Chong Yu, Shuai Li, Yujiao Zhang, Baocang Wang, Zhe Liu, Na Han, Jianxiu Zhai, Sikai Li, Jun Yin, Zhihui Liu
{"title":"基于UHPLC-Q-TOF-MS/MS、网络药理学、分子对接和体内外实验验证，探讨黄阳宁分散片对阿霉素致心脏毒性的保护作用。","authors":"Chong Yu, Shuai Li, Yujiao Zhang, Baocang Wang, Zhe Liu, Na Han, Jianxiu Zhai, Sikai Li, Jun Yin, Zhihui Liu","doi":"10.1016/j.jep.2025.120388","DOIUrl":null,"url":null,"abstract":"<p><strong>Ethnopharmacological relevance: </strong>Huangyangning dispersible tablets (HYN), derived from Buxus microphylla Sieb, are used in traditional Chinese medicine to promote blood circulation, relieve pain, and treat cardiovascular disorders. HYN is a potential Chinese medicine for treating dose-dependent cardiotoxicity (DIC), but its mechanism of action is unclear.</p><p><strong>Aim of the study: </strong>This study aimed to evaluate the potential therapeutic benefits of HYN against DIC and explore its underlying mechanisms in treating DIC.</p><p><strong>Materials and methods: </strong>This study used Doxorubicin-induced H9C2 cells and DIC mice models to assess HYN's therapeutic effects and potential mechanism against DIC. The main compounds of HYN were identified by ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS/MS) and online databases. Network pharmacology predicted potential targets, which were further analyzed by protein-protein interaction (PPI), kyoto encyclopedia of genes and genomes (KEGG), gene ontology (GO), molecular docking, and dynamics simulations, with validation by Western Blot.</p><p><strong>Results: </strong>In vitro and in vivo experiments showed that Doxorubicin can inflict cardiomyocyte damage by diminishing cell viability, perturbing cellular morphology, and initiating ferroptosis. Pretreatment with HYN and FER-1 reversed these effects, indicating HYN combated DIC by inhibiting ferroptosis. UHPLC-Q-TOF-MS/MS identified five major alkaloids in HYN. Network pharmacology suggested the ROS pathway plays a key role, with Keap1 and Nrf2 regulating oxidative stress. Molecular simulations revealed CVB-D and CB-D in HYN inhibit Keap1, activating Nrf2 to upregulate HO-1 and neutralize oxidative stress, confirmed by Western Blot.</p><p><strong>Conclusion: </strong>HYN effectively improved the DIC through alleviating ferroptosis, achieved by interfering with the interaction between Keap1 and Nrf2.</p>","PeriodicalId":15761,"journal":{"name":"Journal of ethnopharmacology","volume":" ","pages":"120388"},"PeriodicalIF":5.4000,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Exploring the protective effects of Huangyangning dispersible tablets against Doxorubicin-induced cardiotoxicity based on UHPLC-Q-TOF-MS/MS, network pharmacology, molecular docking and experimental validation in vivo and in vitro.\",\"authors\":\"Chong Yu, Shuai Li, Yujiao Zhang, Baocang Wang, Zhe Liu, Na Han, Jianxiu Zhai, Sikai Li, Jun Yin, Zhihui Liu\",\"doi\":\"10.1016/j.jep.2025.120388\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Ethnopharmacological relevance: </strong>Huangyangning dispersible tablets (HYN), derived from Buxus microphylla Sieb, are used in traditional Chinese medicine to promote blood circulation, relieve pain, and treat cardiovascular disorders. HYN is a potential Chinese medicine for treating dose-dependent cardiotoxicity (DIC), but its mechanism of action is unclear.</p><p><strong>Aim of the study: </strong>This study aimed to evaluate the potential therapeutic benefits of HYN against DIC and explore its underlying mechanisms in treating DIC.</p><p><strong>Materials and methods: </strong>This study used Doxorubicin-induced H9C2 cells and DIC mice models to assess HYN's therapeutic effects and potential mechanism against DIC. The main compounds of HYN were identified by ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS/MS) and online databases. Network pharmacology predicted potential targets, which were further analyzed by protein-protein interaction (PPI), kyoto encyclopedia of genes and genomes (KEGG), gene ontology (GO), molecular docking, and dynamics simulations, with validation by Western Blot.</p><p><strong>Results: </strong>In vitro and in vivo experiments showed that Doxorubicin can inflict cardiomyocyte damage by diminishing cell viability, perturbing cellular morphology, and initiating ferroptosis. Pretreatment with HYN and FER-1 reversed these effects, indicating HYN combated DIC by inhibiting ferroptosis. UHPLC-Q-TOF-MS/MS identified five major alkaloids in HYN. Network pharmacology suggested the ROS pathway plays a key role, with Keap1 and Nrf2 regulating oxidative stress. Molecular simulations revealed CVB-D and CB-D in HYN inhibit Keap1, activating Nrf2 to upregulate HO-1 and neutralize oxidative stress, confirmed by Western Blot.</p><p><strong>Conclusion: </strong>HYN effectively improved the DIC through alleviating ferroptosis, achieved by interfering with the interaction between Keap1 and Nrf2.</p>\",\"PeriodicalId\":15761,\"journal\":{\"name\":\"Journal of ethnopharmacology\",\"volume\":\" \",\"pages\":\"120388\"},\"PeriodicalIF\":5.4000,\"publicationDate\":\"2025-09-25\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of ethnopharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.jep.2025.120388\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/8/6 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of ethnopharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.jep.2025.120388","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/8/6 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Exploring the protective effects of Huangyangning dispersible tablets against Doxorubicin-induced cardiotoxicity based on UHPLC-Q-TOF-MS/MS, network pharmacology, molecular docking and experimental validation in vivo and in vitro.
Ethnopharmacological relevance: Huangyangning dispersible tablets (HYN), derived from Buxus microphylla Sieb, are used in traditional Chinese medicine to promote blood circulation, relieve pain, and treat cardiovascular disorders. HYN is a potential Chinese medicine for treating dose-dependent cardiotoxicity (DIC), but its mechanism of action is unclear.
Aim of the study: This study aimed to evaluate the potential therapeutic benefits of HYN against DIC and explore its underlying mechanisms in treating DIC.
Materials and methods: This study used Doxorubicin-induced H9C2 cells and DIC mice models to assess HYN's therapeutic effects and potential mechanism against DIC. The main compounds of HYN were identified by ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS/MS) and online databases. Network pharmacology predicted potential targets, which were further analyzed by protein-protein interaction (PPI), kyoto encyclopedia of genes and genomes (KEGG), gene ontology (GO), molecular docking, and dynamics simulations, with validation by Western Blot.
Results: In vitro and in vivo experiments showed that Doxorubicin can inflict cardiomyocyte damage by diminishing cell viability, perturbing cellular morphology, and initiating ferroptosis. Pretreatment with HYN and FER-1 reversed these effects, indicating HYN combated DIC by inhibiting ferroptosis. UHPLC-Q-TOF-MS/MS identified five major alkaloids in HYN. Network pharmacology suggested the ROS pathway plays a key role, with Keap1 and Nrf2 regulating oxidative stress. Molecular simulations revealed CVB-D and CB-D in HYN inhibit Keap1, activating Nrf2 to upregulate HO-1 and neutralize oxidative stress, confirmed by Western Blot.
Conclusion: HYN effectively improved the DIC through alleviating ferroptosis, achieved by interfering with the interaction between Keap1 and Nrf2.
期刊介绍：
The Journal of Ethnopharmacology is dedicated to the exchange of information and understandings about people''s use of plants, fungi, animals, microorganisms and minerals and their biological and pharmacological effects based on the principles established through international conventions. Early people confronted with illness and disease, discovered a wealth of useful therapeutic agents in the plant and animal kingdoms. The empirical knowledge of these medicinal substances and their toxic potential was passed on by oral tradition and sometimes recorded in herbals and other texts on materia medica. Many valuable drugs of today (e.g., atropine, ephedrine, tubocurarine, digoxin, reserpine) came into use through the study of indigenous remedies. Chemists continue to use plant-derived drugs (e.g., morphine, taxol, physostigmine, quinidine, emetine) as prototypes in their attempts to develop more effective and less toxic medicinals.
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