Discovery of the toxicity-related quality markers and mechanisms of Zhi-Zi-Hou-Po decoction based on Chinmedomics combined with differentially absorbed components and network pharmacology.
Zhi-Zi-Hou-Po decoction (ZZHPD), as a representative traditional Chinese medicine (TCM) formula for the treatment of depression, has frequently triggered hepatorenal toxicity in recent years. However, its toxic effect, material basis, and underlying mechanisms have not been fully elucidated. To expl...
| Publicado en: | Journal of Ethnopharmacology Vol. 320 |
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| Autores principales: | , , , |
| Formato: | research Journal Article |
| Publicado: |
Elsevier B.V.
Feb2024
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=173976865&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 173976865 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 03788741 3MS jtl: Journal of Ethnopharmacology issn: 03788741 maglogo: N pubinfo: dt: Feb2024 vid: 320 pid: 1004 pub: Elsevier B.V. artinfo: ui: 173976865 173976865 173976865 10.1016/j.jep.2023.117408 173976865 ppct: 1 formats: tig: atl: Discovery of the toxicity-related quality markers and mechanisms of Zhi-Zi-Hou-Po decoction based on Chinmedomics combined with differentially absorbed components and network pharmacology. aug: au: Wan, Shulin Xie, Xiaoxia Yang, Gongjun Feng, Fang affil: Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 210009, China sug: subj: Drugs, Chinese Herbal Pharmacodynamics Depression Drug Therapy Hepatotoxicity Nephrotoxicity Biological Markers Network Pharmacology Quality Assessment Animal Studies Rats Multivariate Analysis Molecular Docking Simulation Polymerase Chain Reaction Metabolomics Arginine Metabolism Proline Metabolism ab: Zhi-Zi-Hou-Po decoction (ZZHPD), as a representative traditional Chinese medicine (TCM) formula for the treatment of depression, has frequently triggered hepatorenal toxicity in recent years. However, its toxic effect, material basis, and underlying mechanisms have not been fully elucidated. To explore the hepatorenal toxicity-material basis-quality markers (Q-markers) and multiple mechanisms of ZZHPD. ZZHPD-induced rat model of toxicity was evaluated by behavioral indicators, biochemical parameters, and histopathological sections. Then, UHPLC-Q-Exactive Orbitrap-MS combined with multivariate data analysis was utilized to identify the endogenous differential metabolites and the prototype components of ZZHPD in the plasma. A comprehensive strategy integrating in-house library, diagnostic ions, Compound Discover software, and network databases was constructed to identify the chemical constituents of ZZHPD. Additionally, the differentially absorbed components of ZZHPD were screened out based on the spectrum-effect relationship (toxic state and normal state), feature extraction of exogenous components, and variable influence on projection (VIP). Further, Chinmedomics and network pharmacology oriented by differentially absorbed components were performed to predict toxicity-related Q-markers and core targets, as well as relevant pathways. Finally, the binding ability between components and targets was predicted using molecular docking, and the mRNA expression of core target genes was determined by real-time qPCR experiment. ZZHPD exerted significant hepatotoxicity and nephrotoxicity in rats accompanied by body weight loss, abnormal biochemical indicators, and pathologic characteristics with mild inflammation and cell damage. The results of plasma metabolomics indicated that 22 differential metabolites interfered by ZZHPD mainly involved in primary bile acid biosynthesis, arginine and proline metabolism, phenylalanine metabolism and biosynthesis, sphingolipid metabolism, pyrimidine and purine metabolism. Firstly, 106 chemical substances of ZZHPD were identified, 44 of them were absorbed into the blood, mainly including 7 iridoid glycosides, 15 flavonoids, 5 lignans, and others. Then, the correlation analysis results suggested that 12 of 19 differentially absorbed constituents were highly correlated with 22 differential metabolites and recognized as potential Q-markers. Finally, 9 toxicity-related Q-markers were predicted and confirmed with better binding ability to 5 core targets (PTGS2, CASP3, TNF, PPARG, HMOX1), including 3 flavonoids (naringin, hesperidin, and neohesperidin), 2 iridoid glycosides (geniposide and genipin-1-β-D-gentiobioside), 2 lignans (honokiol and magnolol), organic acid (chlorogenic acid), and crocin (crocetin). The real-time qPCR results showed that the mRNA levels of CASP3, TNF-α, and PPARG significantly increased in the damaged liver. Combining metabolomics and network pharmacology results, the multiple mechanisms of toxicity might involve in oxidative damage, inflammation, and apoptosis pathways. Taken together, the toxicity-related Q-markers of ZZHPD screened for the first time in this work were reliable, and the holistic intervention for hepatorenal toxicity further revealed the multi-component, multi-target, and multi-pathway features in TCM. The integrated approach provides a novel perspective for the discovery of toxicity/efficacy-related substances and mechanistic studies in TCM. [Display omitted] • ZZHPD showed obvious hepatorenal toxicity based on toxicological evaluation. • 44 plasma migrant ingredients from 106 compounds of ZZHPD were first identified. • 9 toxicity-related Q-markers was preliminarily clarified through an integrated strategy. • Metabolic pathways included arginine and proline metabolism, primary bile acid biosynthesis. pubtype: Academic Journal doctype: research Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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