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Research ArticleSpecial Section on Natural Products: Experimental Approaches to Elucidate Disposition Mechanisms and Predict Pharmacokinetic Drug Interactions

Multiomics Profiling Reveals Protective Function of Schisandra Lignans against Acetaminophen-Induced Hepatotoxicity

Caixia Yan, Huimin Guo, Qingqing Ding, Yuhao Shao, Dian Kang, Tengjie Yu, Changjian Li, Haoran Huang, Yisha Du, He Wang, Kangrui Hu, Lin Xie, Guangji Wang and Yan Liang
Drug Metabolism and Disposition October 2020, 48 (10) 1092-1103; DOI: https://doi.org/10.1124/dmd.120.000083
Caixia Yan
Key Laboratory of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, P.R. China (C.Y., H.G., Y.S., D.K., T.Y., C.L., H.H., Y.D., H.W., K.H., L.X., G.W., Y.L.) and Department of Geriatric Oncology, First Affiliated Hospital of Nanjing Medical University (Jiangsu People’s Hospital), Nanjing, P.R. China (Q.D.)
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Huimin Guo
Key Laboratory of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, P.R. China (C.Y., H.G., Y.S., D.K., T.Y., C.L., H.H., Y.D., H.W., K.H., L.X., G.W., Y.L.) and Department of Geriatric Oncology, First Affiliated Hospital of Nanjing Medical University (Jiangsu People’s Hospital), Nanjing, P.R. China (Q.D.)
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Qingqing Ding
Key Laboratory of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, P.R. China (C.Y., H.G., Y.S., D.K., T.Y., C.L., H.H., Y.D., H.W., K.H., L.X., G.W., Y.L.) and Department of Geriatric Oncology, First Affiliated Hospital of Nanjing Medical University (Jiangsu People’s Hospital), Nanjing, P.R. China (Q.D.)
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Yuhao Shao
Key Laboratory of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, P.R. China (C.Y., H.G., Y.S., D.K., T.Y., C.L., H.H., Y.D., H.W., K.H., L.X., G.W., Y.L.) and Department of Geriatric Oncology, First Affiliated Hospital of Nanjing Medical University (Jiangsu People’s Hospital), Nanjing, P.R. China (Q.D.)
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Dian Kang
Key Laboratory of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, P.R. China (C.Y., H.G., Y.S., D.K., T.Y., C.L., H.H., Y.D., H.W., K.H., L.X., G.W., Y.L.) and Department of Geriatric Oncology, First Affiliated Hospital of Nanjing Medical University (Jiangsu People’s Hospital), Nanjing, P.R. China (Q.D.)
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Tengjie Yu
Key Laboratory of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, P.R. China (C.Y., H.G., Y.S., D.K., T.Y., C.L., H.H., Y.D., H.W., K.H., L.X., G.W., Y.L.) and Department of Geriatric Oncology, First Affiliated Hospital of Nanjing Medical University (Jiangsu People’s Hospital), Nanjing, P.R. China (Q.D.)
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Changjian Li
Key Laboratory of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, P.R. China (C.Y., H.G., Y.S., D.K., T.Y., C.L., H.H., Y.D., H.W., K.H., L.X., G.W., Y.L.) and Department of Geriatric Oncology, First Affiliated Hospital of Nanjing Medical University (Jiangsu People’s Hospital), Nanjing, P.R. China (Q.D.)
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Haoran Huang
Key Laboratory of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, P.R. China (C.Y., H.G., Y.S., D.K., T.Y., C.L., H.H., Y.D., H.W., K.H., L.X., G.W., Y.L.) and Department of Geriatric Oncology, First Affiliated Hospital of Nanjing Medical University (Jiangsu People’s Hospital), Nanjing, P.R. China (Q.D.)
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Yisha Du
Key Laboratory of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, P.R. China (C.Y., H.G., Y.S., D.K., T.Y., C.L., H.H., Y.D., H.W., K.H., L.X., G.W., Y.L.) and Department of Geriatric Oncology, First Affiliated Hospital of Nanjing Medical University (Jiangsu People’s Hospital), Nanjing, P.R. China (Q.D.)
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He Wang
Key Laboratory of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, P.R. China (C.Y., H.G., Y.S., D.K., T.Y., C.L., H.H., Y.D., H.W., K.H., L.X., G.W., Y.L.) and Department of Geriatric Oncology, First Affiliated Hospital of Nanjing Medical University (Jiangsu People’s Hospital), Nanjing, P.R. China (Q.D.)
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Kangrui Hu
Key Laboratory of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, P.R. China (C.Y., H.G., Y.S., D.K., T.Y., C.L., H.H., Y.D., H.W., K.H., L.X., G.W., Y.L.) and Department of Geriatric Oncology, First Affiliated Hospital of Nanjing Medical University (Jiangsu People’s Hospital), Nanjing, P.R. China (Q.D.)
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Lin Xie
Key Laboratory of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, P.R. China (C.Y., H.G., Y.S., D.K., T.Y., C.L., H.H., Y.D., H.W., K.H., L.X., G.W., Y.L.) and Department of Geriatric Oncology, First Affiliated Hospital of Nanjing Medical University (Jiangsu People’s Hospital), Nanjing, P.R. China (Q.D.)
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Guangji Wang
Key Laboratory of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, P.R. China (C.Y., H.G., Y.S., D.K., T.Y., C.L., H.H., Y.D., H.W., K.H., L.X., G.W., Y.L.) and Department of Geriatric Oncology, First Affiliated Hospital of Nanjing Medical University (Jiangsu People’s Hospital), Nanjing, P.R. China (Q.D.)
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  • For correspondence: guangjiwang@hotmail.com
Yan Liang
Key Laboratory of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, P.R. China (C.Y., H.G., Y.S., D.K., T.Y., C.L., H.H., Y.D., H.W., K.H., L.X., G.W., Y.L.) and Department of Geriatric Oncology, First Affiliated Hospital of Nanjing Medical University (Jiangsu People’s Hospital), Nanjing, P.R. China (Q.D.)
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  • For correspondence: liangyan0679@163.com
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Abstract

The action principles of traditional Chinese medicines (TCMs) feature multiactive components, multitarget sites, and weak combination with action targets. In the present study, we performed an integrated analysis of metabonomics, proteomics, and lipidomics to establish a scientific research system on the underlying mechanism of TCMs, and Schisandra lignan extract (SLE) was selected as a model TCM. In metabonomics, several metabolic pathways were found to mediate the liver injury induced by acetaminophen (APAP), and SLE could regulate the disorder of lipid metabolism. The proteomic study further proved that the hepatoprotective effect of SLE was closely related to the regulation of lipid metabolism. Indeed, the results of lipidomics demonstrated that SLE dosing has an obvious callback effect on APAP-induced lipidic profile shift. The contents of 25 diglycerides (DAGs) and 21 triglycerides (TAGs) were enhanced significantly by APAP-induced liver injury, which could further induce liver injury and inflammatory response by upregulating protein kinase C (PKCβ, PKCγ, PKCδ, and PKCθ). The upregulated lipids and PKCs could be reversed to the normal level by SLE dosing. More importantly, phosphatidic acid phosphatase, fatty acid transport protein 5, and diacylglycerol acyltransferase 2 were proved to be positively associated with the regulation of DAGs and TAGs.

SIGNIFICANCE STATEMENT Integrated multiomics was first used to reveal the mechanism of APAP-induced acute liver failure (ALF) and the hepatoprotective role of SLE. The results showed that the ALF caused by APAP was closely related to lipid regulation and that SLE dosing could exert a hepatoprotective role by reducing intrahepatic diglyceride and triglyceride levels. Our research can not only promote the application of multicomponent technology in the study of the mechanism of traditional Chinese medicines but also provide an effective approach for the prevention and treatment of ALF.

Footnotes

    • Received April 22, 2020.
    • Accepted June 30, 2020.
  • ↵This study was supported by the Nature Science Foundation of Jiangsu Province [Grant BK20171395]; the National Nature Science Foundation of China [Grant 81530098]; and “Double First-Class” University project [Grant CPU2018GF01].

  • None of the authors have any financial conflicts of interest.

  • 1 C.Y., H.G., and Q.D. contributed equally to this work.

  • https://doi.org/10.1124/dmd.120.000083.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 48 (10)
Drug Metabolism and Disposition
Vol. 48, Issue 10
1 Oct 2020
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Research ArticleSpecial Section on Natural Products: Experimental Approaches to Elucidate Disposition Mechanisms and Predict Pharmacokinetic Drug Interactions

Multiomics Analysis of Schisandra Lignans Liver Protection

Caixia Yan, Huimin Guo, Qingqing Ding, Yuhao Shao, Dian Kang, Tengjie Yu, Changjian Li, Haoran Huang, Yisha Du, He Wang, Kangrui Hu, Lin Xie, Guangji Wang and Yan Liang
Drug Metabolism and Disposition October 1, 2020, 48 (10) 1092-1103; DOI: https://doi.org/10.1124/dmd.120.000083

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Research ArticleSpecial Section on Natural Products: Experimental Approaches to Elucidate Disposition Mechanisms and Predict Pharmacokinetic Drug Interactions

Multiomics Analysis of Schisandra Lignans Liver Protection

Caixia Yan, Huimin Guo, Qingqing Ding, Yuhao Shao, Dian Kang, Tengjie Yu, Changjian Li, Haoran Huang, Yisha Du, He Wang, Kangrui Hu, Lin Xie, Guangji Wang and Yan Liang
Drug Metabolism and Disposition October 1, 2020, 48 (10) 1092-1103; DOI: https://doi.org/10.1124/dmd.120.000083
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