcid":false,"given":"Yubo","family":"Li","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Jian Kang Chan Ye Yuan, Jinghai Dist., Tianjin 301617, China. Fax: +86-22-59596223; Tel: +86-22-59596223"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,8,29]]},"reference":[{"issue":"4","key":"2020012303460419300_cit1","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1016\/j.molimm.2013.05.006","article-title":"Triptolide ameliorates ileocolonic anastomosis inflammation in IL-10 deficient mice by mechanism involving suppression of miR-155\/SHIP-1 signaling pathway","volume":"56","author":"Wu","year":"2013","journal-title":"Mol. Immunol."},{"issue":"2","key":"2020012303460419300_cit2","first-page":"551","article-title":"Triptolide induces apoptosis in human adrenal cancer NCI-H295 cells through a mitochondrial-dependent pathway","volume":"25","author":"Wu","year":"2011","journal-title":"Oncol. 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Ther."},{"key":"2020012303460419300_cit5","unstructured":"National Center for ADR Monitoring of China , Notification of Drug Adverse Reactions (Issue 46) Concerns About the Safety of Tripterygium wilfordii Preparations (2012) http:\/\/www.cfda.gov.cn\/WS01\/CL0078\/70473.html."},{"key":"2020012303460419300_cit6","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.jep.2015.01.004","article-title":"Investigation of the active components in Tripterygium wilfordii leading to its acute hepatotoxicty and nephrotoxicity","volume":"162","author":"Li","year":"2015","journal-title":"J. Ethnopharmacol."},{"issue":"1","key":"2020012303460419300_cit7","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1681\/ASN.V12129","article-title":"Adenosine activates aromatic L-amino acid decarboxylase activity in the kidney and increases dopamine","volume":"12","author":"Takezako","year":"2001","journal-title":"J. Am. Soc. 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